Abstract
Background
Chronic spontaneous urticaria (CSU) is characterised by the development of crops of red, itchy, raised weals or hives with no identifiable external cause.
Objectives
To assess the effects of H1‐antihistamines for CSU.
Search methods
We searched the following databases up to June 2014: Cochrane Skin Group Specialised Register, CENTRAL (2014, Issue 5), MEDLINE (from 1946), EMBASE (from 1974) and PsycINFO (from 1806). We searched five trials registers and checked articles for references to relevant randomised controlled trials.
Selection criteria
We included randomised controlled trials of H1‐antihistamines for CSU. Interventions included single therapy or a combination of H1‐antihistamines compared with no treatment (placebo) or another active pharmacological compound at any dose.
Data collection and analysis
We used standard methodological procedures as expected by The Cochrane Collaboration.
Our primary outcome measures were proportion of participants with complete suppression of urticaria: 'good or excellent' response, 50% or greater improvement in quality of life measures, and adverse events. We present risk ratios (RR) with 95% confidence intervals (CIs).
Main results
We identified 73 studies (9759 participants); 34 studies provided data for 23 comparisons. The duration of the intervention was up to two weeks (short‐term) or longer than two weeks and up to three months (intermediate‐term).
Cetirizine 10 mg once daily in the short term and in the intermediate term led to complete suppression of urticaria by more participants than was seen with placebo (RR 2.72, 95% CI 1.51 to 4.91). For this same outcome, comparison of desloratadine versus placebo in the intermediate term (5 mg) (RR 37.00, 95% CI 2.31 to 593.70) and in the short term (20 mg) (RR 15.97, 95% CI 1.04 to 245.04) favoured desloratadine, but no differences were seen between 5 mg and 10 mg for short‐term treatment.
Levocetirizine 20 mg per day (short‐term) was more effective for complete suppression of urticaria compared with placebo (RR 20.87, 95% CI 1.37 to 317.60), and at 5 mg was effective in the intermediate term (RR 52.88, 95% CI 3.31 to 843.81) but not in the short term, nor was 10 mg effective in the short term.
Rupatadine at 10 mg and 20 mg in the intermediate term achieved a 'good or excellent response' compared with placebo (RR 1.35, 95% CI 1.03 to 1.77).
Loratadine (10 mg) versus placebo (RR 1.86, 95% CI 0.91 to 3.79) and loratadine (10 mg) versus cetirizine (10 mg) (RR 1.05, 95% CI 0.76 to 1.43) over short‐term and intermediate‐term treatment showed no significant difference for 'good or excellent response' or for complete suppression of urticaria, respectively.
Loratadine (10 mg) versus desloratadine (5 mg) (intermediate‐term) showed no statistically significant difference for complete suppression of urticaria (RR 0.91, 95% CI 0.78 to 1.06) or for 'good or excellent response' (RR 1.04, 95% CI 0.64 to 1.71). For loratadine (10 mg) versus mizolastine (10 mg) (intermediate‐term), no statistically significant difference was seen for complete suppression of urticaria (RR 0.86, 95% CI 0.64 to 1.16) or for 'good or excellent response' (RR 0.88, 95% CI 0.55 to 1.42).
Loratadine (10 mg) versus emedastine (2 mg) (intermediate‐term) showed no statistically significant difference for complete suppression (RR 1.04, 95% CI 0.78 to 1.39) or for 'good or excellent response' (RR 1.09, 95% CI 0.96 to 1.24); the quality of the evidence was moderate for this comparison.
No difference in short‐term treatment was noted between loratadine (10 mg) and hydroxyzine (25 mg) in terms of complete suppression (RR 1.00, 95% CI 0.32 to 3.10).
When desloratadine (5 to 20 mg) was compared with levocetirizine (5 to 20 mg), levocetirizine appeared to be the more effective (P value < 0.02).
In a comparison of fexofenadine versus cetirizine, more participants in the cetirizine group showed complete suppression of urticaria (P value < 0.001).
Adverse events leading to withdrawals were not significantly different in the following comparisons: cetirizine versus placebo at 10 mg and 20 mg (RR 3.00, 95% CI 0.68 to 13.22); desloratadine 5 mg versus placebo (RR 1.46, 95% CI 0.42 to 5.10); loratadine 10 mg versus mizolastine 10 mg (RR 0.38, 95% CI 0.04 to 3.60); loratadine 10 mg versus emedastine 2 mg (RR 1.09, 95% CI 0.07 to 17.14); cetirizine 10 mg versus hydroxyzine 25 mg (RR 0.78, 95% CI 0.25 to 2.45); and hydroxyzine 25 mg versus placebo (RR 3.64, 95% CI 0.77 to 17.23), all intermediate term.
No difference was seen between loratadine 10 mg versus mizolastine 10 mg in the proportion of participants with at least 50% improvement in quality of life (RR 3.21, 95% CI 0.32 to 32.33).
Authors' conclusions
Although the results of our review indicate that at standard doses of treatment, several antihistamines are effective when compared with placebo, all results were gathered from a few studies or, in some cases, from single‐study estimates. The quality of the evidence was affected by the small number of studies in each comparison and the small sample size for many of the outcomes, prompting us to downgrade the quality of evidence for imprecision (unless stated for each comparison, the quality of the evidence was low).
No single H1‐antihistamine stands out as most effective. Cetirizine at 10 mg once daily in the short term and in the intermediate term was found to be effective in completely suppressing urticaria. Evidence is limited for desloratadine given at 5 mg once daily in the intermediate term and at 20 mg in the short term. Levocetirizine at 5 mg in the intermediate but not short term was effective for complete suppression. Levocetirizine 20 mg was effective in the short term, but 10 mg was not. No difference in rates of withdrawal due to adverse events was noted between active and placebo groups. Evidence for improvement in quality of life was insufficient.
Keywords: Humans, Cetirizine, Cetirizine/therapeutic use, Cyproheptadine, Cyproheptadine/analogs & derivatives, Cyproheptadine/therapeutic use, Histamine H1 Antagonists, Histamine H1 Antagonists/adverse effects, Histamine H1 Antagonists/therapeutic use, Hydroxyzine, Hydroxyzine/therapeutic use, Loratadine, Loratadine/analogs & derivatives, Loratadine/therapeutic use, Randomized Controlled Trials as Topic, Urticaria, Urticaria/drug therapy
Plain language summary
H1‐antihistamines for chronic spontaneous urticaria
Background
Chronic spontaneous urticaria (CSU) is a condition characterised by a rash of red itchy raised weals or hives, which appear for no identifiable reason. Other names include chronic idiopathic or chronic ordinary urticaria. 'Spontaneous' differentiates this type of urticaria from 'inducible' or 'physical' urticaria, for which there are specific triggers such as cold or pressure. 'Chronic' indicates that the condition has continued for at least six weeks. Hives may be intensely itchy, and the appearance may be unsightly and distressing to sufferers. In some cases, hives can be accompanied by deeper swelling, known as angio‐oedema, which is most common around the eyes and mouth.
Antihistamine drugs, specifically H1 antihistamines, are the mainstay of treatment for urticaria, although they control the condition rather than cure it. Many antihistamines are available to buy without a prescription, including brand names such as Clarityn, Piriton, Zirtek, Benadryl and Phenergan (brand names may differ by country).
Review question
Which H1‐antihistamines are effective and safe for CSU?
Study characteristics
We included 73 randomised controlled trials, with 9759 participants of all ages and looked for complete suppression of urticaria. The duration of the intervention was up to two weeks (short‐term) or longer than two weeks and up to three months (intermediate‐term).
Key results
We investigated clinical trials in which one therapy was compared against another or against placebo (direct comparisons). We found that for general use, 10 mg once daily of cetirizine for short‐term and intermediate‐term duration was effective in completely suppressing urticaria, although not in all individuals. Some benefit may be associated with use of desloratadine at 5 mg for at least an intermediate term and at 20 mg in the short term. Levocetirizine at 5 mg was effective for complete suppression in the intermediate term but not in the short term. A higher dose of 20 mg was effective in the short term, but 10 mg was not.
Adverse events, such as headache or dry mouth, are tolerable with most antihistamines. Evidence is less clear for improvement in quality of life (e.g. reduction in sleep disturbance from itching, less distress from the appearance of hives) as many studies did not address this.
We cannot say whether one antihistamine works better than all the rest, as we did not have head‐to‐head evidence for every possible treatment comparison.
Quality of the evidence
The overall quality of the evidence found for most outcomes was low. Further well‐designed and carefully reported comparative studies are required, if we are to find out how well these medicines work, and if any adverse effects are reported, especially over periods of up to several months.
Summary of findings
Summary of findings for the main comparison. Cetirizine 10 to 20 mg versus placebo for chronic spontaneous urticaria.
Cetirizine 10 to 20 mg versus placebo for chronic spontaneous urticaria | ||||||
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: cetirizine 10 to 20 mg versus placebo | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed risk | Corresponding risk | |||||
Control (placebo) | Cetirizine 10 to 20 mg | |||||
Complete suppression of urticaria Global assessment of symptom scores | Study population | RR 2.72 (1.51 to 4.91) | 178 (2 studies) | ⊕⊕⊝⊝ Lowa,b | Favours cetirizine | |
133 per 1000 | 363 per 1000 (201 to 655) | |||||
Moderate | ||||||
146 per 1000 | 397 per 1000 (220 to 717) | |||||
Adverse events leading to withdrawal | Study population | RR 3 (0.68 to 13.22) | 389 (3 studies) | ⊕⊕⊝⊝ Lowa,b | Favours neither intervention nor control | |
10 per 1000 | 30 per 1000 (7 to 132) | |||||
Moderate | ||||||
14 per 1000 | 42 per 1000 (10 to 185) | |||||
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. | ||||||
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |
aDesign limitation (risk of bias). bRelatively few participants and few events and/or wide confidence intervals.
Summary of findings 2. Desloratadine 5 to 20 mg versus placebo for chronic spontaneous urticaria.
Desloratadine 5 to 20 mg versus placebo for chronic spontaneous urticaria | ||||||
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: desloratadine 5 to 20 mg versus placebo | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed risk | Corresponding risk | |||||
Control (placebo) |
Desloratadine 5 to 20 mg |
|||||
Complete suppression of urticaria: short‐term duration of intervention (desloratadine 5 mg) Global assessment of symptom scores | See comment | See comment | Not estimable | 46 (1 study) | ⊕⊕⊝⊝ Lowa,b | Favours neither intervention nor control Only 1 study, a conference abstract (Hoxha 2011) |
Complete suppression of urticaria: short‐term duration of intervention (desloratadine 10 mg) Global assessment of symptom scores | See comment | See comment | Not estimable | 46 (1 study) | ⊕⊕⊝⊝ Lowa,b | Favours neither intervention nor control Only 1 study, a conference abstract (Hoxha 2011) |
Complete suppression of urticaria: short‐term duration of intervention (desloratadine 20 mg) Global assessment of symptom scores | See comment | See comment | Not estimable | 46 (1 study) | ⊕⊕⊝⊝ Lowa,b | Favours desloratadine Only 1 study, a conference abstract (Hoxha 2011) |
Complete suppression of urticaria: intermediate‐term duration of intervention (desloratadine 5 mg) Global assessment of symptom scores | See comment | See comment | Not estimable | 80 (1 study) | ⊕⊕⊝⊝ Lowa,b | Favours desloratadine Only 1 study (Di Lorenzo 2004) |
Adverse effects leading to withdrawal: intermediate‐term duration of 5 mg of intervention | Study population | RR 1.46 (0.42 to 5.1) | 466 (3 studies) | ⊕⊕⊝⊝ Lowa,b | Favours neither intervention nor control | |
17 per 1000 | 25 per 1000 (7 to 89) | |||||
Moderate | ||||||
18 per 1000 | 26 per 1000 (8 to 92) | |||||
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. | ||||||
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |
aDesign limitation (risk of bias). bRelatively few participants and few events and/or wide confidence intervals.
Summary of findings 3. Levocetirizine 5 to 20 mg versus placebo for chronic spontaneous urticaria.
Levocetirizine 5 to 20 mg versus placebo for chronic spontaneous urticaria | ||||||
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: levocetirizine 5 to 20 mg versus placebo | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed risk | Corresponding risk | |||||
Control (placebo) |
Levocetirizine 5 to 20 mg |
|||||
Complete suppression of urticaria: short‐term duration of intervention (levocetirizine 5 mg) Global assessment of symptom scores | See comment | See comment | Not estimable | 49 (1 study) | ⊕⊕⊝⊝ Lowa,b | Favours neither intervention nor control Only 1 study, a conference abstract (Hoxha 2011) |
Complete suppression of urticaria: short‐term duration of intervention (levocetirizine 10 mg) Global assessment of symptom scores | See comment | See comment | Not estimable | 49 (1 study) | ⊕⊕⊝⊝ Lowa,b | Favours neither intervention nor control Only 1 study, a conference abstract (Hoxha 2011) |
Complete suppression of urticaria: short‐term duration of intervention (levocetirizine 20 mg) Global assessment of symptom scores | See comment | See comment | Not estimable | 49 (1 study) | ⊕⊕⊝⊝ Lowa,b | Favours levocetirizine Only 1 study, a conference abstract (Hoxha 2011) |
Complete suppression of urticaria: intermediate‐term duration of intervention (levocetirizine 5 mg) Global assessment of symptom scores | See comment | See comment | Not estimable | 100 (1 study) | ⊕⊕⊝⊝ Lowa,b | Favours levocetirizine Only 1 study (Nettis 2006) |
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval. | ||||||
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |
aDesign limitation (risk of bias). bRelatively few participants and few events and/or wide confidence intervals.
Summary of findings 4. Rupatadine 10 to 20 mg versus placebo for chronic spontaneous urticaria.
Rupatadine 10 to 20 mg versus placebo for chronic spontaneous urticaria | ||||||
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: rupatadine 10 to 20 mg versus placebo | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed risk | Corresponding risk | |||||
Control (placebo) |
Rupatadine 10 to 20 mg |
|||||
Good or excellent response Global assessment of symptom scores | Study population | RR 1.35 (1.03 to 1.77) | 245 (1 study) | ⊕⊕⊝⊝ Lowa,b | Favours rupatadine | |
509 per 1000 | 687 per 1000 (524 to 901) | |||||
Moderate | ||||||
509 per 1000 | 687 per 1000 (524 to 901) | |||||
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. | ||||||
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |
aDesign limitation (risk of bias). bRelatively few participants and few events and/or wide confidence intervals.
Summary of findings 5. Loratadine 10 mg versus placebo for chronic spontaneous urticaria.
Loratadine 10 mg versus placebo for chronic spontaneous urticaria | ||||||
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: loratadine 10 mg versus placebo | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed risk | Corresponding risk | |||||
Control (placebo) |
Loratadine 10 mg |
|||||
Good or excellent response Global assessment of symptom scores | Study population | RR 1.86 (0.91 to 3.79) | 124 (2 studies) | ⊕⊕⊝⊝ Lowa,b | Favours neither intervention nor control | |
155 per 1000 | 289 per 1000 (141 to 588) | |||||
Moderate | ||||||
160 per 1000 | 298 per 1000 (146 to 606) | |||||
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. | ||||||
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |
aDesign limitation (risk of bias). bRelatively few participants and few events and/or wide confidence intervals.
Summary of findings 6. Loratadine 10 mg versus cetirizine 10 mg for chronic spontaneous urticaria.
Loratadine 10 mg versus cetirizine 10 mg for chronic spontaneous urticaria | ||||||
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: loratadine 10 mg versus cetirizine 10 mg | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed risk | Corresponding risk | |||||
Control (cetirizine 10 mg) |
Loratadine 10 mg |
|||||
Complete cessation of urticaria Global assessment of symptom scores | Study population | RR 1.05 (0.76 to 1.43) | 103 (2 studies) | ⊕⊕⊝⊝ Lowa,b | Combined short and intermediate‐term duration of intervention. Favours neither intervention nor control |
|
588 per 1000 | 618 per 1000 (447 to 841) | |||||
Moderate | ||||||
574 per 1000 | 603 per 1000 (436 to 821) | |||||
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. | ||||||
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |
aDesign limitation (risk of bias). bRelatively few participants and few events and/or wide confidence intervals.
Summary of findings 7. Loratadine 10 mg versus desloratadine 5 mg for chronic spontaneous urticaria.
Loratadine 10 mg versus desloratadine 5 mg for chronic spontaneous urticaria | ||||||
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: loratadine 10 mg versus desloratadine 5 mg | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed risk | Corresponding risk | |||||
Control (desloratadine 5 mg) |
Loratadine 10 mg |
|||||
Complete suppression of urticaria: intermediate‐term duration of intervention | Study population | RR 0.91 (0.78 to 1.06) | 369 (2 studies) | ⊕⊕⊝⊝ Lowa,b | Favours neither intervention nor control | |
658 per 1000 | 598 per 1000 (513 to 697) | |||||
Moderate | ||||||
670 per 1000 | 610 per 1000 (523 to 710) | |||||
Good or excellent response: intermediate‐term duration of intervention Global assessment of symptom scores | Study population | RR 1.04 (0.64 to 1.71) | 410 (3 studies) | ⊕⊕⊝⊝ Lowa,b | Favours neither intervention nor control No participants reported a good or excellent response in the loratadine group in Zou 2002 We found low levels of statistical heterogeneity in this analysis I2 = 40%) |
|
263 per 1000 | 274 per 1000 (169 to 450) | |||||
Moderate | ||||||
228 per 1000 | 237 per 1000 (146 to 390) | |||||
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. | ||||||
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |
aDesign limitation (risk of bias). bRelatively few participants and few events and/or wide confidence intervals.
Summary of findings 8. Loratadine 10 mg versus mizolastine 10 mg for chronic spontaneous urticaria.
Loratadine 10 mg compared to mizolastine 10 mg for chronic spontaneous urticaria | ||||||
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: loratadine 10 mg Comparison: mizolastine 10 mg | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed risk | Corresponding risk | |||||
Control (mizolastine 10 mg) |
Loratadine 10 mg |
|||||
Complete cessation of urticaria: intermediate‐term duration of intervention Global assessment of symptom scores | Study population | RR 0.86 (0.64 to 1.16) | 316 (3 studies) | ⊕⊝⊝⊝ Very lowa,b,c | Overall, favours neither loratadine nor mizolastine In Guo 2003, more participants in mizolastine group had complete cessation of urticaria than in the other 2 studies (Liu 2003 and Yin 2003b) |
|
675 per 1000 | 581 per 1000 (432 to 783) | |||||
Moderate | ||||||
667 per 1000 | 574 per 1000 (427 to 774) | |||||
Good or excellent response: intermediate‐term duration of intervention Global assessment of symptom scores | Study population | RR 0.88 (0.55 to 1.42) | 314 (3 studies) | ⊕⊕⊝⊝ Lowa,c | Favours neither loratadine nor mizolastine | |
187 per 1000 | 165 per 1000 (103 to 266) | |||||
Moderate | ||||||
174 per 1000 | 153 per 1000 (96 to 247) | |||||
Adverse events leading to withdrawal: intermediate‐term duration of intervention | Study population | RR 0.38 (0.04 to 3.6) | 267 (2 studies) | ⊕⊕⊝⊝ Lowa,c | Favours neither loratadine nor mizolastine | |
15 per 1000 | 6 per 1000 (1 to 53) | |||||
Moderate | ||||||
19 per 1000 | 7 per 1000 (1 to 68) | |||||
Proportion of participants with at least 50% improvement in QoL: intermediate‐term duration of intervention Symptom score reducing index (SSRI) | Study population | RR 3.21 (0.32 to 32.33) | 252 (2 studies) | ⊕⊝⊝⊝ Very lowa,b,c | Favours neither loratadine nor mizolastine No participants in the mizolastine group in Guo 2003 reported at least 50% improvement in QoL |
|
104 per 1000 | 334 per 1000 (33 to 1000) | |||||
Moderate | ||||||
64 per 1000 | 205 per 1000 (20 to 1000) | |||||
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. | ||||||
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |
aDesign limitation (risk of bias). bWidely differing estimates of the treatment effect (i.e. heterogeneity or variability in results) across studies. cRelatively few participants and few events and/or wide confidence intervals.
Summary of findings 9. Loratadine 10 mg versus emedastine 2 mg for chronic spontaneous urticaria.
Loratadine 10 mg versus emedastine 2 mg for chronic spontaneous urticaria | ||||||
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: loratadine 10 mg versus emedastine 2 mg | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed risk | Corresponding risk | |||||
Control (emedastine 2 mg) |
Loratadine 10 mg |
|||||
Complete cessation of urticaria: intermediate‐term duration of intervention Global assessment of symptom scores | Study population | RR 1.04 (0.78 to 1.39) | 161 (1 study) | ⊕⊕⊕⊝ Moderatea | Favours neither loratadine nor emedastine Only 1 study (Pons‐Guiraud 2006) |
|
524 per 1000 | 545 per 1000 (409 to 728) | |||||
Moderate | ||||||
524 per 1000 | 545 per 1000 (409 to 728) | |||||
Good or excellent response: intermediate‐term duration of intervention Global assessment of symptom scores | Study population | RR 1.09 (0.96 to 1.24) | 160 (1 study) | ⊕⊕⊕⊝ Moderatea | Favours neither loratadine nor emedastine Only 1 study (Pons‐Guiraud 2006) |
|
819 per 1000 | 893 per 1000 (787 to 1000) | |||||
Moderate | ||||||
819 per 1000 | 893 per 1000 (786 to 1000) | |||||
Adverse events leading to withdrawal: intermediate‐term duration of intervention | Study population | RR 1.09 (0.07 to 17.14) | 161 (1 study) | ⊕⊕⊕⊝ Moderatea | Favours neither loratadine nor emedastine Only 1 study (Pons‐Guiraud 2006) |
|
12 per 1000 | 13 per 1000 (1 to 204) | |||||
Moderate | ||||||
12 per 1000 | 13 per 1000 (1 to 206) | |||||
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. | ||||||
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |
aRelatively few participants and few events and/or wide confidence intervals.
Summary of findings 10. Loratadine 10 mg versus hydroxyzine 25 mg for chronic spontaneous urticaria.
Loratadine 10 mg versus hydroxyzine 25 mg for chronic spontaneous urticaria | ||||||
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: loratadine 10 mg versus hydroxyzine 25 mg | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed risk | Corresponding risk | |||||
Control (hydroxyzine 25 mg) |
Loratadine 10 mg |
|||||
Complete suppression of urticaria: short‐term duration of intervention Global assessment of symptom scores | Study population | RR 1 (0.32 to 3.1) | 12 (1 study) | ⊕⊕⊝⊝ Lowa,b | Favours neither intervention or control Only 1 study (Monroe 1992) |
|
500 per 1000 | 500 per 1000 (160 to 1000) | |||||
Moderate | ||||||
500 per 1000 | 500 per 1000 (160 to 1000) | |||||
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. | ||||||
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |
aDesign limitation (risk of bias). bRelatively few participants and few events and/or wide confidence intervals.
Summary of findings 11. Cetirizine 10 mg versus hydroxyzine 25 mg for chronic spontaneous urticaria.
Cetirizine 10 mg versus hydroxyzine 25 mg for chronic spontaneous urticaria | ||||||
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: cetirizine 10 mg versus hydroxyzine 25 mg | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed risk | Corresponding risk | |||||
Control (hydroxyzine 25 mg) |
Cetirizine 10 mg |
|||||
Adverse events leading to withdrawal | Study population | RR 0.78 (0.25 to 2.45) | 261 (2 studies) | ⊕⊕⊝⊝ Lowa,b | Favours neither cetirizine nor hydroxyzine | |
53 per 1000 | 41 per 1000 (13 to 130) | |||||
Moderate | ||||||
54 per 1000 | 42 per 1000 (14 to 132) | |||||
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. | ||||||
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |
aDesign limitation (risk of bias). bRelatively few participants and few events and/or wide confidence intervals.
Summary of findings 12. Hydroxyzine 25 mg versus placebo for chronic spontaneous urticaria.
Hydroxyzine 25 mg versus placebo for chronic spontaneous urticaria | ||||||
Patient or population: patients with chronic spontaneous urticaria Setting: research clinic Intervention: hydroxyzine 25 mg versus placebo | ||||||
Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Quality of the evidence (GRADE) | Comments | |
Assumed risk | Corresponding risk | |||||
Control (placebo) |
Hydroxyzine 25 mg |
|||||
Adverse events leading to withdrawal: intermediate‐term duration of intervention | Study population | RR 3.64 (0.77 to 17.23) | 270 (2 studies) | ⊕⊕⊝⊝ Lowa,b | Favours neither intervention nor control | |
14 per 1000 | 53 per 1000 (11 to 250) | |||||
Moderate | ||||||
15 per 1000 | 55 per 1000 (12 to 258) | |||||
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. | ||||||
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. |
aDesign limitation (risk of bias). bRelatively few participants and few events and/or wide confidence intervals.
Background
Description of the condition
Urticaria is a condition characterised by the development of a rash of red itchy raised weals or hives that blanch with pressure. The main associated symptom is itching, which may be intense. Although individual weals typically come and go within 24 hours, the overall condition may persist, with fresh crops of weals occurring on other areas of the body, even as the original lesions resolve. In some cases, the weals are accompanied by deeper swelling, known as angio‐oedema. If recurrent crops of urticaria continue to occur for longer than six weeks, the condition is known as chronic urticaria (to distinguish this from the more common acute urticaria, for which a cause is more often identified) (James 2011; Sarbijt 2014). Chronic spontaneous urticaria may occur at any age (Hellgren 1972). Recent publications show a female‐to‐male predominance of 2:1 (Gaig 2004) with a prevalence of between 0.5% and 1% (Maurer 2011).
Causes
A careful history and physical examination are important, but an underlying cause is never identified in most individuals with chronic urticaria (Grattan 2001; Charlesworth 2002). In such cases, the condition has also been called 'chronic idiopathic urticaria.' This term was replaced by 'chronic ordinary urticaria' to include the subset of people who appear to have autoimmune disease, with a circulating antibody that is able to bind to mast cells, thereby causing histamine release and weal formation. This group makes up about 30% of those with chronic urticaria, but such individuals tend to respond in the same way to treatment as those with non‐autoimmune urticaria (Hauser 2003). Current consensus is to use the term 'chronic spontaneous urticaria' (Maurer 2013), which describes the behaviour of the disease rather than assuming a particular level of knowledge of its pathogenesis. By contrast, when a trigger for urticaria can be identified, the term 'inducible' is now preferred. In practice, chronic spontaneous urticaria covers the population of individuals who were previously labelled as having chronic idiopathic or ordinary urticaria. Most of the extant literature employs these outmoded terms. We therefore deemed it appropriate to include such studies, whilst adhering to the term 'chronic spontaneous urticaria (CSU)' throughout our review.
Impact
The severity of urticaria varies between individuals. Some of those with the condition have several attacks each day for many months; others may have an attack every week or every month. This can be a very debilitating condition, particularly if the attacks are frequent. The inability to predict an attack and the lack of an identifiable cause are often sources of great frustration. Historically it has been reported that after 10 years, at least 20% of those with urticaria still suffer from it (Champion 1969; Humphreys 1998) and that half of those with chronic urticaria and angio‐oedema still had chronic urticaria at five years (Champion 1969). However, the condition is rarely permanent, and recent surveys suggest a higher chance of disease remission (Kozel 2001).
Description of the intervention
The aim of treatment is to suppress urticarial activity completely. In some individuals, only symptomatic improvement can be achieved by reducing the severity and frequency of attacks. H1‐antihistamines (commonly called 'antihistamines,' which are available over the counter for various complaints, including hay fever and allergies) form the basis of treatment, providing symptomatic relief for many affected individuals. Older (or 'first‐generation') H1‐antihistamines (e.g. hydroxyzine) are no longer recommended for use in chronic urticaria, as they are more sedating than the newer 'second generation' of antihistamines (e.g. cetirizine) and carry a higher risk of side effects such as dry mouth, blurred vision, headache, glaucoma and urinary retention.
Antihistamines may have to be taken over extended periods of time to control the disease. High doses of H1‐antihistamines may be required to obtain sufficient symptom control in urticaria. Adverse effects of H1‐antihistamines vary between individuals, and some of those with the condition may tolerate one antihistamine better than another (Nolen 1997). Terfenadine and astemizole have been associated with cardiac arrhythmias (DuBuske 1999) in a small proportion of people and have been withdrawn from the market. Oral corticosteroids have an occasional role as rescue therapy in severe exacerbations of chronic urticaria.
Other treatments for difficult to control CSU include H2‐antihistamines (also known as H2‐receptor antagonists, or H2RAs) such as ranitidine (these are not commonly referred to as antihistamines and are usually used for acid‐related stomach conditions). (This class of medications was systematically reviewed in Fedorowicz 2012.) Other interventions include the leukotriene receptor antagonist montelukast, immunosuppressive agents (e.g. ciclosporin), diets and food avoidance, doxepin and the anti‐immunoglobulin E (IgE) monoclonal antibody omalizumab.
Why it is important to do this review
Patients with chronic spontaneous urticaria can be difficult to treat. Many of those with the condition do not respond to initial treatment, and clear guidance is needed on which antihistamines to use, appropriate dosing regimens and likely responses. As treatment is usually aimed at reducing symptoms and improving the lives of people with CSU, evidence regarding quality of life was sought so an important outcome for this review could be assessed.
Many randomised controlled trials (RCTs) related to the use of antihistamines in CSU have been conducted. We sought to investigate:
whether one antihistamine is superior to another;
if combination therapy is superior to monotherapy;
whether high‐dose therapy is superior to standard doses;
the duration of benefit from H1‐antihistamines;
risks and side effects of H1‐antihistamines when used in the treatment of individuals with chronic urticaria; and
the effects of treatment on quality of life.
We have provided an assessment of the level and quality of currently available evidence, and we have identified areas that require further research on this important condition.
Objectives
To assess the effects of H1‐antihistamines for chronic spontaneous urticaria (CSU).
Methods
Criteria for considering studies for this review
Types of studies
We included only RCTs that evaluated the effectiveness of H1‐antihistamines compared with placebo or another active treatment (including another H1‐antihistamine) and those that compared different doses. We did not include studies of other designs.
Types of participants
Participants were individuals of any age (children and adults) who had been clinically diagnosed with CSU. The following were excluded.
Participants with urticaria of less than six weeks' duration;
Participants with immune complex urticaria (urticarial vasculitis or serum sickness), papular urticaria, angio‐oedema without weals or contact urticaria; and
Participants with predominantly physical or cholinergic urticaria, or other urticaria with a clearly identifiable causative agent (e.g. medication), and those with auto‐inflammatory syndromes (e.g. Muckle‐Wells syndrome, Schnitzler's syndrome).
Types of interventions
Any first‐generation ('sedating') or second‐generation ('non‐sedating') H1‐antihistamines in current use, given at any dose (including topical interventions and H2RAs given concomitantly). We specifically excluded studies that would yield comparison data only for terfenadine and astemizole, as these drugs have been withdrawn because of safety issues. Interventions could be given as single therapy or combination therapy. Comparators consisted of no treatment (i.e. placebo) or another active compound.
Duration of the intervention was categorised as follows: up to two weeks (short‐term), longer than two weeks and up to three months (intermediate‐term) and longer than three months (long‐term).
Types of outcome measures
Primary outcomes
Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.
Proportion of participants with 'good' or 'excellent' response to H1‐antihistamines whilst taking H1‐antihistamines.
Proportion of participants with 50% or greater improvement in quality of life measurements whilst taking H1‐antihistamines.
The above measures were based predominantly on participant self‐reporting because of the transient nature of urticaria. We looked at participant and clinician assessments separately and in combination.
Secondary outcomes
Serious adverse events (i.e. serious enough to require withdrawal of treatment).
Minor participant‐reported adverse events not requiring withdrawal of treatment.
Proportion of participants who relapse within one month of stopping H1‐antihistamines.
Search methods for identification of studies
We aimed to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press or in progress).
Electronic searches
We revised our draft search strategy to update the names of specific H1‐antihistamines used to treat urticaria.
We searched the following databases up to 3 June 2014.
Cochrane Skin Group Specialised Register (strategy in Appendix 1).
Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 5) (strategy in Appendix 2).
MEDLINE via OVID (from 1946) (strategy in Appendix 3).
EMBASE via OVID (from 1974) (strategy in Appendix 4).
PsycINFO via OVID (from 1806) (strategy in Appendix 5).
Trials registers
We searched the following trials registers on 9 June 2014.
For the first three registers listed, we used the following search string: 'chronic idiopathic urticaria AND anti‐histamine AND placebo.' For the EU Clinical Trials Register and the World Health Organization International Clinical Trials Registry, we used the phrase 'chronic idiopathic urticaria.'
metaRegister of Controlled Trials (www.controlled‐trials.com).
US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov).
Australian New Zealand Clinical Trials Registry (www.anzctr.org.au).
World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch).
EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/).
Searching other resources
References from published papers
We checked the bibliographies of reviews on treatment of individuals with CSU to look for additional references to relevant RCTs.
Adverse effects
We did not perform a separate search for adverse effects of the target intervention. We considered adverse and side effects described in the included studies. We checked the bibliographies of review articles to look for additional references to relevant reports of adverse effects.
Data collection and analysis
Selection of studies
We included in this review only RCTs evaluating H1‐antihistamines for chronic urticaria. We sought advice from translators when the study report was written in a language other than English. At least two review authors (MS, CB and SNC) assessed all titles and abstracts identified by the searches. These review authors independently assessed each included study to determine whether the predefined selection criteria had been met, and they resolved differences of opinion through discussion within the review team. We listed the excluded studies and the reasons for their exclusion in the Characteristics of excluded studies section of the review and presented the study flow chart in PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) (Figure 1).
1.
Study flow diagram.
Data extraction and management
Three review authors (MS, CB and SNC) extracted data independently using a data extraction form, and disagreements on data extraction were resolved by consensus. In the case of studies written in Chinese, German or another foreign language, a translator extracted data, and MS and SNC checked the numerical outcomes. We contacted principal investigators of trials and asked them to provide missing data when possible. Review authors (MS, CB and BC) checked and entered the data (numerical outcomes data and non‐numerical data) into RevMan 2014.
Assessment of risk of bias in included studies
At least two review authors (MS, CB and SNC) independently assessed the risk of bias in included studies using the risk of bias assessment tool provided in Chapter 8 of theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We compared the evaluations and discussed and resolved inconsistencies between review authors' decisions.
We rated the following domains separately for each of the included studies as 'low risk of bias,' 'high risk of bias' and 'unclear' if the risk of bias was uncertain or unknown. These assessments are reported in the 'Risk of bias' table for each individual study in the Characteristics of included studies section of the review.
Allocation sequence was adequately generated ('sequence generation').
Allocation was adequately concealed ('allocation concealment').
Knowledge of allocated interventions was adequately prevented during the study ('blinding').
Incomplete outcome data were adequately addressed.
Reports of the study were free of suggestions of selective outcome reporting.
The study was apparently free of other sources of bias that could put it at high risk of bias (i.e. potential conflicts of interest, pharmaceutical funding/support or both).
We also categorised and reported the overall risk of bias of each of the included studies according to the following.
Low risk of bias: plausible bias unlikely to seriously alter the results if all criteria were met.
Unclear risk of bias: plausible bias that raises some doubt about the results if one or more criteria were assessed as unclear.
High risk of bias: plausible bias that seriously weakens confidence in the results if one or more criteria were not met.
We reported these assessments in the Risk of bias in included studies section of this review.
Measures of treatment effect
We planned to present continuous outcomes on the original scale as reported in each individual study. We will report standardised mean differences (SMDs) for continuous data in future updates (i.e. if similar outcomes are reported using different scales, we will standardise these by dividing the estimated coefficient by its standard deviation (SD) to permit comparisons between scales).
We presented dichotomous outcomes data as risk ratios (RRs) along with their associated 95% confidence intervals (CIs); we analysed these in RevMan using the Mantel‐Haenszel test, unless stated otherwise.
Unit of analysis issues
Cross‐over studies
We planned to analyse cross‐over studies using first period data only, unless an adequate washout between periods took place and baseline data were presented for each period.
Multi‐armed studies
To ensure that analyses from these studies were not falsely powered, we partitioned the number of participants analysed in the comparison arm into each pair‐wise comparison; thus a three‐arm study with 30 participants in each arm that resulted in two pair‐wise comparisons of placebo versus A and placebo versus B was allocated the following numbers of participants: 15 versus 30, and 15 versus 30. Mean and standard deviation summary statistics for comparator participants remained unchanged.
Dealing with missing data
We attempted to contact investigators to retrieve missing data. We reanalysed data according to a treatment by allocation principle when possible, and in accordance with Section 16.2.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If data were not reported and study authors had conducted a per‐protocol analysis, we assessed whether there was any imbalance in the dropout rate between trial arms to determine the potential impact of bias. In the absence of intention‐to‐treat data, we used available case population data (per protocol) and reported these accordingly.
Assessment of heterogeneity
We assessed clinical heterogeneity by examining trial conditions (i.e. characteristics of the studies, similarity between types of participants and the interventions). We assessed the degree of statistical heterogeneity between studies using the I² statistic. We reported heterogeneity as important if it was at least moderate to substantial by the I² statistic > 60% (Higgins 2011). If this could be explained by clinical reasoning and a coherent argument could be made for combining the studies, we conducted a meta‐analysis. In many cases, heterogeneity could not be adequately explained, and we did not pool the data.
Clinical diversity among the studies included in this review, as well as the limited number of studies that could be combined for each intervention, allowed us to assess heterogeneity between studies for only one of the comparisons.
Assessment of reporting biases
We planned to carry out assessments of reporting bias when at least 10 studies were included in a meta‐analysis, according to the recommendations on testing for funnel plot asymmetry as described in Section 10.4.3.1 of the Cochrane Handbook for systematic Reviews of Interventions (Higgins 2011). We planned to explore possible sources of asymmetry by performing an additional sensitivity analysis.
Data synthesis
Review authors (MS, CB and BC) analysed the data in RevMan 2014 and reported them in accordance with the advice provided in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If we were able to identify more than one study that was clinically similar and exhibited not less than moderate heterogeneity, we pooled the data into a meta‐analysis using a random‐effects model, and we carried out a sensitivity analysis using a fixed‐effect model to assess the degree of heterogeneity.
For some comparisons, we carried out reanalysis using Fisher's exact test because of the small number of participants,
Subgroup analysis and investigation of heterogeneity
We conducted subgroup analyses based on the duration of the intervention. Duration of the intervention was categorised as follows: up to two weeks (short‐term) and longer than two weeks up to three months (intermediate‐term).
Sensitivity analysis
We planned to conduct sensitivity analyses for primary outcome measures to assess the effects of including only those studies with low risk of bias and to assess the robustness of the results of this review. Included studies with low risk of bias were too few to permit this analysis.
Results
Description of studies
Results of the search
We identified 1080 records in total through our electronic database searches up to June 2014. We identified an additional 45 potential study reports from databases of clinical trials in progress and from bibliographical searches. In total we screened 1125 records and excluded 841 on the basis of examination of titles and abstracts. We examined the remaining 284 records in detail. Sixteen records could not be obtained in full text, and we list these in the Characteristics of studies awaiting classification tables. Fourteen studies were listed as ongoing (see Characteristics of ongoing studies), and we will include these in future updates if the results become available (Figure 1). We excluded 169 studies accounting for 172 records. The remaining 82 records described 73 studies, which were included.
At each stage of the selection process, at least two review authors independently reviewed the search results and selected trials for inclusion. The final list was agreed upon by two review authors (MS and SNC), with involvement of a third review author (CB) if necessary to resolve disagreements.
Included studies
Design
All included studies were randomised, and none was of quasi‐randomised design.
Some unusual designs were reported: Garavaglia 1995 reported a randomised trial in which dropouts were replaced with new recruits. It was unclear whether the new participants were randomly assigned or were simply assigned to the intervention group of the most recent dropout. Thompson 2000 Study 1 and Thompson 2000 Study 2 reported two trials within the same study report; it is unclear why the results from both studies were not aggregated and presented as a single two‐centre trial, as trial conditions were the same. Wang 2012 was a dose reduction study, and Weller 2013 selected a single body area for each participant. Staevska 2014 employed a cross‐over trial design but after randomisation and initial in‐hospital treatment assessment tested the effectiveness and tolerability of levocetirizine versus hydroxyzine in an alternate‐day regimen. After five days, participants from arms 1 and 2 were crossed over to the alternative treatment without washout between phases.
Twenty‐six of the included trials were multi‐centre in design (Belaich 1990; Breneman 1995; Breneman 1996; Bronsky 2001; Brostoff 1996; Dubertret 1999; Finn 1999; Gale 1989; Gimenez‐Arnau 2007; Godse 2007; Grant 1988; Gu 2002; Hao 2003; Kalivas 1990; Kaplan 2005; Kint 1989; Monroe 1988; Monroe 2003; Nelson 2000; Ollert 1999; Ortonne 2007; Paul 1998; Peyri 1991; Pons‐Guiraud 2006; Potter 2009; Zuberbier 2010).
Fourteen included studies were of a cross‐over design. However, none of these contributed data to the meta‐analyses in this review, although we discuss the results narratively below (Commens 1978; Gale 1989; Go 1989; Goh 1991; Harvey 1981; Hjorth 1988; Juhlin 1987; Juhlin 1991; Kint 1989; Leyh 1989; Liu H‐N 1990; Marks 1980; Salo 1989; Staevska 2014).
Sample sizes
We included 73 studies with a total of 9759 randomly assigned participants. Details of all included studies are provided in the Characteristics of included studies tables. Sample sizes ranged from several hundred, for example, 886 (Potter 2009), 525 (Zuberbier 2010), 468 (Nelson 2000), 334 (Gimenez‐Arnau 2007) and 314 NCT00536380) to fewer than 25 (Gale 1989; Harvey 1981; Juhlin 1987; Leyh 1989; Liu H‐N 1990; Marks 1980; Salo 1989).
Setting
Most studies were carried out in a secondary care setting, including hospital clinics, research clinics and dermatology centres. None were based in primary care.
Studies were carried out mostly, but not exclusively, in Europe and the USA. Outside these continents, Anuradha 2010; Dakhale 2014; Ghosh 1990; Godse 2007; Handa 2004 and Maiti 2011 were undertaken in India. Gu 2002; Hao 2003; Liu 2003; Wang 2012; Wu 2008; Yin 2003a; Yin 2003b and Zou 2002 were undertaken in China, and Makino 2012 in Japan. Garavaglia 1995 and Zuberbier 2010 were carried out in Argentina, Goh 1991 in Singapore and Liu H‐N 1990 and Wan 2009 in Taiwan. Marks 1980 took place in Australia, Monroe 2003 in the USA and Chile and Phanuphak 1987 in Thailand. The location was not stated for Patel 1997, although the study authors worked in American and Canadian research centres.
Participants
The total number of participants randomly assigned was 9759. Participants consisted of adults (i.e. over 18 years old) or mixed groups including adolescents (i.e. over 12 years old). Most participants were female.
The inclusion criteria were tightly defined as CSU, alternatively described as chronic idiopathic or ordinary urticaria, of at least six weeks' duration. In Hjorth 1988, the diagnosis was not clearly defined, and investigators may have included some participants with atopic dermatitis. In Wang 2012, disease duration and symptoms were comparable but were not defined clearly in the study. Dakhale 2014; Finn 1999; Grant 1988; Kaplan 2005; Monroe 2003; Nelson 2000; Ortonne 2004 and Pons‐Guiraud 2006 excluded participants who were previously unresponsive to antihistamines, and in the Ghosh 1990 study, all participants were previously refractory to antihistamine treatment.
Interventions and comparisons
Intervention
H1‐antihistamines usually are classified as first or second generation, according to their chemical structure and properties. First‐generation antihistamines may cause sedation and can be useful for treating sleep disturbance due to itching. Second‐generation antihistamines are less sedating, as the molecule is less likely to cross the blood‐brain barrier; however, they are not without the possibility of sedative effects, and some (particularly terfenadine and astemizole) may also cause irregularities in heart rhythm (cardiac arrhythmia). A category of third‐generation antihistamines has been used to describe some of the later antihistamines. This term is not generally accepted, as such agents do not differ sufficiently from earlier drugs in terms of desirable and undesirable effects (Holgate 2003). In our analyses (of those trials that yielded outcome data), we included the following.
First‐generation antihistamines
Hydroxyzine.
Pheniramine.
Second‐generation antihistamines
Cetirizine.
Desloratadine.
Ebastine.
Emedastine.
Fexofenadine.
Levocetirizine.
Loratadine.
Ketotifen.
Mizolastine.
Rupatadine.
Other interventions
Di Lorenzo 2004 used montelukast, a non‐H1‐antihistamine intervention, as the comparator with desloratadine. Montelukast is a leukotriene receptor antagonist (LTRA). Ghosh 1990 used as a comparator doxepin, a sedative tricyclic antidepressant that has antihistaminic properties.
Duration of intervention
Interventions were categorised by duration as follows: up to two weeks (short‐term), longer than two weeks and up to three months (intermediate‐term) and longer than three months (long‐term). Seventeen studies were short‐term (Commens 1978; Go 1989; Goh 1991; Harvey 1981; Hjorth 1988; Juhlin 1987; Juhlin 1991; Kint 1989; Leyh 1989; Leynadier 2000; Locci 1991; Monroe 1992; Patel 1997; Peyri 1991; Phanuphak 1987; Salo 1989; Staevska 2014); the duration of intervention was not explicitly stated in Hoxha 2011, but we categorised this as short‐term on the basis of information given in the abstract report. One study (Weller 2013) was of very short duration (five hours). The remaining 55 studies were categorised as having an intermediate‐term duration of intervention. None of the studies had an intervention period categorised as long‐term.
Comparisons
A total of 73 trials met our inclusion criteria. Of these, only 34 trials provided outcome data for the following comparisons.
Loratadine 10 mg versus placebo (Belaich 1990; Monroe 1992).
Loratadine 10 mg versus cetirizine 10 mg (Patel 1997; Yin 2003b).
Loratadine 10 mg versus desloratadine 5 mg (Gu 2002; Hao 2003; Zou 2002).
Loratadine 10 mg versus mizolastine 10 mg (Guo 2003; Leynadier 2000; Liu 2003; Yin 2003b).
Loratadine 10 mg versus emedastine 2 mg (Pons‐Guiraud 2006).
Loratadine 10 mg versus hydroxyzine 25 mg (Monroe 1992).
Cetirizine 10 mg versus placebo (Breneman 1995; Breneman 1996; Go 1989; Kalivas 1990)..
Cetirizine 10 mg versus hydroxyzine 25 mg (Breneman 1996; Kalivas 1990).
Cetirizine 10 mg versus fexofenadine 180 mg (Handa 2004).
Cetirizine 10 mg versus levocetirizine 5 mg (Yin 2003a).
Cetirizine 10 mg versus mizolastine 10 mg (Yin 2003b).
Desloratadine 5 mg to 20 mg versus placebo (Di Lorenzo 2004; Hoxha 2011; Monroe 2003; Nettis 2004; Ortonne 2007; Ring 2001).
Hydroxyzine 25 mg versus placebo (Breneman 1996; Kalivas 1990; Monroe 1992).
Levocetirizine 5 mg to 20 mg versus placebo (Hoxha 2011; Nettis 2006).
Rupatadine 10 mg to 20 mg versus placebo (Gimenez‐Arnau 2007).
Desloratadine 5 mg to 20 mg versus levocetirizine 5 to 20 mg (Hoxha 2011; Potter 2009).
Ebastine 10 mg versus placebo (Peyri 1991).
Desloratadine 5 mg versus montelukast 10 mg (Di Lorenzo 2004).
Fexofenadine 180 mg versus placebo (Kaplan 2005).
Ketotifen 1 mg versus placebo (Phanuphak 1987).
Cetirizine 5 mg and hydroxyzine 25 mg versus placebo (Wan 2009).
Azelastine 2 mg versus azelastine 4 mg (Wu 2008).
Doxepin 10 mg versus pheniramine 22.5 mg (Ghosh 1990).
A number of studies compared interventions that could not be included in our analyses because the outcomes measured did not fit our inclusion criteria.
Acrivastine 4 mg, placebo, clemastine 1 mg (Leynadier 2000).
Acrivastine 8 mg, chlorphen(ir)amine maleate 4 mg (Gale 1989).
Acrivastine 8 mg, clemastine 1 mg, placebo (Juhlin 1987).
Acrivastine 8 mg, hydroxyzine hydrochloride 20 mg (Salo 1989).
Azelastine 2 mg, azelastine 4 mg, azelastine and cimetidine (H2RA) 2 mg (Wu 2008).
Cetirizine 10 mg, placebo (Juhlin 1991).
Cetirizine 10 mg plus placebo, terfenadine 60 mg, placebo (Go 1989; Kint 1989).
Cetirizine 10 mg, terfenadine 120 mg, placebo (Garavaglia 1995).
Cetirizine 10 mg, placebo (cross‐over) (Goh 1991); non‐cross‐over (Alomar 1990a).
Cetirizine 10 mg versus rupatadine 10 mg (Dakhale 2014).
Chlorphen(ir)amine 4 mg, chlorphen(ir)amine 4 mg plus cimetidine 400 mg (H1 + H2 antagonist), placebo (Marks 1980)
Cimetidine 200 mg plus chlorphen(ir)amine 4 mg, chlorphen(ir)amine 4 mg plus placebo, placebo (Commens 1978).
Desloratadine 5 mg, placebo (Bronsky 2001; Monroe 2003; Ortonne 2004; Ortonne 2007Ring 2001).
Desloratadine 5 mg, desloratadine 10 mg, desloratadine 20 mg (NCT00536380).
Desloratadine 5 mg, desloratadine 20 mg (Weller 2013).
Desloratadine 5 mg and placebo, desloratadine 5 mg and montelukast 10 mg, placebo (Nettis 2004).
Fexofenadine 60 mg, 120 mg, 180 mg and 240 mg; placebo (Paul 1988).
Fexofenadine 60 mg, placebo (Thompson 2000 Study 1; Thompson 2000 Study 2).
Fexofenadine HCl 180 mg, levocetirizine 5 mg (Godse 2007).
Fexofenadine HCl 20 mg, 60 mg,120 mg and 240 mg; placebo (Finn 1999; Nelson 2000).
Fexofenadine 180 mg, placebo (Degonda 2002).
Hydroxyzine plus terbutaline (beta agonist) (25 mg plus 5 mg), hydroxyzine plus cyproheptadine (25 mg plus 4 mg), hydroxyzine plus chlorphen(ir)amine (25 mg plus 4 mg), hydroxyzine plus cimetidine (H2RA) (25 mg plus 300 mg), hydroxyzine plus placebo (25 mg ) (Harvey 1981).
Ketotifen 1 mg, fluoxetine 20 mg (selective serotonin reuptake inhibitor–type antidepressant) (Sener 1999).
Levocetirizine 5 mg, bilastine 20 mg (Zuberbier 2010).
Levocetirizine 5 mg, desloratadine 5 mg (Potter 2009).
Levocetirizine 20 mg, levocetirizine 15 mg plus hydroxyzine 50 mg (Staevska 2014).
Loratadine 10 mg, levocetirizine 5 mg (Anuradha 2010).
Loratadine 10 mg, placebo (Monroe 1988).
Mizolastine 10 mg, loratadine 10 mg, placebo (Dubertret 1999).
Mizolastine 10 mg, placebo (Brostoff 1996; Ollert 1999).
Mizolastine 10 mg in decreasing dose, mizolastine 10 mg daily (Wang 2012).
Nifedipine 10 mg, chlorphen(ir)amine 4 mg (Liu H‐N 1990).
Olopatadine 10 mg, olopatadine 5 mg, no medication (Makino 2012).
Oxatomide 30 mg, clemastine 1 mg (Beck 1985).
Oxatomide gel 5%, dechlorpheniramine cream (Locci 1991).
Rupatadine 10 mg, levocetirizine 5 mg (Maiti 2011).
Rupatadine 10 mg, rupatadine 20 mg, placebo (Gimenez‐Arnau 2007).
Rupatadine 5 mg, rupatadine 10 mg, rupatadine 20 mg, placebo (Dubertret 2007).
Terfenadine 60 mg, clemastine 1 mg, placebo (Hjorth 1988).
Terfenadine 60 mg, chlorphen(ir)amine 4 mg, placebo (Grant 1988).
Outcomes
Timing of outcome assessment varied considerably. Studies reported outcomes assessed at baseline and at the end of the intervention period, with interim outcome assessments performed in some studies. If a study reported serial times of duration of intervention for the same participants, to reduce bias, we summarised these only at the latest time point.
Nine studies reported outcomes measured after the treatment period had ended (Di Lorenzo 2004; Ghosh 1990; Go 1989; Nettis 2006; Pons‐Guiraud 2006; Potter 2009; Thompson 2000 Study 1; Thompson 2000 Study 2; Yin 2003b).
Outcomes included measures of weals, redness and itching assessed through both participant diaries or reports and clinician assessments, as well as size of weals and assessment of redness based on visual analogue scales. Numbers of participants experiencing improvement or cessation of symptoms were also reported.
Few of the studies directly reported our prespecified review outcomes (Objectives).
Few studies reported quality of life measures: Degonda 2002 provided participant‐assessed summaries of changes in quality of life, and Maiti 2011 provided modified Dermatology Life Quality Index (DLQI) scores. Nettis 2004 and Nettis 2006 also provided quality of life assessment based on the DLQI. Potter 2009 reported the results of a self‐administered DLQI questionnaire; Staevska 2014 and Zuberbier 2010 also reported DLQI results. Ortonne 2007 reported disruption of sleep and daily activities, and Staevska 2014 reported effects on quality of nighttime sleep. Thompson 2000 Study 1 and Thompson 2000 Study 2 commented on significant improvements in DLQI with fexofenadine.
Excluded studies
We excluded 169 studies. These consisted of studies that described only chronic urticaria unless the text mentioned or provided details that confirmed a diagnosis of chronic spontaneous or idiopathic or ordinary urticaria. Studies that were conducted with only terfenadine or astemizole were excluded because the medications had already been withdrawn for safety reasons. Further details can be found in Characteristics of excluded studies.
Ongoing studies and studies awaiting assessment
We identified 14 ongoing studies through our searches of clinical trials databases. Further details may be found in the Characteristics of ongoing studies tables. Data from these studies if available will be included in future updates of the review.
We identified 16 studies awaiting assessment, because we were unable to obtain full‐text copies at the time of writing of this review. Further details are available in the tables of Characteristics of studies awaiting classification.
Risk of bias in included studies
In this review, we included 'Risk of bias' assessments. Please see Figure 2, which shows our judgements about each 'Risk of bias' item expressed as percentages of included studies in each category of risk, and Figure 3, which shows the judgement for each domain by study. When 'Risk of bias' information was missing from the trial report, we contacted the principal investigators of studies published from 2001 onwards to ask for missing information.
2.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
For studies with items judged as 'unclear,' we requested clarification from trial investigators, but no further information was forthcoming at the time that this review was prepared. No study provided complete clarity on every item in our 'Risk of bias' assessment, indicating widespread suboptimal reporting of methodology or results. Of the 73 included studies, 37 (50%) had at least one domain that we rated as at high risk of bias.
Allocation
The randomisation process and concealment of allocation are the most important and sensitive indicators that bias has been minimised in clinical trials. In one of the included studies (Garavaglia 1995), we assessed risk of bias as high, as the report of the study stated that the participant group was "randomly divided (by triplets) into three groups," using a preestablished randomisation list. As participants who dropped out were replaced with new participants, it is unclear whether the trial design is truly randomised, and whether new participants were randomly assigned de novo or were assigned to the group of the most recent dropout. We were unable to obtain further information from trial investigators to clarify this. Among all 73 included studies, only 12 (Brostoff 1996; Dakhale 2014; Di Lorenzo 2004; Gimenez‐Arnau 2007; Handa 2004; Kint 1989; Monroe 2003; Ortonne 2007; Pons‐Guiraud 2006; Ring 2001; Weller 2013; Zuberbier 2010) clearly described adequate randomisation methods. For the rest, the method of randomisation was not described or was unclear, and either we were unable to obtain further information or the trial was published before 2001 and we did not attempt to do so.
Five studies demonstrated adequate concealment of allocation using codes sealed within envelopes (Dakhale 2014; Gimenez‐Arnau 2007; Handa 2004; Monroe 2003; Pons‐Guiraud 2006). We assessed five of the studies to be at high risk of bias, as no attempt to conceal allocation was made (Anuradha 2010; Goh 1991; Makino 2012; Wu 2008; Yin 2003b). (Of these, Anuradha 2010; Wu 2008 and Yin 2003b were explicitly open‐label trials).
Blinding
Eight studies (Anuradha 2010; Kalivas 1990; Locci 1991; Makino 2012; Sener 1999; Wang 2012; Wu 2008; Yin 2003b) did not blind participants or personnel to the intervention being studied so were classed at high risk of bias. Twenty‐two studies (Dakhale 2014; Degonda 2002; Di Lorenzo 2004; Garavaglia 1995; Gimenez‐Arnau 2007; Go 1989; Goh 1991; Handa 2004; Kaplan 2005; Kint 1989; Monroe 1992; Monroe 2003; NCT00536380; Nettis 2004; Nettis 2006; Ortonne 2007; Phanuphak 1987; Pons‐Guiraud 2006; Ring 2001; Staevska 2014; Weller 2013; Zuberbier 2010) adequately blinded participants and personnel to the intervention so were judged at low risk of bias. In the remaining 45, it was unclear whether blinding was adequate. In Goh 1991, participants appear to have been adequately blinded as to the identity of the medication studied.
Only 14 of the included trials demonstrated adequate blinding of outcome assessment (Dakhale 2014; Degonda 2002; Di Lorenzo 2004; Gimenez‐Arnau 2007; Handa 2004; Kaplan 2005; Monroe 1992; Monroe 2003; Nelson 2000; Nettis 2004; Nettis 2006; Pons‐Guiraud 2006; Staevska 2014; Weller 2013); eight studies did not attempt this and were judged at high risk of bias (Anuradha 2010; Kalivas 1990; Locci 1991; Makino 2012; Sener 1999; Wang 2012; Wu 2008; Yin 2003b). For the remaining 51 studies, we rated risk of bias due to blinding of outcome assessment as unclear.
Incomplete outcome data
Some study investigators analysed their study data to show that the numbers of participants who dropped out or were withdrawn were not significantly different from the numbers analysed, but this did not mean that bias was absent, as there may have been imbalance between groups, or the reasons for dropout might have differed between groups (e.g. adverse events, lack of efficacy).
The high rate of attrition in the included trials was a problem and a potential source of bias. In 20 trials, the distribution or high number of dropouts or losses to follow‐up could have introduced bias (Beck 1985; Belaich 1990; Breneman 1995; Brostoff 1996; Commens 1978; Di Lorenzo 2004; Garavaglia 1995; Godse 2007; Goh 1991; Guo 2003; Harvey 1981; Kalivas 1990; Leynadier 2000; Marks 1980; Monroe 1988; Monroe 2003; Nelson 2000; Salo 1989; Thompson 2000 Study 2; Wu 2008); we rated these as at high risk).
A high level of dropout was a feature of seven of the included studies. In Brostoff 1996 51% of participants failed to complete the study, and Breneman 1995 had 27.3% dropouts; in Commens 1978 24% dropped out. In the four‐arm study of Di Lorenzo 2004, 38.8% of participants overall dropped out after randomisation with high losses to follow‐up, particularly in the placebo group (88%) and the montelukast group (68%). Garavaglia 1995 experienced high levels of dropout and recruited additional participants into the trial in an attempt to compensate. In Monroe 2003 19% dropped out of the desloratadine group and 31% from the placebo group. A total of 34% dropped out from the Salo 1989 study.
Eighteen studies were rated as having low risk of attrition bias (Anuradha 2010; Breneman 1996; Degonda 2002; Dubertret 1999; Grant 1988; Juhlin 1987; Kint 1989; Liu H‐N 1990; NCT00536380; Nettis 2004; Nettis 2006; Ollert 1999; Ortonne 2007; Patel 1997; Paul 1998; Peyri 1991; Phanuphak 1987; Wang 2012). In many trials, attrition data were poorly reported or were absent; despite our attempts to request further information from trial investigators, we judged the remaining 35 as having unclear risk of bias.
Selective reporting
We judged that 24 studies were at low risk of bias (Alomar 1990a; Anuradha 2010; Belaich 1990; Breneman 1995; Brostoff 1996; Dakhale 2014; Dubertret 2007; Gimenez‐Arnau 2007; Go 1989; Guo 2003; Hao 2003; Kalivas 1990; Makino 2012; NCT00536380; Nettis 2004; Nettis 2006; Ortonne 2007; Patel 1997; Phanuphak 1987; Pons‐Guiraud 2006; Ring 2001; Staevska 2014; Weller 2013; Zuberbier 2010).
We judged that 20 studies could have introduced an element of bias through selective outcome reporting (Beck 1985; Breneman 1996; Bronsky 2001; Commens 1978; Finn 1999; Gale 1989; Garavaglia 1995; Godse 2007; Goh 1991; Grant 1988; Harvey 1981; Hjorth 1988; Juhlin 1987; Juhlin 1991; Kaplan 2005; Kint 1989; Liu H‐N 1990; Monroe 1988; Salo 1989; Wu 2008). Specifically, in Beck 1985 and in Breneman 1996, outcomes were reported only in graph form or by percentage and statistical difference (with no participant numbers stated). Similarly, in Commens 1978, Gale 1989 and Godse 2007, the results for numbers of participants in each group were not reported—only mean scores with standard deviations. In Grant 1988 and Hjorth 1988, results were presented in graph form only. In Monroe 1988 only percentages and P values were given, and the origin of the P values was not stated. Salo 1989 provided only mean scores, and investigators offered a subjective judgement as to the best treatment. In Bronsky 2001 scores were given on different days; Harvey 1981 did not report adverse event results; and in Finn 1999 the analysis included results only for participants with baseline and at least one postbaseline mean pruritus score, thus a true intention‐to‐treat analysis was not provided. Juhlin 1987 states that both physician and participant self‐assessments were carried out, but the study report provides only participant perceptions with no objective data. In Juhlin 1991, extensive laboratory tests were carried out (for adverse events) but were not reported. Kaplan 2005 combined DLQI score results from two weeks and four weeks and did not provide separate scores for each time point; as we were unable to obtain the disaggregated data, we could not use these conflated interim and endpoint outcome results. Kint 1989 did not report results clearly, and as rescue medication was permitted, we could not be sure that any benefits were due to the study medications. We were unable to determine the duration of follow‐up in Liu H‐N 1990, and it was unclear whether concomitant medications were permitted, or whether study participants were compliant. Garavaglia 1995 reported no results for the placebo arm.
For the remaining 29 studies, information was insufficient to allow a judgement to be reached; we rated these as having unclear risk of bias for this domain.
Other potential sources of bias
We assessed whether each study appeared to be free of other sources of bias that could put it at high risk of bias (e.g. potential conflicts of interest, pharmaceutical funding or support). We judged studies as having unclear risk when the extent to which other factors may have introduced bias could not be determined. Of the 73 included studies, most reports were unclear in terms of other bias (Figure 2). This was the result of insufficient information to assess whether risk of bias existed in some studies (Bronsky 2001; Hoxha 2011; Marks 1980; Monroe 1988; Ortonne 2004; Sener 1999; Staevska 2014), or it reflected baseline imbalance between groups (e.g. Breneman 1995; Finn 1999). In the remaining studies judged as unclear, potential bias may have been present in the form of industry sponsorship and funding.
A total of 19 studies for which no funding or sponsorship was declared were assessed as having low risk of bias, as we detected no other bias.
Effects of interventions
See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9; Table 10; Table 11; Table 12
We have indicated in this section when our 23 comparisons of interventions addressed our prespecified outcomes (for details of outcomes, please see Types of outcome measures).
Numbers given show the total numbers of participants included in the analysis. When it was possible to calculate an effect size, we reported this with the 95% confidence interval. When the calculated effect size was statistically significant (P value < 0.05), we stated whether the result favoured the intervention group or the control condition. In the text below, an I² statistical value for heterogeneity is reported as high if it exceeds 50%.
We have summarised the results of included studies that could not be combined in meta‐analyses because of differences between studies in terms of design. We present the results of studies that could not be pooled in meta‐analyses using data and information derived from the reports of individual studies (along with P values when applicable).
Comparison 1
Loratadine 10 mg versus placebo
Two studies that compared these interventions were identified (Belaich 1990; Monroe 1992). Both studies reported short‐term and intermediate‐term interventions that favoured loratadine.
Primary outcome 2: proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines
Short‐term duration of intervention
In this subgroup we found only one relevant trial (Monroe 1992) (n = 12, risk ratio (RR) 3.0, 95% confidence interval (CI) 0.42 to 21.3; Analysis 1.1) (no statistically significant difference).
1.1. Analysis.
Comparison 1 Loratadine 10 mg versus placebo, Outcome 1 Proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines.
Intermediate‐term duration of intervention
In this subgroup we found only one relevant trial (Belaich 1990) (n = 112, RR 1.73, 95% CI 0.81 to 3.72) (no statistically significant difference). The study report states that 22/60 (loratadine) and 5/52 (placebo) participants experienced complete cessation of urticaria following an intermediate‐term duration of the intervention and that loratadine was significantly more effective than placebo (P value < 0.01).
Our meta‐analysis of Monroe 1992 and Belaich 1990, combining data from short‐ and intermediate‐term durations of intervention (n = 124), found that loratadine may increase the chance that a participant will experience a good response, expressed as RR of 1.86 (95% CI 0.91 to 3.79; P value 0.09; I² = 0%; Analysis 1.1), but this difference was not statistically significant.
Comparison 2
Loratadine 10 mg versus cetirizine 10 mg
Two studies that compared these interventions were identified (Patel 1997; Yin 2003b) (n = 103). The individual studies reported similar proportions of participants with complete suppression of urticaria.
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
Short‐term duration of intervention
In this subgroup we found only one relevant trial (Patel 1997). No statistically significant difference between groups was noted (RR 1.13, 95% CI 0.64 to 2.01; participants = 37; I2 = 0%); Analysis 2.1).
2.1. Analysis.
Comparison 2 Loratadine 10 mg versus cetirizine 10 mg, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.
Intermediate‐term duration of intervention
In this subgroup we found only one relevant trial (Yin 2003b). No statistically significant difference between groups was noted (RR 1.01, 95% CI 0.69 to 1.47; participants = 66; I2 = 0%; Analysis 2.1).
Overall, combining data from both studies (RR 1.05, 95% CI 0.76 to 1.43; n = 103; I2 = 0%); Analysis 2.1) yielded no evidence of a difference in rates of complete cessation of urticaria. Data from Yin 2003b showed that an additional proportion of participants experienced at least a good response following treatment with either drug (10/32 in the loratadine arm and 11/34 in the cetirizine arm).
Comparison 3
Loratadine 10 mg versus desloratadine 5 mg
Three studies that compared these interventions were identified (Gu 2002; Hao 2003; Zou 2002). Zou 2002 reported no significant differences in efficacy between desloratadine 5 mg once daily for four weeks and loratadine 10 mg once daily for four weeks.
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
Intermediate‐term duration of intervention
Individual studies reported similar proportions of participants with complete suppression of urticaria. Comparing loratadine with desloratadine (Gu 2002; Hao 2003) revealed no significant differences between loratadine 10 mg and desloratadine 5 mg for complete suppression of disease (RR 0.91, 95% CI 0.78 to 1.06; P value 0.22; I² = 0%; Analysis 3.1).
3.1. Analysis.
Comparison 3 Loratadine 10 mg versus desloratadine 5 mg, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.
Primary outcome 2: proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines
Intermediate‐term duration of intervention
In this subgroup we found three relevant trials (Guo 2003; Hao 2003; Zou 2002) (n = 410). Individual studies reported similar proportions of participants with at least good response to treatment. No significant differences between loratadine 10 mg and desloratadine 5 mg were noted (RR 1.04, 95% CI 0.64 to 1.71; Analysis 3.2), and moderate heterogeneity was exhibited (I² = 40%; P value 0.191).
3.2. Analysis.
Comparison 3 Loratadine 10 mg versus desloratadine 5 mg, Outcome 2 Proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines.
Primary outcome 3: proportion of participants with 50% or greater improvement in quality of life measurements whilst taking H1‐antihistamines
Hao 2003 reported that at four weeks, 16/106 (loratadine) and 9/105 (desloratadine) participants described at least 50% improvement in quality of life (QoL) (P value 0.25).
Secondary outcome 2: minor participant‐reported adverse events not requiring withdrawal of treatment
All three studies (Guo 2003; Hao 2003; Zou 2002) individually concluded that desloratadine was a safe and effective treatment for CSU. However, we were unable to pool data on adverse events in a meta‐analysis. Desloratadine was found to be at least as effective as loratadine in each individual study but was not compared with placebo. Therefore it may be the case that desloratadine is as effective as loratadine, but this is assumed through speculative non‐superiority to loratadine.
We were unable to combine adverse effect data in a meta‐analysis because the study reports are unclear about the number of participants presenting with adverse effects in each group at each time point. Zou 2002 reported that in the desloratadine group, four participants had side effects: one severe headache, one dry mouth and two sleepiness. In the loratadine group, one participant had dry mouth and three experienced sleepiness. Hao 2003 reported that adverse effect rates of desloratadine and loratadine were 11.32% and 13.21%, respectively. The main side effects included dry mouth, dizziness and headache. Gu 2002 reported that no serious adverse effects were recorded for the duration of the study.
Comparison 4
Loratadine 10 mg versus mizolastine 10 mg
Four studies that compared these interventions were identified (Guo 2003; Leynadier 2000; Liu 2003; Yin 2003b).
The authors of Guo 2003 reported that scores for pruritus and weal number, size and persistence in the mizolastine group were much lower than those in the loratadine group (P value < 0.05). They concluded that mizolastine could be considered the preferred treatment for CSU (Guo 2003).
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
Intermediate‐term duration of intervention
In this subgroup we found three relevant trials (Guo 2003; Liu 2003; Yin 2003b) (n = 316). These studies reported similar proportions of participants with complete suppression of urticaria, and no significant difference between loratadine 10 mg and mizolastine 10 mg was noted (RR 0.86, 95% CI 0.64 to 1.16; Analysis 4.1); heterogeneity was substantial (I² = 55%; P value 0.11; Analysis 4.1).
4.1. Analysis.
Comparison 4 Loratadine 10 mg versus mizolastine 10 mg, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.
Primary outcome 2: proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines
These three studies also reported the proportions of participants experiencing at least a good response to treatment. In comparing loratadine with mizolastine, we found no significant differences between loratadine 10 mg and mizolastine 10 mg (RR 0.88, 95% CI 0.55 to 1.42; Analysis 4.2; P value 0.78; I² = 0%).
4.2. Analysis.
Comparison 4 Loratadine 10 mg versus mizolastine 10 mg, Outcome 2 Proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines.
Primary outcome 3: proportion of participants with 50% or greater improvement in quality of life measurements whilst taking H1‐antihistamines
Intermediate‐term duration of intervention
In this subgroup we found two relevant trials (Guo 2003; Liu 2003) (n = 252). These studies reported the proportions of participants who experienced improvement in QoL of at least 50%. This amounted to 26/125 and 13/127 (loratadine and mizolastine, respectively). No significant difference between loratadine 10 mg and mizolastine 10 mg was reported in either study; when data were pooled (RR 3.21, 95% CI 0.32 to 32.33; Analysis 4.3), important levels of heterogeneity were noted (Chi² = 2.86; df = 1; P value 0.091; I² = 65%).
4.3. Analysis.
Comparison 4 Loratadine 10 mg versus mizolastine 10 mg, Outcome 3 Proportion of participants with at least 50% improvement in QoL whilst taking H1‐antihistamines.
Secondary outcome 1: serious adverse events (i.e. serious enough to require withdrawal of treatment)
Liu 2003 reported that the incidences of adverse events for mizolastine and loratadine were 28.6% and 25.5%, respectively; no statistically significant differences between the two groups were noted (Chi2 = 0.25; P value 0.62).
Leynadier 2000 reported minor adverse events requiring withdrawal: in the mizolastine group, fatigue (n = 2) and drowsiness (n = 1); in the loratadine group, drowsiness (n = 1), dizziness (n = 1) and rhinitis (n = 1).
Guo 2003 reported that data on one participant were excluded from the analysis, but it is unclear whether this occurred because of withdrawal due to adverse effects. No clear data about adverse effects were presented, although study authors noted that no differences between the two groups were noted. Adverse effects included dry mouth, sleepiness and lethargy, but the numbers in each group experiencing these effects were not stated.
Intermediate‐term duration of intervention
Two studies (Leynadier 2000; Liu 2003) reported the numbers of participants who experienced an adverse event that led to withdrawal: One participant in the mizolastine group in Liu 2003 had severe diarrhoea, and one in Leynadier 2000 had painful erythema of the hands. In comparing loratadine with mizolastine in 267 participants, we found no significant differences between loratadine 10 mg and mizolastine 10 mg (RR 0.38, 95% CI 0.04 to 3.6; P value 0.40; I² value 0%; Analysis 4.4) in terms of the numbers of participants withdrawing because of an adverse event.
4.4. Analysis.
Comparison 4 Loratadine 10 mg versus mizolastine 10 mg, Outcome 4 Serious adverse events (i.e. serious enough to require withdrawal of treatment).
Comparison 5
Loratadine 10 mg versus emedastine 2 mg
We report the results of our analysis of a single study for this comparison (Pons‐Guiraud 2006).
The study report states that the key finding was that no significant differences between treatments at four weeks were noted by investigators or participants. Mean symptom scores improved significantly from baseline in both groups. The study authors state: "Also the proportion of patients with no symptoms at the end of treatment was similar (emedastine 52.4% versus loratadine 54.5% P = 0.41) and so was the proportion of patients with mild symptoms (total score ≤ 8) (emedastine 92.9% versus loratadine 96.1% P = 0.37)"; they also comment: "After 28 days of treatment mean symptom scores recorded in patients improved significantly versus baseline both with emedastine and loratadine (both P < 0.00005, t test for paired samples). No significant difference between groups was found (P = 0.48 for intensity of erythema, P = 0.30 for number of hives, P = 0.39 for size of the largest hive, P = 0.45 for the extent of the skin area involved and P = 0.19 for the overall assessment of urticaria symptoms)."
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
Intermediate‐term duration of intervention
Among 161 participants after four weeks of therapy in Pons‐Guiraud 2006, no difference between loratadine 10 mg and emedastine 2 mg was noted for complete cessation of urticaria (RR 1.04, 95% CI 0.78 to 1.39; Analysis 5.1).
5.1. Analysis.
Comparison 5 Loratadine 10 mg versus emedastine 2 mg, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.
Primary outcome 2: proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines
Intermediate‐term duration of intervention
Among 160 participants after four weeks of therapy in Pons‐Guiraud 2006, no difference between loratadine 10 mg and emedastine 2 mg was noted for good or excellent response (RR 1.09, 95% CI 0.96 to 1.24; Analysis 5.2).
5.2. Analysis.
Comparison 5 Loratadine 10 mg versus emedastine 2 mg, Outcome 2 Proportion of participants with good or excellent response whilst taking H1‐antihistamines.
Secondary outcome 1: serious adverse events (i.e. serious enough to require withdrawal of treatment)
Intermediate‐term duration of intervention
In an analysis of 161 participants in total, one participant in each group withdrew because of adverse effects. The study report states: "Two patients were withdrawn because of serious adverse events: a suicide attempt not related to study treatment (loratadine) and a bilateral fracture of the calcaneum following a fall, which led to hospitalisation, in the emedastine group. Although the patient who fell was taking a number of medicinal products besides emedastine (paracetamol, hydroxyzine, enoxaparin, ketoprofen and omeprazole), the causal relationship with emedastine was not ruled out and considered possible."
In our analysis, no statistically significant differences between groups were noted (RR 1.09, 95% CI 0.07 to 17.14; Analysis 5.3).
5.3. Analysis.
Comparison 5 Loratadine 10 mg versus emedastine 2 mg, Outcome 3 Serious adverse events (i.e. serious enough to require withdrawal of treatment).
Comparison 6
Loratadine 10 mg versus hydroxyzine 25 mg
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
Short‐term duration of intervention
One study that compared these interventions was identified (Monroe 1992). The number of participants who experienced marked or complete relief of symptoms was 3/6 with loratadine and 3/6 with hydroxyzine (RR 1.00, 95% CI 0.32 to 3.10; Analysis 6.1).
6.1. Analysis.
Comparison 6 Loratadine 10 mg versus hydroxyzine 25 mg, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.
This study reported that total symptoms score value decreased by 43% in the loratadine group and by 47% in the hydroxyzine group, although actual mean scores for each group were not reported.
Secondary outcome 2: minor participant‐reported adverse events not requiring withdrawal of treatment
Overall in Monroe 1992, eight of 20 participants in the hydroxyzine group and one of 20 in the loratadine group (some with dermatitis rather than CSU) reported sedation, a minor adverse event that did not require withdrawal of the drug; the study report states that differences between groups were significant (P value 0.02).
Comparison 7
Cetirizine 10 mg versus placebo
Four studies that compared these interventions were identified (Breneman 1995; Breneman 1996; Go 1989; Kalivas 1990).
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
Short‐term duration of intervention
In this subgroup we found only one relevant trial (Go 1989) (n = 56). A statistically significant difference between cetirizine 10 mg to 20 mg and placebo was reported (RR 2.80, 95% CI 1.17 to 6.73; Analysis 7.1).
7.1. Analysis.
Comparison 7 Cetirizine 10 to 20 mg versus placebo, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.
Intermediate‐term duration of intervention
In this subgroup we found only one relevant trial (Breneman 1995) (n = 122). A statistically significant difference between cetirizine 10 mg to 20 mg and placebo was reported (RR 2.66, 95% CI 1.2 to 5.9; Analysis 7.1).
Meta‐analysis
Combining the results of two studies across short‐term and Intermediate‐term durations of intervention revealed that 32/88 and 12/90 participants experienced complete cessation of urticaria following treatment (cetirizine and placebo, respectively) (RR 2.72, 95% CI 1.51 to 4.91; P value < 0.001; I² = 0%; Analysis 7.1). Thus, strong evidence showed that cetirizine increased the chance of complete cessation of disease.
Primary outcome 2: proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines
One study (Breneman 1995) reported that at least a good response following treatment was seen in 45/60 and 29/62 participants (cetirizine and placebo, respectively) (P value 0.001).
Secondary outcome 1: serious adverse events (i.e. serious enough to require withdrawal of treatment)
Intermediate‐term duration of intervention
In this subgroup we found two relevant trials (Breneman 1995; Breneman 1996) (n = 247). No significant differences between cetirizine 10 mg to 20 mg and placebo were reported (RR 4.6, 95% CI 0.79 to 26.67; Analysis 7.2).
7.2. Analysis.
Comparison 7 Cetirizine 10 to 20 mg versus placebo, Outcome 2 Serious adverse events (i.e. serious enough to require withdrawal of treatment).
Intermediate‐term duration of intervention
In this subgroup we found only one relevant trial (Kalivas 1990) (n = 142). No significant differences between cetirizine 10 mg to 20 mg and placebo were reported (RR 1.06, 95% CI 0.07 to 16.59; Analysis 7.2).
Meta‐analysis
These three studies (Breneman 1995; Breneman 1996; Kalivas 1990) of 389 participants in total, reported that seven participants withdrew because of adverse events whilst taking cetirizine, and two withdrew whilst taking placebo (RR 3.00, 95% CI 0.68 to 13.22; P value 0.15; I² = 0%; Analysis 7.2). This does not constitute adequate evidence to suggest that cetirizine is associated with increased risk of withdrawal due to an adverse event.
Comparison 8
Cetirizine 10 mg versus hydroxyzine 25 mg
Efficacy was not reported in a form commensurate with the outcome measures of our review in either of the two studies that compared these interventions (Breneman 1996; Kalivas 1990).
Secondary outcome 1: serious adverse events (i.e. serious enough to require withdrawal of treatment)
Intermediate‐term duration of intervention (cetirizine 10 mg)
In this subgroup we found only one relevant trial (Breneman 1996) (n = 123). No significant differences between cetirizine 10 mg and hydroxyzine 25 mg were noted (RR 1.05, 95% CI 0.27 to 4.01; Analysis 8.1).
8.1. Analysis.
Comparison 8 Cetirizine 10 mg versus hydroxyzine 25 mg, Outcome 1 Serious adverse events (i.e. serious enough to require withdrawal of treatment).
Intermediate‐term duration of intervention (cetirizine 5 mg to 25 mg)
In this subgroup we found only one relevant trial (Kalivas 1990) (n = 138). No significant differences between cetirizine 10 mg and hydroxyzine 25 mg were noted (RR 0.33, 95% CI 0.04 to 3.13; Analysis 8.1).
Meta‐analysis
Both studies reported the numbers of participants who withdrew because of an adverse event. Combining the two (n= 260 participants) (RR of withdrawal 0.78, 95% CI 0.25 to 2.45; P value 0.67; I² = 0%; Analysis 8.1) revealed no evidence of a difference.
Comparison 9
Cetirizine 10 mg versus fexofenadine 180 mg
One study that compared these interventions was identified (Handa 2004). No analysis was possible for this comparison.
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
The key finding was that at four weeks, 27/59 participants in the cetirizine group had complete suppression of urticaria compared with 2/57 in the fexofenadine group (P value < 0.001). According to the study authors, partial improvement was seen in a further 19 participants in each group. No improvement was noted among six participants in the cetirizine group and 24 in the fexofenadine group.
Secondary outcome 2: minor participant‐reported adverse events not requiring withdrawal of treatment
Minor adverse events noted in the cetirizine group included drowsiness (four), constipation (three), epigastric pain (two) and cough (two). In the fexofenadine group, drowsiness was experienced by two participants; headache, swollen feet and abdominal pain were reported by one participant.
Comparison 10
Cetirizine 10 mg versus levocetirizine 5 mg
One study that compared these interventions was identified (Yin 2003a). No analysis was possible for this comparison.
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
This study reported that 16/22 and 19/22 participants had complete suppression of urticaria following treatment with cetirizine and levocetirizine, respectively, at 28 days (P value 0.309). A further two participants had at least a good response to cetirizine and one to levocetirizine, but without complete clearance. Overall there was no statistically significant difference in clinical efficacy between the two groups was noted (P value > 0.05).
Secondary outcome 1: serious adverse events (i.e. serious enough to require withdrawal of treatment)
No participants withdrew from this study as the result of an adverse event.
Comparison 11
Cetirizine 10 mg versus mizolastine 10 mg
One study that compared these interventions was identified (Yin 2003b). No analysis was possible for this comparison.
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
This study reported that 21/34 and 20/30 participants had complete suppression of urticaria following treatment with cetirizine and mizolastine, respectively (P value 0.600). This study also reported that a further 11/34 and 9/30 had a good response to treatment.
Comparison 12
Desloratadine 5 mg to 20 mg versus placebo
Six studies that compared these interventions were identified (Di Lorenzo 2004; Hoxha 2011; Monroe 2003; Nettis 2004; Ortonne 2007; Ring 2001). Ortonne 2007 did not provide outcome data on efficacy that could be included in our meta‐analyses.
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
Two studies (Di Lorenzo 2004; Hoxha 2011) reported on complete suppression of urticaria. A short‐term duration of intervention was used in one study (Hoxha 2011), which investigated three doses compared with placebo and reported that 4/34, 11/34, 21/34 and 0/36 (desloratadine 5 mg, 10 mg and 20 mg and placebo) achieved resolution of symptoms. Following an intermediate‐term duration of intervention, one study (Di Lorenzo 2004) reported complete suppression of urticaria in 18/40 (desloratadine 5 mg) and 0/40 (placebo) (additional data supplied by investigator); the report of the study states that the difference between the total symptom scores for the desloratadine and placebo groups was statistically significant (P value < 0.001).
These data from Hoxha 2011 suggest an association between dosage and an increased chance of complete suppression of urticaria. We did not pool data across all dosages and durations of intervention (Analysis 9.1), but as no participants allocated to placebo exhibited suppression of urticaria, Fisher's exact test was used to compare the two interventions (53/142 desloratadine and 0/76 placebo), resulting in a 95% CI for the odds ratio (OR) of between 7.12 and infinity (P value < 0.001),
9.1. Analysis.
Comparison 9 Desloratadine 5 to 20 mg versus placebo, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.
Additional data obtained from the principal investigator of Di Lorenzo 2004 revealed that 22/40 in the intervention group and 0/40 in the placebo group experienced an 'excellent' response (P value < 0.001).
Primary outcome 3: proportion of participants with 50% or greater improvement in quality of life measurements whilst taking H1‐antihistamines
The numbers of participants who exhibited improvement in QoL (Ortonne 2007) were 34/49 and 23/36 in the desloratadine 5 mg and placebo groups, respectively. The study report states: "Desloratadine treatment was associated with significantly greater improvements from baseline to day 42 compared with placebo in DLQI overall score (–6 versus –2.2 points; P < 0.002) and VQ‐Dermato score (18.5 versus 29.1 points; P = 0.009)."
Secondary outcome 1: serious adverse events (i.e. serious enough to require withdrawal of treatment)
Intermediate‐term duration of 5 mg of intervention
In this subgroup we found three relevant trials (n = 466).
Three studies (Monroe 2003; Nettis 2004; Ring 2001) of 466 participants, reported similar numbers of participants who withdrew as the result of adverse events, totalling 6/236 and 4/230 (desloratadine 5 mg and placebo, respectively). No significant difference between desloratadine 5 mg and placebo were noted (RR 1.46, 95% CI 0.42 to 5.1; Analysis 9.2).
9.2. Analysis.
Comparison 9 Desloratadine 5 to 20 mg versus placebo, Outcome 2 Serious adverse events (i.e. serious enough to require withdrawal of treatment).
Differences between the three studies were examined: Monroe 2003 excluded participants with previous lack of response to antihistamines, but this exclusion criterion was not stated in the reports of Nettis 2004 and Ring 2001.
Comparison 13
Hydroxyzine 25 mg versus placebo
Three studies that compared these interventions were identified (Breneman 1996; Kalivas 1990; Monroe 1992). Efficacy was not reported in Breneman 1995 or Kalivas 1990 in a form commensurate with the outcome measures of our review.
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
Short‐term duration of intervention
One study (Monroe 1992) stated that 3/6 and 1/6 participants exhibited at least a good response (marked or complete relief of symptoms) following treatment (hydroxyzine and placebo, respectively). After a reanalysis using Fisher's exact test because of the small number of participants, no difference between interventions was reported (P value 0.27).
The study report stated that for this outcome, differences between the placebo group and the two treated groups (hydroxyzine and loratadine) were statistically significant (P value < 0.05). The small number of included participants limits firm conclusions that can be drawn from this outcome.
Secondary outcome 1: serious adverse events (i.e. serious enough to require withdrawal of treatment)
Intermediate‐term duration of intervention
In a meta‐analysis of Breneman 1996 and Kalivas 1990 (n = 270), the pooled RR was 3.64 (95% CI 0.77 to 17.23; P value 0.10; I² = 0%; Analysis 10.1). Therefore little evidence of differences between interventions was found.
10.1. Analysis.
Comparison 10 Hydroxyzine 25 mg versus placebo, Outcome 1 Serious adverse events (i.e. serious enough to require withdrawal of treatment to withdrawal).
Comparison 14
Levocetirizine 5 mg to 20 mg versus placebo
Two studies that compared these interventions were identified (Hoxha 2011; Nettis 2006).
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
Following a short‐term duration of intervention, Hoxha 2011 reported complete suppression of urticaria as 9/37, 17/37, 30/37 and 0/37 (levocetirizine 5 mg, 10 mg, 20 mg and placebo). In one intermediate‐term duration of intervention study (Nettis 2006), complete suppression was noted in 27/51 and 0/51 participants (levocetirizine 5 mg and placebo). No participants in the placebo arm achieved complete suppression of urticaria (Analysis 11.1).
11.1. Analysis.
Comparison 11 Levocetirizine 5 to 20 mg versus placebo, Outcome 1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines.
Analysis of the total counts was carried out with Fisher's exact test; the 95% CI for the OR was between 11.12 and infinity (P value < 0.001), suggesting that use of levocetirizine at least 5 mg increased the chance of complete suppression of CSU.
Secondary outcome 1: serious adverse events (i.e. serious enough to require withdrawal of treatment)
No withdrawals due to adverse events were seen in either arm following treatment (0/51 and 0/49, levocetirizine 5 mg and placebo; Nettis 2006). No serious adverse events were noted with levocetirizine (at any dose) in the study by Hoxha 2011.
No data are available on the adverse events that followed when a higher than standard dosage (10 mg and 20 mg per day) of levocetirizine was prescribed.
Comparison 15
Rupatadine 10 mg to 20 mg versus placebo
Primary outcome 2: proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines
Intermediate‐term duration of intervention (rupatadine 10 mg)
In this subgroup we found only one relevant trial (Gimenez‐Arnau 2007) (n = 122). No significant difference between rupatadine 10 mg and placebo was reported (RR 1.28, 95% CI 0.86 to 1.91; Analysis 12.1).
12.1. Analysis.
Comparison 12 Rupatadine 10 to 20 mg versus placebo, Outcome 1 Proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines.
Intermediate‐term duration of intervention (rupatadine 20 mg)
In this subgroup we found only one relevant trial (Gimenez‐Arnau 2007) (n = 123). No significant difference between rupatadine 20 mg and placebo was reported (RR 1.42, 95% CI 0.98 to 2.06; Analysis 12.1).
Meta‐analysis
The pooled RR between rupatadine (at both doses) and placebo in 245 participants was 1.35 (95% CI 1.03 to 1.77; P value 0.03; I² = 0%; Analysis 12.1); thus rupatadine increased the chance of a good response, but little evidence was found to indicate that 10 mg is more effective than 20 mg.
Comparison 16
Desloratadine 5 mg to 20 mg versus levocetirizine 5 mg to 20 mg
Two studies that compared these interventions were identified (Hoxha 2011; Potter 2009). No meta‐analysis was possible for this comparison.
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
In Hoxha 2011, a three‐arm study, 107 participants were randomly assigned to double‐blind treatment with levocetirizine, desloratadine or placebo (37/34/36). Treatment started at a dose of 5 mg and then was increased weekly to 10 mg and 20 mg. The numbers of participants who exhibited complete suppression of urticaria following a week at each dose were as follows: 9/37, 17/37 and 30/37 (levocetirizine 5 mg, 10 mg and 20 mg) and 4/34, 11/34 and 21/34 (desloratadine 5 mg, 10 mg and 20 mg).
Primary outcome 2: proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines
A total of 294/438 and 256/448 participants in Potter 2009 exhibited at least a good response following treatment with levocetirizine 5 mg and desloratadine 5 mg. The report of the study states that levocetirizine "Decreased pruritus duration and the mean CSU composite scores to a significantly greater extent than desloratadine during the first week (P=0.002 and 0.005, respectively) and over the entire study (P=0.009 and P<0.05, respectively)."
Secondary outcome 2: minor participant‐reported adverse events not requiring withdrawal of treatment
No serious adverse effects occurred with desloratadine. The authors of Hoxha 2011 concluded that increasing the dose of either drug up to four‐fold was beneficial without compromising safety, and that levocetirizine appeared to be more effective than desloratadine (P value < 0.02).
Comparison 17
Ebastine 10 mg versus placebo
One study that compared these interventions was identified (Peyri 1991).
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
In this study, 38/91 and 22/86 participants (ebastine and placebo, respectively) exhibited complete suppression of urticaria following an intermediate‐term duration of intervention (Fisher's exact test P value 0.13). According to the investigators' assessment, overall efficacy was good or moderate in 76/95 participants (80%) treated with ebastine compared with 52/102 participants (51%) treated with placebo (P value < 0.001). Study investigators concluded that ebastine could be an affective alternative to other non‐sedating antihistamines.
Secondary outcome 1: serious adverse events (i.e. serious enough to require withdrawal of treatment)
A similar number of participants in each group withdrew from this study because of an adverse event: 2/91 and 3/86 (ebastine and placebo, respectively; Fisher's exact test P value 0.68).
Comparison 18
Desloratadine 5 mg versus montelukast 10 mg
One study that compared these interventions was identified (Di Lorenzo 2004). No analysis was possible for this comparison.
In the desloratadine group, 18/40 achieved complete suppression of CSU and 22/40 had an excellent response, whilst in the montelukast group, 4/40 achieved remission and 1/40 had an excellent response (P value 0.008 and P value < 0.001). It is interesting to note that 33/40 in the montelukast group showed no change with the intervention, and two individuals actually felt worse. Significant differences in total symptoms score, pruritus, number of hives and size of largest hive were noted (P value < 0.001, P value < 0.001, P value 0.017 and P value 0.003, respectively). Similar significant difference were noted between groups of desloratadine plus montelukast versus montelukast alone (P value < 0.001, P value < 0.001, P value 0.01 and P value 0.003). No difference was found between the group treated with desloratadine alone and the group treated with desloratadine plus montelukast.
Secondary outcome 2: minor participant‐reported adverse events not requiring withdrawal of treatment
Adverse events were noted to be of low incidence and mild in all groups. Withdrawals, reported in large numbers in this study, appear to have been due to lack of efficacy in the groups not receiving desloratadine—not to adverse effects.
Comparison 19
Fexofenadine 180 mg versus placebo
One study that compared this intervention was identified (Kaplan 2005). No analysis was possible for this comparison.
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
No significant differences in complete suppression were reported between the interventions: 6/91 and 19/162 (placebo and fexofenadine, respectively; P value 0.272).
Primary outcome 2: proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines
However, a difference was suggested between the proportions of participants who experienced at least a good response (11/91 and 57/162, placebo and fexofenadine, respectively; P value < 0.001). This study excluded participants who were previously unresponsive to antihistamines, so this result may not be generalisable.
Secondary outcome 2: minor participant‐reported adverse events not requiring withdrawal of treatment
Whether any participants required treatment withdrawal as the result of adverse effects was not stated, although one individual in the fexofenadine group required hospital admission for asthma. We conclude that this event is not likely to have been related to the intervention.
Comparison 20
Ketotifen 1 mg versus placebo
One study that compared these interventions was identified (Phanuphak 1987). No analysis was possible for this comparison.
Primary outcome 2: proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines
A total of 12/16 (ketotifen) and 2/14 (placebo) participants reported at least a good response (P value < 0.005). Notably, participants were permitted to take a different H1‐antihistamine, chlorpheniramine 4 mg as required up to six‐hourly, then were randomly assigned to ketotifen or placebo and were still allowed to take chlorpheniramine concomitantly. Investigators recorded the number of chlorpheniramine tablets taken, but this information was not reported explicitly. Study investigators noted that the requirement for chlorpheniramine dropped in significantly more participants taking ketotifen than placebo (94% vs 7%). It is still possible that positive results in the ketotifen group might have been caused by this alone, or by taking a combination of ketotifen and chlorpheniramine.
Secondary outcome 2: minor participant‐reported adverse events not requiring withdrawal of treatment
No participants were withdrawn from either treatment as the result of an adverse event.
Comparison 21
Cetirizine 5 mg and hydroxyzine 25 mg (CH) versus placebo
These interventions were compared in one study on the clinical efficacy of a leukotriene receptor antagonist (LRA) plus an H1‐antihistamine, an H1‐antihistamine plus H2RA, two H1‐antihistamines in combination and placebo for treating participants with CSU (Wan 2009). We compared only the H1‐antihistamine combination and placebo arms. No analysis was possible for this comparison.
Primary outcome 2: proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines
This study reported that 7/30 participants in the CH group and 0/30 in the placebo group experienced at least a good response following treatment after an intermediate‐term duration of intervention (P value 0.01). Investigators concluded: "The combination of LRA and H1 receptor antagonist is promising for CSU treatment and is reasonably well tolerated by participants. The combination of H1‐ and H2‐receptor antagonists provided the greatest treatment efficacy by the measures used in this small study."
Comparison 22
Azelastine 2 mg versus azelastine 4 mg
One study that compared these interventions was identified (Wu 2008). No analysis was possible for this comparison.
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
This study reported that 21/34 (2 mg) and 27/33 (4 mg) participants experienced complete suppression of CSU following an intermediate intervention (P value 0.103).
Primary outcome 2: proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines
A further 6/34 (2 mg) and 4/33 (4 mg) participants exhibited good or excellent response to treatment over the same period (P value 0.637).
Comparison 23
Doxepin 10 mg versus pheniramine 22.5 mg
One study that compared these interventions was identified, although participants previously non‐responsive to antihistamines were excluded (Ghosh 1990). No analysis was possible for this comparison.
Primary outcome 1: proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines
Following an intermediate‐term duration of intervention, 8/28 and 3/28 participants experienced complete suppression of urticaria (doxepin and pheniramine, respectively; P value < 0.001). Within seven days of treatment cessation, symptoms recurred in three of the participants (37.5%) who had taken doxepin and in all three who had taken pheniramine (P value 1.00).
Secondary outcome 2: minor participant‐reported adverse events not requiring withdrawal of treatment
Although drowsiness and dry mouth were commonly reported in both groups (doxepin 37.5% and 64.3%, respectively; pheniramine 60.7% and 46.4%, respectively), no withdrawals from this study were reported.
Sensitivity and subgroup analyses
Only one comparison consisting of two studies (n = 260) compared hydroxyzine first‐generation ('sedating') and cetirizine second‐generation ('non‐sedating') antihistamines individually (see Comparison 8). No difference in adverse effects leading to withdrawal was reported between these two groups (RR 0.78, 95% CI 0.25 to 2.45; Analysis 8.1).
Discussion
Summary of main results
This review included 73 randomised studies with 9759 participants. For inclusion in our review, we would have preferred all studies to define their inclusion criteria explicitly as individuals with urticaria for a duration of at least six weeks, with the exclusion of those with inducible urticaria. To avoid excluding multiple studies that were likely to be relevant, we included studies that clearly stated the diagnosis under investigation as chronic spontaneous (or idiopathic or ordinary) urticaria, with nothing included in the paper to contradict this.
All studies were carried out in a secondary care setting, which included hospitals, research centres and dermatology centres. Participants were adults or were 12 years of age or older, and most were female.
Seventeen studies looked at short‐term response to treatment of up to 2 weeks' duration, whilst 55 assessed intermediate response (longer than two weeks to three months). One study did not mention the duration of treatment or follow‐up. No study looked at a long‐term response of three months and beyond. Chronic spontaneous urticaria (CSU) can persist for years, and it would be useful for future studies to address whether treatments are effective over a longer period.
Considerable variation was noted in the interventions and comparators used in included studies; this limited the number of analyses that we could carry out. Additionally, pooling of data was not feasible for most of the treatment options, as the outcomes reported were not comparable. Of the 23 comparisons we were able to make, 10 provided outcome data that could be combined in meta‐analyses. Thus most of our findings are based on results from individual trials.
Evidence suggests that some antihistamines appear to be more effective than placebo in achieving complete suppression of urticaria. This is the case for cetirizine 10 mg in the short term and in the intermediate term. Levocetirizine 20 mg over the short term also appears to be effective for complete suppression of urticaria (Hoxha 2011); however Hoxha 2011 has been published only as a conference abstract, and a fuller report or further information was unavailable at the time of writing of this review. The Nettis 2006 study found levocetirizine 5 mg to be considerably more likely to lead to complete suppression of urticaria over an intermediate‐term duration than Hoxha 2011 over a short duration. Given that this information was derived from only two studies, each with some factors carrying an unclear risk of bias, it may be the case that levocetirizine is more beneficial when used for a longer duration.
Rupatadine in the study of Gimenez‐Arnau 2007 was effective (good or excellent response) at 10 mg or 20 mg when compared against placebo. However, no difference was demonstrated between doses.
Meta‐analyses assessing response to treatment with loratadine 10 mg indicate that its efficacy was not significantly different from that of placebo in the short and intermediate time frame (intervention for up to three months) for the outcome of 'good or excellent response' (Belaich 1990; Monroe 1992).
Comparisons of desloratadine versus placebo suggested a possible relationship between dose, duration and response: Lower doses (5 mg) with a shorter intervention period led to similar results, but a longer duration of a low dose (5 mg) or a shorter duration of a higher dose (20 mg) led to a higher rate of complete suppression of urticaria. In Hoxha 2011, different doses of desloratadine 5 mg to 20 mg were compared with doses of levocetirizine 5 mg to 20 mg; study investigators concluded: "increasing dose up to four‐fold in both active groups was beneficial without compromising safety. Levocetirizine appeared to be more effective than desloratadine" (P value < 0.02).
In comparisons of more than one active intervention, no significant difference was found between loratadine 10 mg and cetirizine 10 mg at short‐ or intermediate‐term durations in bringing about complete suppression of urticaria (Patel 1997; Yin 2003b).
Similarly, for loratadine 10 mg versus desloratadine 5 mg for complete suppression of urticaria and for good or excellent response, no statistically significant difference was noted between groups over an intermediate term of intervention (Gu 2002; Zou 2002).
For loratadine 10 mg versus mizolastine 10 mg, again with an intermediate term of intervention, no statistically significant difference was noted between groups for complete suppression of urticaria and for 'good or excellent response' (Guo 2003; Liu 2003; Liu H‐N 1990; Yin 2003b). Loratadine 10 mg versus emedastine 2 mg (one study; n = 161) showed no statistically significant difference for complete suppression or good or excellent response, or for withdrawals due to adverse effects (Pons‐Guiraud 2006).
We investigated the frequency with which adverse events led to withdrawal of treatment. No significant differences were observed in efficacy or adverse events compared with placebo in the intermediate term for cetirizine (doses from 5 mg to 20 mg) (Breneman 1995; Breneman 1996; Kalivas 1990), desloratadine (5 mg) (Monroe 2003; Nettis 2004; Ring 2001) or hydroxyzine (25 mg) (Breneman 1996; Kalivas 1990).
For withdrawals in comparisons of two active interventions, no significant differences were noted between loratadine 10 mg and mizolastine 10 mg (Leynadier 2000; Liu 2003), loratadine 10 mg and emedastine 2 mg (Pons‐Guiraud 2006), cetirizine 10 mg and hydroxyzine 25 mg (Breneman 1996) and cetirizine 5 mg to 25 mg and hydroxyzine 25 mg (Kalivas 1990).
Quality of life was assessed in one comparison of two trials (Guo 2003; Liu 2003), but no difference was noted between loratadine 10 mg and mizolastine 10 mg in the proportion of participants with at least 50% improvement in quality of life.
Overall completeness and applicability of evidence
The studies that met our criteria for inclusion in this review were conducted all over the world. We searched exhaustively and identified studies conducted in many disparate populations, including those in the USA, Australia, various European countries, South America, China, Taiwan and India. We also searched for reports on clinical trials in progress and for data from completed but unpublished clinical trials. Translation of all relevant non‐English studies was conducted, and data were extracted and included. Most Japanese studies defined CSU as lasting four weeks or longer, and as this differed from our more generally recognised definition of CSU as lasting six weeks or longer, they could not be included. Evidence within this review should be applicable to all populations in which antihistamines are used for the treatment of CSU.
After discussion and consensus, we excluded studies that compared terfenadine and astemizole unless other comparison trial arms included interventions. These drugs are no longer in use for the treatment of urticaria because of safety concerns.
It is interesting to note that eight studies excluded participants previously unresponsive to antihistamines. The effect of this is that a subset of those with CSU who were more likely to be refractory to the intervention were screened out. These may be individuals with more severe disease. This could have a large effect on observed efficacy of an antihistamine in this trial, although it does not render in‐trial comparisons of different antihistamines completely invalid.
The duration of CSU varies among individuals, although the mean duration may be prolonged (three to five years), and a small proportion of people can have CSU for longer than 20 years (Demera 2001; Kaplan 2005). It was disappointing to note that the duration of interventions used in the studies included in this review was relatively short (up to six weeks), and longer‐term data are not available.
It would also have been of interest to analyse each study by itch, weal numbers and angio‐oedema separately, as itch is a different symptom from swellings, even though both are mediated by histamine. Some of the original product licences for classical antihistamines were based on itch suppression rather than reduction in wealing. Itch is often the most troublesome symptom for people in terms of impairment of quality of life because of its effect on sleep and its general propensity to cause distress. In clinical practice, patients may refer to improvement in itch but not weals (or the opposite) rather than both, so treatment effects should ideally be reported separately rather than as an overall assessment of improvement. Furthermore, physician‐rated scales of itch are a contradiction, as it is only the individual with the symptom who can rate this. In our review, we were unable to look at itch or weal numbers separately because not all of the included studies reported these consistently. and our focus was on urticaria rather than angio‐oedema. We were reluctant to undertake further subgroup analyses because the likelihood of false‐positive significance tests increases as more subgroup analyses are performed.
Quality of the evidence
The included studies had notable methodological limitations; only 12 were clearly adequately randomised, and the randomisation method used in the rest was unclear or at high risk. Only four described adequate allocation concealment; in the remaining studies, this was unclear or was judged to confer high risk of selection bias. Blinding of participants and personnel was adequate in only 20 studies, and blinding of outcome assessors was adequate in 14. Twenty studies were at risk of bias from incomplete reporting of outcome data (attrition bias), and 20 studies were at high risk of selective reporting bias. We detected other sources of bias including baseline imbalance within groups and potential bias from industry sponsorship or funding in 55 of the included studies, but the extent to which these factors may have introduced bias was unclear. It is therefore important to emphasise that any conclusions that we have drawn are reliant on primary studies with varying degrees of bias. Risk of bias should be considered when these results are interpreted (Figure 2), and findings derived from studies with high or unclear risk of bias should be viewed with caution.
Although we included a large number of studies, only a few for each comparison reported outcome data that could be incorporated in meta‐analyses. Several studies included small numbers of participants. We have drawn limited conclusions from single study analyses, or we have reported the results of the trial narratively or we have presented results from small meta‐analyses of up to three studies (e.g. loratadine vs desloratadine, n = 410 from three studies; loratadine vs mizolastine, n = 204 from three studies).
Some studies showed some statistical heterogeneity, for example, for the comparison of loratadine versus desloratadine, and loratadine versus mizolastine. We give reasons for downgrading the quality of the body of evidence for each comparison in the 'Summary of findings' tables (Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9; Table 10; Table 11; Table 12) (as described in the footnotes of each table). Overall, the quality of evidence in each comparison was rated as low in most studies or of moderate quality, meaning that further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. The current body of evidence does not, therefore, allow robust conclusions.
Potential biases in the review process
Risk of bias was assessed for all studies. Although we requested additional details of trial conditions from study investigators, in many cases we were unable to determine whether randomisation and allocation concealment methods were adequate. Overall, a high proportion of the included studies were assessed as having unclear or high risk of bias. Most although not all trials published within the past 10 years provided enough information to enable full assessment of risk of bias. Many studies were at high risk of attrition bias as the result of dropouts and losses to follow‐up. This could often be attributed to participants who did not experience symptomatic relief in the placebo arm of trials.
Of the 73 included studies with 9759 randomly assigned participants, 31 were stated to be sponsored by the pharmaceutical industry, and six through research grants or non‐profit organisations. It is unclear whether sponsorship was a source of bias in these trials.
We attempted to minimise publication bias by seeking out results of unpublished trials. This review included 73 studies, of which 35 provided outcome data for 23 comparisons. Therefore, even though we have included a large number of studies, clinical diversity and variation in the ways in which results were reported led to only a few meta‐analyses. Whilst every effort was made to minimise the introduction of bias in this review, clinically divergent interventions led to wide confidence intervals and potentially imprecise results. Sensitivity analysis was not possible for primary outcomes measures for studies at low risk of bias, as studies were too few to permit assessment of the results of the review in this way.
Although the evidence for cetirizine is somewhat more robust than for other antihistamines, it should be borne in mind that cetirizine was effective in suppressing urticaria completely in only some participants. Bias may be present here because cetirizine has been on the market for a long time and more data are available for this agent in comparison with other drugs.
We were unable to include data from studies of participants with varying types of urticaria if no disaggregated data specific to the participants with CSU were available. Although some such studies may provide valuable information, we excluded them, as any conclusions that we derived from studies with mixed populations may not be applicable to populations with CSU.
The clinical heterogeneity that was present in the included studies in terms of populations, interventions and outcomes contributed to difficulties in pooling data for analysis. In some cases, smaller unpublished studies that reported outcomes that fit our inclusion criteria contributed data to several meta‐analyses (e.g. Hoxha 2011).
Agreements and disagreements with other studies or reviews
Kavosh 2011 reviewed second‐generation H1‐antihistamines and found that limited data on comparisons of antihistamines led to the recommendation to use cetirizine in preference to fexofenadine. In our review, the main finding from the key study (Handa 2004) was that at four weeks, 27/59 participants in the cetirizine group had complete suppression of urticaria as compared with 2/57 in the fexofenadine group (P value < 0.001). However, this result was derived from only 116 participants and no meta‐analysis was possible, so the finding may not be wholly conclusive.
The findings of this review are broadly in agreement with those of the Kavosh 2011 review, which recommended use of levocetirizine in preference to desloratadine. In our review, two studies were identified that compared these interventions (Hoxha 2011; Potter 2009). In Hoxha 2011, study investigators concluded: "Increasing dose up to four‐fold in both active groups was beneficial without compromising safety. Levocetirizine appeared to be more effective than desloratadine" (P value < 0.02). However, this study was published only as a conference abstract, and we were unable to obtain study data from study investigators. Participants in Potter 2009 demonstrated at least good response following treatment with levocetirizine 5 mg and desloratadine 5 mg. Levocetirizine "...decreased pruritus duration and the mean CSU composite scores to a significantly greater extent than desloratadine during the first week (P=0.002 and 0.005, respectively) and over the entire study (P=0.009 and P<0.05, respectively)." No meta‐analysis was possible for this comparison.
Other studies have investigated treatment with H1‐antihistamines at higher than recommended licensed doses (e.g. Finn 1999; Nelson 2000; Weller 2013). In our review, one study compared different doses of fexofenadine, but the outcomes did not fit our criteria (Nelson 2000). Furthermore, in this trial, participants previously unresponsive to antihistamines were excluded.
A review by Church 2012 concluded that three clinical studies (Hong 2010; Potter 2009; Staevska 2010) suggested that H1‐antihistamines, or at least desloratadine and levocetirizine, are efficacious in the treatment of CSU. However, we excluded Hong 2010 and Staevska 2010 from our review, as they included participants outside our inclusion criteria. We agree with the authors of Church 2012 that an independent multi‐centre study could provide valuable information about the relative efficacy of these interventions. Currently available evidence for use of higher doses of H1‐antihistamines for CSU is limited, and no long‐term data are available for any of the trials.
Guidelines of the British Association of Dermatologists for management of urticaria (Grattan 2007) suggested that patients should be offered the choice of at least two non‐sedating H1‐antihistamines, and that benefits of increasing the dose to above the licensed limit may outweigh risks, but we found limited evidence in our included studies to support this approach.
Authors' conclusions
Implications for practice.
This review has found limited quality evidence to establish the efficacy of H1‐antihistamines compared with placebo in the treatment of CSU. Several antihistamines were found to be superior to placebo at standard (licensed) doses of treatment. Although the quality of evidence for adverse events was low, the direction of effects in most of the analyses suggest that users generally found these medicines tolerable.
Symptomatic relief has been demonstrated to a variable extent with different antihistamines. However, only few studies have assessed their effects on quality of life in urticaria.
On the basis of our data collection and analysis, it is evident that a clear message does not emerge regarding whether one antihistamine is better than another. Given the quality of trials and of their reporting, as well as the wide variation in comparisons and few opportunities to combine results in meta‐analyses, we must be guarded in putting forward specific treatment algorithms.
For general use, cetirizine at 10 mg once daily for short‐ and intermediate‐term duration was found to be effective in completely suppressing urticaria. However, three of the four trials that compared this treatment against placebo did have factors that we rated as suggesting high risk of bias. The two trials of loratadine 10 mg once daily versus placebo failed to demonstrate efficacy and were also at some risk of bias. Only two trials compared these two drugs: They failed to show a difference in efficacy, although they were not designed to demonstrate equivalence. Cetirizine and loratadine offer the advantages of being cheap and widely available. It would be reasonable to regard cetirizine as a first‐line option.
Some benefit (for complete suppression of urticaria) may be derived from using desloratadine at 5 mg once daily for at least an intermediate term of intervention and 20 mg desloratadine in the short term. Once again, risks of bias in trials of this drug were significant.
Levocetirizine at 5 mg once daily in the intermediate term appears to be effective in achieving complete suppression of CSU. This is based on the results of only three trials. We rated two of these as carrying an unclear risk of bias in every domain, although the third, whilst small, was relatively well conducted and reported. Evidence of benefit from increasing the dose to a ceiling of 20 mg per day is limited. It is common practice to use higher than licensed doses of various H1‐antihistamines, at least in Europe, where the guidelines recommend this (Zuberbier 2012). We included very few RCTs that assessed the effects of this and found insufficient evidence to support the practice, especially over longer durations. For clarity, the maximum licensed dose for both cetirizine and loratadine is 10 mg once daily, and for both levocetirizine and desloratadine, 5 mg once daily.
Although we included trials on various other drugs, their data are too sparse to allow firm conclusions about their relative efficacy. Furthermore, very few trials assessed combinations of antihistamines at conventional or higher doses; although such prescribing does occur in clinical practice, we have no basis on which to make recommendations.
Implications for research.
We found little research on the use of higher doses of H1‐antihistamines, and no included studies continued over longer durations. Very few assessed whether responses were sustained after the intervention was stopped; future work should address these gaps.
Study investigators should provide information about the duration of urticaria for each participant before entry into a trial, as it is conceivable that urticaria that has persisted for many years may be more refractory to treatment than urticaria of only six weeks' duration.
We would welcome trials with two (or more) active treatment arms rather than a placebo that performed comparisons of different doses over longer periods. Although trials including a placebo yield useful data, particularly for new compounds, participants receiving placebo may find little benefit from taking part and seem to be more likely to withdraw or to fail to comply with the medication schedule. This can lead to very high levels of dropout and resulting difficulties in interpretation of study results. Trials should preferably be conducted independently of involvement of pharmaceutical companies.
Many dermatologists recommend higher, unlicensed doses of H1‐antihistamines in difficult cases of urticaria. Future studies should address whether this is justified in terms of effectiveness and safety.
In this review, primary outcome scores were variable for several of the trials, making it difficult for review authors to draw direct comparisons. This would be enabled by the use of a standardised outcome score such as the Urticaria Activity Score. This instrument is recommended in the European guidelines (Zuberbier 2012) and comprises the sum of 4‐point scales (0‐3) for number of weals and pruritus over a 24‐hour period. In several studies, outcome measures were not clearly defined, and for some measures, it was not clear how improvements in composite scores really correlated with symptomatic relief. For example, level of pruritus is likely to be of far greater importance to an individual with urticaria than the size of the largest weal.
In terms of reporting of results, we find that it is more meaningful to the clinician and to the participant if outcomes can be related to numbers of individuals who achieve a particular response. For example, five out of 10 of those with CSU will attain complete symptom relief, and a further three will experience greater than 50% improvement, rather than a particular drug will, on average, lead to a 3‐point reduction in total symptoms score. The latter approach is often accompanied by a P value < 0.05, but clinical significance and the spread of responses may be less clear: Was there some improvement for all participants, or were complete responses noted for a few and no response for others? We favour clear outcomes such as number of participants achieving complete suppression of urticaria, or 75% reduction in itch severity (which could be equated with a good response).
Wider use of standardised and validated quality of life (QoL) scores for trial participants diagnosed with this often disabling condition would provide measurable data to aid treatment decisions. For example, QoL scores would help investigators to monitor change in dosage or drug, or cessation of therapy.
Virtually no long‐term studies have looked at treatment and outcomes over much longer periods of time. Longer‐term studies should be designed, so that the extent of relief from symptoms from participants' perspective (symptoms, quality of life) and safety and efficacy should be included in the design of such studies. We do recognise that long‐term studies may be difficult to perform for reasons including expense and attrition, with fewer participants remaining in the study over long periods of time.
What's new
Date | Event | Description |
---|---|---|
17 May 2017 | Amended | Author information (affiliation) updated |
History
Protocol first published: Issue 3, 2006 Review first published: Issue 11, 2014
Date | Event | Description |
---|---|---|
15 July 2015 | Amended | Correction to publication date of included study Zou 2002. Previously cited as 2003. 2002 is the correct publication year. |
Notes
We provide brand names as a guide to the consumer and do not endorse any product over another.
Acknowledgements
Many thanks to Dr Gudula Kirtschig and the Cochrane Skin Group for guidance and assistance with this project.
We would also like to thank Dr Chih‐Mei Chen, Dr Amy Stanway, Dr Lynda Binney and Dr Conrad Hauser, who were co‐authors on the protocol for this review.
Dr Jonathan Batchelor, Dr Carsten Flohr, Dr Marcello Di Bonito and Dr Kim Varma provided assistance with translations. Dr Sujoy Ray provided support with data extraction and risk of bias assessments.
We thank the following study investigators, who provided additional details of study results for included trials: Dr Ana Gimenez‐Arneau, Dr Ganesh Dakhale, Dr Gabriele Di Lorenzo, Prof Louis Dubertret, Dr Jean‐Jacques Grob, Dr Sanjeev Handa and Dr Arthur Helbling.
The Cochrane Skin Group editorial base wishes to thank Sam Gibbs, who was the Cochrane Dermatology Editor for this review; Jo Leonardi‐Bee, who was the Statistical Editor; Ching‐Chi Chi, who was Methods Editor; the clinical referees, Clive Grattan and Karsten Weller; and the consumer referee, who wishes to remain anonymous.
Appendices
Appendix 1. Skin Group Specialised Register search strategy
(Urticaria or hives) and (astemizole or brompheniramine or chlorpheniramine or cinnarizine or clemastine or cyclizine or cyproheptadine or dimenhydrinate or dimethindene or diphenhydramine or doxylamine or flunarizine or hydroxyzine or ketotifen or meclizine or methapyrilene or mianserin or pheniramine or promethazine or pyrilamine or terfenadine or tripelennamine or triprolidine or azelastine or bromodiphenhydramine or carbinoxamine or cetirizine or chlorodiphenhydramine or chlorphenamine or deschlorpheniramine or loratadine or desloratadine or dexbrompheniramine or dexchlorpheniramine or dimetindene or ebastine or embramine or fexofenadine or levocetirizine or meclozine or olopatadine or phenindamine or phenyltoloxamine or rupatadine or "H1 receptor antagonist*" or "H1 antagonist*" or "h1 antihistamine*")
Appendix 2. CENTRAL search strategy
#1 (urticaria):ti,ab,kw #2 MeSH descriptor Urticaria explode all trees in MeSH products #3 (hives):ti,ab,kw #4 (#1 OR #2 OR #3) #5 "H1 antihistamine*":ti,ab,kw #6 ("H1 antagonist*"):ti,ab,kw #7 MeSH descriptor Histamine H1 Antagonists explode all trees in MeSH products #8 astemizole in Title, Abstract or Keywords in all products #9 brompheniramine or chlorpheniramine in Title, Abstract or Keywords in all products #10 cinnarizine or clemastine or cyclizine or cyproheptadine in Title, Abstract or Keywords in all products #11 dimenhydrinate or dimethindene or diphenhydramine in Title, Abstract or Keywords in all products #12 doxylamine or flunarizine or hydroxyzine or ketotifen or meclizine or methapyrilene in Title, Abstract or Keywords in all products #13 mianserin or pheniramine or promethazine or pyrilamine in Title, Abstract or Keywords in all products #14 terfenadine or tripelennamine or triprolidine in Title, Abstract or Keywords in all products #15 "H1 receptor antagonist*":ti,ab,kw #16 MeSH descriptor Astemizole explode all trees #17 MeSH descriptor Brompheniramine explode all trees #18 MeSH descriptor Chlorpheniramine explode all trees #19 MeSH descriptor Cinnarizine explode all trees #20 MeSH descriptor Clemastine explode all trees #21 MeSH descriptor Cyclizine explode all trees #22 MeSH descriptor Cyproheptadine explode all trees #23 MeSH descriptor Dimenhydrinate explode all trees #24 MeSH descriptor Dimethindene explode all trees #25 MeSH descriptor Diphenhydramine explode all trees #26 MeSH descriptor Doxylamine explode all trees #27 MeSH descriptor Flunarizine explode all trees #28 MeSH descriptor Hydroxyzine explode all trees #29 MeSH descriptor Ketotifen explode all trees #30 MeSH descriptor Meclizine explode all trees #31 MeSH descriptor Methapyrilene explode all trees #32 MeSH descriptor Mianserin explode all trees #33 MeSH descriptor Pheniramine explode all trees #34 MeSH descriptor Promethazine explode all trees #35 MeSH descriptor Pyrilamine explode all trees #36 MeSH descriptor Terfenadine explode all trees #37 MeSH descriptor Tripelennamine explode all trees #38 MeSH descriptor Triprolidine explode all trees #39 (azelastine or bromodiphenhydramine or carbinoxamine or cetirizine ):ti,ab,kw #40 (Chlorodiphenhydramine or chlorphenamine or Deschlorpheniramine):ti,ab,kw #41 MeSH descriptor Loratadine explode all trees #42 (desloratadine or loratadine or Dexbrompheniramine):ti,ab,kw #43 (Dexchlorpheniramine or Dimetindene or ebastine or Embramine ):ti,ab,kw #44 (Fexofenadine or Levocetirizine or Meclozine or Olopatadine):ti,ab,kw #45 (Phenindamine or Phenyltoloxamine or Rupatadine):ti,ab,kw #46 MeSH descriptor Cetirizine explode all trees #47 (#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46) #48 (#4 AND #47)
Appendix 3. MEDLINE (Ovid) search strategy
1. randomised controlled trial.pt. 2. controlled clinical trial.pt. 3. randomized.ab. 4. placebo.ab. 5. clinical trials as topic.sh. 6. randomly.ab. 7. trial.ti. 8. 1 or 2 or 3 or 4 or 5 or 6 or 7 9. (animals not (human and animals)).sh. 10. 8 not 9 11. exp Urticaria/ or urticaria.ti,ab. 12. hives.ti,ab. 13. or/11‐12 14. exp Histamine H1 Antagonists/ or h1 antihistamine$.ti,ab. 15. astemizole.ti,ab. or exp Astemizole/ 16. brompheniramine.ti,ab. or exp Brompheniramine/ 17. chlorpheniramine.ti,ab. or exp Chlorpheniramine/ 18. cinnarizine.ti,ab. or exp Cinnarizine/ 19. clemastine.ti,ab. or exp Clemastine/ 20. cyclizine.ti,ab. or exp Cyclizine/ 21. cyproheptadine.ti,ab. or exp Cyproheptadine/ 22. dimenhydrinate.ti,ab. or exp Dimenhydrinate/ 23. dimethindene.ti,ab. or exp Dimethindene/ 24. diphenhydramine.ti,ab. or exp Diphenhydramine/ 25. doxylamine.ti,ab. or exp Doxylamine/ 26. flunarizine.ti,ab. or exp Flunarizine/ 27. hydroxyzine.ti,ab. or exp Hydroxyzine/ 28. ketotifen.ti,ab. or exp Ketotifen/ 29. meclizine.ti,ab. or exp Meclizine/ 30. methapyrilene.ti,ab. or exp Methapyrilene/ 31. mianserin.ti,ab. or exp Mianserin/ 32. pheniramine.mp. or exp Pheniramine/ 33. promethazine.ti,ab. or exp Promethazine/ 34. pyrilamine.ti,ab. or exp Pyrilamine/ 35. terfenadine.ti,ab. or exp Terfenadine/ 36. tripelennamine.ti,ab. or exp Tripelennamine/ 37. triprolidine.ti,ab. or exp Triprolidine/ 38. azelastine.ti,ab. 39. bromodiphenhydramine.ti,ab. 40. Carbinoxamine.ti,ab. 41. exp Cetirizine/ 42. cetirizine.ti,ab. 43. Chlorodiphenhydramine.ti,ab. 44. chlorphenamine.ti,ab. 45. Deschlorpheniramine.ti,ab. 46. exp Loratadine/ 47. desloratadine.ti,ab. 48. loratadine.ti,ab. 49. Dexbrompheniramine.ti,ab. 50. Dexchlorpheniramine.ti,ab. 51. Dimetindene.ti,ab. 52. ebastine.ti,ab. 53. Embramine.ti,ab. 54. Fexofenadine.ti,ab. 55. Levocetirizine.ti,ab. 56. Meclozine.ti,ab. 57. Olopatadine.ti,ab. 58. Phenindamine.ti,ab. 59. Phenyltoloxamine.ti,ab. 60. Rupatadine.ti,ab. 61. H1 receptor antagonist$.ti,ab. 62. H1 antagonist$.ti,ab. 63. or/14‐62 64. 10 and 13 and 63
Appendix 4. EMBASE (Ovid) search strategy
1. astemizole.ti,ab. or exp Astemizole/ 2. brompheniramine.ti,ab. or exp Brompheniramine/ 3. chlorpheniramine.ti,ab. or exp Chlorpheniramine/ 4. cinnarizine.ti,ab. or exp Cinnarizine/ 5. clemastine.ti,ab. or exp Clemastine/ 6. cyclizine.ti,ab. or exp Cyclizine/ 7. cyproheptadine.ti,ab. or exp Cyproheptadine/ 8. dimenhydrinate.ti,ab. or exp Dimenhydrinate/ 9. dimethindene.ti,ab. or exp Dimethindene/ 10. diphenhydramine.ti,ab. or exp Diphenhydramine/ 11. doxylamine.ti,ab. or exp Doxylamine/ 12. flunarizine.ti,ab. or exp Flunarizine/ 13. hydroxyzine.ti,ab. or exp Hydroxyzine/ 14. ketotifen.ti,ab. or exp Ketotifen/ 15. meclizine.ti,ab. or exp Meclizine/ 16. methapyrilene.ti,ab. or exp Methapyrilene/ 17. mianserin.ti,ab. or exp Mianserin/ 18. pheniramine.mp. or exp Pheniramine/ 19. promethazine.ti,ab. or exp Promethazine/ 20. pyrilamine.ti,ab. or exp Pyrilamine/ 21. terfenadine.ti,ab. or exp Terfenadine/ 22. tripelennamine.ti,ab. or exp Tripelennamine/ 23. triprolidine.ti,ab. or exp Triprolidine/ 24. azelastine.ti,ab. 25. bromodiphenhydramine.ti,ab. 26. Carbinoxamine.ti,ab. 27. exp Cetirizine/ 28. cetirizine.ti,ab. 29. Chlorodiphenhydramine.ti,ab. 30. chlorphenamine.ti,ab. 31. Deschlorpheniramine.ti,ab. 32. exp Loratadine/ 33. desloratadine.ti,ab. 34. loratadine.ti,ab. 35. Dexbrompheniramine.ti,ab. 36. Dexchlorpheniramine.ti,ab. 37. Dimetindene.ti,ab. 38. ebastine.ti,ab. 39. Embramine.ti,ab. 40. Fexofenadine.ti,ab. 41. Levocetirizine.ti,ab. 42. Meclozine.ti,ab. 43. Olopatadine.ti,ab. 44. Phenindamine.ti,ab. 45. Phenyltoloxamine.ti,ab. 46. Rupatadine.ti,ab. 47. H1 receptor antagonist$.ti,ab. 48. H1 antagonist$.ti,ab. 49. exp histamine H1 receptor antagonist/ 50. exp azelastine/ 51. exp bromodiphenhydramine/ 52. exp carbinoxamine/ 53. exp desloratadine/ 54. exp dexbrompheniramine/ 55. exp dexchlorpheniramine/ 56. exp dimetindene/ 57. exp ebastine/ 58. exp embramine/ 59. exp fexofenadine/ 60. exp levocetirizine/ 61. exp meclozine/ 62. exp olopatadine/ 63. exp phenindamine/ 64. exp phenyltoloxamine/ 65. exp rupatadine/ 66. h1 antihistamine$.ti,ab. 67. or/1‐66 68. exp *urticaria/ 69. urticaria.ti,ab. 70. hives.ti,ab. 71. or/68‐70 72. random$.mp. 73. factorial$.mp. 74. (crossover$ or cross‐over$).mp. 75. placebo$.mp. or PLACEBO/ 76. (doubl$ adj blind$).mp. 77. (singl$ adj blind$).mp. 78. (assign$ or allocat$).mp. 79. volunteer$.mp. or VOLUNTEER/ 80. Crossover Procedure/ 81. Double Blind Procedure/ 82. Randomized Controlled Trial/ 83. Single Blind Procedure/ 84. 72 or 73 or 74 or 75 or 76 or 77 or 78 or 79 or 80 or 81 or 82 or 83 85. 67 and 71 and 84
Appendix 5. PsycINFO (Ovid) search strategy
1. double‐blind.tw. 2. random$ assigned.tw. 3. control.tw. 4. 1 or 2 or 3 5. urticaria.ti,ab. 6. hives.ti,ab. 7. 5 or 6 8. 4 and 7
Lines 1‐3 of this strategy are a therapy filter for PsycINFO (Ovid) created by the Health Information Research Unit at McMaster University.
Data and analyses
Comparison 1. Loratadine 10 mg versus placebo.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1 Proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines | 2 | 124 | Risk Ratio (M‐H, Random, 95% CI) | 1.86 [0.91, 3.79] |
1.1 Short‐term duration of intervention (10 mg) | 1 | 12 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.42, 21.30] |
1.2 Intermediate‐term duration of intervention (10 mg) | 1 | 112 | Risk Ratio (M‐H, Random, 95% CI) | 1.73 [0.81, 3.72] |
Comparison 2. Loratadine 10 mg versus cetirizine 10 mg.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines | 2 | 103 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.76, 1.43] |
1.1 Short‐term duration of intervention | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.64, 2.01] |
1.2 Intermediate‐term duration of intervention | 1 | 66 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.69, 1.47] |
Comparison 3. Loratadine 10 mg versus desloratadine 5 mg.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
1.1 Intermediate‐term duration of intervention | 2 | 369 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.78, 1.06] |
2 Proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
2.1 Intermediate‐term duration of intervention | 3 | 410 | Risk Ratio (M‐H, Random, 95% CI) | 1.04 [0.64, 1.71] |
Comparison 4. Loratadine 10 mg versus mizolastine 10 mg.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
1.1 Intermediate‐term duration of intervention | 3 | 316 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.64, 1.16] |
2 Proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
2.1 Intermediate‐term duration of intervention | 3 | 314 | Risk Ratio (M‐H, Random, 95% CI) | 0.88 [0.55, 1.42] |
3 Proportion of participants with at least 50% improvement in QoL whilst taking H1‐antihistamines | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
3.1 Intermediate‐term duration of intervention | 2 | 252 | Risk Ratio (M‐H, Random, 95% CI) | 3.21 [0.32, 32.33] |
4 Serious adverse events (i.e. serious enough to require withdrawal of treatment) | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
4.1 Intermediate‐term duration of intervention | 2 | 267 | Risk Ratio (M‐H, Random, 95% CI) | 0.38 [0.04, 3.60] |
Comparison 5. Loratadine 10 mg versus emedastine 2 mg.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
1.1 Intermediate‐term duration of intervention | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
2 Proportion of participants with good or excellent response whilst taking H1‐antihistamines | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
2.1 Intermediate‐term duration of intervention | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
3 Serious adverse events (i.e. serious enough to require withdrawal of treatment) | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
3.1 Intermediate‐term duration of intervention | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
Comparison 6. Loratadine 10 mg versus hydroxyzine 25 mg.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
1.1 Short‐term duration of intervention | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
Comparison 7. Cetirizine 10 to 20 mg versus placebo.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines | 2 | 178 | Risk Ratio (M‐H, Random, 95% CI) | 2.72 [1.51, 4.91] |
1.1 Short‐term duration of intervention (cetirizine 10 mg) | 1 | 56 | Risk Ratio (M‐H, Random, 95% CI) | 2.8 [1.17, 6.73] |
1.2 Intermediate‐term duration of intervention (cetirizine 10 mg) | 1 | 122 | Risk Ratio (M‐H, Random, 95% CI) | 2.66 [1.20, 5.90] |
2 Serious adverse events (i.e. serious enough to require withdrawal of treatment) | 3 | 389 | Risk Ratio (M‐H, Random, 95% CI) | 3.00 [0.68, 13.22] |
2.1 Intermediate‐term duration of intervention (cetirizine 10 mg) | 2 | 247 | Risk Ratio (M‐H, Random, 95% CI) | 4.60 [0.79, 26.67] |
2.2 Intermediate‐term duration of intervention (cetirizine 10 to 20 mg) | 1 | 142 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.07, 16.59] |
Comparison 8. Cetirizine 10 mg versus hydroxyzine 25 mg.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1 Serious adverse events (i.e. serious enough to require withdrawal of treatment) | 2 | 261 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.25, 2.45] |
1.1 Intermediate‐term duration of intervention (cetirizine 10 mg) | 1 | 123 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.27, 4.01] |
1.2 Intermediate‐term duration of intervention (cetirizine 5 to 25 mg) | 1 | 138 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.04, 3.13] |
Comparison 9. Desloratadine 5 to 20 mg versus placebo.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines | 2 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
1.1 Short‐term duration of intervention (desloratadine 5 mg) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
1.2 Short‐term duration of intervention (desloratadine 10 mg) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
1.3 Short‐term duration of intervention (desloratadine 20 mg) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
1.4 Intermediate‐term duration of intervention (desloratadine 5 mg) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
2 Serious adverse events (i.e. serious enough to require withdrawal of treatment) | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
2.1 Intermediate‐term duration of 5 mg of intervention | 3 | 466 | Risk Ratio (M‐H, Random, 95% CI) | 1.46 [0.42, 5.10] |
Comparison 10. Hydroxyzine 25 mg versus placebo.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1 Serious adverse events (i.e. serious enough to require withdrawal of treatment to withdrawal) | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
1.1 Intermediate‐term duration of intervention | 2 | 270 | Risk Ratio (M‐H, Random, 95% CI) | 3.64 [0.77, 17.23] |
Comparison 11. Levocetirizine 5 to 20 mg versus placebo.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1 Proportion of participants with complete suppression of urticaria whilst taking H1‐antihistamines | 2 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
1.1 Short‐term duration of intervention (levocetirizine 5 mg) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
1.2 Short‐term duration of intervention (levocetirizine 10 mg) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
1.3 Short‐term duration of intervention (levocetirizine 20 mg) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
1.4 Intermediate‐term duration of intervention (levocetirizine 5 mg) | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
Comparison 12. Rupatadine 10 to 20 mg versus placebo.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1 Proportion of participants with 'good' or 'excellent' response whilst taking H1‐antihistamines | 1 | 245 | Risk Ratio (M‐H, Random, 95% CI) | 1.35 [1.03, 1.77] |
1.1 Intermediate‐term duration of intervention (rupatadine 10 mg) | 1 | 122 | Risk Ratio (M‐H, Random, 95% CI) | 1.28 [0.86, 1.91] |
1.2 Intermediate‐term duration of intervention (rupatadine 20 mg) | 1 | 123 | Risk Ratio (M‐H, Random, 95% CI) | 1.42 [0.98, 2.06] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Alomar 1990a.
Methods | Design: randomised double‐blind 2‐arm parallel‐group study of cetirizine hydrochloride vs placebo Duration: 15 days |
|
Participants | Number randomly assigned: 30 participants Sex: 44% male, 56% female Age of participants, years: 21 to 64 Unit of allocation: participant Country and setting: Spain; secondary care, hospital clinic Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (15 days) Length of follow‐up: 15 days |
|
Outcomes | Timing of outcome assessment: baseline and 15 days Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and clinician |
|
Notes | In Spanish with English abstract Investigators concluded that cetirizine was more active than placebo in terms of clinician reports of efficacy; findings were not statistically significantly different |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Described as random allocation, no details given |
Allocation concealment (selection bias) | Unclear risk | Not described in published report |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Stated to be double‐blind, details of blinding not stated |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 30 randomly assigned: 15 intervention, 15 control. 13/15 completed intervention, 12/15 control. 5 from each group experienced adverse effects, but it is unclear whether they withdrew from the study. Reasons for dropout not stated |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Low risk | None detected. Funder: not stated |
Anuradha 2010.
Methods | Design: randomised open comparative clinical study of loratadine vs levocetirizine Duration: 4 weeks |
|
Participants | Number randomly assigned: 60 (loratadine n = 30; levocetirizine n = 30) Sex: 40% male, 60% female; in loratadine group, 43.3% male; in levocetirizine group, 56.7% female Age of participants, years: 12 to 60 (mean age 33.4 and 34.8 in loratadine and levocetirizine groups, respectively) Unit of allocation: participant Country and setting: India; secondary, outpatient Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
|
Outcomes | Timing of outcome assessment: 4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician and participant |
|
Notes | Study authors conclude that this safety and efficacy study proves the superiority of levocetirizine over loratadine for CSU | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Unclear (described as quote from ‘Subjects’ section of report of study as ‘systematic randomisation’) |
Allocation concealment (selection bias) | High risk | Not stated, but trial described as 'open' |
Blinding of participants and personnel (performance bias) All outcomes | High risk | No blinding in this open study |
Blinding of outcome assessment (detection bias) All outcomes | High risk | No blinding in this open study |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 51/60 completed. Six participants did not report for follow‐up (no reasons given), and 3 participants were non‐compliant with treatment |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Low risk | None detected. Funder: none (drugs free of charge from hospital pharmacy) |
Beck 1985.
Methods | Design: randomised double‐blind 2‐arm parallel‐group trial of oxatomide vs clemastine Duration: 6 weeks |
|
Participants | Number randomly assigned: 30 participants (15 in each group) Sex: 43% (13) male, 57% (17) female Age of participants, years: between 15 and 67 Unit of allocation: participant Country and setting: Denmark; setting unclear Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Doses could be increased to 4 capsules daily. Cinnarizine 5 mg every 4 hours could be added if insufficient efficacy in either group Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: 6 weeks (duration of study) |
|
Outcomes | Timing of outcome assessment: 1, 3 and 6 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participants and clinician |
|
Notes | Study investigators concluded that the effect of oxatomide was equal to that of clemastine | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Quote (page 50): "the 30 patients were randomly assigned to a 6 weeks double‐blind treatment...'' Unclear which method of randomisation was used |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote (page 50): "double‐blind treatment'' Method used not described, no further information available |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote (page 50): "double‐blind treatment'' Method used not described, no further information available |
Incomplete outcome data (attrition bias) All outcomes | High risk | 0/30 dropped out |
Selective reporting (reporting bias) | High risk | No participant numbers given in results, only statistical differences (and percentages for adverse events). No figures given (graph only) Severity of weals, erythema and itching noted but not mentioned in the results. No figures given, graph only. No further information available |
Other bias | Unclear risk | No clear definition of disease given; washout period not specified; concomitant treatment permitted Funder: not stated |
Belaich 1990.
Methods | Design: randomised double‐blind 3‐arm parallel‐group multi‐centre study of loratadine vs terfenadine vs placebo Duration: 28 days |
|
Participants | Number of participants randomly assigned: 187 (61 in loratadine group; 64 in terfenadine group; 62 in placebo group) Sex: 46% male, 53% female. Number of male/female: 32/27 loratadine; 36/24 terfenadine; 20/32 placebo Age of participants, years: average 37 Unit of allocation: participant Country and setting: France, Belgium, Germany; setting unclear, included private practice and dermatology clinics Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Loratadine 10 mg (active drug in the morning and placebo in the evening), 60 mg terfenadine twice daily or placebo twice daily for 28 days Duration of intervention: intermediate‐term (28 days) Length of follow‐up: 28 days |
|
Outcomes | Timing of outcome assessment: participants seen at baseline (day 1), then at days 7, 14 and 28 Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator report |
|
Notes | Study investigators concluded that loratadine 10 mg once daily is safe and effective | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | ''Qualified patients were randomly assigned...'' Method of randomisation not stated |
Allocation concealment (selection bias) | Unclear risk | Not stated, unclear whether allocation was concealed |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Stated to be a double‐blind study, method of blinding not described |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Stated to be a double‐blind study, method of blinding not described |
Incomplete outcome data (attrition bias) All outcomes | High risk | No ITT. 15/187 dropouts due to protocol violation (no details given): 1/61 loratadine; 4/64 terfenadine; 52/62 placebo dropped out |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Low risk | Groups were comparable at baseline Funder: not stated |
Breneman 1995.
Methods | Design: double‐blind multi‐centre 3‐arm randomised trial of cetirizine vs astemizole vs placebo Duration: 4 weeks |
|
Participants | Number randomly assigned: 187 (62 patients in cetirizine group; 62 in astemizole group; 63 in placebo group) Sex: 27% male, 73% female Age of participants, years: > 12, average 37.7 Unit of allocation: participant Country and setting: USA; university medical centres
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
|
Outcomes | Timing of outcome assessment: 1, 2, 3 and 4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and investigator |
|
Notes | Study investigators concluded that cetirizine provides effective relief of symptoms | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Quote (page 192): "...patients were randomly assigned to receive either 10 mg cetirizine, 10 mg astemizole, or placebo once each night for 4 weeks." No further details given |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Unclear; stated to be ''double‐blind trial'' (page 192) but no details given |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear; stated to be ''double‐blind trial'' (page 192) but no details given |
Incomplete outcome data (attrition bias) All outcomes | High risk | 51/187 randomly assigned participants dropped out/lost to follow‐up; lost to follow‐up were 51 participants (27.3%). 43 participants were withdrawn before trial completion; 1 failed to take astemizole; 7 were lost to follow‐up Serious adverse events (requiring drug withdrawal): cetirizine: n = 2 (headache n = 1; vasovagal/vomiting/palpitations n = 1); astemizole: n = 1 (dizziness, nausea, lethargy, syncope). Evaluable participants: n = 136 Comment: high loss to follow‐up |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Unclear risk | Severity of urticaria comparable at baseline, but statistical differences between other demographic details (age and race) Funder: Pfizer Labs |
Breneman 1996.
Methods | Design: randomised double‐blind placebo‐controlled multi‐centred 3‐arm study of cetirizine vs hydroxyzine vs placebo Duration: 4 weeks |
|
Participants | Number randomly assigned: 188 (60 in cetirizine group; 63 in hydroxyzine group; 65 in placebo group) Sex: 32% male, 68% female Age of participants, years: > 12; mean: cetirizine: 36.8; hydroxyzine: 34.5; placebo: 38.8 Unit of allocation: participant Country and setting: USA; allergy practice settings Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
|
Outcomes | Timing of outcome assessment: 4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and investigator |
|
Notes | Study investigators concluded that cetirizine 10 mg was equivalent to hydroxyzine 25 mg in symptom control | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Quote (page 1076) "randomised, parallel‐group..." but no further details |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double‐dummy used, but blinding not fully described |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear how blinding of outcome assessors was achieved |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 9/188 dropouts were recorded for each group as the result of serious adverse events requiring withdrawal of drug (1/60 in cetirizine group; 4/63 in hydroxyzine group; 4/65 in placebo group) Cetirizine: somnolence (n = 1) Hydroxyzine: somnolence (n = 4) Placebo: (n = 4) consisted of somnolence n = 1; sweating, vertigo and vomiting (n = 1); lethargy n = 1; headache n = 1 Dropouts balanced between groups |
Selective reporting (reporting bias) | High risk | Reporting of results in graph form (means with statistical significance) only |
Other bias | Unclear risk | No power calculation—may have missed significant differences between groups if underpowered Definition of disease partially defined, with physical urticaria not explicitly excluded Funder: Pfizer Laboratories |
Bronsky 2001.
Methods | Design: multi‐centre double‐blind randomised parallel‐group study comparing desloratadine 5 mg vs placebo Duration: 6 weeks |
|
Participants | Number of participants randomly assigned: 225 (115 in desloratadine group and 110 in placebo group) Sex: not stated Age of participants: not stated Unit of allocation: participant Country and setting: USA; setting unclear Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose duration
Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: 6 weeks |
|
Outcomes | Timing of outcome assessment: twice daily for 6 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: unclear |
|
Notes | Study investigators concluded that desloratadine produced substantial efficacy after just 1 dose, which was maintained throughout study. All measures were statistically significant in favour of desloratadine vs placebo and were sustained at all time points | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Not stated |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Stated to be double‐blind, unclear how this was done |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Stated to be double‐blind, unclear how this was done |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No mention of dropouts/adverse events |
Selective reporting (reporting bias) | High risk | Pruritus score given for days 1 to 8, then total symptoms score given for days 2 to 8 |
Other bias | Unclear risk | None detected. Short report (abstract). Funder: not stated |
Brostoff 1996.
Methods | Design: randomised double‐blind multi‐centre 2‐arm trial of mizolastine vs placebo Duration: 28 days |
|
Participants | Number of participants randomly assigned: 56; 28 in each group Sex: 55% male, 45% female Age of participants, years: 18; mean 38 ± 15 Unit of allocation: participant Country and setting: UK; setting research clinics Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration After single‐blind placebo run‐in period of 4 to 10 days:
Duration of intervention: intermediate‐term (28 days) |
|
Outcomes | Timing of outcome assessment: days 7 and 28 Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician and participant |
|
Notes | Study authors concluded that mizolastine controlled symptoms of urticaria | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Quote (page 321): ''a two‐centre, double‐blind randomised, placebo‐controlled parallel group study... allocated according to the randomisation" |
Allocation concealment (selection bias) | Unclear risk | No details given about allocation concealment |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote (page 321): "Patients received single blind placebo medication for a variable period of 4‐10 days (initially, then were allocated to one of two treatment groups)" Quote (page 321): "All tablets were identical in appearance, ensuring double blind nature of trial." Unclear how investigators were blinded to treatment |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear how investigators were blinded to treatment Comment: participants probably blind, as all tablets were identical |
Incomplete outcome data (attrition bias) All outcomes | High risk | 29/56, 51% losses to follow‐up (29/56 with 10/28 in mizolastine arm and 19/28 in placebo arm). A large proportion of participants dropped out; this is unbalanced across trial arms 1 participant in mizolastine group did not take treatment Lack of efficacy in 5 in mizolastine group and in 17 in placebo group Drowsiness in 1 in mizolastine group Loss to follow‐up at day 7 in 2 mizolastine group 1 participant in each group "unco‐operative" 1 in each group discontinued for reasons unrelated to study Analysis in the paper is presented as ITT |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Unclear risk | Funder: Synthelabo Key outcome based on physician VAS estimate of urticaria severity (i.e. totally subjective); no indication of how many participants were cleared on treatment |
Commens 1978.
Methods | Design: double‐blind cross‐over 3‐arm randomised controlled trial of cimetidine and chlorpheniramine vs placebo Duration: 2 weeks |
|
Participants | Number of participants randomly assigned: 25 entered study. Numbers in each group not stated Sex: 32% male, 68% female Age of participants, years: 18 to 66 Unit of allocation: cross‐over, without washout (consecutive 2‐week treatments) Country and setting: UK; outpatient clinic Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: short‐term (2 weeks) |
|
Outcomes | Timing of outcome assessment: 2 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician and participant |
|
Notes | Study investigators concluded that chlorpheniramine is effective in controlling symptoms in some patients with urticaria | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation not stated. Quote: ''On entry to the trial patients were allocated, on a random double blind basis, to the consecutive 2‐week treatment'' Cross‐over study with no apparent washout |
Allocation concealment (selection bias) | Unclear risk | No allocation concealment stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Study stated double‐blinding; method unclear, no indication whether identical tablets/capsules given, no details about methods of blinding. Dosages were different for each intervention, so blinding incomplete (intervention group could potentially be guessed by number of tablets) |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Study stated double‐blinding; method unclear |
Incomplete outcome data (attrition bias) All outcomes | High risk | 6/25 participants recruited (24%) were lost to follow‐up (non‐compliance 5; spontaneous remission 1) and were not included in the analysis. Unclear which group dropouts belonged to. No ITT |
Selective reporting (reporting bias) | High risk | Results not clearly reported. Results for numbers of participants in each group not stated, only mean scores (no SD) provided |
Other bias | Unclear risk | Unclear schedule of assignment, unclear whether each phase was given consecutively, as results reported only for intervention and control—not by phase of the study Funder: Smith Kline and French Laboratories Ltd |
Dakhale 2014.
Methods | Design: double‐blind 2‐arm randomised controlled trial of cetirizine vs rupatadine Duration: 6 weeks |
|
Participants | Number of participants randomly assigned: 70 Sex: cetirizine females 64.5%, rupatadine females 61.2% Age of participants, years: cetirizine 41.5 (SD 11.49); rupatadine 43.81 (SD 12.30) Unit of allocation: participant Country and setting: India; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
Previous unresponsiveness to antihistamine: excluded any with previous failure to respond to antihistamine |
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate Length of follow‐up: 6 weeks |
|
Outcomes | Timing of outcome assessment: 6 weeks Study outcomes Primary outcomes of the trial Trial was undertaken to test whether treatment with rupatadine was more successful than treatment with cetirizine in resolving symptoms as follows:
Secondary outcomes of the trial
Adverse events: general clinical follow‐up and monitoring of adverse events, no serious adverse events requiring withdrawal of treatment; cetirizine group: total affected 12, 38.71% (headache n = 2, gastric irritation n = 1, dry mouth n = 1, sedation n = 8). Rupatadine group: total affected 7, 21.21% (headache n = 2, dry mouth n = 1, sedation n = 4) Quality of life measures: none Clinician or participant report: participant and clinician |
|
Notes | Study investigators concluded that rupatadine led to improvement in all outcomes by the end of the trial, and that rupatadine is a particularly attractive therapeutic modality compared with cetirizine for the treatment of CSU | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Block randomisation, with block sizes of 4 in equal proportions to ensure a uniform allocation ratio. Randomised treatment allocation sequence was generated by a statistician using a random numbers table |
Allocation concealment (selection bias) | Low risk | Quote (page 644): "The codes used in this random allocation sequence were retained in a sealed envelope, which was opened only after the completion of the study" |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Both participants and investigators were unaware of the treatment administered. Drugs (21 tablets of cetirizine or rupatadine) were handed over in identical plastic containers to a third person, who was not directly involved in this study. Drugs were presented in identical format in terms of shape, size, texture and packing |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | Both participants and investigators were unaware of the treatment administered |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 64/70 completed. 5 participants were lost to follow‐up at end of first week of the study (3 in cetirizine group and 2 in rupatadine group). One from cetirizine group was dropped from the study and was shifted to another drug because of non‐response. Data for these 6 participants were not integrated into the analysis |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Low risk | None detected. Funder: none |
Degonda 2002.
Methods | Design: double‐blind 2‐arm randomised controlled trial of fexofenadine vs placebo Duration: 21 days |
|
Participants | Number of participants randomly assigned: 21 (further information obtained from trial investigator); 13 evaluable participants with 6 in fexofenadine group and 7 in placebo group Sex: 38% female Age of participants, years: 38 Unit of allocation: participant Country and setting: Switzerland; hospital allergy clinics Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (21 days) Length of follow‐up: 21 days |
|
Outcomes | Timing of outcome assessment: 21 days Primary outcomes of the trial Assessment scores used were as follows:
Secondary outcomes of the trial
Clinician or participant report: clinician and participant |
|
Notes | Study investigators concluded that fexofenadine had a beneficial effect on urticaria Main report language is German |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Performed by pharmacist who was not involved in the study Comment: Although randomisation sequence was generated offsite, adequacy of sequence generation is unclear, as no further information was provided by trial investigator |
Allocation concealment (selection bias) | Unclear risk | No details about allocation concealment available Comment: Although only allocation number was visible on sealed medication boxes, allocation concealment up to the point of assignment of the intervention is unclear |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Study drugs and placebo were identical in appearance Comment: Further information from trial investigators stated that identical small and white tablet boxes were sealed with a plastic band (only allocation number could identify the participant) |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | Study drugs and placebo were identical in appearance Comment: Further information from trial investigators states that identical small and white tablet boxes were sealed with a plastic band (only allocation number could identify the participant). Outcome assessors were unaware of treatment allocation |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 18 commenced active study (Phase II): 3 dropped out from the fexofenadine group (1 lack of efficacy, 1 worsening of condition, 1 moved house and lost contact). No participants dropped out from the placebo group (i.e. 15/18 completed) (further information supplied by trial investigator) |
Selective reporting (reporting bias) | Unclear risk | All prespecified outcomes were reported, but results were presented in graph format or as percentages; number of once‐daily treated participants in each group is unclear, therefore calculations may be prone to error |
Other bias | Unclear risk | Funder: Aventis Odd and unclear trial design by which all participants were given active drug as run‐in, then were randomly assigned again to fexofenadine or placebo |
Di Lorenzo 2004.
Methods | Design: randomised parallel‐group 4‐arm study conducted to compare desloratadine vs montelukast vs desloratadine plus montelukast vs placebo Duration: 6 weeks |
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Participants | Number of participants randomly assigned: 160 with 40 in each group Sex: 31% male, 69% female Age of participants, years: 18 to 69; mean 43.9 (SD 13.4) Unit of allocation: participant Country and setting: Italy; outpatient clinics of university hospitals Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
Rescue therapy: loratadine 10 mg allowed (frequency and duration unclear) Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: 8 weeks i.e. follow‐up extended after cessation of treatment. |
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Outcomes | Timing of outcome assessment: baseline, after 3 weeks of treatment, after 6 weeks, follow‐up at 8 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician and participant |
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Notes | Study investigators concluded that on average, desloratadine and desloratadine plus montelukast appear to be more effective than placebo or montelukast alone | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Method of randomisation not stated in publication. Further information from trial investigator: "We used the StatsDirect software for the list of randomised patients" |
Allocation concealment (selection bias) | Unclear risk | No details given about allocation concealment; sealed envelopes were used and were opened after the study had ended. Further details supplied by study investigator |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote (page 620): ''The pharmacist of the University Hospital of Verona prepared a specific set with the treatments to be used for the study''; ''The investigators and patients were blinded with respect to the contents of each set'' Comment: unclear whether tablets were of identical appearance but probably adequate |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear whether or how outcome assessors were blinded Participants assessed some outcomes and were blinded |
Incomplete outcome data (attrition bias) All outcomes | High risk | 62/160 initially randomly assigned participants dropped out, but this is unclear. Study investigator states that dropouts resulted from inefficacy and from requests from participants to discontinue therapy Dropouts from the study were included in the analysis Losses to follow‐up: 68% (27/40)in montelukast plus placebo group; 88% (35/40) in placebo only group. Assumed no dropouts in desloratadine monotherapy or in combined therapy dropped out Comment: high dropout rates unevenly distributed between groups Results presented in graph format or as statistical significance; raw data not given |
Selective reporting (reporting bias) | Unclear risk | Results obscure; expressed as numbers of participants not given (mean plus 95% CI or graphs) Adverse events: not stated ("low incidence… mild") |
Other bias | Unclear risk | Funder: Ministero Italiano Universita e Ricerca; no pharmaceutical industry support All data potentially confounded by allowance of rescue medication. Our interpretation suggests that of a possible 1680 patient‐days per group in the active study, Group 1 took rescue medication on average (median) on all but 90.6 days; Group 2 on all but 91 days; Group 3 on all but 45.2 days; Group 4 on all but 54 days |
Dubertret 1999.
Methods | Design: multi‐centre double‐blind 3‐arm placebo‐controlled parallel‐group study of mizolastine vs loratadine vs placebo Duration: 1‐week placebo run‐ in period, then participants received therapy for 4 weeks |
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Participants | Number of participants randomly assigned: 247 enrolled: 88 to mizolastine; 79 to loratadine; 80 to placebo Sex: 36.8% male, 63.2% female Age of participants, years: 42 ± 15 Unit of allocation: participant Country and setting: France, Spain, Italy; secondary care, hospital clinics Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration After 1‐week placebo run‐in period, participants received 4 weeks:
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
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Outcomes | Timing of outcome assessment: 2 weeks and 4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and clinician |
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Notes | Study acronym: 'MILOR' Study investigators concluded that mizolastine 10 mg daily is an effective and well‐tolerated agent |
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Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Described as randomised, but method of randomisation not stated |
Allocation concealment (selection bias) | Unclear risk | No methods of allocation concealment given in the study report, no further information available |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: ''Patients were randomised to a 4‐week double‐blind treatment...'' but no methods of blinding given |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described in the study report |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 205/247 completed Losses to follow‐up: total 17%; mizolastine: 13/88 (14.8%); loratadine: 10/79 (12.9%); placebo: 19/80 (23.7%), with reasons given Mizolastine: lack of efficacy 3; adverse events 4; non‐compliance 2; "other" 2; loss to follow‐up 2 Loratadine: lack of efficacy 5; adverse events 3; non‐compliance 0; "other" 2; loss to follow‐up 0 Placebo: lack of efficacy 11; non‐compliance 4; "other" 2; loss to follow‐up 2 |
Selective reporting (reporting bias) | Unclear risk | All prespecified outcomes were reported, but data were given as mean scores plus SD; no participant numbers were given |
Other bias | Unclear risk | Funder: Synthelabo research |
Dubertret 2007.
Methods | Design: randomised double‐blind placebo‐controlled 4‐arm dose‐ranging study of rupatadine (3 doses) vs placebo Duration: 28 days |
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Participants | Number of participants randomly assigned: 283 (rupatadine 5 mg n = 68, rupatadine 10 mg n = 73, rupatadine 20 mg n = 67, placebo n = 69) Sex: 28% male, 72% female Age of participants, years: range between 12 and 65; average 38.1 ± 13.0 Unit of allocation: participant Country and setting: France, Romania, Argentina, Hungary; secondary care, hospital clinics and skin research clinics Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
(as a single once‐daily tablet) Duration of intervention: intermediate‐term (28 days) Length of follow‐up: 28 days |
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Outcomes | Timing of outcome assessment: 14 days and 28 days Primary outcomes of the trial
Secondary outcomes of the trial "All remaining variables," that is:
Clinician or participant report: clinician and participant |
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Notes | Study investigators concluded that over the 4‐week period, rupatadine 10 mg and 20 mg significantly reduced mean pruritus score compared with placebo | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation not stated |
Allocation concealment (selection bias) | Unclear risk | No methods of allocation concealment given in study report |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote (page 224): ''This was a phase II dose‐ranging, randomised, double‐blind, placebo‐controlled...'' No details given about method of blinding |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote (page 224): ''This was a phase II dose‐ranging, randomised, double‐blind, placebo‐controlled...'' No details given about method of blinding |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 244/283 completed study according to protocol 39 participants (14%); 25 (10 given placebo, 9 given 5 mg, 3 given 10 mg, 3 given 20 mg) withdrew because of lack of efficacy: 1 for adverse event, 2 for incorrect treatment allocation, 11 for other or personal reasons However, 6 participants were excluded from analysis without explanation (i.e. 283 randomly assigned); 277 were included in study ITT analysis |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Unclear risk | Funder: Uriach y Compania (Barcelona, Spain); National Scientific Research Program of the Spanish Minister of Science and Technology Unclear clinical meaning of primary outcome (0.5‐point drop in mean pruritus severity score) |
Finn 1999.
Methods | Design: double‐blind multi‐centre placebo‐controlled 5‐arm trial to evaluate efficacy and safety of 4 different doses of fexofenadine vs placebo Duration: 4 weeks |
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Participants | Number of participants randomly assigned: 476 from 35 centres Number in each group: placebo 78; 20 mg twice daily 81; 60 mg twice daily 79; 120 mg twice daily 86; 240 mg twice daily 80 Sex: 30% male, 70% female Ethnicity: 90% white, 4% black, 4% "Asian" and 2% multi‐racial Age of participants, years: 12 to 65 Unit of allocation: participants Country and setting: USA; setting research clinics Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration Single‐blind placebo run‐in for 24 hours
Twice a day for 4 weeks Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
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Outcomes | Timing of outcome assessments: unclear. Results based on at least 1 postbaseline 12‐hour reflective mean pruritus score (MPS) assessment Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and investigator |
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Notes | Study investigators concluded that fexofenadine HCl was well tolerated and statistically superior to placebo in treating CSU and in ameliorating interference with sleep and daily activities. They concluded that doses of 60 mg twice daily or greater were most effective | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation not described |
Allocation concealment (selection bias) | Unclear risk | No methods of allocation concealment given in the study report |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: ''...4 week double blind treatment period.'' Methods of blinding not described in the study report |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote: ''...4 week double blind treatment period.'' Methods of blinding not described in the study report |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 439/476 available for analyses (baseline scores and 1 postbaseline reflective MPS assessment). 103 (21.6%) lost to follow‐up. Issues with losses to follow‐up with participants involved in total discontinuation of treatment accounting for 21.6% Reasons for withdrawal:
Comment: Table 1 in the study report gives a full description of reasons for dropout by group; however as the level of dropout is high at 21.6%, it is unclear whether dropout was a significant source of bias in this study |
Selective reporting (reporting bias) | High risk | Only participants with baseline and at least 1 postbaseline mean pruritus score were included in analysis |
Other bias | Unclear risk | Groups comparable at baseline except significant differences in interference with daily activities at baseline Funder: Hoechst Marion Roussel |
Gale 1989.
Methods | Design: randomised double‐blind cross‐over 2‐arm study comparing the efficacy of acrivastine vs chlorpheniramine Duration: 24 days |
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Participants | Number of participants randomly assigned: 20 Sex: 55% male, 45% female Age of participants, years: mean 39.2 (range 18‐27) Unit of allocation: cross‐over (24 days) Country and setting: Australia; setting unclear Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
Three times daily for 24 days in this cross‐over study. No wash out period reported, but no participant self‐assessments reported in the first 3 days after cross‐over to eliminate carryover effects from previous therapies Duration of intervention: intermediate‐term (24 days) Length of follow‐up: 24 days |
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Outcomes | Timing of outcome assessment: after each 24‐day treatment period Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and investigator. Participants self‐assessed daily. Participant reviewed by physician after each 24‐day treatment period—physician recorded opinion on which treatment worked best and suited participant best overall |
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Notes | Study investigators concluded that both active drugs were effective, with no significant differences noted between them | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation not stated |
Allocation concealment (selection bias) | Unclear risk | Method of allocation concealment not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Study states that this is a double‐blind study; no methods of blinding given |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Method of blinding of outcome assessors not stated |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 4/20 participants excluded from analysis because of protocol violations (20% lost to follow‐up), with no ITT |
Selective reporting (reporting bias) | High risk | Incomplete reporting of data (only means given); no comment on adverse events |
Other bias | Unclear risk | Definition of disease given but CSU defined as > 4 weeks; however, no included participants had urticaria < 2 months Underpowered Funder: Wellcome Research Laboratories |
Garavaglia 1995.
Methods | Design: randomised double‐blind 6‐week study of cetirizine vs terfenadine vs placebo in CSU; parallel 3‐arm trial Duration: 6 weeks |
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Participants | Number of participants randomly assigned: n = 63 took part in the study; however as participants dropped out, they were replaced, so 47 are presented (number given cetirizine n = 17; terfenadine n = 16; placebo n = 14) Sex: cetirizine: 29.41% male, 70.59% female; terfenadine: 18.75% male, 69.23% female; placebo: 69.23% male, 30.77% female Age of participants, years: cetirizine 33.8 ± 13.8; terfenadine 35.88 ± 17.3; placebo 37.8 ± 16.45 Unit of allocation: participant Country and setting: Argentina; outpatient research clinic Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: 6 weeks |
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Outcomes | Timing of outcome assessment: 3 visits in total, initial at 3 weeks and final at 6 weeks from start of study Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician and participant |
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Notes | Study report written in Spanish Study investigators concluded that cetirizine is superior to terfenadine in terms of efficacy and tolerability; for symptom control, both active drugs were significantly better than placebo |
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Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | High risk | Quote (page 180): "Randomly divided (in threes) into three equal groups" However, if participants dropped out, they were replaced with new participants (14 did not take the medication, 35 did not return for assessment, 37 did not take the correct medication. All of these participants were replaced). As participants who dropped out were replaced with new participants, it is unclear whether the trial design is truly randomised; it is not clear whether new participants were randomly assigned de novo or were assigned to the group of the most recent dropout. The trial report states: "since the randomisation was performed on groups of 3, it was actually necessary for each loss of a patient [to result in resumed] treatment of three patients" (page 182) (page 186) "9 patients were replaced as three were withdrawn due to protocol violations (lost medication, did not attend tests, did not take correct medication). Therefore 9 new [participants] were recruited, as randomisation was [done] in threes" |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Tablets and dosages prepared to be identical (boxes of white round tablets), presented so that each drug or placebo was administered in a uniform way. A scratch‐off label would reveal the drug type in case of emergency |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Outcome assessors (clinicians and participants) would not have had indications of treatment group because of uniform packaging, but methods of blinding are not explicitly stated |
Incomplete outcome data (attrition bias) All outcomes | High risk | 47/63 completed. Dropped out: 3/17 in cetirizine; 3/16 in terfenadine; 9/14 placebo. 15 left the study because of inefficacy and were not replaced; they were "statistically computable" (page 186). It is unclear how results were computed for participants who dropped out because of inefficacy. Note: This may have introduced bias, as the study was possibly biased towards positive results Other reasons for dropout: adverse events: 2/17 in cetirizine; 2/16 in terfenadine due to adverse events No participant left the study because of intolerable adverse reactions |
Selective reporting (reporting bias) | High risk | Only results for the cetirizine and terfenadine arms of the study were included in the published report. No results were presented for the placebo arm The researcher was able to withdraw participants on the basis of his opinion |
Other bias | Unclear risk | Funder: not stated Analyses were not statistically significantly different and placebo results were not presented; therefore conclusions of the study as stated in the study report are unreliable |
Ghosh 1990.
Methods | Design: randomised controlled trial of doxepin 10 mg thrice daily vs pheniramine maleate 22.5 mg thrice daily Duration: 3 weeks |
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Participants | Number of participants randomly assigned: 56 Sex: 67% female in doxepin group, 60% female in pheniramine group Age of participants, years: 18 to 59 Unit of allocation: participant Duration of urticaria: 8 weeks to 4 years Country and setting: India; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
Length of follow‐up: 4 weeks (follow up extended 1 week after cessation of therapy) |
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Outcomes | Timing of outcome assessment: 3 weeks and 4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: both |
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Notes | Study investigators concluded that after 3 weeks of therapy, 8 (28.6%) participants in doxepin group and 3 (10.7%) in pheniramine group were symptom free (complete suppression) | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Participants non‐responsive to other antihistamine treatment excluded |
Allocation concealment (selection bias) | Unclear risk | Unclear allocation concealment |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Does not appear to be blinded: "twenty eight subjects were given doxepin 10 mg thrice weekly for 3 weeks"..."Another 28 subjects...were treated with pheniramine maleate 22.5 mg thrice weekly for 3 weeks" |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Does not appear to be blinded: "twenty eight subjects were given doxepin 10 mg thrice weekly for 3 weeks"..."Another 28 subjects...were treated with pheniramine maleate 22.5 mg thrice weekly for 3 weeks |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No dropouts apparent |
Selective reporting (reporting bias) | Unclear risk | Partial remission/improvement amongst participants is not defined or specific |
Other bias | Low risk | None detected. Funder: none |
Gimenez‐Arnau 2007.
Methods | Design: a randomised multi‐centre multi‐country double‐blind parallel‐group placebo‐controlled 3‐arm study of rupatadine at 2 different doses Duration: 6 weeks |
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Participants | Number of participants randomly assigned: 334 Sex: placebo: male 37.8%, female 62.2%; rupatadine 10 mg: 30% male, 70% female; rupatadine 20 mg: 26.9% male, 73.1% female Age of participants, years: mean (SD): placebo: 35.8 (13.4); rupatadine 10 mg: 40.2 (3.6); rupatadine 20 mg: 37.6 (14.6) Unit of allocation: participant Country and setting: Spain, Romania, Argentina, Poland, Germany, Italy; multi‐centre, research clinics Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
Once daily for 6 weeks Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: up to 6 weeks |
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Outcomes | Timing of outcome assessment: after 2, 4 and 6 weeks of treatment Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and investigator (patient daily diary cards) Adverse events: any adverse events; headache; somnolence; hypertension; "metrorrhagia" |
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Notes | Investigators conclude that rupatadine 10 mg is a fast long‐acting treatment with a better safety profile than rupatadine 20 mg. | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Quote: ''...according to a centralized computer‐generated randomisation code provided by the sponsor of the study'' Further information from the study investigator "The randomisation procedures were carried out at J. Uriach y Compañía, S.A. The Production Quality Management Department of J. Uriach y Compañía, S.A. drew up a randomisation list for the treatments. Afterwards, the Quality Assurance Unit of J. Uriach y Compañía S.A. randomly assigned a treatment to each code. Two copies of the randomisation code and two of the randomised list of patients were obtained" |
Allocation concealment (selection bias) | Low risk | Quote: "A duly closed and sealed copy of each document was kept in the Quality Assurance Unit and in the Production Quality Management Department of J. Uriach y Compañía S.A. A third closed and sealed copy randomised list was prepared for the CRO MDS PS Pharma Services. In addition, once the study was concluded, all the individual envelopes were returned to the monitor, who checked that none of them had been opened for an unjustified reason. After the lock of study database, the copy kept by the Quality Assurance Unit was opened and filed in the master file of the study" (further information obtained from study investigator) |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote from study: ''... double‐blind, placebo‐controlled... study..'' Further information from study investigator: "This was a double‐blind study so that neither the investigator nor the patient knew treatment assignation. To preserve double blinding, medication was packaged identically for both types of treatments, with identical outside appearance of the strips and boxes. Individual envelopes identified with the patient assignation number were prepared. Each one included the identity of the treatment assigned to each patient. These envelopes, duly closed and sealed, were submitted to the investigator" "All medication was given in a two tablets scheme, that is, the 10 mg dose was given in two (10 mg plus placebo) tablets, the 20 mg dose was given in two (10 mg plus 10 mg) tablets, and the placebo was given in two (placebo plus placebo) tablets" Further information from study investigator |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | ''... double‐blind, placebo‐controlled... study..'' Comment: as above |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No ITT; no actual scores given for DLQI, even at baseline 41/334 lost to follow‐up (12.2%) with 293 evaluable participants Reasons for withdrawal: rupatadine 10 mg: participant decision n = 4; loss to follow‐up n = 1; exclusion criteria n = 2; treatment failure n = 7; non‐attendance at scheduled visits n = 2; other n = 1 Rupatadine 20 mg: loss to follow up n = 1; exclusion criteria n = 3; treatment failure n = 4; lack of compliance n = 1 Placebo: participant decision n = 2; loss to follow‐up n = 1; serious adverse event n = 1; treatment failure n = 11 |
Selective reporting (reporting bias) | Low risk | SAF population stands for safety population (i.e. all randomly assigned participants who received any study drug). Figure 2 in the study report is done with the ITT population, as 5 patients did not present the efficacy variables; this is why the intention‐to‐treat analysis was performed in 329 participants In Figure 1, the number of participants completing the trial from the placebo group is 98, not 88 (as confirmed by study investigator) DLQI scores not stated in published report (percentages only) |
Other bias | Unclear risk | Funder: J Uriach y Compania, Spain |
Go 1989.
Methods | Design: double‐blind randomised 3‐arm RCT comparing cetirizine, terfenadine and placebo in a cross‐over study Duration: cross‐over study lasting for 6 weeks, subdivided into 3 periods of 2 weeks |
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Participants | Number of participants randomly assigned: 30 Sex: not stated Age of participants, years: 15 to 69 (mean 48.8), but included at least 1 participant ineligible by age according to exclusion criteria Unit of allocation: cross‐over Country and setting: Netherlands, Belgium; setting not stated Inclusion criteria of the trial
Exclusion criteria of the trial
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|
Interventions |
Interventions, dose, duration
No washout between treatments Participants could elect to finish particular treatment before 2 weeks was up and to move to next treatment in sequence Duration of intervention: short‐term (2 weeks per intervention) Length of follow‐up: 6 weeks (i.e. follow‐up extended beyond cessation of therapy) |
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Outcomes | Timing of outcome assessment: at 2 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: both |
|
Notes | Study investigators concluded as follows: By investigator measures, cetirizine significantly was better than placebo in all outcomes; terfenadine findings were only borderline or were not significant By participant measures, both drugs were equally (and statistically) superior to placebo |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation not stated |
Allocation concealment (selection bias) | Unclear risk | No allocation concealment methods described |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Study states that it was double‐blind Quote: ‘products were given as identical capsules bid, with placebo as the morning intake in the cetirizine sequence’ |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Study states that it was double‐blind. Unclear how outcome assessors were blinded |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 2/30 were excluded after placebo sequence (refusal to participate) (6%) Serious adverse events were unclear for all 3 treatments 10/30 early withdrawals from treatment: inefficacy in placebo group n = 3; adverse events: cetirizine n = 1; placebo n = 1; terfenadine n = 3; unspecified reason: placebo: n = 2. No ITT (although low dropout rate) |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported. Mixed dichotomous and continuous outcome reporting |
Other bias | Unclear risk | Funder: UCB (makers of cetirizine) |
Godse 2007.
Methods | Design: randomised double‐blind placebo‐controlled parallel multi‐centre study comparing efficacy of fexofenadine and levocetirizine Duration: up to 1 month |
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Participants | Number of participants: 40 (20 in each group) Sex: 50% male, 50% female Age of participants, years: 14 to 70 Unit of allocation: participant Country and setting: India; setting hospital clinic Inclusion criteria of the trial
Exclusion criteria of the trial
|
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Interventions |
Interventions, dose, duration
For relief of symptoms up to 1 month Duration of intervention: intermediate‐term (up to 1 month) Length of follow‐up: up to 4 weeks |
|
Outcomes | Timing of outcome assessment: 2 week and 4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician |
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Notes | Study investigators concluded that fexofenadine was superior to levocetirizine | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Quote: ''All participants were divided into two groups,'' described as randomised but no details given |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not stated |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not stated |
Incomplete outcome data (attrition bias) All outcomes | High risk | 2/20 participants in levocetirizine group were lost to follow‐up (no reasons given) and were replaced by 2 new participants. No ITT |
Selective reporting (reporting bias) | High risk | Small study; no raw data; means and SDs of scores only; results not expressed as participant numbers. States placebo controlled, but no placebo results reported |
Other bias | Unclear risk | Sponsor: Sanofi‐Aventis and Systopic Laboratories (provided drugs) |
Goh 1991.
Methods | Design: cross‐over study comparing cetirizine with placebo Duration: 1 week |
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Participants | Number of participants randomly assigned: 32 Sex: 50% female Age of participants, years: range 18 to 46 (mean 30.4 ± 8.2) Unit of allocation: cross‐over Country and setting: Singapore; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Length of follow‐up: 1 week Duration of intervention: short‐term (1 week per intervention) |
|
Outcomes | Timing of outcome assessment: 1 week Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: both |
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Notes | Study investigators concluded that cetirizine yielded significantly better scores than placebo on physician and participant VAS and in participant diaries for itch and weals | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation not stated |
Allocation concealment (selection bias) | High risk | No allocation concealment |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Probably done |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Investigators’ assessment of severity on VAS |
Incomplete outcome data (attrition bias) All outcomes | High risk | No ITT. No mention of serious adverse events or dropouts due to them. 4 participants (12.5%) lost to follow‐up |
Selective reporting (reporting bias) | High risk | Results derived from visual analogue scales; not stated whether groups were comparable at baseline |
Other bias | Unclear risk | Funder: none No washout between treatments, but no sequential effect shown |
Grant 1988.
Methods | Design: double‐blind multi‐centre 3‐arm trial of terfenadine, chlorpheniramine and placebo Duration: 6 weeks |
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Participants | Number of participants randomly assigned: 136 Age group and gender: not stated Unit of allocation: participant Country and setting: USA; setting recruited from medical practices of principal investigators at 10 university research clinics (assumed that the practices were the settings) Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration Participants entered a single‐blind placebo period for a week, and if hives of moderate severity were present for 3 days during the week, participants were assigned to
Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: up to 6 weeks |
|
Outcomes | Timing of outcome assessment: weekly for 6 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigators and participants |
|
Notes | Study investigators concluded that chlorpheniramine was not statistically significantly different from placebo | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation: Quote (page 575): ''participants were randomly assigned to one of three groups of equal size...'' |
Allocation concealment (selection bias) | Unclear risk | Allocation concealment not described |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Method of blinding unclear: Quote (page 575): ''Acceptable participants entered the first phase of the study and were administered placebo in a single‐blind fashion for a week. Those who developed moderately severe hives for at least 3 days that were actually observed by the investigators were then enrolled in the double‐blind phase'' Also, unclear if blinding adequate: quote: "In order to limit the number of drop‐outs, diphenhydramine 25mg capsules were offered as relief medication" |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear method of blinding outcome assessors |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 122/136 who were randomly assigned completed the study (of an undisclosed number, 'more than half' were initially screened but excluded) 14 (10.2%) were lost to follow‐up Withdrawals due only to treatment failure: terfenadine n = 1; chlorpheniramine n = 4; placebo n = 9. Unbalanced between groups but unlikely to introduce bias |
Selective reporting (reporting bias) | High risk | Results presented graphically only, no participant numbers or means with SD |
Other bias | Unclear risk | Participants allowed a different antihistamine if uncontrolled: 22/42 (52%) of placebo group took diphenhydramine; 12/46 (26%) of chlorpheniramine group and 4/46 (9%) of terfenadine group already a subgroup, as participants unresponsive to antihistamines were excluded Funder: none stated |
Gu 2002.
Methods | Design: multi‐centre (4 centres) randomised double‐blind parallel 2‐arm study of desloratadine vs loratadine Duration: 28 days |
|
Participants | Number of participants randomly assigned: 158 Sex: male 45%, female 64% Age of participants, years: 18 to 65, desloratadine mean 38.6; loratadine mean 39.1 Unit of allocation: participant Country and setting: China; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
Duration of disease in desloratadine group 26.9 weeks; loratadine group 26.1 weeks Groups comparable at baseline with t value and P value in Chart 2 |
|
Interventions |
Interventions, dose, duration
Duration of intervention: 28 days (intermediate) Length of follow‐up: seen before treatment, at 14 days, at 28 days Concomitant/rescue treatment: not mentioned |
|
Outcomes | Timing of outcome assessment: 14 days and 28 days Primary outcomes of the trial
Secondary outcomes of the trial
Timing of outcome assessment: seen before treatment, at 14 days and at 28 days Clinician or participant report: clinician and participant |
|
Notes | Study investigators concluded that desloratadine is safe and effective in the treatment of CSU. No significant differences between the 2 groups, no serious adverse events. Desloratadine safe and effective Main study report in Chinese |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Stated to be randomised |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Participants and personnel were blinded to treatment group Not mentioned clearly |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Outcome assessors were blinded to treatment group Not mentioned clearly |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear, no details about dropout in translation of published report. ITT analysis carried out: unclear |
Selective reporting (reporting bias) | Unclear risk | All prespecified outcomes were reported, but reporting of adverse events is unclear. Severity of adverse advents and whether or not these were likely to have been caused by trial medication were specified as an outcome, but reported results are unclear and state only that no serious adverse events occurred |
Other bias | Unclear risk | Funder: not stated Assessment of compliance undertaken but not clearly stated, apart from exclusion criteria |
Guo 2003.
Methods | Design: randomised double‐blind parallel‐group comparison of mizolastine vs loratadine Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 47; n = 24 mizolastine, n = 23 loratadine Sex: 36% male, 55% female Age of participants, years: 17 to 53, mizolastine mean 34.9; loratadine mean 33.0 Unit of allocation: participant Country and setting: China; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
|
Outcomes | Timing of outcome assessment: 7, 14 and 28 days Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician and participant |
|
Notes | Study investigators concluded that no difference in side effects was found between the 2 groups. Findings indicated that the effect of mizolastine was much better than that of loratadine, and it could be selected as the priority treatment for CSU Main study reported in Chinese |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Double‐blind randomisation stated. Quote (page 482): "divided into two groups by randomised method" |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote (page 482): "double‐blind," but no further details given |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote (page 482): "double‐blind," but no further details given |
Incomplete outcome data (attrition bias) All outcomes | High risk | Stated 47 cases, but analyses include 23 in each group; data analysis was based on 46 cases; no reason given for this dropout |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Low risk | None detected Funder: not stated |
Handa 2004.
Methods | Design: randomised 2‐arm double‐blind study of cetirizine vs fexofenadine Duration: 28 days |
|
Participants | Number of participants randomly assigned: 116; n = 59 cetirizine; n = 57 fexofenadine Sex: not stated Age of participants, years: range of 17 to 65 Unit of allocation: participant Country and setting: India; dermatology institute clinic Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (28 days) Length of follow‐up: 28 days |
|
Outcomes | Timing of outcome assessment: days 14 and 28 Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and investigator |
|
Notes | Study investigators concluded that cetirizine seemed to have therapeutic advantage over fexofenadine | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Method of randomisation not stated, described as randomised. Further information from study investigator states: "For the study we generated a randomisation list using a random number table" |
Allocation concealment (selection bias) | Low risk | Study investigator states: "The code was kept with the central authority—not directly involved with the study and assessment of endpoints. Both the investigators and patients were blinded since the central authority provided the patients with similar looking sealed envelopes containing the medication and labelled only as A or B" |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Study investigator states: "Both the investigators and patients were blinded since the central authority provided the patients with similar looking sealed envelopes containing the medication and labelled only as A or B. The blinding was opened after assessing the results and the statistical analysis of the two groups A and B. It was done by inquiring from the central authority which was dispensing the drugs to the patient" |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | Study investigator states: "Both the investigators and patients were blinded since the central authority provided the patients with similar looking sealed envelopes containing the medication and labelled only as A or B. The blinding was opened after assessing the results and the statistical analysis of the two groups A and B. It was done by inquiring from the central authority which was dispensing the drugs to the patient" |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | High dropout rate, no ITT (no ITT confirmed by study investigator); 19/116 lost to follow‐up in total (13%): 7 in cetirizine group and 12 in fexofenadine group within 2 weeks, ''the most common reason being treatment failure.'' Unclear if this contributes to bias |
Selective reporting (reporting bias) | Unclear risk | All prespecified outcomes were reported, but other outcomes were reported as well (e.g. duration of weals, diurnal variation, intensity of itching, presence of weals). Symptoms during the day were not reported by groups |
Other bias | Low risk | Funder: not stated. No indication of comparability of groups at baseline |
Hao 2003.
Methods | Design: randomised multi‐centre double‐blind 2‐arm parallel‐group comparison of desloratadine vs loratadine Duration: 28 days |
|
Participants | Number of participants randomly assigned: 217; desloratadine n = 108; loratadine n = 109 Sex: male 43.8%, female 56.2% Age of participants, years: 18 to 65 Unit of allocation: participant Country and setting: China, secondary care, Southern Hospital, 3rd Military Medical University. Chongqing, China Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (28 days) Length of follow‐up: 28 days |
|
Outcomes | Timing of outcome assessment: 7, 14 and 28 days Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician and participant |
|
Notes | Main study report in Chinese Study investigators concluded that desloratadine is an effective and safe agent for CSU |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Stated to be randomised |
Allocation concealment (selection bias) | Unclear risk | No details given |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Stated to be double‐blind, no further details given about blinding |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Stated to be double‐blind, no further details given about blinding |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 3/105 dropped out or were lost from the desloratadine group; 3/106 dropped out or were lost from the loratadine group; no reasons given |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Low risk | None detected. Funder: not stated |
Harvey 1981.
Methods | Design: double‐blind randomised cross‐over study in which participants were treated sequentially (5‐arm comparison of hydroxyzine plus placebo, hydroxyzine plus terbutaline, hydroxyzine plus chlorpheniramine, hydroxyzine plus cimetidine) Duration: 7 to 10 days |
|
Participants | Number of participants randomly assigned: 23 Sex: 79% female Age of participants, years: mean 37 (range 24‐64) Unit of allocation: cross‐over participants Country and setting: USA; setting University of Colorado Health Sciences Center Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration Cross‐over study in which participants were treated sequentially with 5 regimens in double‐blind random sequence
Duration of intervention: short‐term (7‐10 days each intervention) Length of follow‐up: unclear |
|
Outcomes | Timing of outcome assessment: 7 to 10 days Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and investigator |
|
Notes | Study investigators concluded that hydroxyzine plus cimetidine was significantly better than other combinations. Hydroxyzine had transient soporific effects but was well tolerated. Unclear whether soporific effects were due to hydroxyzine and not to one of the other sedating antihistamines | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation not stated: ''participants were treated orally in a double‐blind randomised serial fashion...'' |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | ''participants were treated orally in a double‐blind randomised serial fashion...'' Method of blinding unclear |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | ''participants were treated orally in a double‐blind randomised serial fashion...'' Method of blinding unclear |
Incomplete outcome data (attrition bias) All outcomes | High risk | 19/23 completed. 4 removed because of non‐compliance (17% lost to follow‐up). One participant not accounted for Extreme tremulousness (n = 2) in terbutaline necessitated "abbreviated treatment course” ITT unclear (some terbutaline participants did not complete the course, but non‐compliant participants were excluded from analysis) |
Selective reporting (reporting bias) | High risk | Adverse events not clearly reported |
Other bias | Unclear risk | Funder: NIH Allergic Disease Center Grants Study duration not clearly defined (''7‐10 days'') No stated exclusions, and physical urticaria may have been included. Two groups were given a combination of 2 first‐generation antihistamines; concomitant treatment with hydroxyzine allowed in all groups |
Hjorth 1988.
Methods | Design: double‐blind randomised 2‐arm cross‐over study of terfenadine vs clemastine Study 1: clemastine vs placebo Study 2: terfenadine vs placebo Duration: 2 weeks |
|
Participants | Number of participants randomly assigned: 60; 30 per group in each cross‐over phase Sex: 33% male, 67% female Age of participants, years: 18‐72 (mean 37) Unit of allocation: cross‐over, no washout period described Country and setting: Denmark; setting unclear Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: short‐term (2 weeks per intervention) Length of follow‐up: 14 days |
|
Outcomes | Timing of outcome assessment: 14 days Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and clinician |
|
Notes | Study author concluded that terfenadine was more efficacious than clemastine or placebo No review outcomes |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | "in random order, participants were assigned...''; no further details given |
Allocation concealment (selection bias) | Unclear risk | Unclear, no details given |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Study is stated to be double‐blind; unclear how this was achieved |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Study is stated to be double‐blind; unclear how this was achieved, as only 1 study author/single investigator was involved |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Number of participants who dropped out from each group not stated. Withdrawals not mentioned |
Selective reporting (reporting bias) | High risk | Results incompletely reported, no numerical data (graphs only); able to rate efficacy only according to number of weals, as symptom score used in results was not defined |
Other bias | Unclear risk | Funder: not stated Diagnosis of CSU not clearly defined; unclear whether concomitant medications allowed; single study author |
Hoxha 2011.
Methods | Design: double‐blind randomised controlled 3‐arm study comparing levocetirizine vs desloratadine vs placebo Duration: not stated |
|
Participants | Number of participants randomly assigned: 107; levocetirizine group: 37; desloratadine group: 34; placebo: 36 Sex: not stated Age of participants, years: 18 to 60 Unit of allocation: participant Country and setting: Albania; tertiary centre Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
(each increasing weekly to 10 mg, then 20 mg) Duration of intervention: unclear Length of follow‐up: not stated |
|
Outcomes |
Primary outcomes of the trial
|
|
Notes | Study investigators concluded that Increasing the dosage of levocetirizine and desloratadine up to 4‐fold improved chronic urticaria symptoms without compromising safety | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Study states randomly assigned, but not clear how done |
Allocation concealment (selection bias) | Unclear risk | Not specified |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Study says double–blind but no other details |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not stated |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | All participants accounted for, but 9 from active arms left the study (reason not stated), and all participants from placebo arm (36) dropped out from the study |
Selective reporting (reporting bias) | Unclear risk | No timing of assessment stated |
Other bias | Unclear risk | Funder: not specified This study was available as a short conference abstract only; we were unable to identify a published report or to obtain further information from the study investigator |
Juhlin 1987.
Methods | Design: randomised double‐blind 3‐arm cross‐over placebo‐controlled study of acrivastine and clemastine Duration: 5 days each cross‐over period |
|
Participants | Number of participants randomly assigned: 18 Sex: 33% male, 67% female Age of participants, years: 14 to 75 (mean 43.2) Unit of allocation: cross‐over Country and setting: UK; setting unclear Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Cycle through each regimen with 2‐day breaks in between with no relevant treatment Duration of intervention: short‐term (5 days per intervention) Length of follow‐up: unclear (at end of each 5‐day treatment period?) |
|
Outcomes | Timing of outcome assessment: 5 days Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator and participant questionnaire |
|
Notes | Study investigators concluded no significant differences in efficacy were noted between acrivastine and clemastine; both were significantly preferred by participants over placebo | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Described as randomised, but randomisation method was unclear |
Allocation concealment (selection bias) | Unclear risk | No allocation concealment described |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | ''A double‐blind, placebo‐controlled study.'' Mentioned only in title; no other details given |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | ''A double‐blind, placebo‐controlled study.'' Mentioned only in title; no other details given |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 18/18 completed. None lost to follow‐up |
Selective reporting (reporting bias) | High risk | Although both doctor questionnaire and participant self‐assessment were carried out, only simple participant perceptions reported; no objective data provided |
Other bias | Unclear risk | Funder: Sponsorship: Wellcome Foundation Ltd No mention of whether concomitant treatments were permitted Underpowered |
Juhlin 1991.
Methods | Design: randomised double‐blind cross‐over 3‐arm trial comparing 10 or 20 mg cetirizine vs placebo Duration: 15 days |
|
Participants | Number of participants randomly assigned: 30 Sex: 27% male, 63% female Age of participants, years: range 15 to 70 (mean 43) Unit of allocation: cross‐over Country and setting: Sweden; setting unclear Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
After 15 days, participants were allowed to cross over with no washout period. Non‐responders were allowed to increase to twice‐daily dosing Duration of intervention: short‐term (15 days) Length of follow‐up: end of each 15‐day treatment period |
|
Outcomes | Timing of outcome assessment: 15 days. Visits at baseline and at end of each treatment phase Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant |
|
Notes | Study investigators concluded that cetirizine was significantly more effective than placebo in reducing incidence of erythema, weals and pruritus Study 2 in the published report was a laboratory study on the effects of certain agonists; the results were not included in this analysis |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Unclear method of randomisation. Participants 'randomly assigned' |
Allocation concealment (selection bias) | Unclear risk | Unclear. Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double‐blind study. Unclear how this was done |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Double‐blind study. Unclear how this was done |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Number of participants who dropped out from the study (if any) unclear |
Selective reporting (reporting bias) | High risk | Extensive laboratory tests were carried out (for adverse effects) but were not reported. Measures of incidence and severity of weals were reported |
Other bias | Low risk | None detected. Funder: not stated |
Kalivas 1990.
Methods | Design: randomised multi‐centre parallel‐group 3‐arm double‐blind placebo‐controlled study of cetirizine vs hydroxyzine vs placebo Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 219; cetirizine: 69, hydroxyzine: 69, placebo: 73 Sex: not stated Age of participants, years: 12+, no further details Unit of allocation: participant Country and setting: USA; centres included medical and science centres and private practice Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Intermediate dose of cetirizine not stated Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
|
Outcomes | Timing of outcome assessment: baseline, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant |
|
Notes | Investigator concludes that cetirizine and hydroxyzine have equivalent efficacy, and both are superior to placebo; no significant differences in adverse effects were noted, except for somnolence and nausea; no significant differences between cetirizine and placebo were observed in terms of somnolence | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Participants "randomly assigned"; quote (page 1015), no further information |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | High risk | Stated to be double‐blinded but unclear how this was achieved; in addition, participants and personnel do not appear blinded Quote (page 1015): ''All patients receiving active drugs began by taking the lowest daily dose... The dose was titrated up as necessary in two steps to respective allowable maximums..." |
Blinding of outcome assessment (detection bias) All outcomes | High risk | Stated to be double‐blinded but unclear how this was achieved; in addition, participants and personnel do not appear blinded Quote (page 1015): ''All patients receiving active drugs began by taking the lowest daily dose... The dose was titrated up as necessary in two steps to respective allowable maximums..." |
Incomplete outcome data (attrition bias) All outcomes | High risk | Losses to follow‐up not clearly described 31/219 randomly assigned lost to follow‐up (14%) Each table provides different numbers of included participants; not clear why and when participants were lost to follow‐up; study authors note in discussion that 10% of cetirizine group, 7% of hydroxyzine group and 24% of placebo group withdrew because of lack of efficacy Adverse events (serious adverse events requiring treatment withdrawal):
|
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Low risk | None detected. Funder: not stated |
Kaplan 2005.
Methods | Design: multi‐centre randomised double‐blind parallel‐group placebo‐controlled 2‐arm study of fexofenadine vs placebo Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 259 Sex: 26% male, 74% female Age of participants, years: 247 younger than 65; 8 older than 65 Unit of allocation: participant Country and setting: US; setting secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Single‐blind placebo run‐in phase for 2 to 5 days At next visit, participants had to qualify for entry into randomised portion of study, then were randomly assigned 2:1 to fexofenadine:placebo Duration of intervention: intermediate‐term (28 days) Length of follow‐up: 4 weeks |
|
Outcomes | Timing of outcome assessment: seen weekly for 4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
|
|
Notes | Same study as Spector 2007 Study investigators concluded that fexofenadine at 180 mg once daily offered effective well‐tolerated relief of the symptoms of urticaria |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Quote (page 662): ''Randomisation in a 2:1 manner to receive either fexofenadine hydrochloride,180mg, or placebo once daily'' |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Study stated as double‐blind. Initial single‐blind run‐in with placebo for 2 to 5 days Quote (page 663): "Patients received double blind study medications packaged in bottles with 40 tablets" (enough for course of treatment) Comment: probably done |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | Study stated as double‐blind. Initial single‐blind run‐in with placebo for 2 to 5 days. Participants received study medication in bottles with 40 tablets (enough for course of treatment) Comment: probably done, but unclear how outcome assessors were blinded |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Did not include participants lacking postbaseline result. Unclear how many dropped out at each time point along with reasons for dropout Losses to follow‐up of 259 randomly assigned: fexofenadine 12/167 (7%); 13/92 (14%): 7% dropped out of fexofenadine group, 14% from placebo group (lack of efficacy) Adverse events: Most common reason for loss to follow‐up was lack of efficacy (6 of 13 from placebo group, and 1 of 12 from fexofenadine group). Other reasons not stated Asthma requiring hospitalisation: n = 1 in fexofenadine group; headache occurred in 5% of fexofenadine group and 3% of placebo group; not stated whether any of these required treatment withdrawal Numbers of participants in each study were very unclear at each time point |
Selective reporting (reporting bias) | High risk | Study authors combined unadjusted mean DLQI scores from 2 weeks and 4 weeks |
Other bias | Unclear risk | Funder: Aventis Inc (Sanofi‐Aventis Group) |
Kint 1989.
Methods | Design: double‐blind randomised multiple (3)‐arm cross‐over study comparing cetirizine, terfenadine and placebo Duration: 6 weeks |
|
Participants | Number of participants randomly assigned: 30 in sequence Sex: 44% male, 56% female Age of participants, years: 41.2 ± 14.7 (range 21‐74) Country and setting: Belgium; secondary care Unit of allocation: cross‐over Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Unclear which treatments were compared at each phase Duration of intervention: short‐term (2 weeks) Length of follow‐up: 2 weeks (for each phase) No washout between treatments; if intolerable, symptoms due to lack of response could progress early to next in sequence (after clinic visit). Seen at each change in treatment 5 instances of rescue medications used in placebo group only (antihistamines n = 4, dexamethasone n = 1) (against protocol) |
|
Outcomes | Timing of outcome assessment: end of weeks 1 and 3 at each phase Primary outcomes of the trial
Secondary outcomes of the trial
|
|
Notes | Study investigators concluded that no significant differences in efficacy were found between the 2 active treatments; both were better than placebo | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | ''Random sequence''; multiple sequence defined by Latin square design |
Allocation concealment (selection bias) | Unclear risk | Unclear, no apparent allocation concealment |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical capsules |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear how outcome assessors were blinded to treatment allocation |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 3/30 participants lost to follow‐up (10%). 2 dropouts due to lack of efficacy during first sequence (cetirizine n = 1 and terfenadine n = 1); 1 dropout in second sequence for same (cetirizine) |
Selective reporting (reporting bias) | High risk | Results not clearly reported; placebo sequence had rescue medication. Study investigators conclude... ''thus only for wheals were borderline or significant differences from placebo recorded by investigator'' 5 instances of rescue medication used in placebo group only (antihistamines n = 4, dexamethasone n = 1) (against protocol) |
Other bias | Unclear risk | Funder: UCB Braine‐L’Alleud |
Leyh 1989.
Methods | Design: randomised double‐blind 4‐arm cross‐over study to investigate efficacy of acrivastine at 2 doses vs clemastine and placebo Duration: 5 days in each arm |
|
Participants | Number of participants randomly assigned: 20 Sex: 60% female Age of participants, years: 18 to 72 (mean 41.3) Country and setting: Lubeck; secondary care Unit of allocation: cross‐over Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Unclear which treatments were compared at each phase 3‐day washout initially, then 2‐day break between treatments Duration of intervention: short‐term (5 days per intervention) Length of follow‐up: 5 days |
|
Outcomes | Timing of outcome assessment: 5 days Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator and participant (self‐assessment form) |
|
Notes | Study investigators concluded that assessment showed all 3 active drugs were better than placebo; no statistically significantly difference was noted between them | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation not stated |
Allocation concealment (selection bias) | Unclear risk | Unclear |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Study stated to be double‐blind, but no details given |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear if blinded. As investigators appear to have made subjective decision on best treatment, it is possible that they were not blinded to treatment allocation |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Only 20 participants; no dropouts; no serious adverse events noted. Raw figures not shown (means only) |
Selective reporting (reporting bias) | Unclear risk | Incomplete reporting of data (mean scores only, without SD of self‐assessment for wealing, itching and overall discomfort). Percentage scores of physician assessment and overall improvement |
Other bias | Unclear risk | Funder: Wellcome Research Laboratories |
Leynadier 2000.
Methods | Design: randomised double‐blind parallel‐group 2‐arm study of mizolastine vs loratadine Duration: 28 days |
|
Participants | Number of participants randomly assigned: 61 Sex: 64% male, 46% female Age of participants, years: 40 ± 13 Country and setting: France; secondary care Unit of allocation: participant Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Not stated whether this was with placebo (although placebo seems likely) Duration of intervention: short‐term (28 days) Length of follow‐up: 4 weeks |
|
Outcomes | Timing of outcome assessment: 4 visits in total: at screening (day 3 or 7), at inclusion (day 10), after 14 and 28 days of treatment Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator and participant |
|
Notes | Study investigators concluded that no statistically significant differences in efficacy were found between drugs, as measured by number of urticarial episodes and discomfort from symptoms; duration of episodes shorter with mizolastine (not statistically significant) | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | ''Patients were randomly allocated...''; no details given about method of randomisation |
Allocation concealment (selection bias) | Unclear risk | Allocation concealment not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double‐blind study. Unclear how blinding was achieved |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Double‐blind study. Unclear how blinding was achieved |
Incomplete outcome data (attrition bias) All outcomes | High risk | Number of participants completing the study and evaluable does not match corresponding information given about non‐completers 7/61 lost to follow‐up (11%): mizolastine group: 3/26, loratadine group: 4/35 Withdrawals: adverse events: serious leading to withdrawal: mizolastine: painful erythema of hands n = 1 Minor events: mizolastine: fatigue n = 2; drowsiness n = 1; loratadine: drowsiness n = 1; dizziness n = 1; rhinitis n = 1 A figure of n = 56 is given as the number of evaluable participants in the published report, but after withdrawals and losses to follow‐up, the number of participants remaining in the trial is 54 |
Selective reporting (reporting bias) | Unclear risk | All outcomes reported but presented only as number of participants free of symptoms, which decreased significantly in both groups (numbers not given; results expressed graphically and related to number of participants free of individual symptom (e.g. pruritus), but not possible to tell how many participants were symptom‐free overall |
Other bias | Unclear risk | Number of participants free of symptoms decreased significantly in both groups, but numbers not given; figures given relate to numbers of participants free of individual symptom (e.g. pruritus), but not possible to tell how many participants were symptom‐free overall Funder: none |
Liu 2003.
Methods | Design: 5‐centre double‐blind parallel‐group randomised trial of mizolastine vs loratadine | |
Participants | Number of participants randomly assigned: 213 enrolled: 104 mizolastine, 102 loratadine, 206 completed the trial Sex: mizolastine: male 46 (42.6%), female 62 (57.4%); loratadine: male 50 (47.6%), female 55 (52.4%) Age of participants, years: mizolastine 39.32; loratadine 37.9 Unit of allocation: participant Country and setting: Beijing, China; multi‐centre secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (28 days) Length of follow‐up: 28 days |
|
Outcomes | Timing of outcome assessment: 7, 14, 28 days Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and clinician. Outcomes reported by clinician apart from VAS score (participant rated severity of itch by visual analogue scale) |
|
Notes | Study investigators concluded that mizolastine is quicker in action than loratadine, with similar efficacy. The incidence of adverse effects is similar in the 2 groups Main study report is written in Chinese |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Quote (page 306): "randomly divided" |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote (page 306): "double blind" |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote (page 306): "double blind" |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 206/213 completed, but study stated that 12 participants dropped out; it is unclear if they dropped out from the number enrolled or the number completing |
Selective reporting (reporting bias) | Unclear risk | All prespecified outcomes were reported |
Other bias | Low risk | None detected. Funder: not stated |
Liu H‐N 1990.
Methods | Design: double‐blind 2‐arm cross‐over trial comparing nifedipine (calcium channel blocker) with chlorpheniramine Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 22 Sex: 13% male, 27% female Age of participants, years: 36 (range 21‐54) Unit of allocation: cross‐over Country and setting: Taiwan; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration Washout of at least 12 hours, then randomised:
Participants had one or another active drug, then 2 days of placebo, then the other active drug; all capsules identical in appearance Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
|
Outcomes | Timing of outcome assessment: unclear (daily scores) Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator and participant |
|
Notes | Study investigators concluded that nifedipine not a first‐line drug for chronic urticaria, and that it is helpful for only some selected patients | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Randomisation method unclear |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double‐blind study. All medication in capsules and identical in appearance; participants blinded. Probably done but no details given |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Double‐blind study. All medication in capsules and identical in appearance; participants blinded. Probably done but no details given |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 18/22 participants completed the study (18% lost to follow‐up): n = 3 military personnel posted elsewhere, n = 1 severe nausea on nifedipine ×1 Minor adverse events: nifedipine: n = 3 dizziness, n = 1 drowsiness, n = 2 mild hypotension Comment: Substantial losses to follow‐up may have introduced a source of bias to the study. No ITT |
Selective reporting (reporting bias) | High risk | Duration of follow‐up not clearly defined Unclear whether concomitant medications were permitted or whether participants were compliant Blood pressure results not reported in full, only in terms of adverse events |
Other bias | Unclear risk | Underpowered Funder: none |
Locci 1991.
Methods | Design: topical treatment of urticaria; randomised controlled 2‐arm study of oxatomide gel vs dechlorpheniramine cream Duration:15 days |
|
Participants | Number of participants randomly assigned: 27; 12 in oxatomide group and 15 in dechlorpheniramine group Sex: 50% female oxatomide group, 33% female dechlorpheniramine group Age of participants, years: oxatomide group: mean 39.6 ± 5.2; dechlorpheniramine group: mean 38.3 ± 2.6 Country and setting: Italy; secondary care Unit of allocation: participant Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: short‐term (15 days) Length of follow‐up: 15 days |
|
Outcomes | Timing of outcome assessment: 15 days Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician and participant |
|
Notes | Study investigators concluded that similar statistically significant improvements were observed in erythema and number of weals. Study authors concluded that both treatments worked | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Quote: ''According to a controlled experimental design completely randomised between patients, half were treated with oxatomide (O) and half with dechlorpheniramine (D)''; no details about method of randomisation |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | High risk | No blinding described Comment: open to bias as 2 different formulations (gel and cream preparations) |
Blinding of outcome assessment (detection bias) All outcomes | High risk | No blinding described Comment: open to bias as 2 different formulations (gel and cream preparations) |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No ITT; 2/27 (13%) lost to follow‐up (did not attend) in dechlorpheniramine group (2/15). No reasons given Comment: unclear whether this degree of loss to follow‐up in a small study introduced a source of bias |
Selective reporting (reporting bias) | Unclear risk | All outcomes reported but presented graphically; improvement in symptoms expressed as percentage (change in mean score and SD), not by participant number Included some participants with localised urticaria. No measurement of actual dose applied Comment: unclear |
Other bias | Low risk | None detected. Funder: not stated |
Maiti 2011.
Methods | Design: randomised single‐blinded single‐centred parallel‐group 2‐arm trial comparing rupatadine with levocetirizine Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 70 (rupatadine n = 35; levocetirizine n = 35) Sex: rupatadine group: male 15 (43%), female 20 (57% ); levocetirizine group: male 16 (45%), female 19 (60%) Age of participants, years: 12 to 60 Unit of allocation: participant Country and setting: India; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
|
Outcomes | Timing of outcome assessment: 4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: both |
|
Notes | Study investigators concluded that the incidence of adverse drug reactions was found to be less in the rupatadine group. Rupatadine is a better choice in CSU in comparison with levocetirizine because of a better efficacy and safety profile | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Not stated |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Unclear which group was blinded |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear which group was blinded |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 54/70 completed (10 did not report for follow‐up, 6 were non‐compliant). No participant stopped treatment because of adverse effects |
Selective reporting (reporting bias) | Unclear risk | All prespecified outcomes were reported |
Other bias | Low risk | None detected. Funder: not stated |
Makino 2012.
Methods | Design: randomised 3‐arm open study Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 97 (olopatadine 10 mg group 35; olopatadine 5 mg group 30; no medication group 32) Sex: olopatadine 10 mg group: male 31.4%, female 68.6%; olopatadine 5 mg group: male 16.7%, female 83.3%; no medication group: male 28.1%, female 71.9% Age of participants, years (mean): olopatadine 10 mg group 55.2 ± 14.9; olopatadine 5 mg group 55.0 ± 13.5; no medication group 59.1 ± 15.1 Unit of allocation: participant Washout period: none, but run‐in phase of 4 to 6 weeks with all participants receiving 10 mg olopatadine; no cross‐over Country and setting: Japan; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
At least moderate to severe disease Duration of disease greater than 6 weeks |
|
Interventions |
Interventions, dose, duration All participants with CSU with a VAS itch score higher than 50 were treated with 10 mg olopatadine hydrochloride daily for 4 to 6 weeks. Of these, participants having a VAS itch score less than 20 were randomly allocated to 1 of 2 groups:
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks Concomitant/rescue treatment not permitted |
|
Outcomes | Timing of outcome assessment: Efficacy end point was defined as length of time the VAS itch score remained less than 50 with no additional treatment and ongoing up to 4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician |
|
Notes | Study investigators concluded that both 10 mg olopatadine and 5 mg olopatadine were effective and were better than no treatment but were not significantly different from each other | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Randomised, but no details |
Allocation concealment (selection bias) | High risk | Allocation not apparently concealed, as the trial was open |
Blinding of participants and personnel (performance bias) All outcomes | High risk | No |
Blinding of outcome assessment (detection bias) All outcomes | High risk | No |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Withdrawals noted were 12 out of 35 in 10 mg group, 6 out of 30 in 5 mg group and 22 out of 32 in no medication group. Reasons for all withdrawals were unclear. ITT analysis was carried out |
Selective reporting (reporting bias) | Low risk | Outcomes reported |
Other bias | Unclear risk | Funder: not stated |
Marks 1980.
Methods | Design: randomised double‐blind 3‐arm cross‐over study of chlorpheniramine vs placebo Duration: not stated |
|
Participants | Number of participants randomly assigned: 24. Numbers in each group not stated Sex: not stated Age of participants: not stated Unit of allocation: cross‐over, chlorpheniramine vs placebo arm data used in this review Country and setting: Australia; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: for all 3 interventions, duration of treatment was not stated Length of follow‐up: not stated |
|
Outcomes | Timing of outcome assessment: not stated Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator |
|
Notes | Study investigators concluded that significant improvement in urticaria was seen with chlorpheniramine and with chlorpheniramine plus cimetidine compared with placebo; no difference was noted between efficacy of active treatments | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Randomisation method not stated |
Allocation concealment (selection bias) | Unclear risk | Method of allocation concealment not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Unclear, no details given |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear, no details given |
Incomplete outcome data (attrition bias) All outcomes | High risk | Numbers in each group not stated. No adverse events described; 2/24 randomly assigned (8%) lost to follow‐up because of irregular tablet intake |
Selective reporting (reporting bias) | Unclear risk | Write‐up published as item of correspondence, unclear whether all prespecified outcomes were reported |
Other bias | Unclear risk | Funder: none Very short report, no further information available |
Monroe 1988.
Methods | Design: double‐blind randomised multi‐centre 2‐arm trial of loratadine vs placebo Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: unclear; 169 evaluated for safety, 153 evaluated for efficacy, numbers randomly assigned to each group unclear Sex: not stated Unit of allocation: participant Age of participants: not stated Country and setting: USA (primary and secondary) Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
|
Outcomes | Timing of outcome assessment: at baseline, then weekly for 4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator |
|
Notes | Study investigators concluded that loratadine is efficacious and safe | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Randomisation method unclear |
Allocation concealment (selection bias) | Unclear risk | No allocation concealment described |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No details given about blinding, described as double‐blind |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No details given about blinding, described as double‐blind |
Incomplete outcome data (attrition bias) All outcomes | High risk | Numbers randomly assigned and number in each group unclear (not stated). 169 evaluated for safety, 153 for efficacy. Treatment failure: loratadine group n = 1; placebo group n = 10; other numbers of and reasons for withdrawal not stated |
Selective reporting (reporting bias) | High risk | Raw figures not given—only percentages and P values. Outcome measures unclear; statistics not specified. Raw figures not stated; origin of P values not stated (i.e. appropriateness of statistical methods unclear) |
Other bias | Unclear risk | Funder: none Very short report |
Monroe 1992.
Methods | Design: randomised double‐blind 3‐arm trial of loratadine vs hydroxyzine vs placebo Duration: 1 week |
|
Participants | Number of participants randomly assigned: 59 total, 18 for urticaria (disaggregated data obtained from study authors for CSU and atopic dermatitis participants) Sex: 29% male, 71% female Age of participants, years: 18 to 63 Unit of allocation: participant Country and setting: USA; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: short‐term (1 week) Length of follow‐up: 1 week |
|
Outcomes | Timing of outcome assessment: 1 week Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator and participant (diary). Diary cards including size and number of weals, erythema and pruritus; scored between 0 and 3; summed for total symptoms score plus global estimation of effect at end |
|
Notes | Study investigators concluded that loratadine is as effective as hydroxyzine in the treatment of urticaria | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation not clear; ''randomly assigned'' |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | No details about blinding given, described as double‐blind |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | No details about blinding given, described as double‐blind |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Number of dropouts from 18 randomly assigned with urticaria not stated. Results expressed as percentages with P values. No outcomes expressed as participant numbers; no baseline values. Unclear how many withdrew with reasons Comment: The report does not contain sufficient information to allow a judgement about whether incomplete outcome data introduced a source of bias |
Selective reporting (reporting bias) | Unclear risk | Laboratory tests conducted at start, unclear whether these were monitored as an outcome. Erythema not reported as an outcome (but included in overall symptom score) Comment: unclear whether outcomes were fully reported. No further information was available from investigators |
Other bias | Unclear risk | Funder: none. Short report with insufficient information to allow a judgement about risk of other bias |
Monroe 2003.
Methods | Design: randomised double‐blind multi‐centre parallel 2‐arm placebo‐controlled study of desloratadine 5 mg vs placebo Duration: 6 weeks |
|
Participants | Number of participants randomly assigned: 226 (116 desloratadine; 110 placebo) Sex: 27% male, 73% female desloratadine group; 24% male, 76% female placebo Age of participants, years: desloratadine 41.8 (range 13‐80); placebo 39.2 (range 13‐84) Unit of allocation: participant Country and setting: US, Chile, Canada, Venezuela, Germany, Norway, Sweden, Belgium; setting unclear Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: 6 weeks |
|
Outcomes | Timing of outcome assessment: 1, 2, 4 and 6 weeks (visits at screening, at baseline (day 1), on day 4, at weeks 1, 2, 4 and 6. Efficacy and safety assessments made at visit day 4 and weeks 1, 2, 4 and 6) Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator and participant |
|
Notes | Study investigators concluded that at week 1: mean improvement from baseline in reflective pruritus score significantly greater in desloratadine group; overall more effective than placebo; significant improvement in total symptoms score and interference in sleep and daily activities in desloratadine group; reduction in number and size of largest hive significantly better in desloratadine group Statistically significant improvements noted by day 2 of study Week 6: statistically significant improvement in pruritus from baseline in desloratadine group compared with placebo; desloratadine‐treated participants had significantly greater control of morning instantaneous total symptoms score compared with placebo patients. Overall, desloratadine was statistically significantly better than placebo |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Quote (page 536): "1:1 ratio according to computer generated schedule" "Blocks of 4 using random numbers generated by SAS function UNIFORM with seed based on clock‐time" Comment: adequate randomisation |
Allocation concealment (selection bias) | Low risk | Quote (page 537): "A set of sealed envelopes containing the identification of test drug corresponding to each subject was provided to each center. This enabled the investigator to identify the treatment assignment of individual subjects in the event of an emergency without compromising the blinding of other subjects. The randomisation schedule for blinding of treatments was disclosed only after study completion" Comment: Sealed envelopes indicate that this was probably done |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote (page 537): "Desloratadine, in 5 mg tablets, and placebo were identical in appearance and packaged identically in sealed coded envelopes. All study personnel were blinded to the identity of medication. A set of sealed envelopes containing the identification of test drug corresponding to each subject was provided to each center. This enabled the investigator to identify the treatment assignment of individual subjects in the event of an emergency without compromising the blinding of other subjects. The randomisation schedule for blinding of treatments was disclosed only after study completion" |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote (page 537): "Desloratadine, in 5 mg tablets, and placebo were identical in appearance and packaged identically in sealed coded envelopes. All study personnel were blinded to the identity of medication. A set of sealed envelopes containing the identification of test drug corresponding to each subject was provided to each center. This enabled the investigator to identify the treatment assignment of individual subjects in the event of an emergency without compromising the blinding of other subjects. The randomisation schedule for blinding of treatments was disclosed only after study completion" |
Incomplete outcome data (attrition bias) All outcomes | High risk | Lost to follow‐up: desloratadine 19/116 (19%); placebo 35/110 (31%) Treatment failure: desloratadine n = 14, placebo n = 29; other adverse events: desloratadine n = 3, placebo n = 2, non‐compliance each group n = 1, loss to follow‐up: desloratadine n = 1, placebo n = 2, lack of desire to continue placebo n = 1 Adverse events: serious (requiring withdrawal): desloratadine: 3 (1 bronchitis/sinusitis, 1 URTI, 1 nausea); placebo: 2 (1 vomiting, 1 sedation); minor adverse events: desloratadine: headache n = 18, nausea n = 7, dry mouth n = 6; placebo: headache n = 11, nausea n = 2, dry mouth n = 5 Actual participant numbers missing from results (percentages of improvement in scores and statistical significance only given); ITT stated by authors but unclear because of lack of provided data Comment: judged as high risk because of high dropout rate |
Selective reporting (reporting bias) | Unclear risk | Prespecified outcomes were reported, other than compliance Excluded participants previously non‐responsive to antihistamines; may involve selective reporting of positive results |
Other bias | Unclear risk | Funder: Schering‐Plough Research Institute |
NCT00536380.
Methods | Design: randomised double‐blind parallel‐group study; desloratadine 5 mg, 10 mg, 20 mg Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 314 Country and setting: Germany; setting unclear Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Intermediate duration of intervention (4 weeks) |
|
Outcomes | Timing of outcome assessment: 4 weeks Primary outcomes of the trial
Clinician or participant report: UAS participant reported |
|
Notes | Study investigators provided no conclusions Study number P04849; also indexed as EudraCT: 2006‐001449‐33. Results available online |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Randomised, no details given |
Allocation concealment (selection bias) | Unclear risk | No details given |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Participants and personnel were blinded to treatment group |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors were blinded to treatment group |
Incomplete outcome data (attrition bias) All outcomes | Low risk | Group 5 mg 12/106
Group 10 mg: 9/104
Group 20 mg: 10/104
Withdrawal and losses accounted for and balanced between groups ITT analysis carried out |
Selective reporting (reporting bias) | Low risk | All outcomes reported |
Other bias | Unclear risk | Underpowered because of poor recruitment; thus study is inconclusive Funder: Schering‐Plough |
Nelson 2000.
Methods | Design: multi‐centre double‐blind randomised placebo‐controlled 5‐arm parallel study with 4 different doses of fexofenadine vs placebo Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 468 Sex: 30% male, 70% female placebo; 31% male, 69% female 20 mg; 29% male, 71% female 60 mg; 33% male, 68% female 120 mg; 27% male, 73% female 240 mg Age of participants, years: range 12 to 65 Country and setting: USA; secondary care Unit of allocation: participant Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
|
Outcomes | Timing of outcome assessment: 1, 2, 3, 4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator and participant |
|
Notes | Study investigators concluded that all fexofenadine groups were significantly better than placebo groups re pruritus, reduction in weal score and reduced interference with sleep/activities | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation unclear, no details given; described as randomised |
Allocation concealment (selection bias) | Unclear risk | No details given |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Described as 24‐hour single‐blind lead‐in, followed by 4‐week double‐blind treatment, but no details given |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | Described as 24‐hour single‐blind lead in, followed by 4‐week double‐blind treatment, but no details given about blinding of outcome assessors |
Incomplete outcome data (attrition bias) All outcomes | High risk | 186/468 randomly assigned lost to follow‐up as follows: 437 had at least 1 postbaseline adverse event assessment; 418 had at least 1 postbaseline 12‐hour mean pruritus score assessment (i.e. for safety analysis, losses of n = 31 (6%); for efficacy assessments, losses of n = 50 (10.6%)) In text, study authors state that only 282 participants completed the study (losses n = 186 (40%)) Serious adverse events present in all groups but not specified. Most common adverse events reported (not specified which led to withdrawal of treatment) were as follows: headache ˜ 25%, URTI ˜ 8%, nausea 5%, dyspepsia 5%, diarrhoea 2%, gastroenteritis 2%, "pain" 4%, abdominal pain 2%, myalgia 4% Frequencies similar across all groups including placebo Incorrectly stated ITT; large number of withdrawals not accounted for Table implies that figures states 325 were evaluated at end of study (4 weeks). This is not resolved in text Study authors state ITT analysis but did not include all participants randomly assigned at the beginning of the study (31 with no data and not included in the analysis) Comment: Discrepancies in number of dropouts and large number of withdrawals suggest that attrition bias could have been introduced |
Selective reporting (reporting bias) | Unclear risk | All prespecified outcomes were reported but excluded persons known to be unresponsive to antihistamines; serious adverse events present in all groups but not specified Comment: unclear whether selective reporting and participant selection introduced a source of bias |
Other bias | Unclear risk | Funder: Hoechst Marion Roussel |
Nettis 2004.
Methods | Design: randomised double‐blind placebo‐controlled 3‐arm study of desloratadine alone vs desloratadine with montelukast (H1‐ and H2‐antagonists) vs placebo Duration: 6 weeks |
|
Participants | Number of participants randomly assigned: 81 (27 in each group) Sex: 24% male, 76% female desloratadine; 15.4% male, 84.6% female desloratadine plus montelukast; 40% male, 60% female placebo Age of participants, years: 37.5 ± 10.9 (desloratadine plus placebo); 35.6 ± 12.8 (desloratadine plus montelukast); 36.8 ± 10.7 (placebo) Country and setting: Italy; secondary care Unit of allocation: participant Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
1‐week single‐blind placebo run‐in ended with 1‐week single‐blind placebo washout. Concomitant medications not allowed during course of trial Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: 6 weeks |
|
Outcomes | Timing of outcome assessment: baseline, 3 weeks and 6 weeks (participants examined by physician 4 times over 8‐week period: first after 1‐week placebo run‐in, second after 3 weeks’ active treatment, third at end of treatment, final at end of placebo washout week) Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator and participant |
|
Notes | Study investigators concluded that both treatments were significantly more effective than placebo | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation unclear |
Allocation concealment (selection bias) | Unclear risk | Methods of allocation concealment not stated. Sealed envelopes in pharmacy Comment: Not entirely clear whether sealed envelopes related to blinding of medication or allocation concealment, judged as unclear |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | 1‐week single‐blind placebo run‐in and run‐out. Double‐blind study, adequately blinded Quote (page 1402): ''Patients were not informed that the treatment would be divided into specific periods'' "The tablets were encapsulated in double blind fashion and sealed in envelopes by a pharmacist along with the instruction sheets at the beginning of the trial. All treatments were dispensed by a third party" |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors were blinded as above Comment: probably done, inferred from text |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 5/81; 5 lost to follow‐up (6%) Number and reasons for withdrawal:
Comment judged as low risk, as withdrawals with reasons were given and were balanced between the 2 groups No ITT; most results reported as number of participants showing any improvement, with no indication of effect size |
Selective reporting (reporting bias) | Unclear risk | Attempt at QoL measurement, but DLQI into non‐validated scale; HRQoL results unclear—presented only graphically; y‐axis (if consistent with other graphs) indicates only % participants showing any improvement (no indication of effect size) Baseline data unclear: Symptom severity scale appears to be out of 12, yet at baseline, mean is stated as about 60 in each group |
Other bias | Unclear risk | Funder: none |
Nettis 2006.
Methods | Design: randomised double‐blind 2‐arm placebo‐controlled study of levocetirizine 5 mg vs placebo Duration: 6 weeks |
|
Participants | Number of participants randomly assigned:106, n = 53 levocetirizine, n = 53 placebo Sex: 33% male, 67% female levocetirizine; 41% male, 59% female placebo Age of participants, age: mean 41.1 (SD 22‐71) levocetirizine; mean 39 (SD 22‐69) placebo Country and setting: Italy; secondary care Unit of allocation: participant Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
1‐week placebo run‐in (single‐blind), then treatment for 6 weeks, then 1‐week placebo washout at end of study Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: 8 weeks i.e. follow‐up extended after cessation of therapy. |
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Outcomes | Timing of outcome assessment: screening, after placebo run‐in, after 3 weeks of active treatment, after 1 week of washout (at 6 weeks) Examined by physician 4 times over 8‐week period: first after placebo run‐in (1 week); second after 3 weeks’ active treatment; third after 6 weeks’ active treatment; fourth after final week of placebo—participants complete visual analogue scale for overall severity of urticaria since last visit (0 = none, 10 = worst) Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: both |
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Notes | Study investigators concluded that mean total symptoms score decreased by 81% vs 1% by end of study period in levocetirizine vs placebo group, respectively Treatment group had statistically significant decrease in number of weals at all visits (overall 79% reduction in score); also statistically significant decrease in urticarial episodes and size of weals (75% reduction); pruritus also (85% reduction) |
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Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation unclear (''randomly assigned'') |
Allocation concealment (selection bias) | Unclear risk | Sealed envelopes in pharmacy. Comment: not entirely clear whether sealed envelopes related to blinding of medication or allocation concealment, judged as unclear |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double‐blind study; participants not informed that treatments would be divided up into specific periods: 1‐week placebo run‐in (single‐blind), then treatment for 6 weeks, then 1‐week placebo washout at end of study. Double‐blind study: ''tablets were encapsulated in a double blind fashion and sealed in envelopes by a pharmacist together with instruction sheets.'' 1‐week placebo run‐in (single‐blind), then treatment for 6 weeks, then 1 week placebo washout at end of study. Medications dispensed by third party |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors were blinded as above Comment: probably done, inferred from text |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 100/106 randomly assigned participants completed Withdrawals: levocetirizine n = 2, n = 4 in placebo group, dropped out in placebo run‐in phase because of non‐compliance n = 2, heart attack n = 1, needed to take oral steroids for aggravated urticaria n = 3 (2 in placebo group and 1 in levocetirizine group) No ITT Comment: low number of dropouts, evenly balanced between groups, not thought to contribute bias |
Selective reporting (reporting bias) | Unclear risk | Results not clearly reported. Attempt at measuring quality of life, but not with validated scale; results of this inadequately reported. Quality of life scores statistically significantly improved from baseline in levocetirizine group but not in placebo group (no scores given) |
Other bias | Low risk | Funder: none |
Ollert 1999.
Methods | Design: randomised 2‐arm multi‐centre (10 centres) parallel‐group comparison of mizolastine vs placebo Duration: 4 weeks |
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Participants | Number of participants randomly assigned: 78 (39 each in mizolastine and placebo) Sex: 40% male, 60% female Age of participants, years: 40 ± 13 Unit of allocation: participant Country and setting: Germany; research clinic Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration Placebo run‐in periods (i.e. variable washout period of any other medications (depending on previous medication type) before study commenced)
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
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Outcomes | Timing of outcome assessment: at days 0, 14 and 28 Primary outcomes of the trial:
Secondary outcomes of the trial
Clinician or participant report: clinician and participant |
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Notes | Study report written in German Study investigators concluded that mizolastine demonstrates clinical and statistical superiority over placebo in the treatment of CSU, and showed a good safety profile |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Stated to be randomised, unclear as method not stated |
Allocation concealment (selection bias) | Unclear risk | Unclear, no details given |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Stated to be double‐blind, identical placebos given |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Stated to be double‐blind, but no details given |
Incomplete outcome data (attrition bias) All outcomes | Low risk | Stated to be ITT analysis. 19 participants dropped out: 11/39 mizolastine, 8/39 placebo. Reasons given: 2 in total for undesirable effects, 12 in total for lack of effect, 5 in total for other reasons (page S26, table 2) |
Selective reporting (reporting bias) | Unclear risk | Unclear; not all physiological measures were reported in full in the study report |
Other bias | Low risk | None detected. Funder: not stated |
Ortonne 2004.
Methods | Design: randomised parallel‐group 2‐arm study of desloratadine vs placebo Duration: 42 days |
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Participants | Number of participants randomly assigned: 137 (desloratadine n = 65, placebo n = 72) Sex: gender not stated Age of participants, years: 18, mean age not stated Unit of allocation: participant Country and setting: France (multicentre), research clinics Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: 42 days |
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Outcomes | Timing of outcome assessment: 14 days and 42 days Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and clinician |
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Notes | Study investigators concluded that desloratadine was effective from the first dose and throughout 6 weeks in CSU | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Not stated, described as randomised |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not stated |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not stated |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear how many out of 137 randomly assigned participants completed the study |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Unclear risk | Funder: Schering‐Plough. Short conference abstract |
Ortonne 2007.
Methods | Design: multi‐centre 2‐arm randomised double‐blind trial of desloratadine vs placebo Duration: 42 days |
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Participants | Number of participants randomly assigned: 142 (desloratadine n = 65, placebo n = 77) Age, years: > 18; desloratadine 41.2 ± 15.4; placebo 41.5 ± 15.2 Gender: desloratadine 36.9% male, 63.1% female; placebo 40.3% male, 59.7% female Unit of allocation: participant Country and setting: France; set in 40 dermatology centres Inclusion criteria of the trial
Exclusion criteria of the trial
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|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: up to 6 weeks |
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Outcomes | Timing of outcome assessment: days 7, 14, 42 (patient diaries collected at these times or at time of early termination, if applicable) Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant diaries, general (non‐directive) questions by investigators, or clinical examination |
|
Notes | Study investigators concluded that desloratadine was shown to be significantly superior to placebo in improving severity of pruritus as measured by reflective pruritus scores measured between days 0 and 14 | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Quote (page 39): "following screening (visit 1), a computer‐generated allocation code was used to randomly assign patients" |
Allocation concealment (selection bias) | Unclear risk | Method of allocation concealment not stated |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Described as double‐blind, medication was provided to participants in a numbered container based on their randomisation code |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Described as double‐blind but method of investigator blinding not stated |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 85/142 randomly assigned participants completed the study Figure 1 of the study report provides an account of dropouts from each group. 142 randomly assigned (65 desloratadine, 77 placebo). 5 withdrawn as received no treatment or had no baseline data. Of remaining 137 (65 desloratadine, 72 placebo), 85 completed (49 desloratadine, 36 placebo). 16 withdrew from desloratadine group (12 lack of efficacy, 1 adverse event (pregnancy, not treatment‐related), 1 withdrew consent, 1 was lost to follow‐up, 1 other reason). 36 withdrew from placebo group (34 lack of efficacy, 2 lost to follow‐up described as 'loss of sight' in fact lost to follow‐up) |
Selective reporting (reporting bias) | Unclear risk | All prespecified outcomes were reported, but results are presented as percentages or as graphs with statistical significance Comment: endpoint at 6 weeks is not clear |
Other bias | Unclear risk | Funder: Schering‐Plough Research Institute |
Patel 1997.
Methods | Design: randomised double‐blind 2‐arm parallel‐group study of loratadine vs cetirizine Duration: 2 weeks |
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Participants | Number of participants randomly assigned: 46 (22 loratadine, 18 cetirizine) Sex: not stated Age of participants: not stated Unit of allocation: participant Country and setting: not stated; investigators located in USA and Canada Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
Duration of intervention: short‐term (2 weeks) Length of follow‐up: 2 weeks |
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Outcomes | Timing of outcome assessment: baseline and days 7 and 14 Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician and participant diary card |
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Notes | Study investigators concluded that loratadine and cetirizine were well tolerated with comparable efficacy | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Stated to be randomised, methods not described |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Stated to be double‐blind, no details given |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Stated to be double‐blind, no details given |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 40/46 complete (22 loratadine, 18 cetirizine). These non‐completers had fewer than 7 days of therapy or lack of valid follow‐up visit or both |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Unclear risk | Funder: Schering‐Plough, USA |
Paul 1998.
Methods | Design: multi‐centre double‐blind randomised parallel‐group study comparing fexofenadine 60 mg, 120 mg, 180 mg, 240 mg or placebo, each once daily Duration: 6 weeks |
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Participants | Number of participants randomly assigned: 222 (details unclear) Age of participants, years: placebo 43 ± 13; fexofenadine 60 mg 44 ± 17; fexofenadine 120 mg 45 ± 12; fexofenadine 180 mg 43 ± 15; fexofenadine 240 mg 44 ± 14 Overall age, years: 44 ± 14 Sex (% female): placebo 54%, fexofenadine 60 mg 58%, fexofenadine 120 mg 47%, fexofenadine 180 mg 68%, fexofenadine 240 mg 59% Total female: 58% Duration of symptoms: 3 years ± 5 Severity of urticaria: unclear Unit of allocation: participant Country and setting: France, UK, Germany; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
(each once daily) Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: 6 weeks |
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Outcomes | Timing of outcome assessment: weekly assessment Total symptoms score (TSS) (0‐4 for number of weals; 0‐3 for itching intensity; 0‐7 combined TSS) Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: both |
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Notes | Study investigators concluded that good or excellent response in 60 mg group = 63%, 120 mg group 50%, 180 mg group 64%, 240 mg group 55% and placebo group 41%; not clear whether timing for this result but may be 6 weeks Fexofenadine is effective at 120 mg and above from week 1 as compared with placebo |
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Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Participants non‐responsive to other antihistamine treatment excluded Method of randomisation not stated |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not stated how |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not stated how |
Incomplete outcome data (attrition bias) All outcomes | Low risk | No ITT. 76 participants withdrew before completion: 30 lost from placebo, 14 from 120 mg group, 16 from 180 mg group and 8 from 240 mg group Treatment group reason for withdrawal: lack of effect 13%, adverse events 7%, patient request 6% Placebo group: lack of effect 33% and adverse events 20% |
Selective reporting (reporting bias) | Unclear risk | No ITT; study says weekly as well as fortnightly; all active drug groups put together and reported only selectively |
Other bias | Unclear risk | Funder: Hoechst Marion Roussel |
Peyri 1991.
Methods | Design: randomised double‐blind multi‐centre placebo‐controlled 2‐arm study of ebastine 10 mg daily vs placebo Duration: 14 days |
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Participants | Number of participants randomly assigned: 204 (ebastine 100, placebo 104) Sex: not stated Age of participants: not stated Unit of allocation: participant Country and setting: Spain; secondary care (outpatient clinics) Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
Duration of intervention: short‐term (14 days) Length of follow‐up: 14 days |
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Outcomes | Timing of outcome assessment: baseline, 7 days, 14 days Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: both |
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Notes | Study investigators concluded that a significantly greater reduction in weal size and weal number was seen in ebastine group over placebo. Pruritus significantly less in ebastine group | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation not stated |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double‐blind study; matching placebo capsules; unclear whether blinding was adequate for both participants and personnel |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear, no details given |
Incomplete outcome data (attrition bias) All outcomes | Low risk | Losses to follow‐up: 27/204 (13%), ebastine 9/100 (9%), placebo 18/104 (17%) Withdrawals due to lack of efficacy: ebastine n = 3 and placebo n = 13; poor tolerability: ebastine n = 1; lack of efficacy plus poor tolerability: ebastine n = 1, placebo n = 3; other reasons not due to treatment: ebastine n = 4, placebo n = 2 Withdrawals with reasons stated and balanced between the 2 groups No ITT |
Selective reporting (reporting bias) | Unclear risk | No clear definition of outcomes, unclear how outcome assessments were used to generate assessments of (Quote) (page 52): "cure, improvement, no change, worsening" Age and sex of participants not known |
Other bias | Unclear risk | Funder: Almirall Note: Groups were well matched for age, sex, duration of urticaria, previous treatment and response to prior antihistamine therapy |
Phanuphak 1987.
Methods | Design: double‐blind randomised placebo‐controlled 2‐arm study of ketotifen (mast cell stabiliser) vs placebo Duration: 2 weeks |
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Participants | Number of participants randomly assigned: 30 (16 ketotifen and 14 placebo) Sex: 25% male, 75% female ketotifen; 26% male, 64% female placebo Age of participants, years: mean 30.4 Unit of allocation: participant Country and setting: Thailand; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
2‐week run‐in: participants allowed to take chlorpheniramine 4 mg prn up to 6‐hourly; then randomly assigned to ketotifen or placebo and still allowed to take chlorpheniramine concomitantly; numbers of chlorpheniramine tablets taken recorded Duration of intervention: short‐term (2 weeks) Length of follow‐up: 2 weeks |
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Outcomes | Timing of outcome assessment: baseline and 2 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator and participant diaries |
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Notes | Study investigators concluded that ketotifen was significantly better than placebo. Chlorphenamine requirement was dropped in significantly more participants taking ketotifen than placebo (94% vs 7%) | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Participants were randomly assigned to 2 groups, method not described |
Allocation concealment (selection bias) | Unclear risk | Third party sealed envelopes with code number, containing active treatment or placebo prepared and sealed by a third person, but unclear if this refers to blinding or to concealment of allocation |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double‐blind study; identical white tablets provided to participants, blinded to participants, as supplied in sealed coded envelopes prepared by a third party |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear whether outcome assessors were blinded and how |
Incomplete outcome data (attrition bias) All outcomes | Low risk | No losses to follow‐up: 30 (16 ketotifen and 14 placebo) |
Selective reporting (reporting bias) | Unclear risk | All prespecified outcomes were reported Comment: The 'slightly effective' and 'ineffective' evaluation of patient score put together as ineffective |
Other bias | Unclear risk | Funder: Sandoz Allowed concomitant treatment with chlorpheniramine such that positive results of ketotifen group might be due to this alone or to the combination of ketotifen plus chlorpheniramine; very small numbers; sponsored by manufacturer |
Pons‐Guiraud 2006.
Methods | Design: randomised double‐blind multi‐centre 2‐arm trial comparing emedastine and loratadine Duration: 4 weeks |
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Participants | Number of participants randomly assigned: 192 (emedastine n = 84, loratadine n = 77) Sex: loratadine: 34.5% male, 65.5% female; emedastine: 25% male, 75% female Age of participants, years: loratadine: 42.6 ± 14.7; emedastine:43.4 ± 13.3 Country and setting: Italy, France, Hungary, Czech Republic; secondary care Unit of allocation: participant Inclusion criteria of the trial
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Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks (plus optional visits 2 weeks after cessation of therapy). |
|
Outcomes | Timing of outcome assessment: 1, 2 and 4 weeks (plus optional visits at week 2 and 2 weeks after discontinuation of treatment)
Secondary outcomes of the trial
Clinician or participant report: both |
|
Notes | Study investigators concluded that no significant differences between treatments were noted at 4 weeks according to investigator and participant scores; mean symptom scores improved significantly from baseline in both groups | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Computer list prepared by sponsor |
Allocation concealment (selection bias) | Low risk | Sealed envelopes containing code breaks were given to each centre |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double‐blind, double‐dummy study; 2 identical capsules; placebo run‐in |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | Double‐blind, double‐dummy study; 2 identical capsules; placebo run‐in, but unclear whether outcome assessors were specifically blinded to allocation Comment: probably done |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 152/192 completed 12 participants excluded after randomisation, as they took prohibited antihistamines. 19 more excluded after randomisation, as they failed to report scores for hives/itching during placebo run‐in period. Only the remaining 161 participants were included in ITT. 31 lost to follow‐up (16%). Per‐protocol (PP) analysis included only 153 participants—8 had major protocol violations or dropped out Two were withdrawn because of serious adverse events: 1 suicide attempt, 1 fracture following a fall in emedastine group No ITT Comment: All dropouts accounted for but not clearly by group |
Selective reporting (reporting bias) | Low risk | No selective reporting Comment: excluded participants unresponsive to antihistamines |
Other bias | Unclear risk | Funder: Saluc‐Pharma S.A. Study drug manufactured and packaged by sponsor; no power calculation |
Potter 2009.
Methods | Design: randomised multi‐centre randomised parallel‐group double‐blind 2‐arm study comparing levocetirizine 5 mg and desloratadine 5 mg Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 886 (levocetirizine n = 438, desloratadine n = 448) Sex: levocetirizine 35.2% male, 64.8% female; desloratadine 36.2% male, 68.3% female Age of participants, years (range): levocetirizine 43.36 (18‐79.2); desloratadine 42.85 (18.1‐81.3) Unit of allocation: participant Country and setting: multi‐centre Germany and UK; secondary Inclusion criteria of the trial
Exclusion criteria of the trial
|
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Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 5 weeks i.e. follow up extended after cessation of therapy. |
|
Outcomes | Timing of outcome assessment: 4 scheduled visits over a period of 5 weeks: screening visit 1 (V1; week ‐1), randomisation visit (V2; week 0), control visit (V3; week 1) and final visit (V4; week 4) Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and clinician |
|
Notes | Study investigators concluded that levocetirizine 5 mg was significantly more efficacious than desloratadine 5 mg in the treatment of CSU symptoms | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Quote (page 597): "Randomization to the study drug was achieved by allocation of a unique study number to each subject and a computer‐generated sequential randomisation number provided by the Biostatistics Department of the study sponsor (UCB S.A., Brussels, Belgium)" |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote (page 597): "capsules identical in shape, size and colour to allow a double‐blind design" |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear how outcome assessors were blinded |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 832/886 completed
In NCT00264303, reasons for withdrawal were given but do not correspond with the number of participants analysed—n = 25 levocetirizine and n = 29 desloratadine—because of adverse event, lack of efficacy, loss to follow‐up, participant preference to withdraw, other reasons. However, number of participants analysed was n = 434 in levocetirizine group and n = 443 (877 total) in desloratadine group (only 9 losses out of 886 specified, reasons unclear). Judged as unclear risk |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Unclear risk | Funder: UCB |
Ring 2001.
Methods | Design: randomised double‐blind placebo‐controlled parallel‐group 2‐arm study of desloratadine vs placebo Duration: 6 weeks |
|
Participants | Number of participants randomly assigned: 190 (95 in each group) Sex: 29% male, 71% female desloratadine; 22% male, 78% female placebo Age of participants, years: 12 to 79 Country and setting: USA and Germany; secondary care Unit of allocation: participant Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
Once daily for 6 weeks (sufficient time for washout of any medications before study was employed) Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: 6 weeks |
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Outcomes | Timing of outcome assessment: days 1 and 4, then weeks 1, 2, 4, 6 Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator and participant |
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Notes | Study investigators concluded that results from week 1 were maintained throughout study duration Desloratadine significantly superior to placebo in reducing average mean reflective pruritus score (56% vs 21%) and total symptoms score (51.6% vs 19.3%). Interference with sleep and daily activities, number of weals, size of largest weal all significantly reduced by desloratadine vs placebo |
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Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Computer‐generated schedule, randomly assigned |
Allocation concealment (selection bias) | Unclear risk | Unclear, no details given |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double‐blind study; matched placebo |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Double‐blind study; unclear how outcome assessors were blinded to treatment allocation |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Losses to follow‐up: desloratadine: 19/95 (20%); placebo: 32/95 (34%) Treatment failure: desloratadine n = 13, placebo n = 21; non‐compliance: desloratadine n = 3, placebo n = 6; adverse events: desloratadine n = 3, placebo n = 2; other losses to follow‐up: desloratadine n = 0, placebo n = 2; did not wish to continue: placebo n = 1 Adverse events: serious adverse events (requiring treatment withdrawal): desloratadine: 3 not specified (not life threatening); placebo: 2 not specified (not life threatening) Comment: high level of loss to follow‐up; more losses in the placebo group; unclear whether this contributed to bias |
Selective reporting (reporting bias) | Unclear risk | Desloratadine significantly superior to placebo in reducing average mean reflective pruritus score (74% vs 49%). Numbers for total symptoms score not given at 6 weeks, but said to be significant. Actual reductions in scores not stated, only percentages; unclear how clinically significant these reductions are |
Other bias | Unclear risk | Funder: Schering‐Plough Research Institute |
Salo 1989.
Methods | Design: randomised double‐blind cross‐over 3‐arm study comparing acrivastine vs hydroxyzine vs placebo Duration: 5 days each treatment |
|
Participants | Number of participants randomly assigned: 21 Sex: 47% female Age of participants, years: 18‐70, mean 38.3 Country and setting: Finland and UK; secondary Unit of allocation: cross‐over participants Inclusion criteria of the trial
Exclusion criteria of the trial
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Interventions |
Interventions, dose, duration
3‐day washout initially; then 2‐day washout period between treatments Duration of intervention: short‐term (5 days per intervention) Length of follow‐up: 5 days for each treatment |
|
Outcomes | Timing of outcome assessment: at 5 days for each treatment Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: investigator and participant (daily diary) |
|
Notes | Study investigators concluded that participant data showed no differences between active treatments; both better than placebo (P value < 0.05) Physician data showed active treatment better than placebo |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation unclear, described as randomised |
Allocation concealment (selection bias) | Unclear risk | Unclear. Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double‐blind study. Method of blinding not stated |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Double‐blind study. Method of blinding not stated |
Incomplete outcome data (attrition bias) All outcomes | High risk | Incomplete reporting of data; reasons for withdrawal not stated. No ITT 3/21 lost to follow‐up (34%) |
Selective reporting (reporting bias) | High risk | Investigators appear to have made subjective decision on best treatment. No raw data—mean scores only. Adverse effects of drowsiness significantly more prevalent with hydroxyzine than with placebo, but numbers of participants experiencing this not stated |
Other bias | Unclear risk | Funder: Wellcome Research Laboratories |
Sener 1999.
Methods | Design: randomised 2‐arm parallel‐group study comparing ketotifen and fluoxetine Duration: 6 weeks |
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Participants | Number of participants randomly assigned: 60 (30 in each group) Sex: 41% female, 59% male Unit of allocation: participant Age of participants, years (SD): 19‐74 (42.08 ± 19.24) Country and setting: Turkey, research clinic Inclusion criteria of the trial
Exclusion criteria of the trial
|
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Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (6 weeks) Length of follow‐up: 6 weeks |
|
Outcomes | Timing of outcome assessment: baseline, weekly and at 6 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: unclear |
|
Notes | Study investigators concluded that significantly greater improvement in symptom score was seen in the ketotifen group (P value < 0.001); fluoxetine led to significant improvement in number of lesions, degree of itch and angio‐oedema | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Method of randomisation unclear ("randomly divided") |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | High risk | No blinding (1 treatment twice daily and the other treatment 4 times daily) |
Blinding of outcome assessment (detection bias) All outcomes | High risk | No blinding (1 treatment twice daily and the other treatment 4 times daily) |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No raw data; adverse events not mentioned, nor withdrawals from study |
Selective reporting (reporting bias) | Unclear risk | Limited report of outcomes, as reported only as abstract for poster presentation |
Other bias | Unclear risk | Funder: not stated. Very short poster abstract |
Staevska 2014.
Methods | Design: prospective randomised double‐blind cross‐over trial Duration: 5 days |
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Participants | Number of participants randomly assigned: 24 Sex: 75% female Age of participants, years: mean 45, range 19 to 68 Unit of allocation: cross‐over (first phase only considered) Country and setting: Bulgaria; tertiary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration Initial in‐hospital treatment, assessment of effectiveness and tolerability of levocetirizine 10 and 20 mg vs hydroxyzine 100 and 200 mg. This was done in a double‐blind fashion on alternate‐day regimens
Length of follow‐up: 5 days on each treatment Short duration of intervention (5 days) Length of follow‐up: 5 days |
|
Outcomes | Timing of outcome assessment: day 5 Primary outcomes of the trial
Secondary outcomes of the trial
Quality of life measures: median CU‐Q2oL scores Clinician or participant report: physicians calculated weal scores and severity of pruritus |
|
Notes | Study investigators concluded that higher than standard doses of cetirizine can improve quality of life in participants discontinuing steroid treatment. Addition of hydroxyzine does not seem to provide benefit but causes increased daytime somnolence Study ID NCT01250652 |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Stated to be randomised. Randomisation, ensuring balanced numbers of cases in the 2 treatment arms, was performed pair‐wise at a specialised website (http://www.randomizer.org/) Comment: Exposure to study medication after randomisation to determine tolerability of medications on alternate‐day regimens may have compromised randomisation through a potential carry‐over effect (insufficient washout period between phases) |
Allocation concealment (selection bias) | Unclear risk | Unclear |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double‐blind: “Medication was given morning and evening in opaque gelatine capsules that were prepared by a technician who was not aware of the clinical work” |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | “The investigators, who were blinded to the treatment groups” |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 25 participants were initially randomly assigned. 24 participants completed the study—1 withdrawal after randomisation (personal reasons) |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Unclear risk | Funder: UCB Pharma. Short report, conference abstract |
Thompson 2000 Study 1.
Methods | Design: randomised multi‐centre double‐blind 2‐arm placebo‐controlled parallel study of fexofenadine vs placebo Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 160 Sex, fexofenadine: 18% male, 72% female; placebo: 30% male, 70% female Age of participants, years: fexofenadine: 40 ± 11; placebo: 38 ± 13 Country and setting: US; secondary care Unit of allocation: participant Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 to 6 weeks i.e. follow‐up extended after the cessation of therapy. |
|
Outcomes | Timing of outcome assessment: 4 or 6 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: Participants completed self‐administered questionnaire, DLQI (score range 0‐30), work productivity and activity impairment questionnaire (WPAI—0‐100%, high = greater productivity) at entry, interim visit (15 ± 2 days’ treatment), final visit (30 ± 4 days) or early termination |
|
Notes | Study investigators concluded that significant differences were demonstrated in only 1 study out of 2. Increase in "work productivity," "overall work productivity," regular daily activities significantly higher in fexofenadine group compared with placebo group (both studies); no differences between groups re time missed from class/work | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Quote: ''Patients were randomised to receive 60 mg fexofenadine HCl twice daily or placebo twice daily...'' |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: ''24 hour single‐blind placebo lead‐in, and a subsequent 4‐week double blind treatment period.'' Unclear how blinding was achieved |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote: ''24 hour single‐blind placebo lead‐in, and a subsequent 4‐week double blind treatment period.'' Unclear how blinding was achieved |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No mention of whether there were dropouts; therefore unable to corroborate ITT analyses as reported in Study 1 |
Selective reporting (reporting bias) | Unclear risk | Ambiguity re duration of trial, as reported methods say 4 weeks and results say 4 to 6 weeks. DLQI measures reported but not as proportions of participants with 50% or greater improvement in quality of life measurements whilst taking H1‐antihistamines; therefore not possible to include DLQI data |
Other bias | Unclear risk | Funder: Hoechst Marion Roussel. Study investigators report 2 identical studies in this paper; if studies identical, unclear why not combined as a single study |
Thompson 2000 Study 2.
Methods | Design: randomised multi‐centre double‐blind 2‐arm placebo‐controlled parallel study of fexofenadine vs placebo Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 165 Sex: fexofenadine: 26% male, 74% female; placebo: 27% male, 77% female Age of participants, years: fexofenadine: 38 ± 13; placebo:40 ± 13 Country and setting: USA; secondary care Unit of allocation: participant Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 to 6 weeks i.e. follow‐up extended after the cessation of therapy. |
|
Outcomes | Timing of outcome assessment: 4 or 6 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant (for QoL questionnaires) and clinician |
|
Notes | Study investigators reported that significantly better improvement in fexofenadine was achieved in both studies in symptoms/feelings, daily activities, work or school and personal relations; for leisure and treatment, significant difference was demonstrated in 1 study out of 2 Increase in "work productivity," "overall work productivity," regular daily activities significantly higher in fexofenadine group compared with placebo group (both studies); no difference between groups re time missed from class/work |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Quote: ''Patients were randomised to receive 60 mg fexofenadine HCl twice daily or placebo twice daily...'' |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: ''24 hour single‐blind placebo lead‐in, and a subsequent 4‐week double blind treatment period.'' Unclear how blinding was achieved |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote: ''24 hour single‐blind placebo lead‐in, and a subsequent 4‐week double blind treatment period.'' Unclear how blinding was achieved |
Incomplete outcome data (attrition bias) All outcomes | High risk | Study 2: number randomly assigned stated in text to be 165; in tables, total number adds up to 167; no mention of whether there were dropouts. Unable to confirm ITT numbers in study report for Study 2 |
Selective reporting (reporting bias) | Unclear risk | Ambiguity regarding duration of trial methods: says 4 weeks; results say 4 to 6 weeks. DLQI measures reported but not as proportions of participants with 50% or greater improvement in quality of life measurements whilst taking H1‐antihistamines; therefore not possible to include DLQI data |
Other bias | Unclear risk | Funder: Hoechst Marion Roussel Study authors report 2 identical studies in this paper; if studies identical, unclear why not combined as a single study |
Wan 2009.
Methods | Design: randomised single‐blind 4‐arm trial comparing a combination of sedating H1‐antihistamine and non‐sedating H1‐antihistamine (hydroxyzine plus cetirizine); combination of H1‐antihistamine and H2‐antihistamine (hydroxyzine plus famotidine); and combination of H1‐antihistamine and LRA (hydroxyzine plus montelukast) vs placebo Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 120 Sex: 38% male, 62% female Age of participants, years: 31 (18–45); 36.4 (20–52); 34.8 (20–54); 33.2 (18–48) Unit of allocation: participant Country and setting: Taiwan; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration 1‐week ‘run‐in’ period to wash out previous antihistamine used for treatment. Randomly assigned to receive:
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: 4 weeks |
|
Outcomes | Timing of outcome assessment: baseline and after 4 weeks of treatment Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant and clinician |
|
Notes | Study investigators concluded that the combination of H1‐ and H2‐receptor antagonists provided the greatest treatment efficacy according to the measures used in this small study | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Not stated |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Participants were not blinded |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote (page 195): ''The same investigating physician who was blinded to the treatment regimens saw the patient'' |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 107/120 randomly assigned completed the study (13 of 30 participants from placebo group dropped out after experiencing no real benefit following therapy for 1–2 weeks) Comment: All dropouts were from the placebo group, but as the reasons for this are given, we have judged the risk of bias as low |
Selective reporting (reporting bias) | Unclear risk | All prespecified outcomes were reported |
Other bias | Unclear risk | Funder: Montelukast provided by manufacturer Merck Sharp Dohme |
Wang 2012.
Methods | Design: randomised controlled trial of mizolastine 10 mg daily for 4 weeks followed by 10 mg every other day for 4 weeks and followed by 10 mg per 3 days in the last 4 weeks for comparison with long‐term mizolastine 10 mg daily for 12 weeks Duration: 12 weeks |
|
Participants | Number of participants randomly assigned: 100 (experimental decremental dose group); control n = 50, long‐term 10 mg mizolastine n = 50 Sex: intervention: men 27, women 23 (46% female); control group: men 28; women 22 (44% female) Age of participants, mean in years: experimental group 32.66; control group 30.86 Unit of allocation: single participants Country and setting: China; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: not mentioned Concomitant/rescue treatment permitted: not mentioned |
|
Outcomes | Timing of outcome assessment: 4, 8, 12 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician |
|
Notes | Study investigators concluded that long‐term decrement in mizolastine therapy is effective, safe and convenient in the treatment of chronic urticaria | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Randomised, no details given |
Allocation concealment (selection bias) | Unclear risk | No details given |
Blinding of participants and personnel (performance bias) All outcomes | High risk | Not blinded |
Blinding of outcome assessment (detection bias) All outcomes | High risk | Not blinded |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 3/50 participants in each group were lost to follow‐up, no reasons given No ITT analysis carried out |
Selective reporting (reporting bias) | Low risk | All outcomes reported |
Other bias | Low risk | Funder: not stated |
Weller 2013.
Methods | Design: randomised double‐blind parallel‐group single‐dose study of desloratadine 5 mg vs 20 mg desloratadine Duration: 5 hours (short‐term) |
|
Participants | Number or participants randomly assigned: n = 29 (5 mg desloratadine n = 13, 20 mg desloratadine n = 16) Sex: 5 mg desloratadine group: 9 women/4 men (64% female); 20 mg desloratadine group: 7 women/9 men (43% female) Age of participants, mean years: 5 mg desloratadine group 43.5 ± 12.9; 20 mg desloratadine group: 41.7 ± 11.3 Unit of allocation: selected body area in single participants Country and setting: Germany; Allergie‐Centrum‐Charité, a tertiary referral centre for allergies and urticaria Inclusion criteria of the trial
Exclusion criteria of the trial
Mild to severe disease, duration of disease longer than 6 weeks |
|
Interventions |
Interventions, dose, duration
short‐term (5 hours) Length of follow‐up: after 5 hours |
|
Outcomes | Timing of outcome assessment (state which time points): 5 hours Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician |
|
Notes | Study investigators concluded that a direct comparison between 5 mg and 20 mg of desloratadine showed no difference in weal area, weal volume or number of weals. "In contrast, a comparison of the reduction in the total weal number after 5 hours during treatment with 5 mg desloratadine minus no treatment versus treatment with 20 mg minus no treatment showed significant differences (p < 0.01)" | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation scheme |
Allocation concealment (selection bias) | Unclear risk | Unclear |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | All participants and clinical staff, for example, study nurses and study physicians involved in the study, were blinded until the end of the trial |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | All participants and clinical staff, for example, study nurses and study physicians involved in the study, were blinded until the end of the trial |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether any were lost to follow‐up and any reasons No ITT analysis carried out |
Selective reporting (reporting bias) | Low risk | No selective outcome reporting |
Other bias | Unclear risk | Funder: This study was financially supported by Schering‐Plough (Essex Pharma GmbH, Germany). In addition, the study medication was provided by Schering‐Plough |
Wu 2008.
Methods | Design: randomised 3‐arm trial of azelastine 2 mg/d; azelastine 4 mg/d vs combined azelastine and cimetidine 2 mg/d Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 103 Sex: male 52%, female 48% (from 100 participants who were available for analysis) Unit of allocation: participant Country and setting: China; secondary care Age between 16‐81 years, mean age 39.16 years Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: not specified but assumed to be at endpoint (i.e. 4 weeks) |
|
Outcomes |
Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician |
|
Notes | Main study report written in Chinese Study investigators concluded that all 3 groups have similar efficacy, but azelastine 4 mg/d and combined azelastine and cimetidine 2 mg had greater efficacy than azelastine 2 mg alone The difference in this comparison was statistically significant (P < 0.05) |
|
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Unclear, described as open randomisation |
Allocation concealment (selection bias) | High risk | No concealment |
Blinding of participants and personnel (performance bias) All outcomes | High risk | Not blinded |
Blinding of outcome assessment (detection bias) All outcomes | High risk | Not blinded |
Incomplete outcome data (attrition bias) All outcomes | High risk | 103 were randomly assigned; 100 are included in the analyses with no reasons given for dropout |
Selective reporting (reporting bias) | High risk | No clear definition of outcomes; unclear whether assessment of compliance was carried out |
Other bias | Low risk | None detected. Funder: not stated |
Yin 2003a.
Methods | Design: randomised double‐blind parallel‐group comparing cetirizine and levocetirizine Duration: 28 days |
|
Participants | Number of participants randomly assigned: 44 (22 in each group) Sex: levocetirizine: 54% (female); cetirizine: 63% (female) Age of participants (between 18 and 65), mean in years: levocetirizine 36.27; cetirizine 36.73 Unit of allocation: participant Country and setting: China; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (28 days) Length of follow‐up: 7, 14, 28 days |
|
Outcomes | Timing of outcome assessment: 7, 14, 28 days Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician |
|
Notes | Study investigators concluded that no significant difference in curative effect was noted between the 2 groups. No serious adverse effects were found. Levocetirizine is effective and safe in the treatment of CSU | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Quote (page 477): ‘randomised, double blinded’ |
Allocation concealment (selection bias) | Unclear risk | Not stated |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: ‘randomised, double blinded,’ but no further details given |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote: ‘randomised, double blinded,’ but no further details given |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether any dropped out; not stated |
Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported |
Other bias | Low risk | None detected. Funder: not stated |
Yin 2003b.
Methods | Design: randomised open‐label parallel‐group 3‐arm comparison of mizolastine vs cetirizine vs loratadine Duration: 28 days |
|
Participants | Number of participants randomly assigned: 96; mizolastine n = 30, cetirizine n = 34, loratadine n = 32 Sex: 60% male, 40% female Age of participants (18 to 72), mean age in years: mizolastine 45, cetirizine 38, loratadine 36.5 Unit of allocation: participant Country and setting: China; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (28 days) Length of follow‐up: 5 weeks i.e. follow‐up extended after the cessation of therapy. |
|
Outcomes | Timing of outcome assessment: 14, 28 and a further follow up at 7 days post intervention Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: clinician |
|
Notes | Study investigators concluded that all 3 antihistamines have high clinical efficacy and safety in the treatment of CSU. No statically significant difference was noted among the 3 groups | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Open‐label. randomised |
Allocation concealment (selection bias) | High risk | No concealment |
Blinding of participants and personnel (performance bias) All outcomes | High risk | Open label, no blinding |
Blinding of outcome assessment (detection bias) All outcomes | High risk | Open label, no blinding |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No dropouts reported |
Selective reporting (reporting bias) | Low risk | All outcomes reported |
Other bias | Low risk | None detected. Funder: not stated |
Zou 2002.
Methods | Design: randomised 2‐arm parallel trial of desloratadine vs loratadine Duration: 4 weeks |
|
Participants | Number of participants randomly assigned: 41 (desloratadine n = 21, loratadine n = 20) Sex: 49% female, 51% male: desloratadine 42% female (12 men/9 women); loratadine 55% female (9 men/11 women) Age of participants, mean in years: desloratadine 32.7; loratadine 31.8 Unit of allocation: participant Country and setting: China; secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
Duration of intervention: intermediate‐term (4 weeks) Length of follow‐up: not mentioned Concomitant rescue treatment not permitted |
|
Outcomes | Timing of outcome assessment: assumed to be at end of intervention period—4 weeks Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: participant |
|
Notes | Study investigators concluded that no significant difference in curative effect was noted between the 2 groups. No serious adverse effects were found. Desloratadine was found to be effective and safe in treating patients with CSU | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Unclear risk | Double‐blind randomised controlled trial |
Allocation concealment (selection bias) | Unclear risk | Not mentioned in this study |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Participants and personnel were blinded to treatment group Not clear about this, as it was not mentioned clearly in the method of assessment |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Outcome assessors were blinded to treatment group Not clear, as it was not mentioned in the method of assessment |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No dropouts reported |
Selective reporting (reporting bias) | Low risk | None, all prespecified outcomes were reported |
Other bias | Unclear risk | Funder: not stated. Severity of disease was not clear. Duration of disease with desloratadine ranged from 6 weeks to 6 years, and with loratadine from 6 weeks to 6.5 years |
Zuberbier 2010.
Methods | Design: international multi‐centre double‐blind randomised placebo and active treatment‐controlled parallel‐group 2‐arm study comparing bilastine 20 mg vs levocetirizine 5 mg once daily and placebo Duration: 28 days |
|
Participants | Number of participants randomly assigned: 525 (bilastine n = 173, levocetirizine n = 166, placebo n = 184, unclear numbers) Sex: bilastine: 63% male, 27% female; levocetirizine: 54% male, 46% female; placebo: 40% male, 60% female Age of participants, years: bilastine 41.7, levocetirizine 39.8, placebo 39.4 Unit of allocation: participants Country and setting: Argentina, Belgium, France, Germany, Poland, Romania, Spain (46 centres); secondary care Inclusion criteria of the trial
Exclusion criteria of the trial
|
|
Interventions |
Interventions, dose, duration
(once daily) Duration of intervention: intermediate‐term (28 days) Length of follow‐up: 28 days |
|
Outcomes | Timing of outcome assessment: 0, 14 and 28 days (or at early discontinuation visit in cases of withdrawal from the study) Primary outcomes of the trial
Secondary outcomes of the trial
Clinician or participant report: both |
|
Notes | Study investigators concluded that no significant difference in efficacy was noted between the 2 active groups; both were better than placebo | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Probably done; quote (page 517): "Randomization to treatment was achieved according to a computer‐generated randomisation code provided by the study sponsor (FAES FARMA, SA, Spain)" |
Allocation concealment (selection bias) | Unclear risk | Quote (page 518): "treatments were allocated to each patient in their chronological order of entry into the study" |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote (page 518): "The study medications were supplied as identical over‐encapsulated tablets in individually coded aluminium blister packs to ensure blinding of both the investigators and the patients to treatment'' |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | As above Comment: unclear whether investigators had access to the randomisation list, but this is unlikely given that randomisation was carried out offsite, so we have judged this as low risk |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 457/525 completed. Withdrawals as follows: placebo (n = 35): lack of efficacy 24, adverse event 1, participant decision 3, poor compliance with protocol 3, loss to follow‐up 2, "other" 2; bilastine (n = 15): lack of efficacy 5, adverse event 3, participant decision 4, loss to follow‐up 1, "other" 1; levocetirizine (n = 15): lack of efficacy 7; participant decision 4, poor compliance with protocol 1, loss to follow‐up 2, "other" 1 Comment: Although the study report states ITT, the analysis did not include 3 participants who were randomly assigned but did not receive any medication; another 6 participants were not included in the analysis |
Selective reporting (reporting bias) | Low risk | All outcomes reported |
Other bias | Unclear risk | Funder: FAES Farma (bilastine makers). MDS Pharma Services Inc for technical assistance for development of study, data management and statistical analysis |
AE: adverse event.
AEQLQ: Aerius Quality of Life Questionnaire.
ALAT: alanine transaminase.
ASAT: aspartate transaminase.
BMI: body mass index.
CIU: chronic idiopathic urticaria.
CPK: creatine phosphokinase.
CSU: chronic spontaneous urticaria.
DLQI: Dermatology Life Quality Index.
ECG: electrocardiogram.
FBC: full blood count.
ITT: intention‐to‐treat.
K+: potassium ion.
LFT: liver function test.
MNW: mean number of weals.
MPS: mean pruritus score.
MTSS: mean total symptoms score.
Na2+: sodium ion.
NSAID: non‐steroidal anti‐inflammatory drug.
QoL: quality of life.
RCT: randomised controlled trial.
SAF: safety population.
SIWS: scale for interference of wheals with sleep
SD: standard deviation.
SSRI: symptom scores reduction index.
TSS: total symptoms score.
UAS: Urticaria Activity Score.
U/E: upper extremity.
URTI: upper respiratory tract infection.
VAS: visual analogue scale.
Characteristics of excluded studies [ordered by study ID]
Study | Reason for exclusion |
---|---|
Aberer 2001 | Letter to editor, no study results, not an RCT |
Abushareeah 1997 | CIU mentioned only in abstract, not defined further, no further information available |
Alomar 1990b | RCT of astemizole vs cetirizine with no placebo group, astemizole excluded as withdrawn |
Andri 1993 | Quote: ''...randomly divided into two 15 participant groups'' Unclear if this is true randomisation. Terfenadine vs cetirizine, terfenadine no longer in use. |
Anon 1992 | RCT on astemizole |
Anonymous 1989 | No chronic ordinary urticaria; does not meet inclusion criteria. Only terfenadine: not in use |
Anonymous 1990 | CIU not defined |
Anonymous 1992 | CIU not defined, described only as urticaria |
Arendt 1989 | Included acute urticaria (less than 1 month's duration) |
Atsushi 1985 | Acute urticaria, not CIU |
Bakos 1985 | Not proper randomisation ('divididos em 2 grupos de 10') |
Baraf 1976 | Chronic urticaria unspecified; other causes of pruritus included |
Bernd 1989 | Included physical urticaria |
Bernstein 1986 | Astemizole (not in use) |
Bernstein 2002 | All participants given same combination of antihistamines |
Bian 1996 | Not CSU by our definition |
Bleehen 1987 | All participants given same H1‐antihistamine |
Bloom 2004 | Included participants with allergic rhinitis ('All patients had allergic rhinitis or CSU') |
Brunet 1990 | Chronic urticaria unspecified; did not exclude physical urticaria/vasculitis |
Cainelli 1986 | Astemizole and terfenadine: not in use |
Camarasa 2001 | No definition of chronic idiopathic urticaria; methods do not state any diagnosis |
Cassano 2007 | Study of ciclosporin |
Cerio 1984 | RCT on terfenadine |
Chatterjee 1996 | RCT on terfenadine |
Chen 2005 | RCT, included other forms of urticaria |
Church 2009 | Chronic urticaria, not further specified |
Cook 1983 | No relevant data, described participants allocated to double‐blind treatment in random order. Not randomised. Compared chlorpheniramine plus cimetidine (no other active treatment). No information about dose |
Demaubeuge 1982 | Chronic urticaria, not CSU |
Devillier 2007 | No clinical trials; not relevant to study |
Devillier 2008 | No clinical trials; review on pharmacokinetics and pharmacodynamics—not relevant to study |
Dhurandhar 1987 | Chronic urticaria treatment described, CSU not defined (duration of urticaria history not stated) |
Diller 1983 | No P values; outcome measures not meaningful |
Dockx 1981 | Included acute urticaria |
Farshchain 2002 | Quote: ''Patients were divided into two 75 person‐groups.'' Not an RCT |
Ferguson 1985 | Terfenadine only (not in use) |
Fox 1986 | Astemizole only (not in use) |
Fredriksson 1986 | Included conditions other than CSU |
Gao 2009 | RCT, included other forms of urticaria |
Ge 1987 | Not a comparison of H1‐antihistamines |
Giannetti 1991 | Included acute urticaria (1 month's duration) |
Gibson 1984 | Included conditions other than CSU |
Godse 2006 | Montelukast vs cetirizine. Chronic urticaria not fully defined in terms of duration |
Gong 1995 | Chronic urticaria, not CSU |
Gonzalez‐Morales 1985 | Terfenadine vs placebo |
Greaves 1981 | Chronic urticaria unspecified, random order administration, unclear whether randomised, self‐assessment questionnaire |
Greene 1985 | Included other causes of urticaria (e.g. vasculitis) |
Grob 2009 | Compared regular vs prn desloratadine in participants known to be responsive to the drug. All participants given desloratadine, no comparison |
Guaglianone 1988 | Terfenadine only (not in use) |
Guerra 1994 | CSU not defined |
Hair 2006 | Review article |
Hamerlinck 1994 | RCT. Multi‐centre parallel‐group 2‐arm double‐blind study of loratadine vs astemizole. Astemizole no longer in use, excluded |
Hampel 2010 | Rhinitis and urticaria put together, no separate data |
Han 1992 | Terfenadine only (not in use); looking at hives, not chronic ordinary urticaria |
Hong 2010 | CSU not defined, no efficacy data |
Honsinger 1990 | Astemizole only (not in use) |
Huo 2014 | Acupuncture combined with bloodletting and regular Western medication (loratadine), loratadine arm not compared with active pharmacological intervention |
Ishibashi 1989 | Included acute urticaria |
Ishibashi 1990 | Included acute urticaria |
Ishibashi 1990a | Included acute urticaria |
Ishibashi 1990b | Included acute urticaria |
Ishibashi 1997 | Included acute urticaria |
Ishibashi 1997a | Included acute urticaria |
Ishibashi 1997b | Included acute urticaria |
Isola 1985 | Terfenadine only (not in use); did not use proper randomisation |
Jauregui 2006 | Review article specific to effects of interventions on driving |
Jia 1998 | Included participants with acute and chronic urticaria with no separate data (CSU not defined) |
Jolliffe 1985 | Included physical urticaria ('1 had cold urticaria') |
Juhlin 1988 | Not randomised |
Jyothi 2011 | Included acute urticaria |
Kailasam 1987 | Astemizole |
Kalimo 1980 | Included physical urticaria |
Kalis 1985 | Included physical urticaria |
Kalis 1996 | Included physical, cholinergic urticaria; urticaria less than 6 weeks' duration |
Kameyoshi 2007 | Included acute urticaria (less than 1 month's duration) |
Kamide 1989 | Included urticaria less than 6 weeks' duration |
Kaplan 2008 | Included autoimmune urticaria |
Kapp 2004 | Included physical urticaria |
Kapp 2006 | Cost‐effectiveness study |
Kapp 2006a | Included physical urticaria |
Kawada 2011 | Chronic urticaria not further specified |
Kawashima 2002 | Phase III study of TAU‐284 (bepotastine besilate) on chronic urticaria: a multi‐centre double‐blind comparative study with placebo. Included urticaria of less than 1 month's duration |
Khalaf 2008 | Both groups received same antihistamine |
Kietzmann 1990 | RCT, compared only cetirizine vs terfenadine with no placebo group; therefore excluded, as terfenadine not in use |
Kim 2013 | Retrospective observational single‐centre study of participants with CSU in Korea; 'divided patients into two study groups' |
Kukita 1985 | Terfenadine only (not in use) |
Kukita 1990 | Duration of disease less than 4 weeks (acute urticaria) |
Kukita 1990a | Duration of disease less than 4 weeks (acute urticaria) |
Kukita 1991 | Included acute urticaria |
Kukita 1994 | Included acute urticaria |
Kukita 1994a | Included acute urticaria |
Kukita1985a | Terfenadine only (not in use) |
Kuokkanen 1971 | Included physical urticaria |
Kuokkanen 1975 | Included physical urticaria |
Kuokkanen 1977 | Included physical urticaria |
La Rosa 2001 | Included acute urticaria |
Lambert 1990 | Astemizole vs terfenadine (not in use) |
Lambert 1993 | Included acute urticaria |
Lambert 1993a | Included acute urticaria |
Lan 2002 | Included acute urticaria with CSU, separate data not available |
Lennox 2004a | Validation study of DLQI |
Li 2004 | CSU not defined (abstract only) |
Liu 2002 | RCT of astemizole vs loratadine, no placebo group. Excluded, as astemizole now withdrawn |
Magerl 2009 | Included physical urticaria |
Magerl 2013 | Randomised double‐blind placebo‐controlled study of safety and efficacy of miltefosine (not an H1‐antihistamine) in antihistamine‐resistant chronic spontaneous urticaria |
Maurer 2013a | Randomised, omalizumab, not an H1‐antihistamine |
Meloy 2009 | CSU not defined, rhinitis and urticaria combined, no separate data |
Monroe 1981 | Combined H1 and H2 therapy |
Monroe 2005 | CSU not defined, abstract only, no other details available |
Monteseirin 1992 | States randomly divided, but not randomised |
Mora 2005 | Abstract states 'randomly divided,' but translation of methods indicates that participants were 'put into groups numbered 1 to 4,' without mention of randomisation |
Nakayama 1980 | Included acute urticaria |
Neumann 1984 | Included acute urticaria (4 weeks' duration) |
Nishiyama 1996 | Included acute urticaria |
Nsouli 2013 | All participants taking same antihistamine, cetirizine |
Ormerod 1986 | RCT, but compared terfenadine with brompheniramine; terfenadine no longer in use, therefore excluded |
Ortonne 1998 | CSU not defined, mentions only chronic urticaria |
Paul 1984 | Chronic urticaria unspecified; no useful data |
Paul 1985 | Chronic urticaria unspecified |
Paul 1988 | Terfenadine only (not in use) |
Paul 1988a | Terfenadine only (not in use) |
Paul 1988b | Terfenadine only (not in use) |
Paul 1989 | Terfenadine only (not in use) |
Paul 1989a | Included acute urticaria |
Paul 1989b | RCT terfenadine |
Pavic 2012 | Review article: treatment in children |
Peremans 1981 | Included physical urticaria, excluded on that basis |
Presch 1996 | RCT, compared only terfenadine with cetirizine, no placebo group, terfenadine no longer in use, therefore excluded |
Saihan 1983 | Lack of data; study authors contacted; data not available |
Salisbury 1987 | Included acute urticaria |
Salmun 2000 | Included participants with allergic rhinitis |
Sanchez‐Borges 2013a | Management of aspirin‐exacerbated urticaria |
Sanchez‐Borges 2013b | Review article on updosing |
Shah 1986 | Chronic urticaria unspecified |
Shareeah 1998 | Chronic urticaria, not CSU |
Shereff 1984 | CCT, not RCT |
Sim‐Davis 1983 | Included acute urticaria (4 weeks' duration) |
Simons 1995 | Randomised, but pharmacology study only, no clinical outcomes |
Singh 1987 | Not properly randomised: medications dispensed ''in random order,'' but unclear whether this was true randomisation. No details on number of participants in each group |
Sobye 1968 | Included acute urticaria (less than 1 month) |
Staevska 2010 | Included delayed pressure urticaria |
Sussman 1991 | Included physical urticaria |
Taskapan 2000a | Participants were divided, not randomly assigned |
Tilles 2005 | Chronic urticaria, not CSU |
Valsecchi 1984 | Chronic urticaria, CSU not defined |
Van Cauwenberge 2004 | Allergic disorders; not chronic ordinary urticaria |
van Joost 1989 | Included acute urticaria (4 weeks' duration or less) |
Vena 2002 | Outcomes are histochemical only |
Verhaegen 1980 | Double‐blind but not an RCT |
Vijay 1994 | RCT on astemizole |
Wang 1998 | Included acute urticaria |
Wang 2000 | Test of domestic vs imported cetirizine, randomised, but no control or placebo group. No CSU, chronic urticaria only |
Warin 1966 | CCT and included cholinergic urticaria |
Watson 2000 | Included acute urticaria |
Weitgasser 1967 | Other dermatoses included; not an RCT; clinical observation study |
Weller 2010 | Included chronic spontaneous urticaria; CSU not defined |
Witte 2006 | Inadequate data and reporting |
Wolfram 1967 | Not an RCT; included other dermatoses |
Wozel 1990 | Combination therapy H1 and H2; all participants took same combination |
Wu 1992 | Combined H1‐ and H2‐antihistamines |
Yamada 1968 | Included physical urticaria, duration not specified |
Youngchaiyud 1988 | Chronic urticaria unspecified |
Zabel 1984 | Included acute urticaria (4 weeks' duration) |
Zhang 1990 | Chronic urticaria unspecified |
Zhang 1991 | RCT taking terfenadine |
Zhang 2001 | Included acute urticaria, no separate data |
Zhao 1994 | RCT of loratadine vs astemizole (not in use), no placebo group |
Zhi 2004 | CSU duration of less than 4 weeks included (i.e. acute urticaria included) |
Zhou 2003 | Described as 'chronic urticaria' but CIU not defined; also included acute urticaria with no separate data |
Zuberbier 1995 | Cholinergic urticaria |
CCT: controlled clinical trial.
CIU: chronic idiopathic urticaria.
DLQI: Dermatology Life Quality Index.
RCT: randomised controlled trial.
Characteristics of studies awaiting assessment [ordered by study ID]
Audi'cana 2007.
Methods | Double‐blind randomised dose‐ranging trial in 4 parallel groups |
Participants | CSU, number randomly assigned unclear |
Interventions | 10, 20 and 30 mg bilastine once daily vs placebo |
Outcomes | Unclear |
Notes | Unable to locate a copy at this time for further assessment |
Blanca Gomez 1984.
Methods | Double‐blind (CCT?) |
Participants | Unclear |
Interventions | H1‐ plus H2‐blockers |
Outcomes | Unclear, included pruritus |
Notes | Unable to locate a copy at this time for further assessment |
Boggs 1989.
Methods | RCT (double‐blind randomised placebo‐controlled parallel study) |
Participants | 37 participants |
Interventions | Terfenadine, 60 mg twice daily, vs placebo vs hydroxyzine, 25 mg four times daily |
Outcomes | Adverse effects including somnolence, therapeutic use |
Notes | Unable to locate a copy at this time for further assessment |
Fan 2000.
Methods | RCT |
Participants | Urticaria |
Interventions | Astemizole and loratadine |
Outcomes | Unclear |
Notes | Unable to locate a copy at this time for further assessment |
Feng 2001.
Methods | Design: unclear, states 'random allocation' |
Participants | Unclear, no abstract available |
Interventions | Unclear, includes cetirizine but no details about comparator arms |
Outcomes | Unclear |
Notes | Unable to locate a copy at this time for further assessment |
Guo 2013.
Methods | RCT (randomly divided into 3 groups) |
Participants | One hundred and twenty cases of chronic urticaria |
Interventions | 38 participants in the combination therapy group orally received half pack of compound FKS decocted in water twice daily and mizolastine tablet 10 mg once daily; 39 participants orally received mizolastine tablet 10 mg once daily; 38 patients in the combination therapy group orally received half pack of compound FKS decocted in water twice daily and mizolastine tablet 10 mg once daily; 39 participants orally received mizolastine tablet 10 mg once daily for 4 weeks |
Outcomes | Efficacy, scores of symptoms and signs, improvement. |
Notes | Chinese language study; awaiting copy of paper and translation |
Guo 2014.
Methods | RCT (randomly divided) |
Participants | 209 participants were randomly divided into 2 groups: experimental group (106 cases) and control group (103 cases) |
Interventions | One arm given mizolastine and ketotifen with gradual dose reduction for 10 weeks, while the other participants were given mizolastine alone with gradual dose reduction for 10 weeks |
Outcomes | Total effective rates for experimental group and control group were 76.1% and 43.5%, respectively (P value < 0.05). 4 weeks after treatment, recurrence rates for experimental group and control group were 10.4% and 22.8%, respectively (P value < 0.05). Adverse effects included dry mouth and drowsiness |
Notes | Chinese language study awaiting copy of paper and translation |
Hatano 1981.
Methods | RCT or CCT, double‐blind |
Participants | 121 participants with chronic urticaria |
Interventions | Azatadine maleate 2 mg/d (1 mg/tablet) was administered for 5 days to 61 participants with chronic urticaria, and clemastine fumarate 2.68 mg/d (1.34 mg/tablet) was given to a matched control group of 60 participants |
Outcomes | Efficacy, itching, adverse effects |
Notes | Unable to locate a copy at this time for further assessment |
Monroe 1992a.
Methods | RCT |
Participants | 203 participants with chronic idiopathic urticaria |
Interventions | Loratadine, hydroxyzine and placebo |
Outcomes | Efficacy and safety |
Notes | Unable to locate a copy at this time for further assessment |
Okubo 2013.
Methods | Prospective randomised non‐blinded comparative clinical study and assessment of quality of life |
Participants | n = 51 |
Interventions | Cetirizine 10 mg once daily to 51 participants with urticaria. Participants with inadequate symptom control were randomly assigned to cetirizine 20 mg once daily (dose‐increase group) or olopatadine 5 mg twice daily (drug‐change group) |
Outcomes | Severity of weal and itching and quality of life (QoL) were measured by Skindex—16 were evaluated |
Notes | Awaiting interlibrary loan and, if available, full translation |
Sil 2013.
Methods | Observer‐blind RCT, single centre |
Participants | Chronic urticaria, characterised by frequent appearance of weals for > 6 weeks |
Interventions | Olopatadine (5 mg twice daily) or levocetirizine (5 mg/d) for 9 weeks, continuously for first 4 weeks and then on demand basis for last 5 weeks |
Outcomes | Primary outcome measures were Urticaria Activity Score (UAS) and urticaria total severity score (TSS). Routine haematological and biochemical tests and treatment‐emergent adverse events were monitored for safety |
Notes | Awaiting interlibrary loan |
Tanizaki 2013.
Methods | Unclear |
Participants | CSU and healthy participants |
Interventions | Conventional and double doses of fexofenadine HCl on CSU (and on histamine‐induced skin responses by iontophoresis using visual and laser Doppler imaging scales in healthy donors) |
Outcomes | Cutaneous manifestations in CSU (and histamine‐induced flare and itch in healthy donors) |
Notes | Awaiting interlibrary loan |
Wang 2002.
Methods | RCT |
Participants | Urticaria |
Interventions | Mizolastine vs cyproheptadine |
Outcomes | Unclear |
Notes | Unable to locate a copy at this time for further assessment |
Zhang 2012.
Methods | RCT |
Participants | 136 participants with chronic idiopathic urticaria |
Interventions | Randomly assigned to 3 groups: mizolastine 10 mg daily; loratadine 10 mg daily; mizolastine 10 mg daily combined with compound glycyrrhizin 75 mg 3 times a day |
Outcomes | Symptom score reduction index (SSRI) |
Notes | Awaiting interlibrary loan and, if available, full translation |
Zhang 2013.
Methods | RCT |
Participants | 92 participants with refractory urticaria |
Interventions | Montelukast combined with cetirizine, and control group with Tripterygium glycoside combined with cetirizine |
Outcomes | Total symptoms scores were calculated for participants at baseline and at week 2 and week 4 during treatment based on individual scores for weal and pruritus; incidence of adverse events was recorded |
Notes | Chinese language study awaiting translation |
Zhu 2012.
Methods | RCT |
Participants | 120 mixed group of acute/chronic urticaria with allergic rhinitis |
Interventions | Mizolastine vs cetirizine |
Outcomes | Therapeutic effect and adverse reactions |
Notes | Awaiting interlibrary loan and, if available, full translation |
CCT: controlled clinical trial.
CSU: chronic spontaneous urticaria.
QoL: quality of life.
RCT: randomised controlled trial.
SSRI: symptom score reduction index.
TSS: total severity score.
UAS: Urticaria Activity Score.
Characteristics of ongoing studies [ordered by study ID]
CTRI/2014/04/004545.
Trial name or title | Comparison of efficacy, safety and cost‐effectiveness of rupatadine and olopatadine, antihistaminics, in study participants with urticaria |
Methods | To compare efficacy, safety and cost‐effectiveness of rupatadine and olopatadine in participants with chronic idiopathic urticaria: a randomised double‐blind comparative parallel‐group study Method of generating randomisation sequence: random numbers table Method of allocation concealment: prenumbered or coded identical containers Blinding and masking: participant and Investigator blinded |
Participants | Target sample size 60, with CSU Inclusion criteria
Exclusion criteria
|
Interventions |
|
Outcomes |
Primary outcomes assessed at 1, 3 and 6 weeks
Secondary outcomes assessed at 1, 3 and 6 weeks
|
Starting date | 17 April 2014 |
Contact information | Dr Ganesh N Dakhale Department of Pharmacology, Government Medical College, Nagpur. 440003 Nagpur, MAHARASHTRA India 8308833593 gndakhle@rediffmail.com Government Medical College Nagpur, India |
Notes | Other study ID CTRI/2014/04/004545, ongoing, sponsored by Indira Gandhi Government Medical College, India |
EudraCT: 2004‐000771‐34.
Trial name or title | A 6‐week multi‐centre double‐blind randomised placebo‐controlled parallel‐group study to assess the efficacy and safety of rupatadine 10 and 20 mg in the treatment of chronic idiopathic urticaria (CIU): a phase III clinical trial |
Methods | RCT |
Participants | Male or female 12 to 65 years of age |
Interventions |
|
Outcomes |
Primary outcomes: Primary endpoint will be based on daily subjective assessment of the severity of each symptom of CSU, as recorded by participants in their diaries:
Secondary outcomes
|
Starting date | 2004‐10‐28 |
Contact information | J Uriach y Compañía, S.A. |
Notes | Ongoing |
EudraCT: 2005‐002749‐38.
Trial name or title | A randomised double‐blind placebo‐controlled exploratory trial to evaluate 1‐week oral treatment with R129160 (60 mg twice daily) in participants with chronic idiopathic urticaria—oral treatment with R129160 (60 mg twice daily) in participants with chronic idiopathic urticaria |
Methods | RCT |
Participants | Male and female 18 to 64 years of age with CSU, Czech Republic, Belgium, Netherlands |
Interventions |
|
Outcomes |
Primary outcomes
|
Starting date | 18 July 2007 |
Contact information | Barrier Therapeutics nv |
Notes | Not recruiting, no results posted |
JPRN‐UMIN000001163.
Trial name or title | Study of optimal treatment duration with antihistamine in idiopathic urticaria patients |
Methods | Parallel cluster‐randomised by institution, open. Allocation concealment by centralised registration |
Participants | 120 (target sample size). Male or female 20 years of age or older Inclusion criteria
Exclusion criteria
|
Interventions | 4 week treatment with fexofenadine (120 mg/d) vs no treatment |
Outcomes |
Primary outcomes
Secondary outcomes
|
Starting date | 23 May 2008 |
Contact information | Motoaki Inoue Clinical Research Support Center Kyusyu Secretariat 3‐1‐1 Umade, Higashi‐ku Fukuoka, 812‐8582 +81‐92‐631‐2920 http://www.cres‐kyusyu.or.jp inoue@cres‐kyushu.or.jp |
Notes | Also known as SOLIDARITIE. Closed, no results posted Sponsored by West Japan Urticaria Therapy Study Group, Clinical Research Support Center Kyusyu |
JPRN‐UMIN000003290.
Trial name or title | A study of the antipruritic effect and onset of sleepiness with oral antihistamines. Comparison of sedative and non‐sedative antihistamine |
Methods | Randomised cross‐over open allocation concealment by numbered containers |
Participants | Male and female 16 years of age and older Inclusion criteria
Exclusion criteria
|
Interventions |
|
Outcomes |
Primary outcomes
Secondary outcomes
|
Starting date | 3 May 2005 |
Contact information | Hiramatsu Yusunari Future Medical Research Institute LLC Japan hiramatsu@ebms.co.jp Telephone: 03‐5777‐1001 EBMs Co, Ltd Clinical Business Division |
Notes | Sponsored by Non‐Profit Organization Health Institute Research of Skin Closed, no results posted |
JPRN‐UMIN000008062.
Trial name or title | A study evaluating efficacy of non‐sedative antihistamine up‐titration in patients with chronic urticaria who did not respond to standard therapy |
Methods | Parallel randomised |
Participants | Male and female 16 years of age and older Inclusion criteria
Exclusion criteria
|
Interventions |
|
Outcomes |
Primary outcomes
Secondary outcomes
|
Starting date | 1 June 2012 |
Contact information | Sayumi Hasegawa World Trade Center Bldg 24F 2‐4‐1, Hamamatsu‐cho, Minato‐ku, Tokyo 105‐6124 Japan, Japan hasegawa@ebms.co.jp EBMs Co, Ltd Business Strategy Division |
Notes | Completed, no results posted Funder: non‐profit organisation, Health Institute Research of Skin |
JPRN‐UMIN000008461.
Trial name or title | A study on the optimal treatment for chronic idiopathic urticaria insufficient for the second‐generation antihistamines |
Methods | Parallel, randomised, open |
Participants | Male and female 20 years of age or older. Inclusion criteria
Exclusion criteria
|
Interventions | Antihistamines (details unclear) |
Outcomes |
Primary outcomes
|
Starting date | 1 April 2011 |
Contact information | Tamotsu Ebihara 35 Shiannomachi Shinjuku‐ku Tokyo, JAPAN, Japan ebitamo@yahoo.co.jp Keio University School of Medicine, Department of Dermatology |
Notes | Ongoing, recruiting Sponsored by Keio University School of Medicine |
JPRN‐UMIN000010265.
Trial name or title | Preliminary trial of the increase in antihistamines in dose and a combination of different antihistamines for refractory spontaneous urticaria |
Methods | Open parallel‐group randomised allocation concealed by numbered containers |
Participants | Target of 32 participants with idiopathic urticaria (definition and duration not stated), male or female 20 years of age or older Inclusion criteria
Exclusion criteria
|
Interventions |
|
Outcomes |
Primary outcomes
Secondary outcomes
|
Starting date | 1 April 2013 |
Contact information | Takuma Kohsaka Hiroshima University Hospital Department of Dermatology 1‐2‐3, Kasumi, Minami‐ku, Hiroshima, 734‐8551 +81‐82‐257‐5237 takumuchi0116@yahoo.co.jp |
Notes | Sponsored by Hiroshima Univeristy, and funded by GlaxoSmithKline, ongoing, completing 31 March 2015 |
NCT00199238.
Trial name or title | A 4‐week dose‐finding multi‐centre double‐blind randomised placebo‐controlled parallel‐group trial to assess the efficacy and safety of different doses of rupatadine compared with placebo in the treatment of chronic idiopathic urticaria |
Methods | RCT |
Participants | Male and female 12 to 65 years of age with CSU |
Interventions |
|
Outcomes |
Primary outcomes
Secondary outcomes
|
Starting date | October 2002 |
Contact information | Eva Arnaiz, PhD, J Uriach y Compania |
Notes | Terminated, no study results posted |
NCT00199251.
Trial name or title | A 6‐week multi‐centre double‐blind randomised placebo‐controlled parallel‐group study to assess the efficacy and safety of rupatadine 10 and 20 mg in the treatment of chronic idiopathic urticaria (CIU): a phase III clinical trial |
Methods | RCT |
Participants | Male and female 12 to 65 years of age with CSU |
Interventions |
|
Outcomes |
Primary outcomes
Secondary outcomes
|
Starting date | April 2004 |
Contact information | J Uriach and Company |
Notes | Terminated, no study results posted Other study ID IC010RUP304 |
NCT00421109.
Trial name or title | Double‐blind, randomised, placebo‐controlled, phase III study comparing the efficacy and safety of bilastine 20 mg once daily and levocetirizine 5 mg for the treatment of chronic idiopathic urticaria |
Methods | RCT |
Participants | Male and female 18 to 70 years of age with CSU |
Interventions |
|
Outcomes |
Primary outcomes
|
Starting date | July 2006 |
Contact information | Faes Farma, S.A. Principal Investigator: Olmos, MD Hosp Clinico San Carlos, Servicio Dermatologia (Madrid, Spain) Principal Investigator: De Weert, MD Uz Gent/De Pintelaan 185 (Belgium) Principal Investigator: Dubertret, MD Hopital St Louis/Sce Dermatologie/1 Av Claude Vellefaux (Paris, France) Principal Investigator: Simon, MD Univ Klinikum Leipzig/Klinik Für Dermatologie (Germany) Principal Investigator: Kapinska‐Mrowiecka, MD Szpital Specjalistyczny Im S Zeromskiego/Oddzial Dermatologii/Os Mlodosci 11 (Krakow, Poland) Principal Investigator: Benea, MD Spit Clin Dermato‐Venero, Prof Dr/Scarlat Longhin/alea Serban Voda 216, Sector4 (Bucharest, Romania) Principal Investigator: Herrero, MD Consultorio De Alergia 1° Piso/Hospital Juan A. Fernandez/Cervino 3355 (Buenos Aires, Argentina) |
Notes | Completed July 2007 (final data collection date for primary outcome measure), no study results posted Other study IDs EudraCT 2006‐001245‐33, BILA 2006/UCI |
NCT00751166.
Trial name or title | A comparative double‐blind double‐dummy study of desloratadine (dl) 5 mg once daily, cetirizine 10 mg once daily and placebo once daily in patients with chronic idiopathic urticaria (CIU) |
Methods | RCT |
Participants | Male and female 12 to 70 years of age with CSU |
Interventions |
|
Outcomes |
Primary outcomes
|
Starting date | March 2004 |
Contact information | Schering‐Plough |
Notes | Terminated May 2005, no study results posted. Study terminated, as could not be resupplied with study medication in a timely manner Other study ID P03736 |
NCT00751218.
Trial name or title | A comparative double‐blind double‐dummy study of desloratadine (dl) 5 mg once daily, cetirizine 10 mg once daily and placebo once daily in patients with chronic idiopathic urticaria (CIU). |
Methods | RCT |
Participants | Male and female 12 to 70 years of age with CSU |
Interventions |
|
Outcomes |
Primary outcomes
|
Starting date | May 2004 |
Contact information | No contacts or locations posted, Schering‐Plough |
Notes | Terminated August 2005, no study results posted Other study ID P03735 |
NCT00783354.
Trial name or title | A pilot multi‐centre double‐blind randomised study for comparison of Aerius® "Continuous Treatment" versus Aerius® "PRN Regimen" on chronic idiopathic urticaria patient quality of life |
Methods | RCT |
Participants | Male and female over 18 years of age with CSU |
Interventions |
|
Outcomes |
Primary outcomes
|
Starting date | April 2003 |
Contact information | Head, Clinical Trials Registry & Results Disclosure Group, Schering‐Plough |
Notes | Known as ATTITUD. Completed April 2004, no study results posted Other study ID P03147 |
CIU: chronic idiopathic urticaria.
CSU: chronic spontaneous urticaria.
DLQI: Dermatology Life Quality Index.
MAO: monoamine oxidase.
MNW: mean number of weals.
MPS: mean pruritus scale.
MTSS: mean total symptoms score.
NRS: numerical rating scale
OPD: Out‐patient Department.
QoL: quality of life.
SIWS: scale for interference of wheals with sleep
VAS: visual analogue scale.
Differences between protocol and review
We now use the term chronic spontaneous urticaria.
We changed the wording of the 'Types of participants' criteria to clarify that we mean angio‐oedema without weals rather than angio‐oedema without urticaria, as the latter uses the term ‘urticaria’ as a descriptor rather than a disease. We used 'autoinflammatory syndrome' rather than ‘associated abnormalities,’ as Muckle‐Wells and Schnitzler's syndrome are not urticaria.
We clarified that we have included any first‐generation ('sedating') or second‐generation ('non‐sedating') H1‐antihistamines at any dose (including topical interventions and H2RAs given concomitantly) given as single therapy or as combination therapy. Comparators consisted of no treatment, that is, placebo, or another active (pharmacological) compound. We included studies that compared the same drug but at different doses, but we excluded non‐pharmacological interventions such as acupuncture.
We collected additional data from the reports of studies, such as country and setting, to obtain further information about clinical heterogeneity between our included studies.
We did not carry out subgroup analyses on the basis of first‐generation ('sedating') and second‐generation ('non‐sedating') antihistamines, as included studies with relevant outcome data were too few to allow meaningful comparisons.
We clarified that duration of intervention is categorised as follows: up to two weeks (short‐term) and longer than two weeks up to three months (intermediate‐term). Our analyses are now subgrouped by duration of intervention, as we are not looking for a cure but would like to identify which antihistamine will suppress or give good or excellent response for urticaria immediately and over the longest time.
We excluded studies that investigated the effects of astemizole or terfenadine (withdrawn from use).
We described moderate statistical heterogeneity as > 50% in the protocol, but we revised this in the full review to moderate heterogeneity at I² > 60%.
For some comparisons, we used Fisher's exact test because of the small number of participants,
We had stated that we would use funnel plots when at least three studies were included in the meta‐analysis, but the Cochrane Handbook for Systematic Reviews of Interventions recommends a minimum of 10 studies for sufficient power.
We included in our methods section updated information about assessment of risk of bias using the 'Risk of bias' tool of The Cochrane Collaboration, and details about how we dealt with cross‐over trials are provided in the Unit of analysis issues section.
Contributions of authors
Link with editorial base and co‐ordinate contributions from co‐authors, supervision (AS, CB). Draft protocol (AS, SNC, CC, LB, CH). Run search (AS, SNC, MS, CB). Identify relevant titles and abstracts from searches (AS, SNC, MS, CB). Obtain copies of trials (AS, MS, SNC, CB). Select trials (AS, SNC, MS, CB, CC). Extract data from trials (AS, CB, MS, SNC, CC). Enter data into RevMan (CB, MS, BC). Carry out data analyses and draft Effects of Interventions section of the review (BC, CB, MS). Interpret data (BC, CB, MS, SNC). Draft final review (CB, MS, SNC, BC). Update review (MS, CB, SNC, BC).
Disclaimer
The views and opinions expressed therein are those of the review authors and do not necessarily reflect those of the National Institute for Health Research (NIHR), the National Health Service (NHS) or the Department of Health, UK.
Sources of support
Internal sources
Queen's Medical Centre, UK.
External sources
-
The National Institute for Health Research (NIHR), UK.
The NIHR, UK, is the largest single funder of the Cochrane Skin Group
Declarations of interest
Maulina Sharma: "I have represented the Cochrane Skin Group as a stakeholder for a NICE (National Institute for Health and Care Excellence) scoping workshop for chronic spontaneous urticaria: omalizumab 2014. I have received an honorarium as a speaker for a general practitioner (GP) educational event, which was donated to the charitable funds of the department. I have attended training and continuing medical education (CME) events that may have been sponsored in part by pharmaceutical industry. I have been a subinvestigator for clinical trials conducted in the Department of Dermatology, George Eliot Hospitals NHS Trust, Nuneaton, UK (2005 to 2006), in particular, the CUTE study (NCT00264303). I was not involved in writing of the results and received no payments for my involvement with the clinical trials." Cathy Bennett: "I am the proprietor of Systematic Research Ltd, a company providing research services; I am an employee of this company and received a consultancy fee for the production of this review. I have also received consultancy fees for other Cochrane reviews and work in evidence‐based medicine." Stuart N Cohen: Nothing to declare. Ben Carter: Nothing to declare.
Dr Karsten Weller was a clinical referee: "I received lecture fees or advisory board fees from Novartis, Uriach, FAES, MSD (Essex Pharma), UCB or was involved in clinical studies with drugs from these companies."
Joint second author
Joint second author
Edited (no change to conclusions)
References
References to studies included in this review
Alomar 1990a {published data only}
- Alomar A, Puig L, Moragas JM. Cetirizine in the treatment of chronic urticaria [Tratamiento de la urticaria cronica con dihidrocloruro de cetirizina]. Actas Dermo‐Sifiliograficas 1990;81(3):181‐3. [EMBASE: 1990175012] [Google Scholar]
Anuradha 2010 {published data only}
- Anuradha P, Maiti R, Jyothirmai J, Mujeebuddin O, Anuradha M. Loratadine versus levocetirizine in chronic idiopathic urticaria: a comparative study of efficacy and safety. Indian Journal of Pharmacology 2010; Vol. 42, issue 1:12‐6. [MEDLINE: ] [DOI] [PMC free article] [PubMed]
Beck 1985 {published data only}
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