Study ID	Detail of results
Amayasu 2000	Clarithromycin vs placebo in cross‐over trial. 15/17 participants improved their symptom score; 2 reported no improvement. Mean symptom score decreased significantly after treatment with clarithromycin (1.64 SD 0.48 vs 0.88 SD 0.72; P < 0.05). No change in FVC and FEV1 during clarithromycin therapy. No bronchodilating effect of the macrolide. Blood eosinophil count and serum and sputum ECP levels were significantly decreased after clarithromycin treatment (blood eosinophils: 46.3 SD 6.9 vs 12.0 SD 2.4; P < 0.1; sputum eosinophils: 90 SD 32 vs 11 SD 6; P < 0.05; both serum and sputum ECP: P < 0.05; 15.2 SD 7.3 vs 3.7 SD 1.5 and 1.7 SD 0.9 vs 0.4 SD 0.1, respectively). Methacholine provocation test caused an obstructive reaction in all participants independently of treatment. PC20‐methacholine was higher in the clarithromycin than in the placebo group (mean log PC20 methacholine was 2.96 SD 0.57 in clarithromycin vs 2.60 SD 0.51 in placebo; P < 0.01). No statistically significant association between increased PC20 methacholine and ECP levels. No adverse reactions during treatment with clarithromycin. Authors concluded that clarithromycin has not only antibacterial, but also an anti‐inflammatory activity, associated with a reduction of the eosinophilic infiltration in people with asthma. It is able to improve symptoms and bronchial hyperresponsiveness, but further trials are needed to investigate its clinical utility.
Belotserkovskaya 2007	Azithromycin vs control (no details) Only in abstract form from the ERS congress 2007. Data only partially reported. No significant difference for FEV1, PEF, rescue medications and symptoms between the azithromycin and placebo groups. Subgroup analysis for participants treated with azithromycin and with serological positivity for C pneumoniae showed a statistically significant improvement from the baseline for FEV1 (from 1.99 L to 2.25 L; P = 0.01) and PEF (from 305.1 L/minute to 348 L/minute; P = 0.03).
Black 2001	Roxithromycin vs placebo At end of 6 weeks' treatment, increase in mean values of morning PEF were significantly higher with roxithromycin (14 L/minute) compared to placebo (8 L/minute). There was a subsequent increase of morning PEF values in both groups over the following 6 months after the end of treatment, where the improvement over baseline was 18 L/minute with roxithromycin compared to 12 L/minute with placebo (P = not significant). For evening PEF values, roxithromycin significantly improved PEF values (15 L/minute vs 3 L/minute in the placebo group) at the end of the treatment (P = 0.02), but not at later time points. Both daytime and night‐time symptom scores showed a non‐significant improvement with roxithromycin compared to with placebo over the 6‐month study period. Non‐significant trend for improved AQLQ score with treatment. No statistically significant difference for daytime and night‐time symptoms scores. No difference for rescue medications or for Chlamydophila antibody titres measured during the study. No difference for adverse effects between groups. Only mild and reversible liver function test alterations were recorded in 2 participants treated with roxithromycin. Authors concluded that the (not statistically significant) trend of improvement of pulmonary function test as seen in the 3 months following end of treatment with roxithromycin compared to with placebo suggest that the effect of macrolide therapy on PEF values could be due more to the antimicrobial effect than to the anti‐inflammatory effect of the drug, and that the onset time and persistence of the effect could be due to a suppression more than a eradication of the C pneumoniae infection. The authors also suggested a study with the use of 2 antibiotics active against C pneumoniae.
Brusselle 2013	Azithromycin vs placebo No difference between groups in rate of severe asthma exacerbations (defined as need for hospitalisation, need for systemic steroids for ≥ 3 days or ED visits) or lower respiratory tract infections requiring antibiotics. No effect of azithromycin compared with placebo after 26 weeks for lung function (FEV1 and morning and evening PEF), or for ACQ. AQLQ score was significantly improved after 26 weeks from baseline with azithromycin, but with placebo. No significant difference between groups in AQLQ score after 26 weeks of treatment. No differences in rate of adverse events with azithromycin or placebo. A significantly higher proportion of participants with azithromycin compared with placebo had macrolide‐resistant strains of streptococci at end of study (87% with azithromycin vs 35% with placebo; P < 0.001). A predefined subgroup analysis for the main outcome showed a statistically significant reduction in rate of exacerbations in participants with non‐eosinophilic severe asthma (defined as blood eosinophils ≤ 200/μL) treated with macrolides vs placebo (0.44 primary endpoint rate, 95% CI 0.25 to 0.78 with azithromycin vs 1.03 primary endpoint rate, 95% CI 0.72 to 1.48 with placebo; P = 0.01). Conversely, there was a higher primary endpoint rate with azithromycin (0.96, 95% CI 0.66 to 1.41) compared with placebo (0.50, 95% CI 0.28 to 0.88) among the participants with severe asthma and blood eosinophils > 200/μL.
Cameron 2013	Azithromycin vs placebo No significant differences between the azithromycin and placebo groups. Change from the baseline of the morning PEF (primary outcome): mean difference −10.3 L/minute, 95% CI −47.1 to 26.5 (P = 0.58); FEV1 at 12 weeks (pre‐albuterol): 2.41, SD 0.77 L/second with azithromycin vs 2.46, SD 0.75 L/second with placebo (P = NS); bronchial hyperreactivity: 0.20, SD 1.52 Log PC20 mg/mL with azithromycin vs 0.19, SD 1.29 Log PC20 mg/mL with placebo (P = NS). After 12‐week study period: use of rescue medications: 2.7, SD 2.5 times/day with azithromycin vs 3.0, SD 4.0 times/day with placebo; P = NS); ACQ score: 1.75, SD 0.83 with azithromycin vs 1.58, SD 0.96 with placebo (P = NS); AQLQ score: 5.2, SD 1.06 with azithromycin vs 5.42, SD 1.31 with placebo (P = NS); eosinophil count in induced sputum: 10.3, SD 20.1 × 104 with azithromycin vs 6.8, SD 13.9 × 104 with placebo (P = NS). No adverse events in either groups.
Gibson 2017	Azithromycin vs placebo Participants had a median age of 60 years (IQR 50–68), with history of atopic asthma (76%) for a median of 32 years (IQR 14–48). Ex‐smokers (38% of the total) were also included. Most participants entering this trial were receiving high‐dose ICS, and all had prescribed long‐acting bronchodilators such as LABA, LAMA or theophylline. Their asthma was uncontrolled (ACQ6 1.55, SD 0.79; FEV1 73% predicted). All these characteristics were similar in the 2 groups. Withdrawals: 45 with azithromycin vs 41 with placebo. Azithromycin reduced frequency of total asthma exacerbations (1.07 exacerbations per year per person, 95% CI 0.85 to 1.29) compared to placebo (1.86 exacerbations per person per year, 95% CI 1.54 to 2.18) (IRR 0.59, 95% CI 0.47 to 0.74; P < 0.0001). Azithromycin reduced time to exacerbation (HR 0.65, 95% CI 0.50 to 0.85; P = 0.001). Severe exacerbations (defined as worsening of symptoms causing a cure with oral steroids (or variation of their dosage), a hospitalisation or an ED visit) were significantly fewer with azithromycin (IRR 0.59, 95% CI 0.42 to 0.83; P = 0.002). Reduction of exacerbations was consistent in participants with both eosinophilic and non‐eosinophilic asthma. FEV1 at end of the treatment was lower with azithromycin compared to placebo, but this difference was not clinically relevant (adjusted mean −0.06 L, 95% CI −0.12 to −0.001). Azithromycin improved quality of life (AQLQ adjusted mean difference 0.36, 95% CI 0.21 to 0.52; P = 0.001) and asthma control (ACQ6 adjusted mean difference −0.20, 95% CI −0.34 to −0.05). No significant difference in incidence of adverse events, except for diarrhoea, which was more frequent among participants treated with azithromycin (n = 72, 34%) than in the placebo group (n = 39, 19%) (P = 0.001). No difference in isolation of resistant strains detected in sputum cultures at end of treatment between groups.
Hahn 2006	Azithromycin vs placebo No significant difference at 3 months after completion of 6‐week treatment for Juniper AQLQ (0.59, SD 0.8 with azithromycin vs 0.34, SD 1.0 with placebo; P = NS) and rescue medications (0.43, SD 1.8 times per day with azithromycin vs −0.16, SD 1.3 times per day with placebo; P = NS). Symptoms and daily activities, recorded with a homemade scale from 0 = no symptoms to 4 = worse than ever, were significantly improved with azithromycin (0.55, SD 0.7 with azithromycin vs −0.13, SD 0.9 with placebo; P = 0.04). 3 participants per group withdrew consent during study, while 1 participant in azithromycin group discontinued the study. No adverse events with azithromycin vs 1 serious adverse event with placebo (death from asthma‐related causes).
Hahn 2012	Azithromycin vs placebo Only data from randomised treatment group and the placebo group were considered in our review/meta‐analysis; the open‐label group was excluded. Of 304 screened patients, 97 (32%) were enrolled: 38 to azithromycin, 37 to placebo and 22 to open‐label group. No significant difference for severe exacerbations across groups, but rates were not reported. 1 year after randomisation, no significant differences for symptoms with a home scale from 0 = no symptoms to 4 = worse than ever (−0.31, SD 0.74 with azithromycin vs −0.48, SD 1.16 with placebo; P = NS), ACQ score (−0.40, SD 0.8 with azithromycin vs −0.41, SD 1.1 with placebo; P = NS) and Juniper AQLQ (0.67, SD 1.10 with azithromycin vs 0.50, SD 0.95 with placebo). Withdrawal was high and uneven between groups (19 (50%) participants with azithromycin and 12 (32.4%) participants with placebo at 12‐month‐follow‐up). 1 participant discontinued study with placebo because of acute coronary syndrome; 1 participant discontinued study with placebo because of adverse effects. Mild adverse effects were common with azithromycin (nausea: 33% with azithromycin vs 9% with placebo; stomach pain: 42% with azithromycin vs 12% with placebo; diarrhoea: 42% with azithromycin vs 15% with placebo), but no‐one discontinued medications because of the adverse effects.
Kamada 1993	Troleandomycin + methylprednisolone (n = 6) vs troleandomycin + prednisone (n = 8) vs placebo + methylprednisolone (n = 5) Significant glucocorticoid dosage reduction in all 3 groups. The maximum tolerated percentage dosage reductions were 80%, SD 6% with troleandomycin + methyl prednisone (P < 0.001), 55%, SD 8% (P < 0.001) with troleandomycin + prednisone and 44%, SD 14% (P = 0.04) with placebo + methylprednisolone. Significant difference only between the troleandomycin + methylprednisolone and placebo + methylprednisolone groups. No statistically significant difference for days of supplemental prednisone for exacerbations. Symptom score was reduced by nearly 50% with troleandomycin + methylprednisolone (P = 0.03). No significant differences in other groups. Pulmonary function tests were slightly reduced in all groups, with a significant reduction of prebronchodilator FEV1 and FEF25‒75 in the troleandomycin + prednisone group (FEV1: P = 0.03; FEF25‒75: P = 0.01). Methacholine PC20 was significantly reduced only in the troleandomycin + methylprednisolone group and slightly increased in the troleandomycin + prednisone group, but the difference may reflect glucocorticoid dosage taper and supplemental prednisone before the final evaluation. Safety aspects: 13 participants received troleandomycin. 1 participant in the troleandomycin + prednisone group experienced an elevation of liver enzymes that was resolved by the discontinuation of troleandomycin. 1 participant in the troleandomycin + methylprednisolone group reported a mild elevation of liver enzymes, which resolved spontaneously without discontinuation of the treatment. No significant alterations of serum and urine cortisol concentrations, whereas there was an increase in the methylprednisolone group. Bone density was unchanged in all groups. There was a slight decrease (NS) in bone density in the 2 groups receiving troleandomycin. 1 participant in the troleandomycin + prednisone group had severe osteopenia before the start of the study and experienced a vertebral compression fracture that was attributed to her previous glucocorticoid exposure. 1 participant in the troleandomycin + prednisone group developed marked striae on the arms and trunk. She was also affected by Marfan's syndrome. Authors concluded that, despite the absence of a control group with only prednisone and the low numbers of participants for each group, some conclusions could be drawn from this study: it was not possible to improve lung function by tapering the steroid dose; the only goal reached was to keep the same level of lung function when reducing the dose of steroids, without severe adverse effect.
Kapoor 2010	Roxithromycin vs placebo Presented in abstract at the ERS Congress 2010 in Barcelona. Significant improvement from baseline for the ACT score in both groups, but no difference when comparing the improvements between the 2 groups after the 6 weeks of treatment (2.68, SD 3.17 with roxithromycin vs 1.80, SD 2.83 with placebo; P = NS). No significant difference between groups for FEV1 at end of study. There was only very limited information on participants' characteristics and randomisation available. There were no data for withdrawal or adverse events, and data on lung function and impulse oscillometry were described only as not significantly different in the 2 groups.
Kostadima 2004	Clarithromycin twice daily vs clarithromycin 3 times daily vs placebo Significant increase in FEV1% only with clarithromycin 250 mg 3 times daily (from 85, SD 13 at baseline to 88, SD 12 at end of study; P < 0.05). No difference in other groups (from 85, SD 14 at baseline to 86, SD 14 at end of study with clarithromycin 250 mg twice daily; from 85, SD 12 at baseline to 88, SD 15 at end of study with placebo). Compared to baseline, there was a significant increase in the median PD20 with clarithromycin 250 mg twice daily and clarithromycin 250 mg 3 times daily but not with placebo. Median (IQR) in the 3 groups were before and after the treatment were: clarithromycin 250 mg twice daily: 0.3 (IQR 0.1 to 1) and 1.3 (IQR 0.6 to 2) mg (P < 0.001); clarithromycin 250 mg 3 times daily: 0.4 (IQR 0.1 tp 0.9) and 2.0 (IQR 2.0 to 2.0) mg (P < 0.001); and placebo: 0.4 (IQR 0.1 to 0.9) and 0.3 (IQR 0.1 to 0.6) mg (P = NS). No adverse effects were clearly reported, but 1 participant in the clarithromycin 250 mg 3 times daily group withdrew for a gastrointestinal disorder (no further details reported). Cortisol levels were measured in 40 participants, and there were no differences at the baseline and after the treatment with the macrolide.
Kraft 2002	Clarithromycin vs placebo Of 55 participants included in the study, 3 were not randomised due to scheduling difficulties (n = 1) and non‐compliance (n = 2). Clarithromycin n = 26, control n = 26. 14 participants in the clarithromycin group and 13 participants in the placebo group showed a positive PCR for M pneumoniae or C pneumoniae at the baseline on samples obtained via bronchoscopy. No change in FEV1 mean values between clarithromycin and placebo at end of treatment (2.64, SD 0.14 L with clarithromycin vs 2.69, SD 0.16 with placebo; P = 0.75). A subanalysis for PCR status found participants with a positive PCR for M pneumoniae or C pneumoniae showed a significant increase after clarithromycin (FEV1 mean value 2.50, SD 0.16 at baseline to 2.69, SD 0.16 after treatment; P = 0.05; n = 14), while there was no change in participants with a positive or negative PCR who received placebo (data not reported in the paper) or with a negative PCR who received the macrolide (FEV1 mean value from 2.59, SD 0.24 L at baseline to 2.54, SD 0.18 L after treatment; P = 0.85; n = 12). Study was also designed to investigate the modulation of inflammatory cytokines in BAL and bronchial biopsies during the treatment with clarithromycin. Significant reduction in the expression of TNF‐alpha, IL‐5 and IL‐12 mRNA in BAL and TNF‐alpha in airways tissue among the PCR‐positive participants treated with macrolides and the PCR‐negative participants receiving clarithromycin showed a significant reduction in the expression of TNF‐alpha and IL‐12 mRNA in BAL and TNF‐alpha in airways tissue. There was no significant difference in cytokine expression among participants receiving placebo. Unclear why the participants underwent a sinus computer tomography evaluation if they were not affected by chronic sinusitis and if 1 of the exclusion criteria was a history of upper airways infection in the last 3 months before the study. No data on adverse events.
Nelson 1993	Troleandomycin + methylprednisolone (n = 37) vs placebo + methylprednisolone (n = 38) Significant reduction in the requirement for hospitalisation and steroid boost relative to the year before the study in both groups. Similar results during the 2 years of follow‐up. Data were expressed as rate per year, not as number of events. The authors remarked that the tapering of steroid dose was performed only in situations of complete symptom control and that symptom control was not an evaluable outcome. Corticosteroid dose: mean steroid dose at enrolment was not significantly different between groups. Mean dose reported in the placebo group during the year preceding the study entry was significantly higher with troleandomycin + methylprednisolone (22.8, SD 1.9 mg/day with troleandomycin + methylprednisolone vs 17.6, SD 1.5 mg/day with placebo + methylprednisolone; P = 0.02). Significant reduction from the previous corticosteroid usage for the lowest stable dose in both groups, with troleandomycin‐treated participants reaching a lower dose (10.4, SD 1.3 mg/day with troleandomycin + methylprednisolone vs 6.3, SD 1.3 mg/day with placebo + methylprednisolone; P = 0.03). Neither the 1‐year nor the 2‐year reduction of the dose was significantly different in the 2 groups. Corticosteroid effects: eosinophil counts were significantly increased at the 1‐year evaluation in both groups. Similarly, the 60‐minute stimulated cortisol levels rose during the study, and after 1 year the difference was significant in both groups, but not between groups. Dual‐photon densitometry of the L2‐4 vertebrae showed a continued decline in both groups of bone density when adjusted for age‐matched controls. The mean decline over 1 and 2 years was twice as great, but significant only in the troleandomycin + methylprednisolone group (1 year: P = 0.01; 2 years: P = 0.001). Significant differences between groups for mean IgG level decreased with troleandomycin + methylprednisolone, and this change was not observed with placebo + methylprednisolone (2 years: P = 0.03); fasting blood sugar increased with troleandomycin + methylprednisolone and decreased with placebo + methylprednisolone (2 years: P = 0.02); mean cholesterol level increased with troleandomycin + methylprednisolone, although not significantly; it was lower with placebo + methylprednisolone after 1 (P = 0.03) and 2 years (P = 0.01), with a significant difference between groups (1 year: P = 0.02; 2 years: P = 0.03). Methacholine challenge was performed in only 13 with troleandomycin + methylprednisolone and 11 participants with placebo + methylprednisolone. The dose producing a 20% fall in FEV1 rose with 13 with troleandomycin + methylprednisolone, indicating less airway responsiveness (1.86 mg/mL with troleandomycin + methylprednisolone vs 0.55 mg/mL with placebo + methylprednisolone; P = 0.08). 3 participants died during study (2 with troleandomycin + methylprednisolone vs 1 with placebo + methylprednisolone; 0 related to asthma). Number of dropouts at 1 year of the study were higher with placebo + methylprednisolone (n = 11, 28.9%) than with troleandomycin + methylprednisolone (n = 7, 18.9%). The authors highlighted the importance of adequately educating the patients regarding the use of anti‐asthma drugs, especially steroids. Although the study showed a significant difference in the lower stable dose reached with troleandomycin + methylprednisolone, the increase in indicators of adverse effects such as cholesterol and fasting blood sugar, and a less significant reduction in bone densitometry, did not confirm the utility of the steroid‐sparing effect of troleandomycin but showed a detrimental action with increasing the potential for adverse effects of steroid treatment.
Piacentini 2007	Azithromycin (n = 8) vs placebo (n = 8). No statistically significant variation for FEV1 within and between groups (azithromycin FEV1 % of reference value: 73.5, 12.90 at time point 0 and 74.62, SD 9.76 after treatment; P = NS; placebo FEV1 % of reference value: 84.25, SD 9.58 at time point 0 and 86.00, SD 9.85 after treatment; P = NS). Comparison between azithromycin and placebo group at end of study not statistically significant. Bronchial hyperresponsiveness was assessed with a hypertonic saline challenge and expressed as dose–response slope rather than PD15, reflecting the fall of FEV1 per unit of substance inhaled. Significant reduction from baseline in dose–response slope observed with azithromycin at the end of the study (from 2.75, SD 2.12 to 1.42, SD 1.54; P = 0.02), but not with placebo (from 1.48, SD 1.75 to 1.01, SD 1.38; P = NS). No between‐group differences. Sputum analysis was conducted in 6 participants in the azithromycin group and in 7 participants in the placebo group. Percentage of neutrophils in the sputum was significantly decreased from baseline with azithromycin (from 10%, SD 5% to 2.2%, SD 2.4%; P < 0.01), but with placebo (from 7.2%, SD 4.2% to 3.2%, SD 3.6%; P = NS). There were no between‐group differences. Dropouts and adverse events not reported.
Shoji 1999	Roxithromycin vs placebo in cross‐over trial Symptom score significantly decreased after roxithromycin treatment (1.63, SD 0.48 vs 0.87, SD 0.70; P < 0.05). No statistically significant differences in FEV1 between roxithromycin and placebo groups after 8 weeks (2.37, SD 0.30 with roxithromycin vs 2.25, SD 0.26 with placebo; P = NS) or for the provocation test with sulpyrine (PC20 sulpyrine 1.18, SD 0.40 with roxithromycin vs 1.15, SD 0.43 with placebo at end of study; P = NS). No difference in leukotriene E4 elimination in the urine after the treatment within and between groups. Mean ECP and eosinophils count both in serum and sputum showed a significant decrease after 8‐week treatment with the antibiotic (blood eosinophils: from 43.36, SD 7.3 × 104/mL to 12.4, SD 2.3 × 104/mL; P < 0.01; sputum eosinophils: from 94, SD 28 × 104/mL to 10, SD 6 × 104/mL; serum ECP: 15.8, SD 6.3 mg/L to 3.6, SD 1.4 mg/L; P < 0.05; sputum ECP: 1.8, SD 0.4 mg/L to 0.4, SD 0.1 mg/L; P < 0.05). Dropouts were not reported. None of the participants reported any adverse effects.
Simpson 2008	Clarithromycin vs placebo Study designed and powered primarily to detect a difference in the IL‐8 expression in sputum supernatants of people with refractory asthma after treatment with macrolides. Results reported as median and IQR for most of the descriptive statistics. Levels of IL‐8 were significantly reduced from the baseline with clarithromycin, with 6.6 ng/mL (IQR 2.7–11.9) before and 3.9 ng/mL (IQR 1.8–5.4) after treatment (P = 0.001). Statistically significant difference (with a cut‐off point of 0.05 used to determine significance) in IL‐8 levels with clarithromycin at the end of the study vs with placebo (6.3 ng/mL, IQR 3.1–17.3 at beginning and 6.4 ng/mL, IQR 3.711.3 at end). Number of neutrophils in the sputum significantly reduced with clarithromycin from the baseline at end of treatment (from 142.9 × 104/mL to 66.7 × 104/mL; P < 0.04), but no difference with placebo. No effect of clarithromycin on FEV1 % within the treatment arm (73.6, SD 15.8 at time point 0 and 74.6, SD 17.1 at end of treatment; P = NS) or with placebo group (P = NS). No effect of clarithromycin on bronchial hyperresponsiveness within the treatment group, with a dose‐related slope in the hypertonic saline challenge (median 1.8, IQR 0.6–6.4 at time points 0 vs 1, IQR 0.5–4.2 at end of treatment; P = NS), or compared with placebo (P = NS). Total score for the AQLQ was significantly improved with clarithromycin from baseline (score 5.5, IQR 4.8–6.4) after the treatment period (score 6.2, IQR 5.4–6.6, P = 0.014), but not compared with placebo (score 6.4, IQR 5.2–6.7 at time point 0 and score 6.4, IQR 5.7–6.8, P = NS) both within the placebo group and compared with the treatment arm). Total asthma control score was not significantly improved in the clarithromycin group from the baseline (score 1.6, SD 0.6) after the treatment period (score 1.3, SD 0.7, P = NS); no difference in the comparison with and within the placebo group (score 1.3, 1.0 at time point 0 and 1.2, SD 0.8; P = NS both within the placebo group and for the comparison with the treatment arm). A predefined subanalysis showed that most of the significant differences for IL‐8 levels, MMP‐9 and AQLQ were driven by the effect of macrolides in a subgroup of participants with non‐eosinophilic asthma defined as proportion of neutrophils in induced sputum ≥ 61%.
Strunk 2008	Study was designed to test a potential inhaled steroid‐sparing effect of azithromycin compared with montelukast and placebo, in children with persistent‐to‐severe asthma. After a 6‐week run‐in period, when participants were treated with salmeterol and an increasing dose of inhaled budesonide to obtain good control of asthma, participants were randomised to azithromycin or montelukast or placebo, holding the same dose of inhaled steroids for 6 weeks. Inhaled steroids were then reduced according to a predefined protocol every 6 weeks. Only 55/292 (19%) participants enrolled for inclusion in the study reached the randomisation. Of the 55 participants randomised, 35 (63.6%) reached inadequately controlled status of asthma within a median of 5.1 weeks (range 2.4–23.4) after randomisation. The study was prematurely terminated by the Data Safety Monitoring Board. No difference in time regarding inadequate control among the 3 groups (median: azithromycin: 8.4 weeks, 95% CI 4.3 to 17.3; montelukast: 13.9 weeks, 95% CI 4.7 to 20.6; placebo: 19.1 weeks, 95% CI 11.7 to infinity). A futility analysis with the available data indicated that the study might have shown negative results even if the planned sample size of 210 children was reached. PCR for C pneumoniae or M pneumoniae showed no evidence of infection in 140 samples collected from the 55 participants randomised to the treatment groups.
Sutherland 2010	Clarithromycin vs placebo Study investigated role of clarithromycin in adults with mild‐to‐moderate persistent asthma not optimally controlled by inhaled steroids and analysed the results according to the PCR status for M pneumoniae and C Pneumonia on bronchoscopy samples. A sample size of ≥ 72 participants for PCR status was required to achieve a 90% power to detect a difference of 0.5 in ACQ score. Of 253 people meeting the criteria for inclusion, only 92 were randomised in the 2 treatment groups due to suboptimal asthma control during the 4‐week run‐in period. Among them, 12 (13%) had a positive PCR for M pneumoniae or C pneumoniae, while 80 (87%) had a negative PCR. The original purpose to reach 72 participants with evidence of infection was judged as not feasible, and further enrolment stopped. ACQ score was not significantly improved in any comparison within and between the treatment arms and PCR status at the end of the study period: difference in ACQ score between groups irrespective of PCR status (0.2, SD 0.2; P = 0.2; n = 92); difference in ACQ score between groups in participants with a positive PCR status (0.3, SD 0.5; P = 0.6; n = 12); difference in ACQ score between groups in participants with a negative PCR status (0.2, SD 0.2; P = 0.3; n = 80). FEV1 (pre‐albuterol) was not significantly improved in any comparison at the end of the study period: difference in FEV1 (L) between groups irrespective of PCR status (0, SD 0.1; P = 0.8; n = 92); difference in FEV1 (L) between groups in participants with a positive PCR status (0.4, SD 0.2; P = 0.9; n = 12); difference in FEV1 (L) between groups in participants with a negative PCR status (−0.2, SD 0.1; P = 0.8; n = 80). There were similar results for FEV1 %, morning and evening PEF, and rescue medications, with no statistically significant differences for any within‐ and between‐groups analyses, even in the PCR status comparisons. Bronchial hyperresponsiveness was significantly improved by clarithromycin compared to placebo in the whole population and in the PCR‐negative groups, but not among the PCR‐positive participants: difference in PC20 doubling dose between groups irrespective of PCR status (1.2, SD 0.5; P = 0.01; n = 92); difference in PC20 doubling dose between groups in participants with a positive PCR status (+0.9, SD 1.8; P = 0.6; n = 12); difference in PC20 doubling dose between groups in participants with a negative PCR status (+1.2, SD 0.5; P = 0.02; n = 80). Incidence of adverse events was not different between groups; there were no severe adverse events.
Wan 2016	Clarithromycin vs placebo Study, performed in Taiwan, enrolled 58 children (aged 5–16 years, 32 boys) with newly diagnosed mild persistent asthma. All participants had atopic asthma and were sensitive to ≥ 2 inhaled antigens. Children were randomised to clarithromycin 5 mg/kg daily (n = 36) or placebo (n = 22) for 4 weeks. 2 participants withdrew from placebo group, all the others completed the study. Increase of FEV1 (% of predicted) and of FEF25–75; and a decrease in blood eosinophil count, ECP and FeNO in the treatment group before and after the treatment with clarithromycin. However, the reporting of data/results was scanty, and no statistics, no comparisons with the control group were presented in the manuscript.
ACQ: Asthma Control Questionnaire; ACT: Asthma Control Test; AQLQ: Asthma Quality of Life Questionnaire; BAL: bronchoalveolar lavage; CI: confidence interval; CT: computed tomography; DRS: dose–response slope; ECP: eosinophil cationic protein; ED: emergency department; ERS: European Respiratory Society; FEF25‐75: the average forced expiratory flow during the mid (25% to 75%) portion of the FVC; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; HR: hazard ratio; ICS: inhaled corticosteroid: IgG: immunoglobulin G; IL: interleukin; IQR: interquartile range; IRR: incidence rate ratio: LABA: long‐acting beta‐agonists; LAMA: long‐acting muscarinic antagonists; MMP: matrix metallopeptidase; mRNA: messenger ribonucleic acid; n: number of participants; NS: not significant; PCR: polymerase chain reaction; PEF: peak expiratory flow; PC20 or PD20: provocative concentration (or dose) causing a 20% fall in forced expiratory volume in 1 second (FEV1); SD: standard deviation; TNF‐alpha: tumour necrosis factor alpha.