Treatment with EPs 7630, a Pelargonium Sidoides Root Extract, Is Effective and Safe in Patients with the Common Cold: Results From a Randomized, Double Blind, Placebo-Controlled Clinical Trial

Abstract

Background

EPs 7630 was shown to be effective and safe in the treatment of acute respiratory tract infections such as acute bronchitis, acute rhinosinusitis, and acute tonsillopharyngitis. A clinical trial was conducted to investigate its efficacy and safety in the common cold.

Methods

In this multicenter, randomized, double-blind phase 3 clinical trial, 105 adults suffering from common cold symptoms were randomized to a thrice-daily administration of either 1 film-coated tablet containing 40 mg EPs 7630 or matched placebo for a treatment period of 10 days. The primary outcome measure was the sum of differences in the cold intensity score (CIS) from day 1 to day 5, defined as the Sum of the Symptom Intensity Differences (SSID), indicating the degree of symptom improvement in the course of 5 days of treatment. Among the secondary outcomes were clinical cure defined as (a) complete resolution of all cold symptoms (CIS = 0 points) or (b) complete resolution of all or all but one cold symptom, treatment outcome, satisfaction with treatment, and safety parameters.

Results

On day 5, the mean (±SD) SSID was significantly higher in the EPs 7630 group compared with the placebo group (12.5 ± 4.4 points versus 8.8 ± 6.8 points). Moreover, 55% of patients in the EPs 7630 group rated the treatment outcome as at least “major improvement” compared with 15% of patients in the placebo group. On day 10, 45% of patients of the EPs 7630 group and 12% of patients of the placebo group had reached 0 points on the CIS (=clinical cure, definition a), whereas all or all but one symptom (clinical cure, definition b) had completely resolved in 74% (EPs 7630) and 25% of patients (placebo), respectively. Satisfaction with treatment was higher in the EPs 7630 than in the placebo group (75% vs 37%) (P values ≤ .0002). During the clinical trial, adverse events occurred in 5 patients (9.4%) in the EPs 7630 and in 7 (13.5%) in the placebo group. All adverse events were of mild intensity, with the exception of 3 events in the placebo group, which were classified as moderate.

Conclusions

Treatment with EPs 7630 was shown to be superior to placebo in patients with the common cold indicating faster reduction of symptom intensity and distinctly more pronounced effects achieved by administration of the investigational drug in patients suffering from the common cold. Results extend previous findings on efficacy, safety, and tolerability of this active substance.

Background

The common cold (CC), usually a viral infection with various symptoms such as sneezing, sore throat, runny nose, nasal congestion, dry cough, headache, and fever, is one of the most prevalent infectious diseases in humans and continues to be a great burden on society in terms of human suffering and economic losses.¹ Not only treatment costs and visits to doctors, but also days off work contribute to the high costs of this disorder.

There is a scientifically acknowledged overlap between the signs and symptoms of the CC and other virus-induced acute respiratory tract infections (aRTI) such as acute bronchitis (AB), which has in the past triggered a change of focus in aRTI research. Hueston and colleagues hypothesized that sinusitis, (viral) upper respiratory tract infections/CC and AB are all variations of the same clinical condition (ie, aRTI) and should be conceptualized as a single clinical entity with primary symptoms related to different anatomic areas, rather than as different clinical conditions.² Similarly, Kardos and Malek³ describe that a location-based differentiation of respiratory tract infection is—due to similar and greatly overlapping symptoms—misleading, also in terms of effective treatment.

In this context, the herbal extract EPs 76301 could be an interesting treatment option. Data from meta-analyses of placebo-controlled trials provide evidence that EPs 7630 is effective for the treatment of patients suffering from AB,^4-6 acute rhinosinusitis (ARS),⁶ and acute nongroup A beta-hemolytic streptococcus (non-GABHS) tonsillopharyngitis (ATP).⁶ Furthermore, there are several placebo-controlled clinical trials demonstrating the herbal extract EPs 7630 to be effective in the CC.^7,8 Moreover, positive results were reported in the add-on therapy of chronic obstructive pulmonary disease (COPD),^9-11 treatment of aRTI in children with transient hypogammaglobulinemia of infancy,¹² and in the prevention of asthma attacks during viral infections of the respiratory tract in children.¹³

For adolescents and adults, the marketed medicinal product is available as EPs 7630 solution and as EPs 7630 film-coated tablets. Up to now, most clinical trials investigating EPs 7630 in several aRTI applied the solution formulation. Clinical trials with the EPs 7630 tablet formulation have already been conducted in the indication AB.^14,15 The present clinical trial was conducted in order to additionally investigate the efficacy and safety of EPs 7630 40-mg film-coated tablets compared with placebo in adults suffering from CC.

Methods

Design

The study was conducted in clinics and practices in the Ukraine from December 2003 to May 2004 as a multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled, phase 3 clinical trial. The primary objective was to evaluate the efficacy and safety of EPs 7630 compared with placebo in patients suffering from the CC. The trial was planned and performed with a group-sequential design with a maximum of three interim analyses which allow for early stopping. The trial was performed according to good clinical practice and the Declaration of Helsinki and was approved by the Ethics Committee. Informed consent was obtained from all participants prior to enrolment.

Patients

Male and female patients aged 18 to 55 years (inclusive) and suffering from symptoms of the CC were included. At the time point of inclusion, symptoms had to be present for 24 to 48 hours. CC was diagnosed as the presence of either 2 major (nasal drainage, sore throat) and at least 1 minor cold symptom (nasal congestion, sneezing, scratchy throat, hoarseness, cough, headache, muscle aches, or fever) or 1 major and three minor cold symptoms. Main exclusion criteria were obstructive anatomic lesions in the nasopharynx such as nasal polyps, tumors or severe septal deviations; previous surgery or need for surgery of the nose or paranasal sinuses; presence of any other acute ear/nose/throat (ENT) and respiratory tract disease than the CC; positive rapid test for GABHS; recurrent tonsillitis, sinusitis or otitis of ≥3 episodes or recurrent bronchitis of ≥6 episodes during the past 12 months prior to enrolment into the trial or any chronic ENT and respiratory tract disease; treatment with antibiotics, glucocorticosteroids, or antihistamines during the 4 weeks prior to enrolment into the trial; or treatment with cold medications (eg, decongestants, local anesthetics, zinc, echinacea, vitamin C ≥ 100 mg/d), cough medications, or pain relief medications and/or any other treatment for the CC during the past 7 days prior to enrolment into the trial; or known or suspected hypersensitivity to the investigational product.

Interventions

Eligible patients were randomly allocated—sequentially in ascending order at each trial site—to the EPs 7630 or placebo group, respectively, according to a computer-generated randomization list which was prepared with a balanced (1:1) block randomization by using a validated electronic data processing-random number generator (R-Code, version 4.9, M. Wrobel, Karlsruhe, Germany). Each investigator received a set of blocks with correspondingly numbered trial medication without knowing the block length itself.

EPs 7630 is an herbal drug preparation from the roots of Pelargonium sidoides, drug-extract ratio 1:8–10, extraction solvent: ethanol 11% (w/w). The investigation medication was administered as film-coated tablets containing 40 mg EPs 7630 or matched placebo, respectively, and had to be taken as 1 tablet 3 times per day for a period of 10 consecutive days. The medication was administered orally, at least 30 minutes before or after meals.

Outcomes

As primary outcome variable served the sum of symptom intensity differences (SSID) of the Cold Intensity Score (CIS from day 1 to day 5), which adds up the degree of symptom reduction achieved in the course of this timespan, to compare the 2 treatment groups. The CIS provides the symptom intensity values and is based on the score initially developed by Jackson and coworkers,¹⁶ which has been validated in several subsequent studies.^17,18

The CIS consists of 10 symptoms considered to be associated with the CC, which are designated as either major (nasal drainage, sore throat) or minor (nasal congestion, sneezing, scratchy throat, hoarseness, cough, headache, muscle aches, and fever).

With the exception of fever, CIS symptoms were rated by means of a 5-point verbal rating scale, from 0 (not present) to 4 (very severe) with assessments taking place on days 1, 3, and 5. Fever was assessed as oral temperature according to the following staging: ≤37°C (not present; 0 points), >37°C to 38°C (mild; 1 point), >38°C to 39°C (moderate; 2 points), >39°C to 40°C (severe; 3 points), and >40°C (very severe; 4vpoints) at each contact. The total CIS could thus reach a maximum of 40 points. Based on the CIS assessments on day 1, 3 and 5, a sum score (SSID) was calculated taking into account the changes of the CIS between baseline (day 1) and day 3 and 5, respectively. The equation used was as follows: (CIS on day 3 – CIS on day 1) + (CIS on day 5 (LOCF) – CIS on day 1).

Secondary outcome criteria were time until onset of treatment effect, clinical cure, definition (a) (complete resolution of all cold symptoms (CIS = 0 points)) or clinical cure, definition (b) (complete resolution of all or all but 1 cold symptom), treatment outcome, satisfaction with treatment and responder rates, as well as safety parameters. Response was defined as either reduction of baseline value of CIS by 50%, reduction of CIS below 7 points or reduction of CIS by at least 7 points. Treatment outcome was assessed according to the Integrative Medicine Outcomes Scale (IMOS),¹⁹ whereas satisfaction with treatment was rated by patients on the Integrative Medicine Patient Satisfaction Scale (IMPSS).¹⁹ In addition, changes in health-related quality of life (HRQL) criteria were measured, such as activity level, general well-being, and assessments of the EQ-5D questionnaire including EQ-VAS.²⁰ Further secondary outcome measures were change of the individual CIS symptoms, as well as the cold-relevant symptoms limb pain, weakness all over, exhaustion, fatigue, and chilliness.

Statistical Methods

For confirmatory testing of the primary outcome variable (SSID), a 2-factorial analysis of covariance (ANCOVA) with the 2 factors treatment group and center, and the baseline value as covariate was applied. An overall type 1 error rate of α = .05 (2-sided) was controlled by application of the decision boundaries of O’Brien and Fleming in the interim analyses²⁵ to account for the 3-stage adaptive group sequential design. With respect to the secondary outcome variables, descriptive statistical methods were used for the comparison of treatment groups and the resulting P values were interpreted accordingly. Statistical results reported here were generated from all available data of the final analysis (intention-to-treat [ITT] analysis by using last observation carried forward [LOCF]) unless stated otherwise. Depending on the outcome variable different statistical tests were used for comparison of the treatment groups (ie, Wilcoxon 2-sample test for quantitative outcomes (eg, EQ-VAS status) and Mantel-Haenszel χ² test for categorial outcomes (eg, clinical cure, satisfaction with treatment, activity level, general well-being).

Results

A significant superiority of EPs 7630 compared with placebo was already demonstrated after the second interim analysis (combined test statistic Z for the first and second stage computed according to the inverse normal method was 3.499 and exceeded the critical value of 2.863; P = .0002; 1-sided; ANCOVA), recruitment of patients was stopped thereafter. Since the second interim analysis comprised 90 patients and another 15 patients were already included in the trial, the results of the final analysis include a total of 105 patients. Subsequently, the results of the final analysis will be presented. The ITT and safety data set consisted of 105 patients (EPs 7630: 53, placebo: 52; Figure 1).

Figure 1.

Flowchart of EPs 7630 Compared With Placebo, Including Reasons for Withdrawals

The per-protocol (PP) analysis was performed on the basis of 97 patients (EPs 7630: 49, placebo: 48). Treatment compliance and the extent of exposure were almost identical in both treatment groups. A total of 77.1% of the 105 patients recruited were female, 22.9% were male. Baseline characteristics and demographic data are shown in Table 1. The treatment groups were comparable with respect to gender, age, weight, height, body mass index and other demographic data.

Table 1.

Baseline Characteristics and Demographic Data (mean ± SD or Absolute (Relative) Frequency)

	EPs 7630 n = 53	Placebo n = 52
Sex male female	13 (24.5%) patients 40 (75.5%) patients	11 (21.2%) patients 41 (78.8%) patients
Age	35.0 (10.9) years	37.7 (10.5) years
Weight	71.7 (12.9) kg	73.6 (15.5) kg
Height	168.6 (7.7) cm	168.8 (9.1) cm
BMI	25.1 (3.9) kg/m2	25.7 (4.5) kg/m2
Alcohol consumption	17 (32.1%) patients	25 (48.1) patients
Active smokers	5 (9.4%) patients	8 (15.4%) patients
Former smokers	4 (7.5%) patients	2 (3.8%) patients
Non-smokers	44 (83.0%) patients	42 (80.8%) patients
Caffeine consumption	51 (96.2%) patients	50 (96.2%) patients
Systolic blood pressure	120.3 ± 10.3 mmHg	121.9 ±11.1 mmHg
Diastolic blood pressure	76.5 ± 7.3 mmHg	77.2 ± 6.7 mmHg
Pulse rate	85.0 ± 7.1 beats/min	84.7 ± 5.4 beats/min
Intake of previous medication other than antibiotics during the past 12 months before screening	13 (24.5%) patients	11 (21.2%) patients
Intake of antibiotics during the past 12 months before screening	1 (1.9%) patient	1 (1.9%) patient
Recurrence of common cold during the past 12 months before screening	16 (30.2%) patients	12 (23.1%) patients

The primary outcome measure, the SSID, improved from day 1 to day 5 by 12.5 ± 4.4 points (mean ± SD) in the EPs 7630 group and by 8.8 ± 6.8 points in the placebo group (P = .0002; 2-sided; final analysis, confirming the results of the interim analysis).

The change of the CIS over time, which provides the source data for the calculation of the SSID, is depicted in Figure 2. Both treatment groups showed comparable values at baseline. Whereas the total CIS continuously decreased in all patients, the decrease on day 5 was clearly more pronounced in the EPs 7630 group than in the placebo group. On day 10, differences in CIS reduction between EPs 7630 and placebo were still obvious, though less pronounced.

Figure 2.

CIS: Mean Total Score and 95% CI (n = 105, ITT Analysis)

All secondary parameters showed a more favorable course of the disease and a faster recovery from the CC under treatment with EPs 7630 compared with placebo. The time until onset of treatment effect was significantly shorter in the EPs 7630 group than in the placebo group (P = .0006, 2-sided; Figure 3).

Figure 3.

Time Until Onset of Treatment Effect During the Clinical Trial

The rate of responders was higher in the EPs 7630 group than in the placebo group (Figure 4). On day 10, the rate of patients with clinical cure according to definitions (a) and (b), respectively, was significantly higher in the EPs 7630 group than in the placebo group ([a]: P = .0001; [b]: P < .0001; 2-sided): Clinical cure according to definition (a) (CIS = 0) was reached by 24/53 (45%) of patients in the EPs 7630 and 6/52 (12%) in the placebo group. The number of patients fulfilling criteria of clinical cure, definition (b) (all or all but one symptom resolved) was 39/53 (74%) in the EPs 7630 group, and 13/52 (25%) out of those receiving placebo.

Figure 4.

Cured Patients and Responders on Day 5 and Day 10, Respectively, According to Different Cold Intensity Score Criteria

Furthermore, the mean decrease in all individual symptoms of the CIS from day 1 to day 5/day 10 was noticeably higher in the EPs 7630 group than in the placebo group. On day 5, an improvement of cough could only be observed in the EPs 7630 group, whereas an increase in this symptom was seen in the placebo group (data not shown). In addition, all further cold relevant symptoms assessed (limb pain, weakness all over, exhaustion, fatigue, and chilliness) showed higher rates of remission and improvement in the EPs 7630 group than in the placebo group (data not shown).

Treatment outcome according to the IMOS was assessed as significantly better in the EPs 7630 group than in the placebo group by both the investigators and the patients on day 5 (P < .0001 each). Investigators rated the treatment outcome as “major improvement” for 27/53 (51%) patients treated with EPs 7630 and for 6/52 (12%) patients treated with placebo. Comparable results were shown for the patients’ assessment (Figure 5). On day 10, assessment of treatment outcome of patients was also significantly better for EPs 7630 compared with placebo (patient’s diary; P = .0015) (Figure 5).

Figure 5.

Treatment Outcome According to the Integrative Medicine Outcomes Scale Assessed by the Patients on Day 5 and Day 10, Respectively (n=105, ITT analysis; P values of the two-sided Mantel-Haenszel chi-squared test).

Satisfaction with treatment according to the IMPSS was also rated higher in the EPs 7630 group than in the placebo group (P < .0001; 2-sided): A total of 40/53 (75%) patients treated with EPs 7630 were satisfied or very satisfied with the treatment compared with 19/52 (37%) patients in the placebo group (Figure 6).

Figure 6.

Satisfaction With Treatment Assessed by the Patients According to the Integrative Medicine Patient Satisfaction Scale on Day 10

Moreover, HRQL was more improved in the EPs 7630 group as assessed by the EQ-5D questionnaire on day 5: The number and rate of patients with remission or improvement of symptoms was higher in the EPs 7630 group than in the placebo group across the items mobility, self-care, usual activities and anxiety/depression (data not shown). On day 10 (LOCF), the EQ-VAS status (P < .0001; 2-sided), the activity level (P = .0470; 2-sided), and the general well-being (P = .0005; 2-sided) were significantly better in the EPs 7630 group than in the placebo group.

Safety and Tolerability

Adverse events (AEs) occurred in five patients (9.4%) of the EPs 7630 group and in 7 patients (13.5 %) of the placebo group. All adverse events were of mild intensity, with the exception of 3 events in the placebo group, which were classified as moderate. None of the AEs was classified as serious or severe in intensity. In a total of 10 patients, a causal relationship of at least 1 AE to the investigational medication could not be excluded. This applied to 5 patients in the EPs 7630 group (epigastric discomfort [2 patients], flatulence [1 patient], nausea [2 patients]) and 5 patients in the placebo group (epigastric discomfort [1 patient], nausea [2 patients], macular rash [1 patient], papular rash [1 patient]).

The study drug was discontinued in 2 patients in the placebo group due to an AE (macular rash and papular rash, respectively). Subjective tolerability of the investigational medication assessed by the patient was better in the EPs 7630 group than in the placebo group.

Discussion

In the present clinical trial, the use of EPs 7630 was significantly associated with a reduction in CC symptoms compared with the placebo group. This was shown for the primary efficacy variable (the SSID) and was also confirmed by the results of the secondary outcome criteria clinical cure (definition (a): CIS = 0 points; definition (b): complete resolution of all or all but one cold symptom) and satisfaction with treatment according to IMPSS.

On a first glance, the duration of CC symptoms observed in this trial seems to be comparably long compared with the average total length of the illness as given by current guidelines (ie, about 1.5 weeks).²² Individual symptoms, however, may persist for more than 3 weeks.1 Cough as a prevalent symptom in the CC is even reported to last up to eight weeks in its acute presentation and may thus considerably exceed the duration of other CC symptoms.^23,24 In children, for example, a systematic review has already shown, that the duration of the CC is considerably longer than the current guidance given.²⁵ However, regardless of these considerations, the results of the present clinical trial demonstrate that, even after 10 days, symptom intensity in the placebo group did not reduce to a degree comparable to that achieved by the investigation medication. Furthermore, treatment effects have also to be considered with respect to HRQL and activity levels. Compared with placebo, the HRQL and activity criteria measured in the course of the present trial were clearly more improved after EPs 7630 administration.

In overall terms, the results of the present clinical trial show a more favorable course of the disease, a faster recovery from the CC, as well as a good safety and tolerability of EPs 7630. The favorable efficacy and safety profiles are supported by patient-rated assessments on symptom improvement and overall satisfaction with the treatment. The findings of the clinical trial presented here are in accordance with the results of an earlier published clinical trial by Lizogub et al⁷ in which a treatment of 30 drops EPs 7630 three times daily was investigated in patients suffering from the CC. In this earlier clinical trial, authors report a significant improvement of SSID, total CIS, and all individual CIS symptoms under administration of EPs 7630 solution as compared with placebo, as well as a superior rating of symptom intensity reduction and treatment satisfaction by those patients randomized to EPs 7630. On day 5, the improvement of the mean (±SD) SSID in the EPs 7630 group was comparable to the clinical trial at hand (14.6 ± 5.3 points compared with 12.5 ± 4.4 points). In both trials, the amount of patients who were randomized to EPs 7630 treatment and free from all or all but 1 CC symptom at treatment end had increased toward 3 quarters by day 10 (74% and 79%, respectively). Recently, another clinical trial investigating EPs 7630 treatment in adults suffering from the CC has been published.⁸ This clinical trial investigated the efficacy and tolerability of EPs 7630 solution dosed twice as high as the standard dose. The reported results also support the findings of Lizogub et al⁷ and of the clinical trial presented here.

Although there are already data from meta-analysis of randomized placebo-controlled trials providing evidence that EPs 7630 is effective in the treatment of AB, ARS and ATP,^4-6 there is no meta-analysis available for the indication CC. A systematic review published by the Cochrane Collaboration⁵ was solely able to evaluate the aforementioned investigation by Lizogub et al⁷ as this was the only such trial published within the review’s search time frame (up to 26 April 2013). The now available results^7,8 will—in concert with the results reported here—enable future reviews and meta-analyses to include these data to achieve reliable evaluations of the efficacy of EPs 7630 in the treatment of the CC.

A systematic review of clinical trial results has shown that EPs 7630 is safe and well-tolerated.²⁶ This is in line with the findings of the present clinical trial, in which AEs occurred in only 9.4% of patients in the EPs 7630 group compared with 13.5% of patients in the placebo group. None of the AEs was classified as serious or severe in intensity. The observed gastrointestinal complaints are known side effects of EPs 7630. Moreover, it has recently been shown that in patients suffering from COPD an add-on treatment with EPs 7630 can lead to a reduced antibiotic prescribing in this health condition, which decreases the risk of the development of antibiotic resistance.¹⁰

EPs 7630 has been shown to be a safe and effective treatment option in aRTI^14,15,26-41 including CC,^7,8 regardless of the formulation administered. The overlap of symptoms in aRTI/CC as emphasized by Hueston et al² and Kardos and Malek³ is an aspect explanatory of the broad efficacy of EPs 7630 in these conditions. Another explanatory aspect is the multidimensional mode of action of EPs 7630 as demonstrated in numerous in vitro evaluations for both virus- and bacteria-induced infections, including immunomodulatory and moderate direct anti-bacterial effects,⁴² strong indirect anti-bacterial activities such as inhibition of interaction between group A-streptococci and host epithelia,⁴³ intracellular killing by human peripheral blood phagocytes, an improved oxidative burst and improved phagocytosis,⁴⁴ release of tumor necrosis factor and nitric oxide,⁴² as well as stimulation of interferon-β, and increase of natural killer cell activity.⁴⁵ EPs 7630 can therefore be considered as a good treatment option for the CC, a condition with variable and changing manifestations on different sites of the aerodigestive tract.³

In conclusion, the drug under study was proved to be an efficacious, safe, and well-tolerated therapy option in the CC. Administration of the study drug led to a significantly faster and more pronounced intensity reduction of symptoms and improved the treatment outcome.