Reviewed: Matthys H, Pliskevich DA, Bondarchuk OM, Malek FA, Tribanek M, Kieser M. Randomised, double-blind, placebo-controlled trial of EPs 7630 in adults with COPD. Respir Med. 2013;107(5):691-701.

Chronic obstructive pulmonary disease (COPD) is a condition that entails persistent and usually progressive airflow blockage. It is not fully reversible, and it is associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Acute exacerbations (worsening of symptoms like breathlessness, cough, and/or sputum production) can lead to death.

EPs 7630 (Umckaloabo^®, Dr. Willmar Schwabe GmbH & Co. KG; Karlsruhe, Germany) is an herbal preparation from Pelargonium sidoides (Geraniaceae) root. EPs 7630 is an 11% per weight ethanol extract of the dried root (plant-solvent ratio 1:8-10) that has been shown in vitro to have anti-infective and immunomodulatory activity. In addition, a systematic review and meta-analysis of randomized controlled clinical trials revealed that EPs 7630 is more effective than placebo in treating acute bronchitis.1 The purpose of this multicenter, randomized, placebo-controlled, double-blind study was to evaluate whether EPs 7630, as an add-on therapy, prolongs time to first exacerbation and reduces exacerbation frequency compared to placebo in patients being treated for moderate-to-severe COPD.

The study was conducted in 18 centers in Kiev and Lugansk, Ukraine. It included patients (n=200, 18 years and older) with a history of chronic bronchitis (characterized by cough and sputum production on most days for ≥ [greater than or equal to] three months per year for at least two consecutive years), stable disease, ≥ three exacerbations in the prior 12 months, and a forced expiratory volume during one second (FEV1) less than 80% and ≥ 30% of predicted normal value (COPD-II/III). The spirometry for grading and reversibility testing of patients with COPD was performed ≥ six hours after the last inhalation of the combined conventional pharmaceutical drugs ipratropium bromide and fenoterol. Only patients with an improvement of FEV1 ≤ [less than or equal to] 0.3 liters after two puffs of ipratropium bromide/fenoterol were included in the study.

There were numerous major exclusion criteria: relevant cardiac diseases; pneumonia; active pulmonary tuberculosis; cystic fibrosis; bronchiectasis; lung cancer; asthma; infiltrates or other abnormalities of the lungs; COPD-IV; acute exacerbation within 4 weeks; known concomitant bacterial infection or respiratory tract infections; AIDS; concomitant medication with beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, regular inhalative glucocorticoids (except COPD-III) or oral glucocorticosteroids (except during exacerbation); use of anticholinergics (except ipratropium bromide), beta-2-agonists (other than salmeterol or fenoterol), analgesics (except acetaminophen), mucolytics and antitussives (other than dextromethorphan/bromhexine/ammonium chloride), immune modulators (e.g., bacterial vaccines) or coumarin derivatives; known alcohol or drug abuse; tendency to bleed; gastrointestinal disorders; immunosuppression; and severe heart, renal, or liver diseases.

Patients received standard treatment for COPD. Specifically, inhalation baseline-treatment for COPD-II included regular salmeterol, and ipratropium bromide/fenoterol as needed; for COPD-III, treatment included salmeterol and budesonide regularly and ipratropium bromide/fenoterol as needed. In the event of exacerbations, additional oral prednisolone and the antibiotics amoxicillin/clavulanic acid or ofloxacin were prescribed. As an add-on therapy, patients received either 30 drops three times a day of placebo orally or EPs 7630 for 24 weeks. The primary efficacy variable was time to first exacerbation of COPD. Exacerbations were defined as a subjective increase in ≥ one chronic symptom over baseline; these included increased sputum production, sputum purulence (yellow pus), and/or dyspnea (shortness of breath) that required an extra visit to the doctor (moderate exacerbations) or an increased use of ≥ two-fold mean doses of ipratropium bromide/fenoterol for five consecutive days due to increased respiratory symptoms, self-managed by the patient (mild exacerbations). Secondary efficacy variables were number and duration of exacerbations during treatment, health status, patient satisfaction with treatment, and duration of inability to work.

Compliance was nearly 100% in both groups. The median time to first exacerbation was 57 days in the EPs 7630 group and 43 days in the placebo group (P=0.005). When evaluating mild and moderate exacerbations separately, the time to moderate exacerbation was significantly greater with EPs 7630 than with placebo (P<0.0001), whereas the time to mild exacerbation was not significantly different between groups. The probability of remaining free of exacerbations was significantly greater for the EPs 7630 group than the placebo group (P=0.005). The median duration of moderate exacerbations was about one day shorter in the EPs 7630 group.

Additionally, significantly fewer patients in the EPs 7630 group needed antibiotic treatment during exacerbations compared to placebo patients (P<0.0001; 37.8% and 73.3%, respectively), and antibiotic treatment had a shorter mean duration (P=0.0466; 8 days and 9.8 days, respectively). After 24 weeks, patient satisfaction with treatment was significantly higher with EPs 7630 compared to placebo (P<0.0001). The EPs 7630 group had a significantly lower average number of missed work days during a mild or moderate exacerbation compared with the placebo group (P=0.004; 1.97 and 4.08 days, respectively). Also, the mean total number of days off work due to exacerbations during the study was significantly less in the EPs 7630 group than placebo (P<0.001; 2.96 vs. 7.17 days, respectively).

A total of 51.5% of patients taking EPs 7630 suffered from adverse events (AEs) compared with 40.0% of patients taking placebo. A causal relationship between AEs and EPs 7630 could not be excluded for 18 patients but was assessed as unlikely. Gastrointestinal disorders were the most frequently reported system organ class for which a causal relationship could not be excluded.

The authors conclude that EPs 7630 add-on therapy was superior to placebo, particularly for moderate exacerbations, as measured by less consumption of antibiotics, improved quality of life, and fewer days of missed work. Health economic studies are needed to determine whether using EPs 7630 as an add-on therapy provides a benefit in terms of both patient outcomes and financial concerns (i.e., taking into consideration cost of treatment, healthcare utilization, loss of productivity, and mortality rate).

—Heather S. Oliff, PhD

Reference

1. Oliff HS. Pelargonium sidoides use for acute bronchitis. HerbClip. September 15, 2008 (No. 050583-360). Austin, TX: American Botanical Council. Review of Pelargonium sidoides for acute bronchitis: a systematic review and meta-analysis by Agbabiaka TB, Guo R, Ernst E. Phytomedicine 2008;15(5):378-385.