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Acute bronchitis therapy with ivy leaves extracts in a two-arm study. A double-blind, randomised study vs. an other ivy leaves extract.

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Keywords: Hedera helix Ivy Bronchitis Double-blind randomised study

ABSTRACT

Ivy leaves extracts are authorised in medicinal products for the treatment of acute bronchitis. Different studies and the long experience on the market show safety and efficacy of this drug. A double-blind, randomised study was conducted to assess the efficacy and tolerability of ivy leaves soft extract with an other ivy leaves extract. 590 patients with acute bronchitis participated in this study. They were treated with test or comparator for 7 days ([+ or -] 1). The Bronchitis Severity Score (BSS) decreased gradually and to a similar extent from Day 1 to Day 7 in both treatment groups. Starting from values of 6.2-6.3 [+ or -] 1.2, the BSS decreased by approximately 4.7-4.9 points until Day 7, so that patients left the study with a mean BSS of 1.4-1.6. The BSS subscales cough, sputum, rhales/rhonchi, chest pain during coughing, and dyspnoea improved to a similar extent in both treatment groups. Overall, 2.7% of patients (per group and overall) experienced an adverse event, all of which were non-serious. Fewer patients younger than ten years had adverse events than would have been expected from their share of the study population (p = 0.015; Fisher's exact test). As a conclusion, the test product with ivy leaves soft extract proved to be non-inferior to the comparator ivy leaves extract in improving symptoms of acute bronchitis. [c] 2011 Elsevier GmbH. All rights reserved.

Introduction

Acute bronchitis is one of the main reasons for seeing a doctor and it is also one of the most frequent causes for days off work (Matthys 2004; Gonzales and Sande 2000). It is predominantly caused by viral infections, particularly the Respiratory Syncytial Virus (RSV), Coxsackie, influenza, parainfluenza, and ECHO-viruses or adenoviruses (Matthys et al. 2003). Treatment of uncomplicated acute bronchitis should be symptomatically orientated, but in practice it is frequently treated primarily with antibiotics. Antibiotics may be indicated in cases of bacterial super infection, but generally they do not shorten the duration of uncomplicated disease. Therefore, medical associations like the Medicines Commission of the German Physicians (AKDAE) recommend treating patients with acute uncomplicated bronchitis primarily symptomatically (Recommendations of the AKDAE 2002).

In this symptomatic therapy so-called expectorants play an important role. A review of the Cochrane Collaboration, though in chronic bronchitis, showed that these drugs reduced exacerbations and days off work (Poole and Black 2001). One class of herbal expectorants, ivy leaves extracts, has had its long standing place in traditional medicine and its use was standardised by a Commission monograph of the German regulatory authority in 1988. The medication evaluated in this study conforms to this monograph.

Ivy leaves extracts have been well tolerated, with adverse effects generally limited to gastrointestinal reactions; very rarely also allergic skin reactions have been reported (Kraft 2004).

The mode of action of ivy leaves extracts has recently been elucidated. Originally it was assumed that the extract non-specifically stimulates the gastric mucosa and that parasympathicotonic reflexes in turn stimulate the secretion of bronchial mucus. Recent work, however, has shown that [alpha] -hederin, one of the active ingredients of the ivy leaves extracts, increases the beta-2-adrenergic bronchial reagibility. This leads to a relaxation of the smooth bronchial musculature and furthermore to an increased secretion of surfactant factors (Haberlein and Prenner 2005).

In several controlled clinical studies, the ivy leaves extract of the comparator product in this study has shown improvement of pulmonary function tests compared to placebo or active control. Furthermore a recently published open postmarketing study confirmed the safety and clinical effectiveness of the comparator in this study (Fazio et al. 2009). Non-interventional studies have examined the ivy leaves extract used in the test product in children up to 12 years of age. These studies showed safety and efficacy for this special patient group (Schmidt 2002a, b).

Plant extracts

The test product manufactured by Krewel Meuselbach GmbH (Hedelix drops, batch no.: 74842A) is authorised in several countries. The active substance, ivy leaves extract is produced from ivy leaves with an extraction solvent of 50% (v/v) ethanol and propylene glycol (98:2). The ethanol of this fluid extract was then removed by vacuum distillation. The volume of ethanol was supplemented by propylene glycol. The drug to extract ratio (DER) of the final spissum extract was 2.2-2.9:1. The dried ivy leaves comply with the Hederae folium monograph of the Ph. Eur. (2148). According to the Ph. Eur. the dried ivy leaves contain a minimum of 3% of hederacoside C, the main bidesmosidic triterpene saponine of the plant. Furthermore the plant and the extract contain small amounts of monodesmosides like a-hederin and flavonoids. The ivy leaves extract of the test product contains a minimum of 6.75% of hederacoside C.

The comparator product was obtained from a German wholesaler and manufactured by Engelhard Arzneimittel GmbH and Co. KG (Prospan drops, batch no.: 07B090B). The active ingredient is ivy leaves dry extract, extracted with 30% (m/m) ethanol and a resulting drug to extract ratio (DER) of 5-7.5:1.

The tested concentrations were in accordance with the recommended dosages of the authorised and commercially available medicinal products Hedelix drops and Prospan drops.

Study design, objectives, and outcomes

The study was performed according to ICH-GCP, the Declaration of Helsinki, the authorisation by the relevant national authority and the positive opinion of the involved Ethics Committee. The study was performed under the EudraCT No 2007-003272-19.

This study compared the efficacy and tolerability of two ivy leaves extracts in patients with acute bronchitis. The patients were recruited and randomised to one of two treatment groups: Hedelix[R] or Prospan[R].

Patients took one of the medications three times daily over a period of seven days ([+ or -] 1). After the admission examination, patients returned for further examinations on Day 4 [+ or -] 1 and on Day 7 [+ or -] 1. Adverse events were documented between the time of informed consent and the last study visit.

The BSS (Bronchitis Severity Score) evaluates five symptoms, which are important for acute bronchitis: cough, sputum, rhales/rhonchi, chest pain during coughing, and dyspnoea. Each symptom was scored by the investigator on a scale from 0 to 4, with: 0: absent; 1: mild; 2: moderate; 3: severe; 4: very severe. The BSS is the sum of the five symptom subscores. Other clinical symptoms were scored on an identical 0-4 scale, global efficacy (investigators) and tolerability (investigators and patients) on five-step verbal rating scales. Body temperature was measured in[degrees]C, ability to go to work or school as a yes/no decision at every visit.

European regulatory guidelines on the performance of studies in acute bronchitis do not exist. So target criteria reflect clinical symptoms and are similar to those selected in other studies in acute bronchitis (Matthys et al. 2003). Due to the self-remitting character of acute episodes of bronchitis a parallel group design was chosen in preference over a cross-over study.

Patients

Male or female Caucasian patients at least 2 years of age with a confirmed clinical diagnosis of acute bronchitis and a BSS [greater than or equal to] 5 were eligible for participation in the study. Patients had to present acute complaints, with duration of not more than 48 h.

Selection criteria excluded previous medications which may influence the course of the study indication or the evaluation of the target criteria, such as these stated under "Concomitant therapy". Furthermore, patients with concomitant diseases like allergic asthma or bronchial hyperreactivity, chronic bronchitis, other chronic or inherited lung diseases, or severe cardiac, hepatic, or renal disorders were excluded.

Children and adolescents were explicitly included in the study, because acute bronchitis is especially frequent in this population, which thus constitutes a major target population for the test product. Children under 2 years of age were excluded because of the excipient menthol in the test product.

Interventions, randomisation, blinding, and concealment of allocation

Hedelix[R] is authorised in several countries. The active substance, ivy leaves extract, is extracted with 50% ethanol with a resulting drug to extract ratio (DER) of 2.2-2.9:1.

Prospan[R] contains ivy leaves extract extracted with 30% ethanol with a resulting drug to extract ratio (DER) of 5-7.5:1. The calculated drug intake of the recommended daily dose is comparable in both medicinal products.

Patients were instructed to take the study medication three times daily in a dose of 24, 16, or 12 drops per dose, depending on age group (adults and children from an age of 10 years: 24 drops; children between 4 and 10 years old: 16 drops; children between 2 and 4 years old: 12 drops).

To permit blinding, the test product was fitted with a different drop former compared to the marketed product to have the same number of drops for both products.

Patients received the medication box with the next available number at the site. Treatment allocation was concealed and patients and study personnel at the sites, at the sponsor, and at the CROs responsible for study performance and statistical analyses were blinded to treatment assignment for the duration of the study until after the Blind Review Meeting.

Concomitant therapy

In general, concomitant medication for other indications was permitted during the study, but medication possibly influencing symptoms of acute bronchitis was excluded. These medications included beta-2 agonists, antiviral drugs, antibiotics, corticosteroids, antihistamines, immunosuppressants, homeopathic drugs, household remedies or prophylactics for respiratory infections. Throat lozenges were permitted, but were not allowed within 4 h of a study visit. Paracetamol in a dose of up to 2 g per day was permitted, but was not allowed within 8 h of a study visit. Exceptions were allowed, if treatment for an acute condition became medically necessary. The investigators recorded all administered medications in the patient's case report form.

Sample size and statistics

Published studies in acute bronchitis using the BSS as primary endpoint found a standardised effect size [DELTA] /s of active therapy vs. placebo of 0.64 and higher (Matthys 2004; Matthys et al. 2003; Chuchalin et al. 2005; Kemmerich et al. 2006).

The assumption was that also the test product and the comparator ivy leaves extract would show a similar efficacy. Following Rohmel et al. (2005) the border of non-inferiority for the comparison of the two drugs was set to approximately 50% of the expected effect of the active comparator vs. placebo, i.e. an effect size [DELTA] /s of 0.32. To detect such a clinically relevant difference with a power of 95%, n = 250 evaluable patients per group were required (manufacturer's risk [alpha] = 0.10) and approximately 295 patients per group had to be recruited considering a dropout rate of 15%.

[FIGURE 1 OMITTED]

Efficacy was assumed it the mean improvement of BSS at Visit 3 (Day 7 [+ or -] 1) vs. baseline observed in the group receiving the test product was non-inferior to that observed in the comparator group. The border of non-inferiority was 32% of the standard deviation of BSS change observed in the comparator group, because the expected superiority over placebo would be approximately 64% of the standard deviation. Efficacy could be assumed if the two-sided 95% confidence interval of treatment difference of the ivy leaves extract vs. the comparator ivy leaves extract was completely above the lower limit, i.e. -64% of the standard deviation of BSS change observed in the comparator group. Two-sided 95% confidence intervals (CI) of treatment difference were calculated within the frame of ANCOVA, corresponding to a significance level of p < 0.05 (two-sided). CI was adjusted for baseline inhomogeneities.

Secondary endpoints were compared between groups by t-tests, Mann-Whitney tests, Fisher's exact test or survival curves with Log rank test, as adequate for the scale. Furthermore, responders were calculated from changes in BSS according to three predefined definitions (BSS < 3 points at Visit 3; Decrease of BSS [greater than or equal to] 7 points by Visit 3; BSS < 3 points at Visit 3 and decrease of BSS [greater than or equal to] 7 points by Visit 3). Responder rates were compared between groups using Fishers exact test. All p-values for secondary endpoints do not possess confirmatory value.

Results

Seven study centres recruited 590 patients for this study, 295 each were randomised to the test product and to the comparator group. Distribution of patients is shown in Fig. 1. The most frequent reason for exclusion from the Per Protocol group was a concomitant disease or the study indication requiring therapy with inadmissible medication (10 of 12 and 8 of 10 patients, respectively). Generally, the inadmissible medication was antibiotics.

Over all, 53% of randomised patients were female. The mean age ([+ or -] SD) was 23 [+ or -] 20 years, with the high standard deviation indicating the large age range of patients, which was between 2 and 86 years. The median age was 17 years and thus similar to the mean age. Two third of patients (66%) were over 10 years old, 23% were between 4 and 10, and 11% were between 2 and 4 years old.

Baseline BSS was somewhat higher in the comparator group, especially in the PP dataset. This was accounted for by including baseline value as a covariate into the statistical analysis of covariance. The BSS decreased gradually and to a similar extent in both treatment groups. Starting from values of 6.2-6.3 [+ or -] 1.2, the BSS decreased by approximately 4.7-4.9 points until Visit 3, so that patients left the study with a mean BSS of 1.4-1.6.The improvement in the PP dataset was only marginally higher (by approximately 0.1 score point) compared to the ITT dataset, confirming the general applicability of the results.

The difference in BSS improvement between test product and the other ivy leaves extract from baseline to Visit 3 for the PP dataset was 0.019 (95% confidence interval (CI): -0.2654 to 0.3032). As the lower end of the 95% CI (-0.2654) was clearly above the non-inferiority margin (-0.6208), the non-inferiority of the test product vs. active comparator in improvement of the BSS was confirmed. The corresponding analysis for the ITT dataset corroborated these results. Fig. 2 gives a graphical impression of the primary study results. The non-inferiority range for test product vs. the comparator ivy leaves extract was 20% and therefore considerably narrower than the 50% range used for estimating sample size.

The BSS subscales improved to a similar extent in both treatment groups and also in both datasets. Table 1 compiles the treatment effects and the results of the statistical tests which confirm non-inferiority of the test product to the comparator.
Table 1
Improvement of BSS subscales between baseline and Visit 3.

Population        Difference of       Non-inferiority
                  treatment effect      margin (b)
                  test-comparator (a)

                       PP      ITT         PP       ITT

Symptom Cough       0.05507   0.05037  -0.28128  -0.29024
Sputum             -0.02242  -0.02378  -0.34656   -0.3520
Rhales/rhonchi     0.009601   0.02329  -0.31104  -0.31552
Chest pain         -0.01032  -0.00186  -0.25472  -0.26688
Dyspnoea           -0.00378  0.006750  -0.10592  -0.12416

Population           Lower end 95% CI (a)

                         PP             ITT

Symptom Cough               -0.07812  -0.07691
Sputum                       -0.1327   -0.1305
Rhales/rhonchi              -0.06974  -0.05792
Chest pain                  -0.04871  -0.03837
Dyspnoea                    -0.01691  -0.01642

(a.) ANCOVA.
(b.) 0.32 x SD of improvement of BSS symptom in the comparator group.


Responders were calculated from changes in BSS according to three definitions as stated under "Sample size and statistics". Responders were overall evenly distributed to the two treatment groups, with no significant differences between groups (p between 0.42 and 0.90; Fisher's exact test).

The investigators rated their impression of global efficacy with a mean ([+ or -] SD) of 4.05 [+ or -] 0.97 for the test group and with 3.96 [+ or -] 0.95 for the comparator group. On the rating scale from 1 - very poor to 5 - very good efficacy this corresponds to "good" efficacy in both groups. The ratings were thus comparable and they did not show a statistically significant difference between groups (p = 0.23; t-test; ITT dataset). Results for the PP dataset were similar. Patients rated their impression of global efficacy with a mean ([+ or -] SD) of 78.7 [+ or -] 22.9 mm for the test group and with 76.4 [+ or -] 23.7 mm for the comparator group. On a visual analogue rating scale from 0 mm - 'not at all satisfied' to 100 mm - 'completely satisfied' this indicates a high to very high efficacy in both groups. The ratings were thus comparable and they did not show a statistically significant difference between groups (p = 0.23; t-test; ITT dataset). Results for the PP dataset were similar. By Visit 3t 83.2% of patients previously unable to go to work or school were able to return to this activity. There were no significant differences between groups in this parameter (ITT dataset: p = 0.79; Logrank test; PP dataset: p = 0.69).

[FIGURE 2 OMITTED]

Overall, 2.7% of patients (per group and overall) experienced an adverse event, all of which were non-serious. Fewer patients younger than ten years had adverse events than would have been expected from their share of the study population (p = 0.015; Fisher's exact test). This indicates a very favourable tolerability especially in children as a major target population. The majority of patients suffering from an adverse event had gastrointestinal side effects, mostly of the upper gastrointestinal tract. Such reactions are already known and included in the labelling of both study drugs. The investigators rated their impression of global tolerability with a mean ([+ or -] SD) of 4.21 [+ or -] 0.78 for the test group and with 4.19 [+ or -] 0.79 for the comparator group. On the rating scale from 1 - very poor to 5 - very good tolerability this corresponds to better than "good" tolerability in both groups (p = 0.75; t-test; ITT dataset). Patients' rating were similar with 3.98 [+ or -] 0.97 for the test group and with 3.96 [+ or -] 0.95 for the comparator group (p = 0.76; t-test; ITT dataset).

Discussion

Both from a descriptive and from a formal point of view the test product proved to be non-inferior to the comparator ivy leaves extract in improving symptoms of acute bronchitis. The difference between test product and comparator in improving the Bronchitis Severity Score (BSS) from baseline to Visit 3, the primary endpoint, was fully within the predefined non-inferiority margin. In addition, also the BSS subscales, the additional clinical parameters typical for the disease, and the investigators' and patients' global efficacy evaluations showed that both treatments improved symptoms to a comparable extent.

The test product and comparator ivy leaves extract showed a favourable and comparable safety profile, which confirmed the available safety information and the long experience from the market. Furthermore, data show that the drugs were very well tolerated especially by children less than 10 years of age. This underlines also the high suitability of the ivy leaves extracts in this special patient group.

Prospan was chosen as a comparator ivy leaves extract based on its efficacy in previous studies vs. active controls and placebo. Mansfeld et al. (1998) found an improvement of pulmonary function tests compared to placebo in children with bronchial asthma. Pulmonary function tests in children who were hospitalized due to chronic obstructive pulmonary disease showed a tendency towards superiority of the ivy leaves extract over acetylcysteine, a chemically defined standard drug in this indication (Gulyas 2006). In grown-up patients with chronic bronchitis, the ivy leaves extract was compared to ambroxol, another standard drug used for the study indication (Meyer-Wegener et al. 1993). Both drugs showed an improvement of clinical parameters and of pulmonary function tests, again with a tendency towards superiority of the herbal drug. Accordingly it is sufficiently proven that the comparator ivy leaves extract is effective and improves pulmonary function and clinical parameters in patients with bronchial diseases.

Validated test procedures suitable for this study especially in children were not available before initiation of the study. The BSS as the primary efficacy parameter has been identified as a suitable measurement instrument. It has been used in previous studies in acute bronchitis and was found to be highly sensitive to differentiate between an active drug and placebo. In addition, several studies in acute bronchitis found that the BSS decreased by approximately 70-80% vs. baseline in the active groups (Matthys 2004; Kemmerich et al. 2006; Grunwald et al. 2006). This corresponds to our study, where the BSS decreased by 75-78% over the treatment period, which shows the external validity of our data.

As a conclusion, the test product has established its efficacy in patients with acute bronchitis by proving non-inferiority to an other ivy leaves extract with a recognized efficacy within a very narrow equivalence band. The study furthermore confirms the favourable tolerability of the test product in an overall and especially in a paediatric population with acute bronchitis.

doi: 10.1016/j.phymed.2011.06.014

0944-7113/$ - see front matter [c] 2011 Elsevier GmbH. All rights reserved. doi:10.1016/j.phymed.2011.06.014

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Ute Cwientzek (a), *, Bertram Ottillinger (b), Petr Arenberger (c)

(a.) Krewel Meuselbach GmbH, 53783 Eitorf, Germany

(b.) Life Sciences Consultancy, 85649 Brunnthal-Hofolding, Germany

(c.) Dermatological Clinic of the 3rd Faculty of Medicine of the Charles University Prague, 10034 Prague 10, Czech Republic

* Corresponding author.

E-mail address: ucwientzek@krewel-meuselbach.de (U. Cwientzek).
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Author:Cwientzek, Ute; Ottillinger, Bertram; Arenberger, Petr
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Clinical report
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Date:Oct 15, 2011
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