Phytomedicine 18 (2011) 11051109

Contents lists available at ScienceDirect

Phytomedicine
journal homepage: www.elsevier.de/phymed

Acute bronchitis therapy with ivy leaves extracts in a two-arm study.

A double-blind, randomised study vs. an other ivy leaves extract
Ute Cwientzek a, , Bertram Ottillinger b , Petr Arenberger c
a
b
c

Krewel Meuselbach GmbH, 53783 Eitorf, Germany

Life Sciences Consultancy, 85649 Brunnthal-Hofolding, Germany
Dermatological Clinic of the 3rd Faculty of Medicine of the Charles University Prague, 10034 Prague 10, Czech Republic

a r t i c l e

i n f o

Keywords:
Hedera helix
Ivy
Bronchitis
Double-blind randomised study

a b s t r a c t
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 efcacy of this drug. A double-blind,
randomised study was conducted to assess the efcacy 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 (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 6.26.3 1.2, the BSS
decreased by approximately 4.74.9 points until Day 7, so that patients left the study with a mean BSS
of 1.41.6. 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;
Fishers 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.
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, inuenza, parainuenza, 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 superinfection, 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

Corresponding author.
E-mail address: ucwientzek@krewel-meuselbach.de (U. Cwientzek).
0944-7113/$ see front matter 2011 Elsevier GmbH. All rights reserved.
doi:10.1016/j.phymed.2011.06.014

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-specically
stimulates the gastric mucosa and that parasympathicotonic
reexes in turn stimulate the secretion of bronchial mucus.
Recent work, however, has shown that -hederin, one of the
active ingredients of the ivy leaves extracts, increases the beta2-adrenergic bronchial reagibility. This leads to a relaxation
of the smooth bronchial musculature and furthermore to an
increased secretion of surfactant factors (Hberlein 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 conrmed 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 efcacy for this
special patient group (Schmidt 2002a,b).

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U. Cwientzek et al. / Phytomedicine 18 (2011) 11051109

Materials and methods

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 uid extract was then
removed by vacuum distillation. The volume of ethanol was supplemented by propylene glycol. The drug to extract ratio (DER) of
the nal spissum extract was 2.22.9:1. 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 -hederin and avonoids. 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 und 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 57.5:1.
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 efcacy 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 or Prospan .
Patients took one of the medications three times daily over
a period of seven days (1). After the admission examination,
patients returned for further examinations on Day 4 1 and on
Day 7 1. Adverse events were documented between the time of
informed consent and the last study visit.
The BSS (Bronchitis Severity Score) evaluates ve 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 ve symptom subscores. Other clinical
symptoms were scored on an identical 04 scale, global efcacy
(investigators) and tolerability (investigators and patients) on vestep verbal rating scales. Body temperature was measured in 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 reect 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
conrmed clinical diagnosis of acute bronchitis and a BSS 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

inuence 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 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 2.22.9:1.
Prospan contains ivy leaves extract extracted with 30% ethanol
with a resulting drug to extract ratio (DER) of 57.5:1. 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 tted 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 inuencing
symptoms of acute bronchitis was excluded. These medications
included beta-2 agonists, anti-viral 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 patients case report form.
Sample size and statistics
Published studies in acute bronchitis using the BSS as primary
endpoint found a standardised effect size /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 efcacy. Following
Rhmel 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 /s of
0.32. To detect such a clinically relevant difference with a power of
95%, n = 250 evaluable patients per group were required (manufac-

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1107

590 Patients randomised

(Safety Population)

295 Patients randomised

to Test Product

293 Patients completed

study (ITT Population)

295 Patients randomised

to Comparator

2 Dropouts
Early after visit 1

295 Patients completed

study (ITT Population)

No Dropouts
Early after visit 1

33 Patients excluded from

PP

37 Patients excluded from

PP

260 Patients
PP Population

258 Patients
PP Population

Fig. 1. Distribution of patients.

turers risk = 0.10) and approximately 295 patients per group had
to be recruited considering a dropout rate of 15%.
Efcacy was assumed if the mean improvement of BSS at Visit
3 (Day 7 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. Efcacy could be assumed if
the two-sided 95% condence 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. Twosided 95% condence intervals (CI) of treatment difference were
calculated within the frame of ANCOVA, corresponding to a signicance level of p < 0.05 (two-sided). CI was adjusted for baseline
inhomogeneities.
Secondary endpoints were compared between groups by t-tests,
MannWhitney tests, Fishers 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 predened denitions (BSS < 3 points at Visit 3; Decrease of BSS 7 points by Visit
3; BSS < 3 points at Visit 3 and decrease of BSS 7 points by Visit
3). Responder rates were compared between groups using Fishers exact test. All p-values for secondary endpoints do not possess
conrmatory 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.
Overall, 53% of randomised patients were female. The mean age
(SD) was 23 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 6.26.3 1.2, the BSS
decreased by approximately 4.74.9 points until Visit 3, so that
patients left the study with a mean BSS of 1.41.6. The improvement
in the PP dataset was only marginally higher (by approximately 0.1
score point) compared to the ITT dataset, conrming 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% condence interval (CI): 0.2654 to 0.3032). As
the lower end of the 95% CI (0.2654) was clearly above the noninferiority margin (0.6208), the non-inferiority of the test product
vs. active comparator in improvement of the BSS was conrmed.
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 conrm noninferiority of the test product to the comparator.
Responders were calculated from changes in BSS according
to three denitions as stated under Sample size and statistics.
Responders were overall evenly distributed to the two treatment
groups, with no signicant differences between groups (p between
0.42 and 0.90; Fishers exact test).
The investigators rated their impression of global efcacy with
a mean (SD) of 4.05 0.97 for the test group and with 3.96 0.95
for the comparator group. On the rating scale from 1 very poor
to 5 very good efcacy this corresponds to good efcacy in
both groups. The ratings were thus comparable and they did not
show a statistically signicant difference between groups (p = 0.23;
t-test; ITT dataset). Results for the PP dataset were similar. Patients
rated their impression of global efcacy with a mean (SD) of
78.7 22.9 mm for the test group and with 76.4 23.7 mm for the
comparator group. On a visual analogue rating scale from 0 mm
not at all satised to 100 mm completely satised this indicates a high to very high efcacy in both groups. The ratings were
thus comparable and they did not show a statistically signicant
difference between groups (p = 0.23; t-test; ITT dataset). Results for
the PP dataset were similar. By Visit 3, 83.2% of patients previously
unable to go to work or school were able to return to this activ-

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U. Cwientzek et al. / Phytomedicine 18 (2011) 11051109

Fig. 2. Difference between treatment groups in BSS change.

Table 1
Improvement of BSS subscales between baseline and Visit 3.
Population

Symptom
Cough
Sputum
Rhales/rhonchi
Chest pain
Dyspnoea
a
b

Difference of treatment effect testcomparatora

Non-inferiority marginb

Lower end 95% CIa

PP

ITT

PP

ITT

PP

ITT

0.05507
0.02242
0.009601
0.01032
0.00378

0.05037
0.02378
0.02329
0.00186
0.006750

0.28128
0.34656
0.31104
0.25472
0.10592

0.29024
0.3520
0.31552
0.26688
0.12416

0.07812
0.1327
0.06974
0.04871
0.01691

0.07691
0.1305
0.05792
0.03837
0.01642

ANCOVA.
0.32 SD of improvement of BSS symptom in the comparator group.

ity. There were no signicant differences between groups in this

parameter (ITT dataset: p = 0.79; Logrank test; PP dataset: p = 0.69).
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;
Fishers 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 (SD) of 4.21 0.78 for the test group and with 4.19 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 0.97 for the test group and with
3.96 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 predened non-inferiority margin. In addition,
also the BSS subscales, the additional clinical parameters typical
for the disease, and the investigators and patients global efcacy
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 prole, which conrmed 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 efcacy 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 dened 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 sufciently 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 efcacy parameter has been identied 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 7080% vs. baseline in the active groups (Matthys
2004; Kemmerich et al. 2006; Grnwald et al. 2006). This corresponds to our study, where the BSS decreased by 7578% over
the treatment period, which shows the external validity of our
data.
As a conclusion, the test product has established its efcacy
in patients with acute bronchitis by proving non-inferiority to an
other ivy leaves extract with a recognized efcacy within a very
narrow equivalence band. The study furthermore conrms the
favourable tolerability of the test product in an overall and especially in a paediatric population with acute bronchitis.

U. Cwientzek et al. / Phytomedicine 18 (2011) 11051109

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