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Review article
Treatment of signs and symptoms of the common cold using EPs 7630 -
results of a meta-analysis
Andreas Schapowal
a
,
*
, Gustav Dobos
b
, Holger Cramer
b
, Kian Chung Ong
c
, Martin Adler
d
,
Andrea Zimmermann
e
, Juliette Brandes-Schramm
e
, Walter Lehmacher
f
a
Allergy Clinic, Hochwangstraβe 3, 7302 Landquart, Switzerland
b
Department of Internal and Integrative Medicine, Kliniken Essen-Mitte, Faculty of Medicine, University of Duisburg-Essen, Am Deimelsberg 34a, 45276 Essen, Germany
c
KC Ong Chest &Medical Clinic, 3 Mount Elizabeth #12-03, Mount Elizabeth Medical Centre, Singapore 228510
d
Institute of Integrative Medicine Siegen, University of Münster, L€
archenweg 27, 57078 Siegen, Germany
e
Clinical Research, Dr. Willmar Schwabe GmbH &Co. KG, Willmar-Schwabe-Straβe 4, 76227 Karlsruhe, Germany
f
Emeritus, University of Cologne, Institute of Medical Statistics, Informatics and Epidemiology, Kerpener Straβe 62, 50931 Cologne, Germany
ARTICLE INFO
Keywords:
Respiratory system
Infectious disease
Pharmacology
Evidence-based medicine
Clinical research
Common cold
Efficacy
EPs 7630
Meta-analysis
Pelargonium sidoides
Safety
ABSTRACT
The efficacy of Pelargonium sidoides preparation EPs 7630 in the common cold (CC) was assessed by performing
meta-analyses of randomized, double-blind, placebo-controlled trials. Mean differences (MD) and risk ratios (RR)
with their 95% confidence intervals (CI) were computed. Five trials with a total of 833 patients were included. All
trials had a treatment period of ten days with visits at days 3, 5, and 10 after baseline and used a ten-symptom
Cold Intensity Score (CIS) as the primary outcome. Significant differences favoring EPs 7630 were observed for
total CIS reduction (day 5: MD ¼-2⋅30; 95%CI ¼-4⋅12,-0⋅49; day 10: MD ¼-1⋅16; 95%CI ¼-2⋅22,-0⋅10), pro-
portion of patients with substantial improvement (day 5: RR ¼1⋅73; day 10: RR ¼1⋅06) and complete remission
(day 5: RR ¼2⋅52; day 10: RR ¼2⋅13). Subjects treated with EPs 7630 missed fewer days at work, used less
paracetamol and had an improved sleep quality. No serious adverse reactions to EPs 7630 were reported. The
results support the efficacy of EPs 7630 in adults with CC.
1. Introduction
The common cold (CC) is a highly prevalent, acute respiratory tract
infection (RTI) of viral origin. It is one of the most common diseases
occurring among all age groups. It is estimated that adults may experi-
ence two to five, and children may suffer from seven to ten colds per year
(Eccles, 2005). Symptoms of CC are mainly related to the infected mu-
cosa and affect the nose, sinuses, pharynx, larynx, and other large air-
ways; they include nasal congestion and drainage, sneezing, coughing,
sore throat, general malaise, and fever. Cold symptoms may appear as
early as 10 h after infection and typically reach their maximum intensity
at around three days after onset. Coughing in particular may still persist
after three weeks (Heikkinen and J€
arvinen, 2003;Lorber, 1996).
The management of trivial RTIs such as CC is complicated by confusing
terminology that has arisen to define their anatomic locations, while
ignoring their usually diffuse nature (Manoharan and Winter, 2010). CC is
a non-specific RTI whose characteristic symptoms partly overlap with
other conditions such as acute bronchitis, allergic rhinitis, tonsillophar-
yngitis, rhinosinusitis, otitis media, and influenza. It is therefore not sur-
prising that clinical trials in different acute respiratory infections often use
similar diagnostic criteria. A clinical practitioner may consider an exact
differential diagnosis to be of secondary importance as long as it does not
imply a different type of treatment (e. g., in case of a bacterial infection or
allergic rhinitis). However, despite the variability and overlap of symp-
toms, CC is considered to be a diagnostic entity in its own right.
Although CC is the most frequently encountered disease in primary
care (Mossad, 1998), only a minority of patients with acute viral RTIs
visit a physician (Fendrick et al., 2003). In Western countries CC is often
treated through self-medication (Laven et al., 2014;Satoh et al., 2014), if
at all. Nevertheless, symptoms of CC may interfere significantly with
essential activities of daily living and may thus cause declines in function
and productivity (Bramley et al., 2002;Smith et al., 2000). Consequently,
the costs related to CC, e. g., through decreased productivity and time lost
from work or school (indirect costs), visits to health-care providers, and
* Corresponding author.
E-mail address: andreas@schapowal.ch (A. Schapowal).
Contents lists available at ScienceDirect
Heliyon
journal homepage: www.heliyon.com
https://doi.org/10.1016/j.heliyon.2019.e02904
Received 25 October 2018; Received in revised form 7 November 2019; Accepted 18 November 2019
2405-8440/©2019 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Heliyon 5 (2019) e02904
the amount of drugs used (direct medical costs), are enormous (Bertino,
2002;Birnbaum et al., 2002;Fendrick et al., 2003). Treatment is there-
fore justified and motivated by a reduction of symptom burden and costs
as well as by the prevention of more serious complications such as otitis
media and pneumonia, as well as acute exacerbations of asthma or
chronic obstructive pulmonary disease (Nahas and Balla, 2011).
While several drugs with in vitro activity against human rhinovirus,
the leading cause of CC (M€
akel€
a et al., 1998), are currently under
investigation (Bernard et al., 2014;MacLeod et al., 2013;Mello et al.,
2014), there are yet no licensed effective antivirals for this condition, and
therefore treatment aiming at symptom relief, a shortening of the illness
duration, and a reduction of the risk of complications as well as of the
infectivity to others remains the standard recommendation (Arroll, 2011;
Picon et al., 2013). Symptomatic treatments of CC, including antihista-
mines, decongestants, non-steroidal anti-inflammatory drugs, paraceta-
mol, and phyto-pharmaceutical products, have been extensively
reviewed (Allan and Arroll, 2014;Arroll, 2011;Hemil€
a and Chalker,
2013;Kim et al., 2009;Mossad, 1998;Nahas and Balla, 2011;Science
et al., 2012;Simasek and Blandino, 2007), albeit without providing clear,
universally accepted therapeutic recommendations. Although the use of
antibiotics is explicitly discouraged due to the predominantly viral eti-
ology of the disease and the risk of adverse effects and resistances
(M€
akel€
a et al., 1998), antibiotics over-prescription is still very common
(Dekker et al., 2015;Gulliford et al., 2014), and further efforts are
required to reduce inappropriate antibiotic use for the sake of containing
costs and limiting the spread of antibiotic resistance.
Most reviews devoted to phytotherapy of CC assessed the effect of
Echinacea. However, the results are difficult to interpret as Echinacea is
not a single product, but the products used in clinical trials were based on
different species and parts of the plants and used different methods of
extraction. Moreover, different outcome measures and clinical scoring
systems were used to assess treatment efficacy. While one review
considered each identified trial individually (Nahas and Balla, 2011), the
authors of another review performed a formal meta-analysis although the
trials used different products based on different species and parts of the
plants (Shah et al., 2007). This procedure was questioned by the authors
of a recently updated Cochrane review on Echinacea (Karsch-V€
olk et al.,
2014), who again refrained from pooling the results of trials investigating
the efficacy of Echinacea products in the treatment of CC and argued that
meta-analysis may only lead to meaningful results if all trials investigate
the same treatment for the same purpose. Moreover, since some of the
trials indicated a moderate beneficial effect of the investigated Echinacea
products on CC duration and/or symptom intensity whereas others did
not, it is not surprising that the efficacy conclusions drawn by the re-
viewers were mixed (Karsch-V€
olk et al., 2014;Nahas and Balla, 2011;
Shah et al., 2007).
EPs 7630
z
is a herbal drug preparation from the roots of Pelargonium
sidoides (drug –extract ratio: 1 : 8–10), extraction solvent: ethanol 11%
(w/w), with antiviral and antibacterial activity as well as notable
immune-modulatory capabilities (Moyo and Van Staden, 2014). The
medicinal product is used both in adults and in children from the age of
one year for the treatment of RTIs in several countries in Europe, Asia,
Australia, Central and South America, and is available in three pharma-
ceutical forms, i. e. solution, film-coated tablets and syrup. In adults, the
recommended daily dose is 30 drops of liquid solution or one 20 mg
tablet thrice daily.
It is of interest that EPs 7630 is a single, well characterized phyto-
pharmaceutical product so that an aggregation of information from
several trials in the therapeutic indication of CC appears to be justified as
shown in previous reviews for indications other than CC: for instance, in
2008 a first systematic review and meta-analysis suggested that EPs 7630
is effective for patients with acute bronchitis (Agbabiaka et al., 2008). A
Cochrane review (Timmer et al., 2013) assessed the efficacy of EPs 7630
in various acute RTIs. Moreover, a meta-analysis published by Matthys
et al. (2016) reviewed and supported the efficacy and safety of EPs 7630
in children, adolescents and adult patients with acute bronchitis, acute
rhinosinusitis and acute tonsillopharyngitis. In 2018, a review showed
that EPs 7630 is effective and safe for pediatric patients with acute
bronchitis, acute tonsillopharyngitis and acute RTIs in the context of
chronic preconditions (Careddu and Pettenazzo, 2018). The most recent
meta-analysis of EPs 7630 in RTIs was published in 2019 and involved
children suffering from acute tonsillopharyngitis or acute bronchitis. In
these patients, EPs 7630 alleviated symptoms, accelerated recovery and
reduced the concomitant use of paracetamol (Seifert et al., 2019).
In the current work, we present and discuss important challenges
arising during the investigation of the efficacy of EPs 7630 in the treat-
ment of CC. In a difficult-to-investigate indication like CC, where the
effect sizes observed in clinical trials are variable, meta-analysis may be
helpful for achieving a higher statistical power and obtaining more
robust point estimates than from clinical trials reviewed individually.
Moreover, exploratory, post-hoc meta-analyses may also investigate
outcome measures of interest that need not necessarily have been pre-
specified as such in the original protocols of the trials entered into the
analyses (e. g., Haidich, 2010).
For EPs 7630, the therapeutic evidence for adults having CC with
acute rhinosinusitis as an overlapping symptom has already been
included in a European guideline, and the recommendation for viral and
post-viral acute rhinosinusitis is directly based on category I evidence
(Fokkens et al., 2012). The updated Cochrane review on EPs 7630 pre-
pared by Timmer et al. (2013) assesses the efficacy of the herbal me-
dicinal product in acute respiratory infections (acute bronchitis, sinusitis,
CC, sore throat). For CC, the authors concluded that the herbal drug may
be effective in providing symptom alleviation, but the efficacy of EPs
7630 in CC was difficult to evaluate because data from only a single
randomized, placebo-controlled trial (Lizogub et al., 2007) had been
published when the review was performed.
In order to present the complete clinical evidence with respect to
efficacy and tolerability of EPs 7630 in CC, we performed the first review
and meta-analysis of double-blind, randomized, placebo-controlled,
therapeutic clinical trials with EPs 7630 in the indication of CC
completed by October 2014, also including hitherto unpublished data.
2. Methods
2.1. Search strategy and selection criteria
Double-blind, randomized, placebo-controlled, therapeutic clinical
trials with EPs 7630 in the indication of CC were eligible. Trials were
identified from clinical trial registries (ISRCTN; Clintrials.gov), medical
literature (MEDLINE), using the search term ‘EPs 7630’, and from the
European Medicines Agency's assessment report on Pelargonium sidoides
which was based on both published and otherwise unpublished data
(Committee on Herbal Medicinal Products (HMPC), 2012). Moreover,
the manufacturer of EPs 7630 was contacted for clinical trials meeting
our eligibility criteria to identify any unpublished material.
2.2. Outcome measures
Severity of disease was assessed in all clinical trials using a disease
specific, observer rated Cold Intensity Score (CIS) that included the
symptoms nasal drainage, sore throat, nasal congestion, sneezing,
scratchy throat, hoarseness, cough, headache, muscle aches, and fever.
Each symptom was rated on a 5-point verbal rating scale ranging from
0(‘not present’)to4(‘very severe’). A total score was computed by
adding up the scores of the 10 individual symptoms (theoretical range:
0–40 points).
We assessed total CIS as well as individual symptom change versus
baseline and performed responder analyses based on complete remission
z
EPs
®
7630 is the active ingredient of the product Umckaloabo
®
(ISO Arz-
neimittel, Ettlingen, Germany).
A. Schapowal et al. Heliyon 5 (2019) e02904
2
(defined as a total CIS of 0) as well as on substantial improvement
(defined as an item score 1 for each of the symptoms included in the
CIS). Other efficacy outcome measures of interest included in our ana-
lyses were the number of days until the onset of a meaningful treatment
effect (according to the assessment of the patients), the number of days
off work due to CC, paracetamol use, as well as the 1-item Integrative
Medicine Outcomes Scale (IMOS) (Steinsbekk et al., 1999). Sleep quality
was investigated using a 7-item subscale of the validated SF-A sleep
questionnaire that describes the quality of sleep during the previous
night (G€
ortelmeyer, 1986).
Tolerability was assessed based on adverse events.
2.3. Statistics
Meta-analyses for continuous variables were based on the mean value
difference between the treatment groups and the associated 95% confi-
dence intervals in their original scale. The same procedure was used for
discrete, ordinal outcomes for the sake of illustration. Meta-analyses of
binary outcomes were based on risk ratios and their 95% confidence
intervals. Heterogeneity between the trials was assessed using the I
2
statistic. Random effects models were computed in case of I
2
>5%, and
fixed effect models were used otherwise. Review Manager (RevMan)
Version 5⋅2 software was used for all meta-analyses (Anonymous, 2012).
Treatment differences were considered descriptively significant if the
95% confidence interval of point estimate did not include the value of
0 for differences between means or of 1 for risk ratios. Missing data at
days 5 and 10 were estimated using a last observation carried forward
approach which was considered conservative in a self-limiting disease
like CC (baseline data were not carried forward).
Tolerability was analyzed based on pooleddata from all trials using risk
differences and 95% confidence intervals. Adverse drug reactions (ADRs)
listed in the company's reference safety information of the marketed
product as potential unwanted effects were assigned to system groups of
gastrointestinal complaints, hypersensitivity reactions, nasal bleeding,
gingival bleeding, and liver associated events, which reflect adverse drug
reactions that may occur seldom (i. e., in 1–10 patients out of 10,000
exposed)or occasionally (i. e., in 1–10 patientsout of 1,000 exposed)during
treatmentwith EPs 7630. Events were considered to be potentially relatedif
a causal relationship to the blinded investigational treatment could not be
excluded. 95% confidence intervals for the observed event rates within the
treatment groups were determined using Wilson's score method (New-
combe, 1998b). Confidence intervals for event rate differences were
computed according to Wilson's score method for the single proportion
without continuity correction (Newcombe, 1998a).
The analyses were based on the Full Analysis Sets (FAS; for efficacy)
and on the Safety Analysis Sets (SAF) of the original trials. For all trials
except one both sets were identical (see Table 1). In another clinical trial,
patients who received 3 x 30 and 3 x 60 drops/day were analyzed
separately for efficacy outcomes.
2.4. Role of the funding source
The clinical trials eligible for our meta-analyses were sponsored by
Dr. Willmar Schwabe GmbH &Co. KG, Karlsruhe, Germany, manufac-
turer of EPs 7630, who also provided the subject data and performed the
analyses according to the pre-specifications conceived by the authors.
3. Results
3.1. Eligible trials
We identified five trials (A through E) conducted between 2003 and
2009, which were performed according to similar protocols whose main
characteristics are shown in Table 1. Trials A (Lizogub et al., 2007;Riley
et al., 2018) and B (Riley et al., 2019) are published. Safety data from
trials C and D were included in a safety review (Matthys et al., 2013) and
trial E has not previously been published. As confirmed by the manu-
facturer, this review thus includes evidence from all randomized,
placebo-controlled clinical trials performed with the herbal medicinal
product in the indication common cold. Trials A and B were conducted in
Ukraine, trial C in Germany, trial D in Bulgaria, and trial E in Singapore
and Malaysia. Between 2 and 11 active trial sites participated in each
clinical trial.
The participants of the trials were 833 male or female, adult out-
patients (EPs 7630 417; placebo 416) who suffered from CC. Patient
characteristics are presented in Table 2. The diagnosis was assured either
(a) by the presence of nasal drainage and sore throat as primary CC
symptoms and at least one (trials A þB) or two (trials C-E) of the secondary
symptoms nasal congestion, sneezing, scratchy throat, hoarseness, cough,
headache, muscle aches, and fever, or (b) by the presence of one of the
primary symptoms and at least three of the secondary symptoms. More-
over, patients had to be suffering from CC symptoms for a maximum of 72
h prior to inclusion in the trial (trials C-E; trials A þB: 24–48 h). In all trials,
patients were excluded if they had been taking medicines that could
interfere with the interpretation of the results, including cold medications,
within at least 4 days prior to enrolment. Furthermore, concomitant cold
medications other than the trial medication and paracetamol were pro-
hibited. Patients with co-morbidities in the respiratory system that could
impair the interpretation of the results or patients with other relevant
diseases were excluded from participation.
In all trials, randomized patients were treated for a scheduled period
of ten days. Assessments were performed at baseline (day 1) as well as at
days 3, 5, and 10. Trial E was stopped prematurely due to an outbreak of
a H1N1 virus pandemia in 2009 in the countries where it was performed,
since potential subjects were reluctant to accept a 50% chance of
receiving placebo.
All trials were planned, executed and analyzed under consideration of
the principles of Good Clinical Practice and the Declaration of Helsinki.
The clinical trial protocols and other required documents were approved
by the competent independent ethics committees and regulatory au-
thorities. All trial participants provided informed consent.
3.2. Analysis of overall effect
At baseline, the average total CIS in the five trials ranged between 14⋅9
and 17⋅8 points for the herbal drug and between 14⋅7and17⋅1pointsfor
Table 1
Characteristics of trials included in the meta-analysis.
Clinical
trial
Country Clinical
part
completed
(year)
Formulation Daily dose
A Ukraine 2004 CIS: Sum of total score differences day 3 vs. baseline and day 5 vs. baseline Liquid solution 3 x 30 drops, 3 x 60 drops
B Ukraine 2004 CIS: Sum of total score differences day 3 vs. baseline and day 5 vs. baseline Tablets 3 x 40 mg
C Germany 2008 Total CIS: AUC, baseline through day 5 Liquid solution 3 x 30 drops
D Bulgaria 2009 Total CIS: AUC, baseline through day 5 Liquid solution 3 x 30 drops
E Singapore/
Malaysia
2009 Total CIS: AUC, baseline through day 5 Tablets 3 x 20 mg
A. Schapowal et al. Heliyon 5 (2019) e02904
3
placebo, with higher baseline symptom burdens in trials A and B. This
resulted in considerable heterogeneity between the mean values for total
CIS change observed in the trials under investigation. As an example, Fig. 1
presents theaverage treatment groupdifferences and their 95% confidence
intervals for absolute total CIS change between baseline and treatment day
5. Whereas trials A and B show large treatment effects and significant su-
periority of EPs 7630 over placebo, moderate effects favoring the herbal
extract were observed in trials C and E while trial D showed marginal dif-
ferences between the treatment groups. Similar heterogeneity between the
results of the five trials was also observed for complete remission of all CC
symptoms at or before day 10 (Fig. 2) as well asfor other efficacy outcome
measures. A comparison between the results of the clinical trials also in-
dicates that lower than average treatment group differences were associ-
ated with a higher than average response in the placebo group.
A review of the pooled meta-analysis results reveals a monotonic
decrease of the total CIS in both treatment groups between baseline and
the final visit at day 10. For total score change versus baseline (Table 3),
superiority of EPs 7630 over placebo could already be observed at day 3
(p ¼0⋅05), peaked at day 5 (Fig. 1;p¼0⋅01) and was still significant at
day 10 (p ¼0⋅03). Table 3 also shows that only a small number of pa-
tients were symptom free already after three or five days of treatment
whereas 205/416 patients (49⋅3%) in the EPs 7630 group and 139/416
patients in the placebo group (33⋅4%) were in complete remission at day
10 (Fig. 2;p¼0⋅04). Advantages for the herbal extract were also
observed for substantial improvement, notably at day 5 when improve-
ment rates of 43⋅8% and of 31⋅5% were determined for EPs 7630 and
placebo, respectively, corresponding to a pooled meta-analysis risk ratio
of 1⋅73 (p ¼0⋅02).
Fig. 3 presents the overall meta-analysis results for the treatment
group comparison of the individual CIS symptoms for change between
baseline and day 5. EPs 7630 was more efficacious than placebo in
reducing all symptoms included in the CIS, with significant differences
for sore throat, nasal congestion, sneezing, scratchy throat, hoarseness,
and cough.
Meta-analysis main results for additional efficacy outcome measures
are presented in Table 4. Days missed at work due to CC showed a large
between-trial variability, with averages ranging between 0⋅6 and 5⋅9
days in the EPs 7630 group and between 1⋅0 and 6⋅7 days in the placebo
group, from which a pooled mean value difference of 0⋅74 days favoring
the herbal preparation was determined (Table 4;p¼0⋅01). In both
treatment groups, the lowest average number of days off work was
observed in trial A, whereas the highest numbers were observed in trials
D and E (see Table 1).
Among the five trials, the average time until the onset of a treatment
effect ranged between 5⋅2 and 6⋅9 days for EPs 7630 and between 5⋅0 and
8⋅4 days for placebo. In the meta-analysis, the patients treated with the
herbal preparation showed a more rapid onset of the treatment effect by a
pooled difference to placebo of 1⋅1 days (p ¼0⋅03). 54/416 patients in
the EPs 7630 group (13⋅0%) and 77/416 patients in the placebo group
(18⋅5%) used paracetamol at least once. The amount of paracetamol used
was significantly lower in patients treated with the herbal preparation (p
¼0⋅04). According to the IMOS, the patients treated with EPs 7630 had a
more favorable overall outcome at days 5 (p ¼0⋅02) and 10 (Fig. 4;p¼
0⋅05). Moreover, compared to placebo, their quality of sleep was
significantly better (days 5 and 10: p <0⋅01).
3.3. Tolerability
Among the system groups mentioned in the company's reference
safety information of the marketed product containing EPs 7630
(Table 5), increases of event rates in patients treated with the herbal drug
by more than 1% compared to placebo were observed for gastrointestinal
Table 2
Patient characteristics (percent or mean and standard deviation).
Clinical trial Treatment Number of patients Sex:% female Age (years) Body weight (kg) Body mass index (kg/m
2
)
A 3 x 30 drops/day EPs 7630 52 69⋅2% 34⋅5 (10⋅60) 71⋅3 (15⋅12) 24⋅2(4⋅01)
Placebo 51 68⋅6% 37⋅4 (10⋅52) 70⋅7 (12⋅63) 24⋅3(3⋅46)
3 x 60 drops/day EPs 7630 52 73⋅1% 36⋅8(9⋅91) 70⋅6 (11⋅36) 24⋅8(3⋅71)
Placebo 52 76⋅9% 33⋅8 (10⋅84) 68⋅4 (12⋅96) 23⋅9(3⋅83)
B EPs 7630 53 75⋅5% 35⋅0 (10⋅86) 71⋅7 (12⋅88) 25⋅1(3⋅86)
Placebo 52 78⋅8% 37⋅7 (10⋅48) 73⋅6 (15⋅55) 25⋅7(4⋅52)
C EPs 7630 99 66⋅7% 37⋅1 (13⋅58) 73⋅0 (16⋅19) 24⋅8(4⋅27)
Placebo 101 65⋅3% 37⋅1 (12⋅46) 74⋅7 (15⋅91) 25⋅0(4⋅42)
D EPs 7630 101 63⋅4% 44⋅8 (14⋅10) 73⋅0 (18⋅16) 25⋅4(4⋅84)
Placebo 100 70⋅0% 46⋅2 (14⋅09) 69⋅9 (14⋅14) 24⋅7(3⋅99)
E EPs 7630 59
a
44⋅1% 32⋅6 (11⋅02) 65⋅7 (17⋅53) 23⋅9(5⋅94)
Placebo 60 48⋅3% 33⋅3 (10⋅64) 64⋅0 (16⋅17) 23⋅2(5⋅45)
a
Applies to efficacy; safety: n ¼60.
Study or Subgroup
A (1-Standard Dose)
A (2-High Dose)
B
C
D
E
Total (95% CI)
Heterogeneity: Tau² = 4.51; Chi² = 42.06, df = 5 (P < 0.00001); I² = 88%
Test for overall effect: Z = 2.49 (P = 0.01)
Mean
-10.44
-11.17
-9.25
-8.79
-8.58
-9.93
SD
2.97
4.75
2.71
4.9
5.14
4.9
Total
52
52
53
99
101
59
416
Mean
-5.57
-6.27
-6.06
-8.02
-8.67
-9.73
SD
4.29
4.73
4.2
5.78
5.1
5.24
Total
51
52
52
101
100
60
416
Weight
17.0%
16.0%
17.2%
16.9%
17.0%
16.0%
100.0%
IV, Random, 95% CI
-4.87 [-6.30, -3.44]
-4.90 [-6.72, -3.08]
-3.19 [-4.54, -1.84]
-0.77 [-2.25, 0.71]
0.09 [-1.33, 1.51]
-0.20 [-2.02, 1.62]
-2.30 [-4.12, -0.49]
EPs 7630 Placebo Mean Difference Mean Difference
IV, Random, 95% CI
-4 -2 0 2 4
Favors EPs 7630 Favors Placebo
Fig. 1. Meta-analysis of change of total CIS between baseline and treatment day 5 (FAS).
A. Schapowal et al. Heliyon 5 (2019) e02904
4
complaints, epistaxis, and for all events (including those from system
groups not shown in the table). For all other system groups investigated,
the incidence rates of adverse events under EPs 7630 were similar to
those in patients treated with placebo, with point estimates for the risk
difference not exceeding þ0⋅5%. Our meta-analysis of all five trials,
including events with any causal relationship to EPs 7630, revealed a
pooled risk ratio of 1⋅51 (95% CI: [1⋅07; 2⋅13]; p ¼0⋅02) favoring pla-
cebo. No serious adverse reactions to EPs 7630 were reported in any of
the trials.
In trial A, higher AE rates were observed for the 3 x 60 drops/day dose
as compared to the 3 x 30 drops/day dose. This applied to both EPs 7630
(15⋅4% vs. 7⋅7%) and placebo (5⋅8% vs. 3⋅9%).
4. Discussion
4.1. Clinical efficacy
Our results demonstrate that EPs 7630 is significantly superior to
placebo in alleviating the symptoms of the CC. Should results be aggre-
gated using meta-analysis methods when substantial heterogeneity ex-
ists, with I
2
values of 88% and 93% for total score change at day 5 and
complete remission at day 10, respectively? The I
2
measure can be
thought of as an indicator of the proportion of variance that reflects true
differences in effect size between the trials in a meta-analysis (Higgins
et al., 2003). As such, it reflects the extent by which the confidence in-
tervals for the effect size point estimates overlap. Our interpretation that
the observed differences favoring EPs 7630 in the pooled effect measures
of our meta-analysis represent a true treatment effect rather than bias is
supported by the fact that benefits of the herbal preparation were
consistently observed in four of the five clinical trials included in the
review although the treatment effect sizes in two of these trials were
admittedly small to moderate (Ioannidis, 2008). Heterogeneity observed
between the clinical trials was therefore mainly attributable to
disagreement in the magnitude, not in the direction of the EPs 7630
treatment effect. Moreover, when investigating a drug with no pharma-
cological effects one would rather expect to find only chance differences
to placebo, some of them favoring the investigational drug and some
placebo treatment. This was clearly not the case for the clinical trials
presented in this meta-analysis. Moreover, bias caused by selective
reporting can also be excluded since all trials investigating EPs 7630 in
the indication of CC and completed until the compilation of our
meta-analysis were included in the review.
In clinical trials, overlapping symptoms between indications such as
acute bronchitis and CC almost inevitably lead to overlapping inclusion
criteria and/or efficacy outcome measures. It is therefore essential to
assure that the participants of a trial actually suffer from the particular
diagnostic entity under investigation. It is also noteworthy in this context
that to date, the CIS, which is based on a validated score initially
developed by Jackson and coworkers (Jackson et al., 1958;Mossad et al.,
1996;Prasad et al., 2000), is one of the few observer rated instruments
for assessing the symptoms of CC, and moreover, symptoms severity
assessments, obtained predominantly through patient diaries, are
necessarily subjective and may thus introduce bias (Barrett et al., 2002;
Mossad et al., 1996). Both symptom overlap and the lack of formally
validated symptom severity scales may contribute to heterogeneity be-
tween the results of different trials.
Study or Subgroup
A (1-Standard Dose)
A (2-High Dose)
B
C
D
E
Total (95% CI)
Total events
Heterogeneity: Tau² = 0.70; Chi² = 66.97, df = 5 (P < 0.00001); I² = 93%
Test for overall effect: Z = 2.07 (P = 0.04)
Events
33
38
24
27
53
30
205
Total
52
52
53
99
101
59
416
Events
6
5
6
26
69
27
139
Total
51
52
52
101
100
60
416
Weight
15.5%
15.0%
15.3%
17.6%
18.6%
18.0%
100.0%
M-H, Random, 95% CI
5.39 [2.47, 11.76]
7.60 [3.25, 17.77]
3.92 [1.75, 8.81]
1.06 [0.67, 1.68]
0.76 [0.61, 0.95]
1.13 [0.78, 1.65]
2.13 [1.04, 4.35]
EPs 7630 Placebo Risk Ratio Risk Ratio
M-H, Random, 95% CI
0.05 0.2 1 5 20
Favors Placebo Favors EPs 7630
Fig. 2. Meta-analysis of complete remission of all symptoms contained in the CIS until day 10 (FAS).
Table 3
Meta-analysis results for the Cold Intensity Score: total score change, complete remission, and substantial improvement (FAS).
Visit Responders Point estimate and 95% CI
EPs 7630 (n ¼416) Placebo (n ¼416)
Total score: change versus baseline (mean score difference)
a
Day 3 -0⋅93 [-1⋅87; 0⋅02]
Day 5 -2⋅30 [-4⋅12; -0⋅49]
Day 10 -1⋅16 [-2⋅22; -0⋅10]
Complete remission (risk ratio)
b
Day 3 2 1 1⋅67 [0⋅22; 12⋅56]
Day 5 19 7 2⋅52 [1⋅13; 5⋅64]
Day 10 205 139 2⋅13 [1⋅04; 4⋅35]
Substantial improvement (risk ratio)
b
Day 3 34 39 0⋅89 [0⋅58; 1⋅35]
Day 5 182 131 1⋅73 [1⋅08; 2⋅08]
Day 10 368 343 1.06 [1⋅00; 1⋅13]
a
Point estimates <0 favor EPs 7630.
b
Point estimates >1 favor EPs 7630.
A. Schapowal et al. Heliyon 5 (2019) e02904
5
To explain the heterogeneity between the clinical trials, different
statistical models including factors possibly responsible for the hetero-
geneity were investigated.
4.2. Heterogeneity between clinical trial inclusion criteria
From a clinical point of view, comparing the inclusion criteria of the
clinical trials, the main difference between trials A, B on one side and
trials C, D, E on the other side is the acceptable delay between the onset of
CC symptoms and the inclusion in the clinical trial. In trials A and B, the
delay was between 24 and 48 h compared to between 24 and 72 h in the
other three trials. The higher initial symptom burden in trials A and B
may explain some of the high heterogeneity between trial results.
In other common cold trials with results demonstrating superiority
over placebo using other products, treatment was initiated promptly
when patients had a first subjective feeling of CC because the incubation
period varies but is just under two days for rhinovirus (Allan and Arroll,
2014;Hoheisel et al., 1997;Mossad et al., 1996;Prasad et al., 2000;
Schulten et al., 2001).
4.3. Heterogeneity between clinical trial populations
Another source of heterogeneity may be cultural or socioeconomic
differences between trial populations that are not related to the type or
intensity of symptoms. As an example, days missed at work due to CC
showed a large between-trial variability. In both treatment groups, the
Fig. 3. Change of individual CIS symptoms between baseline and treatment day 5 –overall meta-analysis results (mean value difference; FAS).
Table 4
Meta-analysis results for other efficacy related outcome measures (FAS).
Outcome measure N Mean value difference
and 95% CI
EPs 7630 Placebo
Days off work
a
412 409 -0⋅74 [-1⋅33; -0⋅15]
Paracetamol consumption
(mg)
a
,
c
416 416 -79⋅0 [-152⋅4; -5⋅5]
Days until the onset of a
treatment effect
a
393 395 -1⋅12 [-2⋅14; -0⋅10]
IMOS –investigator rating, day
5
a
416 416 -0⋅39 [-0⋅72; -0⋅06]
Sleep quality –sum of item
scores, day 5
b
405 401 1⋅63 [0⋅45; 2⋅81]
a
Point estimates <0 favor EPs 7630.
b
Point estimates >0 favor EPs 7630.
c
Patients who did not use paracetamol were included in the calculation with a
value of 0.
Study or Subgroup
A (1-Standard Dose)
A (2-High Dose)
B
C
D
E
Total (95% CI)
Heterogeneity: Tau² = 0.20; Chi² = 61.20, df = 5 (P < 0.00001); I² = 92%
Test for overall effect: Z = 2.00 (P = 0.05)
Mean
1.29
1.17
1.47
1.79
1.63
1.81
SD
0.67
0.65
0.67
0.88
0.85
1.07
Total
52
52
53
99
101
59
416
Mean
2.04
2.15
1.98
1.97
1.4
1.93
SD
0.72
0.8
0.46
1.12
0.68
1.18
Total
51
52
52
101
100
60
416
Weight
16.8%
16.7%
17.3%
16.7%
17.4%
15.2%
100.0%
IV, Random, 95% CI
-0.75 [-1.02, -0.48]
-0.98 [-1.26, -0.70]
-0.51 [-0.73, -0.29]
-0.18 [-0.46, 0.10]
0.23 [0.02, 0.44]
-0.12 [-0.52, 0.28]
-0.39 [-0.77, -0.01]
EPs 7630 Placebo Mean Difference Mean Difference
IV, Random, 95% CI
-1 -0.5 00.5 1
Favors EPs 7630 Favors Placebo
Fig. 4. Meta-analysis of IMOS investigator rating, day 10 (FAS).
A. Schapowal et al. Heliyon 5 (2019) e02904
6
lowest average number of days off work was observed in trial A, whereas
the highest numbers were observed in trials D and E. The results thus
point to differences regarding the subjectively perceived disease burden
and/or the inclination to take (or to provide) sick leave between the
countries where the trials were performed.
4.4. Agreement between different outcome measures within clinical trials
The degree of concordance between the different outcome measures
within an investigation may be an important indicator for the internal
validity of the primary results.
The meta-analysis results based on the total CIS are supported by the
fact that benefits of the herbal preparation were consistently observed for
symptomatic improvement, general medical outcome, and other disease
related measures. Our results indicate that compared to placebo, EPs 7630
alleviated the symptoms of CC and decreased the time until substantial
improvement and complete remission, resulting in fewer days missed at
work. Moreover, treatment with the herbal preparation reduced the need
for paracetamol consumption and resulted in improved sleep quality.
Based upon a much broader database, this analysis therefore confirms and
extends the conclusions drawn from previous research according to which
EPs 7630 may offer symptom relief in CC (Timmer et al., 2013).
4.5. Efficacy in a short-term disease
CC is characterized by a comparatively short course of disease when
no complications arise. In a therapeutic clinical trial, this implies a nar-
row window for the initiation of treatment after the appearance of the
first symptoms, as well as a clinically meaningful timing of assessments to
assure comparability of results. Since most symptoms of CC are known to
subside within about 10 days untreated (Heikkinen and J€
arvinen, 2003;
Lorber, 1996), the pharmacological effect of an intervention will likely be
masked by the natural course when the period of observation extends
beyond day 10.
In the analysis performed for EPs 7630, superiority of the herbal
extract over placebo was already detectable at the first post-baseline visit
(day 3), and the effect was most pronounced at the second post-baseline
visit (day 5; Table 3). Although the decrease of CC associated symptoms
was likely increasingly confounded with the natural course of the disease
as treatment progressed, the differences between EPs 7630 and placebo
regarding total CIS change, substantial improvement, and complete
remission were still significant at day 10 after baseline.
4.6. Tolerability
The EPs 7630 meta-analysis of safety data points to a moderate in-
crease of the AE rate in general and of gastrointestinal complaints and
epistaxis. This is consistent with the results of an extensive safety review
performed by Matthys and colleagues based on data from 29 clinical
trials and non-interventional studies, with a total of more than 8,000
participants exposed to EPs 7630, in which the authors found slight in-
creases of the risk of gastrointestinal disorders and epistaxis in patients
receiving the herbal extract (Matthys et al., 2013). However, compared
to placebo, only a slight overall increase in the frequency of adverse
events in the EPs 7630 groups was observed. AEs potentially related to
the trial treatment (EPs 7630 or placebo) were comparable between
groups, and no serious adverse events occurred in any of the groups.
5. Conclusion
The common cold is a common disease that usually has an uncom-
plicated course. Nevertheless, and partly because of this, the efficacy of
therapeutic interventions in CC are difficult to assess. Challenges faced
by investigators include symptom overlap with other acute RTIs, as well
as sociocultural and other differences between trial populations that
influence the patients’subjective perception of the disease as well as of
its consequences, such as whether or not they consult a physician or
remain home from work. Together with a comparatively narrow thera-
peutic window caused by the short natural course, these factors
contribute to substantial heterogeneity between trial results that has
been observed in reviews and meta-analyses for a variety of CC
treatments.
In this regard, the clinical trials performed for Pelargonium sidoides
extract EPs 7630 are no exception. Nevertheless, our meta-analysis sup-
ports the efficacy and safety of the drug in adults with CC. Treatment
with the herbal preparation was associated with symptom alleviation and
more rapid remission and may thus not only reduce the burden on the
individual patient, but also the burden on the healthcare system and the
economic impact of this very common condition. More evidence would
be helpful due to the heterogeneity of the trial results that made the
treatment effect of EPs 7630 difficult to assess. The results also confirm
that this herbal preparation is well-tolerated.
Declarations
Author contribution statement
All authors listed have significantly contributed to the development
and the writing of this article.
Funding statement
This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.
Competing interest statement
The authors declare the following conflict of interests: Andreas
Table 5
Incidence of adverse events based on pooled data –number (%) of patients and 95% confidence intervals.
System group Type EPs 7630
(n ¼417)
Placebo
(n ¼416)
Risk
difference
Gastrointestinal complaints All events 26 (6⋅24%) [4⋅29%; 8⋅98%] 19 (4⋅57%) [2⋅94%; 7⋅02%] 1⋅67% [-1⋅46%; 4⋅86%]
Potentially related events 25 (6⋅00%) [4⋅09%; 8⋅70%] 19 (4⋅57%) [2⋅94%; 7⋅02%] 1⋅43% [-1⋅68%; 4⋅58%]
Hypersensitivity reactions All events 5 (1⋅20%) [0⋅51%; 2⋅78%] 3 (0⋅72%) [0⋅25%; 2⋅10%] 0⋅48% [-1⋅06%; 2⋅12%]
Potentially related events 3 (0⋅72%) [0⋅24%; 2⋅09%] 2 (0⋅48%) [0⋅13%; 1⋅74%] 0⋅24% [-1⋅10%; 1⋅66%]
Epistaxis All events 11 (2⋅64%) [1⋅48%; 4⋅66%] 6 (1⋅44%) [0⋅66%; 3⋅11%] 1⋅20% [-0⋅84%; 3⋅36%]
Potentially related events 9 (2⋅16%) [1⋅14%; 4⋅05%] 4 (0⋅96%) [0⋅37%; 2⋅45%] 1⋅20% [-0⋅60%; 3⋅18%]
Gingival bleeding All events –––
Potentially related events –––
Liver associated events All events 1 (0⋅24%) [0⋅04%; 1⋅35%] 1 (0⋅24%) [0⋅04%; 1⋅35%] -0⋅00% [-1⋅13%; 1⋅12%]
Potentially related events 1 (0⋅24%) [0⋅04%; 1⋅35%] 0 (0⋅00%) [0⋅00%; 0⋅91%] 0⋅24% [-0⋅70%; 1⋅35%]
All system groups
a
All events 66 (15⋅83%) [12⋅64%; 19⋅64%] 44 (10⋅58%) [7⋅97%; 13⋅90%] 5⋅25% [0⋅64%; 9⋅87%]
All potentially related events 39 (9⋅35%) [6⋅92%; 12⋅53%] 25 (6⋅01%) [4⋅10%; 8⋅72%] 3⋅34% [-0⋅30%; 7⋅05%]
a
Also includes events from system groups not shown in this table.
A. Schapowal et al. Heliyon 5 (2019) e02904
7
Schapowal, Gustav Dobos, Kian Chung Ong, Martin Adler, and Walter
Lehmacher have received honoraria from Dr. Willmar Schwabe GmbH &
Co KG, Karlsruhe, Germany; Andrea Zimmermann and Juliette Brandes-
Schramm are employees of Dr. Willmar Schwabe GmbH &Co. KG,
Karlsruhe, Germany. Holger Cramer declares no conflict of interest.
Additional information
No additional information is available for this paper.
Acknowledgements
This work, including provision of all trial data used in this article, was
supported by Dr. Willmar Schwabe GmbH &Co. KG, Karlsruhe, Germany.
During the preparation of the draft manuscript medical writing
assistance was provided by Dr. Andreas V€
olp, Psy Consult Scientific
Services, Hamburg, Germany.
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