Product Monograph For Kaloba.

By Monica van de Weerd

Product Monograph For Kaloba.

If you would like me to e mail you the original: easier to read and oversight. Just e mail me and I will send. monica@naturallyhealthy.co.nz


EPs® 7630
2
3
Contents
1. A t a glance 5
2. A cute respiratory tract infections (RT Is) 7
2.1 Pathophysiology 7
2.2 Pathogen spectrum 8
2.3 C urrent treatments and related problems 9
2.4 A ntibiotic resistance 11
2.5 A ntiviral agents in the treatment of RT Is 12
3. EPs® 7630 - the phytotherapeutic alternative 13
3.1 O rigin and botany 13
3.2 Phytochemistry 14
4. Mode of action 15
4.1 A ntiviral and cytoprotective properties 16
4.2 A ntibacterial properties 19
4.3 Secretomotory properties 21
5. Safety profile 23
5.1 T oxicology 23
5.2 Interaction potential 25
5.3 Pharmacovigilance 25
6. C linical efficacy and safety studies 27
6.1 C linical studies by indication 27
- Acute bronchitis 27
- Acute sinusitis 36
- Tonsillitis / tonsillopharyngitis 39
- Common cold 42
6.2 A dditional clinical studies 44
- CO PD 44
- Asthma 46
6.3 Meta-analyses 48
7. EPs® 7630 - frequently asked questions 51
8. Summary 53
9. R eferences 55
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5
1. At a glance
Origin
Pelargonium sidoides root extract
(South African Cape Province Pelargonium)
Mechanisms of action
Anti-infective (antiviral and antibacterial) by immunomodulation
and prevention of bacteria-host interactions
Secretomotory
Efficacy
Clinical efficacy in respiratory tract infections in adults and
children over 1 year of age confirmed in placebo-controlled trials
BENEFIT
Shortens duration of the disease and
reduces severity of the symptoms
Toxicology
Toxicologically and pharmacologically safe
Excellent tolerability confirmed in clinical trials
Dosage instructions
Adults and adolescents over 12 years of age:
3 x 30 drops or 3 x 1 tablet daily
Children between 6 and 12 years of age:
3 x 20 drops or 2 x 1 tablet daily
Children between 1 and 5 years of age:
3 x 10 drops daily
EPs® 7630
First choice. Fast recovery.
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2. Acute respiratory
trac t infections (RTI s)
Figure 1: Spread of infectious pathogens in the respiratory tract
Acute respiratory tract infections are the most common
diseases treated in general and paediatric practices and
affect all age groups, particularly during the winter
months. During an epidemic they can account for up to
50% of all medical consultations [Marre et al. 2006].
Medical consultations for colds and influenza alone cost
between 650 and 850 million euros a year in Germany
[Fintelmann 2005]. The fact that 90 to 95% of cases are
virus-mediated makes this an even greater therapeutic
challenge [DG PI Handbuch 2003].
Acute respiratory tract infections are diseases with a
self-healing tendency. Nevertheless, if they are left
untreated there is a substantial risk that the clinical
course may be considerably prolonged. This is
unacceptable to patients who suffer from the disease
but have to o r want to return to work or school as
soon as possible.
Acute complications of respiratory tract infections are
highly significant because children, the elderly and
immunocompromised subjects are at particular risk
of developing an acute, potentially life-threatening
infection such as pneumonia as a superinfectioninduced
complication of acute bronchitis.
In addition, there is a considerable risk of developing
a chronic disease, e.g. chronic or recurrent bronchitis.
In conclusion, it must be emphasised that even
respiratory tract infections that appear harmless at first
sight should be treated.
2.1 Pathophysiology
A disrupted immune balance is the basis of any infection.
The immune system can no longer compensate for the
(increased) pathogenic burden. This is primarily the case
with particularly aggressive viruses that are unknown
to the immune system and when the immune system is
weakened by cold weather or stress.
The nasal cavity/pharynx is generally the starting point.
This is where rhinopharyngitis, which is characterised by
the initial symptoms of sore throat, rhinitis and lethargy,
actually develops.
Pathogen ascent subsequently triggers sinusitis,
while pathogen descent causes tonsillitis, laryngitis
and frequently acute tracheobronchitis. This also
explains why acute bronchitis is almost always
associated with other symptoms caused by the
inflammatory processes in the nasal cavities and
pharynx (Figure 1) [Hampl, Mertens 2003].
8
1. Adhesion – prerequisite for infection
2. Internalisation – pathogen proliferation and
reservoir for recurrence
3. Paracellular translocation – spread of infection
in the deep tissues
Internalised and paracellularly translocated pathogens in the
deeper cell layers are often not reached by substances with a
direct antimicrobial effect. This underlines the importance of
protecting the mucosal cells and activating the nonspecific
immune system, especially the natural killer cells, which are
the first line of defence.
Figure 2: Epithelial cells of the mucosa
Adhesion
Internalisation
Translocation
2.2 Pathogen spectrum
Viruses are by far the most important group of
pathogens, accounting for 90 - 95% of respiratory tract
infections (Table 1).
Influenza A and B viruses are the most common
pathogens isolated in patients with uncomplicated
acute bronchitis.
Another frequent aetiology is an infection with
parainfluenza virus. Respiratory syncytial virus (RSV)
is common in children less than 1 year of age and in
elderly patients in nursing homes. Both rhinovirus and
enterovirus generally cause a mild infection. Multiple
viral infections are detected in 30% of cases [Llor 2013].
Primary bacterial pathogens are only rarely detected in
acute sinusitis.
Tonsillitis needs to be categorised more precisely, since
besides simple catarrhal, mostly virus-induced tonsillitis,
streptococcal pharyngitis, which generally requires
antibiotic therapy, can occur. The treatment of acute
tonsillitis therefore falls into the domain of medicine,
though the risk of developing post-streptococcal
complications is now extremely low in countries with
a good standard of hygiene. The post - streptococcal
risk described in many textbooks is most probably a
“phantom risk” in Germany [Porzsolt, Ohletz 1999]. The
incidence of this risk was quantified b y Adam: Even
in 1980 only one case of rheumatic fever was reported
during the working l ife o f 1 2 general practitioners
[Adam et al. 2001]. Based on this minimal risk, the
authors concluded that immediate antibiotic treatment
is not always necessary. It is, however, generally
accepted that patients presenting with acute
symptomatic streptococcus-induced diseases should
receive antimicrobial therapy [McIsaac et al. 2004],
[Gonzales et al. 2004]. However, this treatment is
effective even when started with a delay of up to 9 days.
According to Adam, this means that one can first wait
for the bacteriological test result of a throat swab and
then prescribe an antibiotic appropriate for the pathogen
spectrum identified by culture and sensitivity testing.
2. Acute respiratory tract infections (RTIs)
The onset of infection in terms of interaction with
epithelial cells occurs in three stages (Figure 2):
9
2.3 Current treatments and
related problems
Although 9 out of 10 respiratory tract infections are
caused by viruses, antibiotics are prescribed in over
80% of cases [Kutty 2011].
Identifying the subgroup that will probably benefit
from antibiotic use is difficult; it is most important to
rule out the presence of pneumonia when considering
treatment. Patients with uncomplicated respiratory
tract infections without underlying lung or heart
disease or immunosuppression, and those who have
been ill for less than a week are unlikely to benefit
from antibiotic therapy [Llor 2013].
The most common pathogens in tracheobronchitis are:
Viruses:
Adenovirus (types 1-7, 12) +++ + to +++
Rhinovirus ++ + to ++
Coxsackie virus + +
Other enteroviruses + +
Influenza virus A and B +++ + to ++++
Influenza virus C + +
Parainfluenza virus 1 and 2 ++ ++
Parainfluenza virus 3 +++ +++
RSV (respiratory syncytial virus) +++ + to +++
Bacteria:
Mycoplasma pneumoniae +++ + to +++
Chlamydia pneumoniae + ++
Pathogen Significance Severity
Table 1: Overview of pathogens involved in acute tracheobronchitis
Figure 3: Over 90% of cases of respiratory tract infections are caused by viruses
2. Acute respiratory tract infections (RTIs)
10
Antibiotics in the treatment of
non-group-A-streptococcal pharyngitis
A meta-analysis of 27 studies involving 2,835 patients
conducted by the Cochrane Collaboration led to the
conclusion that antibiotic therapy in this indication
shortens symptoms by 16 hours and that most
patients do not benefit at all from this form of
treatment [Del Mar et al. 2006].
Antibiotics in the treatment of laryngitis
The Cochrane Review by Reveiz et al. of 206 adult
patients did not show a clinically significant advantage.
The authors concluded that antibiotics used in the
management of acute laryngitis did not objectively
improve symptoms and therefore should not be
considered as first-line treatment for acute laryngitis
[Reveiz et al. 2007].
Antibiotics in the treatment of otitis media
In a meta-analysis carried out by the Cochrane
Collaboration, investigation of 8 studies involving a
total of 2,287 children led Glasziou et al. to the conclusion
that administration of antibiotics to children with otitis
media is only slightly beneficial and should be carefully
evaluated in view of the side effects, especially since
otitis media resolves spontaneously in most cases
[Glasziou et al. 2003].
Antibiotics in the treatment of colds and acute
purulent rhinitis
In a Cochrane Review of 6 studies with a total of
1,147 patients, Arroll and Kenealy found that there is
inadequate evidence regarding the use of antibiotics
in this indication and that the routine administration
of these substances cannot be recommended [Arroll,
Kenealy 2005].
Antibiotics in the treatment of acute sinusitis
The Cochrane Review by Williams et al. (meta-analysis
of 49 studies involving a total of 13,660 patients) found
that there is only very limited evidence regarding the use
of antibiotics and that doctors should weigh the limited
therapeutic effect against the known potential for side
effects [Williams et al. 2003].
Antibiotics in the treatment of acute bronchitis
The authors of a Cochrane meta-analysis of 9 studies
involving a total of 750 adults and children concluded
that antibiotics bring only a minimal benefit in the
treatment of acute bronchitis [Fahey et al. 2004].
Current guidelines do not recommend routine use of
antibiotics for uncomplicated acute bronchitis in
otherwise healthy individuals. Arguments against
using antibiotics include the cost, the potential side
effects and the risk of antimicrobial resistance. Because
of the risk of antibiotic resistance and of Clostridium
difficile infection in the community, antibiotics should
not be used routinely in the treatment of acute
bronchtis, especially in younger patients in whom
pertussis is not suspected [Llor 2013].
Antibiotics in the management of acute bronchiolitis
Bronchiolitis is a serious and often life-threatening
disease of the lower respiratory tract that mainly
affects babies. The disease is caused by the RSV
(respirator y syncytial virus). Taking the primary
endpoints, disease duration and death into account,
a Cochrane analysis did not reveal any significant
difference between placebo and antibiotics [Spurling
et al. 2007].
Overall, it was concluded that statistically significant
and clinically relevant differences were apparent only
regarding an increased frequency of side effects,
especially allergic exanthema, gastrointestinal disorders
and mycotic infections.
At this point it is worth mentioning that almost 8 out of
10 children will be treated at least once with antibiotics
between the 2nd and 4th year of life. The average duration
of treatment is 17.6 days/child/year [Dilruba et al. 2002].
The uncritical administration of antibiotics in children
is of particular concern, especially as asthma is 2.5 times
more prevalent in 7-year-old children given antibiotics
at an early age than in their untreated peers. Moreover,
allergies are twice as prevalent in this same patient
category [Henry Ford Health 2005].
2. Acute respiratory tract infections (RTIs)
11
2.4 Antibiotic resistance
Another side effect of antibiotic treatment is bacterial
(antibiotic) resistance, which has become a major
international problem.
A survey showed that 55% of patients believed that
antibiotics were effective for the treatment of viral
upper respiratory tract infections and that nearly 25%
of patients had self-treated an upper respiratory tract
illness in the previous year with antibiotics left over
from earlier infections [Llor 2013].
As long ago as 2002, Bronzwaer highlighted the
correlation between frequency of antibiotic use and
proportion of resistant bacterial strains in the overall
population of Europe [Bronzwaer et al. 2002]. The study
concerned showed that the number of prescribed daily
doses of antibiotics is positively correlated with the
occurrence of bacterial resistance (Figure 4).
1
0
-1
-2
-3
-4
-5
In ([R /1-R])
DDD beta-lactam antibiotics / 1,000 population
0 5 10 15 20 25
B
ES
IR L PL
UK
FIN
S
D
NL
I
B = Belgium
D = Germany
ES = Spain
FIN = Finland
IR = Ireland
I = Italy
L = Luxembourg
NL = Netherlands
PL = Poland
S = Sweden
UK = Great Britain
Figure 4: Resistance as a function of antibiotic consumption
The rapidity with which bacterial resistance can develop
in individuals using antibiotics was confirmed in a study
by Malhotra-Kumar et al. published in The Lancet. Even
short-term use of antibiotics led to a massive and
sustained increase in bacterial resistance. The results
were o btained i n a d ouble-blind, p lacebo-controlled
study of 224 subjects receiving either the macrolides
azithromycin or clarithromycin or placebo. One day after
the final dose of the antibiotics was given, 80% of the
streptococcal strains were found to be resistant.
This resistance continued with a decreasing tendency
throughout the 180-day observation period (Figure 5)
[Malhotra-Kumar et al. 2007].
Azithromycin
Clarithromycin
Placebo 1
Placebo 2
100
80
60
40
20
0
Rate of resista nce to macrolides (%)
Observation days
0 4 8 1 4 2 8 4 2 1 8 0
Figure 5: Development of resistance to macrolides
2. Acute respiratory tract infections (RTIs)
12
2.5 Antiviral agents in the treatment
of respiratory tract infections
Neuraminidase inhibitors, which are authorised only
for use in the management of influenza, are not a
therapeutic alternative for low-risk patients. As with
antibiotics, use of these products in the treatment
of uncomplicated respiratory tract infections involves
a risk of soaring viral resistance. Moreover, anitiviral
medication is often prescribed inappropriately, in that
it is usually started more than one day after symptom
onset [Llor 2013]. The extent of resistance development
now clearly exceeds previous expectations [Kiso et
al. 2004]. Studies show that up to 18% of children
[Moscona 2005] and up to 4% of adults [Gubareva et
al. 2001] may carry oseltamivir-resistant viruses.
Bacterial and viral resistance cannot be considered
merely as a regional/global problem. Particular attention
should be paid to the fact that resistant pathogens are
rapidly transmitted in families and can pose a threat
to young children and/or immunocompromised, elderly
relatives.
Therapeutic nihilism in the sense of just watching and
waiting for the disease to resolve without treatment is
not a recommended option either.
50% of all untreated patients presenting with acute
bronchitis still cough on observation day 21, 25% on
observation day 30 and 2 - 5 % even after 6 months
[Altina 2001].
The most serious acute complication is pneumonia, which
mainly affects young children due to their incompletely
developed immune system, and immunocompromised
subjects, e.g. the elderly. The mortality rate of
community-acquired pneumonia in Germany is estimated
at 11% [Höffgen et al. 2005].
The risk of developing chronic diseases is of both
individual and economic significance. Every third
inadequately treated case of acute bronchitis develops
into chronic bronchitis [Jónsson et al. 1998], which
accounts for 5% of all deaths [NIH Publication 2003].
On no account should respiratory tract infections
be regarded as requiring no treatment because they
are thought to be harmless and self-limiting.
In practical terms, this means that an antibiotic
administered at the beginning of the infectious season
can trigger resistance up to the end of that season.
As a er sult of ni creasing ersistance, a switch ot so -called
reserve antibiotics or to combination therapies with a
significant interaction potential is increasingly required.
As well as generating enormous socioeconomic costs,
this results in more and more pathogens losing their
sensitivity to antibiotics.
The outcome is that every year, 50,000 people in Europe
alone die f rom resistant bacteria-mediated infections
that can no longer be treated with antibiotics [Allianz
Deutschland AG 2007].
2. Acute respiratory tract infections (RTIs)
13
3. EPs® 7630 - the phytotherapeutic  a
lternative
Figure 6: Pelargonium sidoides flower and roots
The EPs® 7630 extract is a herbal remedy obtained
from the roots of Pelargonium sidoides and manufactured
according to a special process. The extraction agent is
11% ethanol (w/w). The excipient is 85% glycerol.
10 g (= 9.75 ml) of EPs® 7630 solution for oral administration
contain 8 g of Pelargonium sidoides root extract in the
ratio of 1 : 8 - 10.
3.1 Origin and botany
For centuries, traditional healers of the South African
tribes have used decoctions obtained from Pelargonium
sidoides to cure various respiratory tract infections.
In the late 19th century the Englishman Major Charles
H. Stevens, who was suffering from tuberculosis, travelled
to South Africa. There he was cured with this traditional
medicine. He introduced this herbal remedy into Europe
under the name of “Stevens’ Consumption Cure”.
The identity of the root drug, Pelargonium sidoides, a South
African plant belonging to the Pelargonium genus,
Geraniaceae family, was first discovered in Germany in
1972. The bush, which grows to a height of 20 - 80 cm, has
greyish-green leaves and purple flowers. As time went
by, modern medical research elucidated many of the
mechanisms of action.
The roots of Pelargonium sidoides provide the raw
material used in the manufacture of extract EPs® 7630.
Three-year-old rhizomes contain an optimal amount of
active substances. Nowadays Pelargonium sidoides is also
grown on specialised farms using ecological cultivation
methods. The entire process of manufacturing the special
extract EPs® 7630 is controlled in accordance with Good
Manufacturing Practice guidelines.
The use of marker substances (e.g. polyphenols) ensures
high batch conformity.
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3.2 Phytochemistry
The extract EPs® 7630 contains characteristic groups
of substances, namely polyphenols, proteins, purines,
minerals, saccharides and, in lower concentrations,
7- hydroxycoumarin derivatives (Figure 7). The polyphenols
mainly comprise the monomeric flavan-3-ols catechin
and gallocatechin.
All 7-hydroxycoumarin derivatives including umckalin
(7-hydroxy - 5, 6 -dimethoxycoumarin), which is found in
the largest quantity and is typical of this plant species,
differ basically in terms of chemical structure from the
known anticoagulant coumarins [Koch, Biber 2007].
Some of the substances contained in Pelargonium
sidoides have not yet been identified – a typical feature
of phytopharmaceuticals.
Tests performed with the individual substances versus
the whole extract have clearly shown that only the whole
extract possesses an optimal therapeutic effect. The
isolated individual substances displayed only very weak
effects or no effect [Kolodziej, Schulz 2003].
Figure 7: Chemical composition of EPs® 7630
unknown to date
22%
minerals
12%
purines
2%
proteins
10%
coumarins
2%
total phenols
40%
saccharides
12%
3. EPs® 7630 - the phytotherapeutic alternative
15
EPs® 7630 has a multifactorial mode of action. The
following mechanisms of action have been found to
be relevant in the treatment of respiratory tract
infections (Figure 8):
4. Mode of ac tion
1. Antiviral and cytoprotective properties
• Modulation of the synthesis of
interferons, pro-inflammatory
cytokines and defensins
• A nti-oxidative properties
• Inhibition of leukocyte elastase
2. Antibacterial properties
• Increased adhesion of bacteria
to dead epithelial cells of the
respiratory tract mucosa
• Inhibition of adhesion of bacteria
to living epithelial cells in the
respiratory tract mucosa
• Stimulation of phagocytosis
and chemotaxis
3. Secremotory properties
• Stimulation of the ciliary beat
frequency of the respiratory
ciliated epithelium
Figure 8: Pathogenesis of respiratory tract infections
and mechanisms of action of EPs® 7630
Virus replication
16
4.1 Antiviral and cytoprotective
properties
EPs® 7630 has no direct virucidal activity [Theisen, Muller
2012]. The antiviral effect of EPs® 7630 is due to inhibition
of virus replication. The extract prevents the proliferation
of the virus, thus limiting the spread of the infection.
In vitro EPs® 7630 inhibited replication of the respiratory
viruses RSV, influenza A H1N1, influenza A H3N2, human
coronavirus HC o-229E, parainfluenza 3 and coxsackie A9.
All viruses inhibited by EPs® 7630 are enveloped viruses
except coxsackie A9, while all non-sensitive viruses were
non-enveloped v iruses. Therefore, E Ps® 7630 a ppears
to target enveloped viruses by interfering with surface
glycoproteins [Michaelis et al. 2011].
Theisen and Muller [2012] investigated at which step of
the virus life cycle EPs® 7630 exerts its antiviral activity.
In vitro studies suggest that the extract inhibits an early
step of viral infection, presumably viral entry into the
host cell. EPs® 7630 efficiently prevented viruses released
from host cells after the first life cycle (i.e. 8 hours postinfection)
from re-entering new host cells and completing
another l ife c ycle. E Ps® 7630 r educes v iral g rowth
without inducing resistant mutants, whereas resistance
to oseltamivir or amantadine can develop after only
2 - 4 life cycles.
Table 2: Comparison of antiviral effects of EPs® 7630
Coxsackie virus A9 ++
Human coronavirus HCo-229E +
Influenza virus A H1N1 +++
Oseltamivir-resistant seasonal H1N1 +++
Influenza virus A H3N2 +++
Parainfluenza virus 3 ++
RSV (respiratory syncytial virus) +++
Adenovirus (types 3, 5, 7) -
Rhinovirus 16 -
Pathogen Inhibition by EPs® 7630
EPs® 7630 a cts b oth o n the v irus a nd o n the h ost c ell.
The cytoprotective effect of EPs® 7630 and its various
ingredients against virus-induced cell destruction was
confirmed by a model in which fibroblasts were
incubated with macrophage residues ( interferon induction
by control substance / EPs® 7630) and infected with the
encephalomyocarditis virus (EMCV).
The graph shows that with greater concentrations of
EPs® 7630 t he s urvival capacity o f c ells i ncreased up
to twice that found in a control group incubated only with
the test substance (100% line) (Figure 9), i.e. the whole
extract and not individual ingredients is responsible for
the cell-protective effect [Kolodziej, Schulz 2003].
EPs® 7 630 a lso i ncreases t he r elease o f a ntimicrobial
peptides from neutrophilic granulocytes [Koch, Wohn
2007]. Defensins were initially discovered in plants, which,
unlike mammals, have no specific immune system, and
which have successfully defended themselves for millions
of years against attack from micro-organisms in a medium
with an extremely high pathogen burden such as the soil.
In humans, defensins, amongst other substances, have
been detected on the surface of CD 4 cells in the skin.
These cells are said to play an essential role in the body’s
defence against pathogens. Current research is focused
on elucidating the underlying mechanism involved.
4. Mode of action
17
Figure 9: Increase in cell vitality with EPs® 7630
200
150
100
50
0
Capacit y for survival (% of co ntrols )
P. sidoides
Polyphenols
Umckalin
μg/ml
0.8 1.6 3.12 6.25 12.5 25 50 100 150 200 250
4. Mode of action
Anti-infective effects due to immunomodulation
The antiviral effect of EPs® 7630 is brought about mostly
by modulation of the non-specific immune system.
A. Increase in interferon synthesis
EPs® 7630 triggers stimulation of interferon
(INF) - ß - synthesis ( Figure 1 0). This i s p articularly
relevant because as a cytokine, the type 1 interferon
INF - ß not only protects cells against v irus - mediated
destruction b ut a lso h as a d irect a ntiviral e ffect a nd
activates natural killer cells [Koch et al. 2002]. The
latter play an important role in the initial stages of
infection as immune cells of the first line of defence.
A study carried out with EPs® 7630 on human cell cultures
using the viral dsRNA analogue polyl: poly C confirmed
this action [Koch et al. 2002].
Moreover, EPs® 7630 induces the other type 1 interferons,
IFN - α and INF - γ, which likewise possess cytoprotective
properties [Kayser et al. 2007], [Trun et al. 2006].
4. Mode of action
pl:pC (2 μg/ml)
pl:pC (4 μg/ml)
pl:pC (8 μg/ml)
Figure 10: Effect of EPs® 7630 on INF-ß-synthesis
500
450
400
350
300
250
200
150
100
20
0
Stimulatio n of interfero n
(INF)-SS-synthesis (%)
(μg/ml) EPs® 7630
0 0.1 0.3 1 3 10
18
B. Improvement of phagocyte function
Increased phagocytosis and the intracellular destruction
of micro-organisms (intracellular killing) are other
pharmacological properties of EPs® 7 630. A s ignificant
improvement in the function of human phagocytes in
peripheral b lood w as d etected in corresponding fl owcytometry
a ssays u sing Candida albicans a s the t arget
organism [Conrad et al. 2007].
In addition to phagocytosis per se, the formation of reactive
oxygen species – so-called oxidative bursts that damage
phagocytised (internalised) pathogens directly – is central
to the activity of these immune cells.
At therapeutically relevant concentrations, EPs® 7630
increased both the active phagocyte count (p < 0.002) and
the proportion of burst-active phagocytes (p < 0.001)
(Figures 11 and 12). The convergence of the four groups
at the end of the test series is due to the fact that all
pathogens are phagocytised at this point.
60
50
40
30
20
10
0
(%)
Phagocytosis-active PBP
Minutes
0 2 4 6 10 30
p < 0.002
repeated measurements
(SD < 50% of the mean value)
Figure 11: Increase in phagocytosis with EPs® 7630
4. Mode of action
Figure 12: Increase in oxidative burst with EPs® 7630
p < 0.001
repeated measurements
(SD < 50% of the mean value)
30 μg/ml
10 μg/ml
3 μg/ml
0 μg/ml
EPs® 7630
Burst-active PBP
90
80
70
60
50
40
30
20
10
0
(%)
Minutes
0 2 4 6 10 30
30 μg/ml
10 μg/ml
3 μg/ml
0 μg/ml
EPs® 7630
4. Mode of action 19
In another study, Conrad et al. showed an increase in
intracellular (intraphagocytic) killing with EPs® 7630. The
number of surviving target organisms was reduced by
up to 31% (p < 0.001) (Figure 13).
Research into mechanisms of action is continuing but
it can a lready be said that t he a nti- infective e ffects
determined so far are directed against a broad spectrum
of pathogens. They play a crucial role, especially in the
management of viral infections.
Figure 13: Increase in intracellular killing with EPs® 7630
p < 0.001
Repeated measurements
ANOVA
0 μg/ml EPs® 7630
10 μg/ml EPs® 7630
30 μg/ml EPs® 7630
5.6
5.5
5.4
5.3
5.2
5.1
5.0
4.9
4.8
4.7
4.6
Survivi ng target orga nisms
log10
Minutes
0 15 30 60 120
Intracellular killing
4.2 Antibacterial properties
The direct bacteriostatic effect of EPs® 7630 is clearly
less than that of conventional antibiotics [Kayser,
Koloziej 1997].
It is nevertheless interesting to note that the susceptibility
of multiresistant strains of Staphylococcus aureus (MRSA) to
EPs® 7630 was found to be relatively favourable compared
to that of a non-resistant reference strain (Staphylococcus
aureus ATCC 25923) [Kolodziej, Schulz 2003].
The indirect antibacterial effects are more important.
EPs® 7 630 i nhibits t he a dhesion o f b acteria t o h ealthy
mucosal cells and thereby counteracts a key mechanism
in the pathogenesis of bacterial erspiratory rtact n ifections.
The effect of EPs® 7630 on the adhesion of bacteria to
90% vital human HEp-2 cells, a cell line of the larynx, was
investigated in an in vitro study by means of flow cytometry.
Group A-streptococci (Streptococcus pyogenes) w ere u sed
as test organisms. Therapeutically relevant concentrations
ranging from 0 to 30 μg EPs® 7630 led to a significant
reduction in the adhesion of A-streptococci to these cells
by up to 46% (p < 0.001) (Figure 14) [Conrad et al. 2007].
20 4. Mode of action
Figure 14: EPs® 7630 inhibits the adhesion of A-streptococci
p < 0.001
repeated measurements
ANOVA
0 μg/ml
0.3 μg/ml
3 μg/ml
10 μg/ml
30 μg/ml
EPs® 7630
Adhesion to HEp-2-cells
Minutes
85
80
75
70
65
60
55
50
45
40
(%)
0 30 60 120 180
This reduction in adhesion was confirmed by fluorescence
microscopy (Figure 15a/b).
Figure 15a: Adhesion of A-streptococci Figure 15b: EPs® 7630 inhibits adhesion
Exactly the same test procedure was then performed using
90% dead epithelial cells of the oral mucosa. It was found
that streptococcal adhesion to these dead cells increased
7-fold with EPs® 7630 (p < 0.001). Pathogenic organisms
can therefore be trapped and eliminated in this way [Conrad
et al. 2007].
Internalisation of bacteria in the host cells plays a central
role in the development of recurrent infections because
internalised bacteria evade the immune system’s defence
mechanisms. Intracellular proliferation of micro -organisms
remaining after the initial infection results in a renewed bout
of infection.
The effect of EPs® 7630 on the penetration of pathogens
into HEp-2 cells was therefore investigated. This showed a
marked reduction in internalisation at test times 30, 60,
120 and 180 minutes (Figure 16) [Conrad et al. 2007].
0 μg/ml EPs® 7630
A-streptococci HEp-2-cells
30 μg/ml EPs® 7630
HEp-2-cells
4. Mode of action 21
0 μg/ml 30 μg/ml
EPs® 7630
Figure 16: Inhibition of internalisation with EPs® 7630
Penetration into HEp-2-cells
6,000
5,000
4,000
3,000
2,000
1,000
0
(cFu)
Minutes
0 30 60 120 180
4.3 Secretomotory properties
Recovery or stimulation of mucociliary clearance plays a
central role in defence against respiratory tract infections.
EPs® 7630 stimulates this mechanism. As was shown in an
in vitro study with human nasal epithelial cells, EPs® 7630
increased ciliary beat frequency in a dose-dependent
manner by 23% and 33% at 30 μg/ml and 100 μg/ml,
respectively (Figure 17) [Neugebauer et al. 2005].
Increased transportation of mucous and pathogens from
the respiratory tract reduces the pathogen count, removes
the nutrient medium for subsequent proliferation of
pathogens and substantially improves respiration.
Figure 17: Increase in ciliary activity with EPs®
7630
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
Hz
Concentration of EPs® 7630
0 μg/ml 1 µg/ml 30 μg/ml 100 μg/ml
7.0 7.2
8.4
9.1
Ciliary activity in epithelial cells
It can be deduced that the herbal anti-infective agent
EPs® 7630 shows complementary anti-infective properties
Thus, as well as inhibiting the adhesion and internalisation
of bacteria and preventing bacterial invasion of the
submucosa it reduces the pathogen burden. The body is
thus protected against bacterial colonisation, infection,
superinfection and recurrence [Conrad et al. 2007].
*statistically significant
22
23
5. SAFETY profile
5.1 Toxicology
The favourable clinical safety profile of EPs® 7630 is
corroborated by toxicological investigations. All standard
tests such as cytotoxicity, acute and chronic toxicity in rats
and dogs, genotoxicity studies (Ames test, chromosome
aberration test and micronucleus test) as well as tests for
carcinogenic potential, local tolerability, immunotoxicity
and reproduction toxicity yielded no significant findings
[Koch].
5.1.1 Coumarins in EPs® 7630
and their effects on the
hepatobiliary system
Coumarins are a large group of compounds for which
hepatotoxic potential has been discussed. It is known that
some members of the large group of coumarin derivates
may have hepatotoxic effects. However, these substances
differ structurally from the 7-hydroxycoumarins contained
in EPs® 7630.
There is no reference in the scientific literature
to hepatotoxic effects with 7-hydroxycoumarins. O n
the contrary, the metabolisation of coumarin via
7-hydroxylation is viewed as detoxification [Vassallo et al.
2004] and there is evidence that 7-hydroxycoumarins (e.g.
4 methyl-umbiliferons) may even have hepatoprotective
effects [National Institute of Health 2007].
Products containing 4 -methylumbiliferon have been
available since the 1990s in both the USA and Europe
as food supplements to improve liver function. They have
also been used to some extent as medicinal products
owing to their spasmolytic and choleretic effects.
As expected, hepatotoxic effects were not observed
in acute or chronic toxicity studies in dogs and rats
following oral administration of up to 3,000 mg/kg
EPs® 7630. This was confirmed in studies carried out on
human hepatocytes and hepatoma cells [Koch 2006].
The species-specific metabolism of this substance group
plays a crucial role in determining whether or not
coumarins develop any toxic effects. Highly toxic epoxides
are formed as metabolites in rats, for instance, but do not
develop in humans (Figure 18) [Loew, Koch 2008].
Human primary hepatocytes (with normal and reduced
CYP2A6-activity) were incubated with the coumarin
derivative umckalin (10 and 100 μM) which is contained
in EPs® 7630. After up to four hours’ incubation, two
metabolites were detected in addition to the intact
starting substance, namely glucuronide and sulphate
conjugate of umckalin [Dr. Willmar Schwabe, XenoTech
Study 2007].
Figure 18: CYP-dependent metabolism of coumarins [XenoTech LLC]
Species-induced differences in CYP-dependent metabolism using coumarin as an example
Coumarin
Humans Rats
7-hydroxycoumarin Coumarin-3.4-epoxide
Conjugation
Elimination
No toxicity Toxicity
Ring opening
Formation of reactive aldehydes
O O
HO O O
O O
O
24
5.1.2 C oumarins in EPs® 7630
and their effects on blood
coagulation
In contrast to the anticoagulant 4-hydroxycoumarins,
the structurally markedly different coumarins contained in
EPs® 7630 do not cause inhibition of vitamin-K-dependent
synthesis of coagulation factors in the liver (Figure 19)
[Koch, Biber 2007].
High-dose studies in rats carried out over 14 days with
10, 75 or 500 mg/kg EPs® 7630 revealed no change in
thrombin time, partial thrombin time and thromboplastin
time. No potentiation of the anticoagulant effect was
observed f ollowing c oncomitant a dministration o f
0.05 mg/kg warfarin. The results suggest that neither
direct e ffects o n h aemostasis n or h aemostatic
effects due to interaction with anti-coagulants are to
be feared during treatment with EPs® 7630 (Figure 20)
[Koch, Biber 2007].
Figure 19: Chemical structure of coumarin in EPs® 7630 compared
to coumarins in anticoagulants
Chemical structure of coumarins in EPs®
7630
and coumarin-type anticoagulants
HO O O
H3CO
OCH3
4
3
7
8
Umckalin
Phenprocoumon
(Marcumar®)
O O
OH
CH
C2H5
O O
OH CH2
CH3
C O
Warfarin (Coumadin®)
Figure 20: EPs® 7630 does not significantly influence the
pharmacodynamics of coumarin-type anticoagulants
#p < 0.05 compared to control
*p < 0.05 compared to EPs® 7630
Control
EPs® 7630
EPs® 7630 + Warfarin
Warfarin
150
140
130
120
110
100
Perce ntage (co ntrol = 100)
TPT
#
PTPT TT
#
*
#
5. Safety profile
*
5. Safety profile 25
5.2 Interaction potential
Interactions with other medicinal products are generally
not to be anticipated, as EPs® 7630 does not affect
liver metabolism except for a clinically irrelevant
inhibition of CYP2C9. No effect on other tested
cytochrome P450 isoenzymes has been observed at
relevant concentrations. This includes CYP3A4, which
is responsible for the metabolization of numerous
pharmacologically active substances [Dr. Willmar
Schwabe, Cerep Study 2005]. Similarly, no induction
of cytochrome P450 isoenzymes has been observed
in human hepatocytes [Dr. Willmar Schwabe, RCC -CCR
Study 2005].
These results are supported by the findings of an
interaction study conducted by Roots et al. who did not
observe any relevant differences for the primary target
criterion, AUC (area under the curve) of penicillin V with
and without concomitant administration of EPs® 7630.
The double-blind, randomised study was conducted
in 2004 with EPs® 7630 and penicillin V (3 x 30 drops
EPs® 7630, 3 x 1,200 000 IU Isocillin® p.o.) for 7 days
[Roots et al. 2004].
5.3 Pharmacovigilance
Approximately 736 million daily doses of EPs® 7630 were
sold between 1992 and 2012, predominantly in Germany.
The incidence of side effects is extremely low, namely
0.93 per million defined daily doses (defined daily
doses – DDD).
This means that only one in 108,000 patients will
experience a side effect during an average treatment
period of 10 days.
These figures corroborate the excellent tolerability of
EPs® 7630 treatment [Buschulte, Köhler 2014].
26
27
6. Clinica l efficac y a nd
safety studies
The efficacy and the safety of EPs® 7630 in the treatment
of respiratory tract infections have been extensively
investigated in clinical studies. Over 10,000 patients were
recruited with over 4,000 enrolled in placebo-controlled
clinical trials.
The EPs® 7630 study programme in children is well
worth mentioning as over 4,000 children were involved.
This is relevant because the anatomy and physiology of
children differ from those of adults. There are differences
in metabolism and in the responses of receptors and
target organs. To date, specific pharmacological studies
have not been carried out for up to 90% of all medicinal
products used in paediatric practice. As a result, only
one medicinal product in two is authorised for use in
children and adolescents [Kanders 2004], and 36 - 100%
of hospital and 20 - 56% of outpatient prescriptions for
children are off-label prescriptions [Schweim 2004].
6.1 Clinical studies by indication
Acute bronchitis
Seven placebo-controlled, double-blind studies were
performed for the product to gain marketing authorisation
in the indication “acute bronchitis”. The most important
results of these studies are summarised below.
Acute bronchitis, though not a severe disease, is the main
cause of time off school or work. In the majority of cases,
acute bronchitis is virally-induced. However, patients are
often treated with antibiotics although there is scant
evidence of any benefit. The costs of antibiotic therapy are
high and there is a great risk of unpleasant side effects
not to mention the danger of bacterial strains becoming
resistant to the antibiotics used. This is of particular
concern in children, whose immune system is not fully
developed. EPs® 7630 has been shown to be safe, welltolerated
and above all effective in treating acute
bronchitis. Recovery from acute bronchitis is faster with
EPs® 7630 than with placebo.
Current guidelines do not specify any particular instrument
for the diagnosis of acute bronchitis or for the assessment
of treatment response in this indication. Furthermore,
the diagnosis of acute bronchitis alone can only be
made if other respiratory tract disorders are excluded. The
Integrative Medicine Outcome Scale (IMOS) and the
Integrative Medicine Patient Satisfaction Scale (IMPSS)
are accepted scales that have been applied in a number
of trials in the indication acute bronchitis. These two
instruments use the observations of clinicians and
patients to assess general treatment outcome and patient
satisfaction. The Bronchitis Severity Score (BSS) was
developed in 1996 to harmonise the evaluation of acute
bronchitis symptoms across patients and studies and
correlates well with these two scales.
The BSS is an observer-rated tool for scoring the severity
of five important symptoms of acute bronchitis i.e. cough,
sputum production, rales, chest pain during coughing
and dyspnoea; a combination of objective and subjective
items. The BSS for standardised use in clinical trials
with patients (adults and children) suffering from acute
bronchitis can be considered as a reliable and suitable
instrument for the diagnosis and assessment of treatment
response in patients with acute bronchitis (review by
Matthys and Kamin 2013). Furthermore, the validity
of the BSS has recently been communicated by the
European Medicines Agency’s Committee on Herbal
Medicinal Products (HMPC) (EMA/HMPC/301544/2013).
The Bronchitis Severity Score (BSS), an expression of
symptom severity and thus of the disease-mediated
impact, was used, among other measures, to assess
efficacy. This score is calculated from the sum of the
cardinal symptoms cough, expectoration, rales, chest
pain on coughing and dyspnoea, as evaluated by the
investigating physician on a scale of 0 (absent) to 4
(very severe). Secondary test criteria included remission
of the individual symptoms, time to onset of action,
patient compliance, tolerability, evaluation of therapeutic
success by doctor and patient using the Integrative
Medicine Outcomes Scale (IMOS), and parameters
recorded in patient diaries such as intensity of
symptoms, general wellbeing and health-related quality
of life.
28
Author Matthys et al. 2003
Study design Randomised, double-blind, placebo-controlled study
Investigational medicinal product EPs® 7630 vs. placebo
No. of patients 468 with BSS ≥ 5
Duration of treatment 7 days
Dosage
3 x 30 drops/day, optional 500 mg paracetamol p.o.
when body temperature rises to ≥ 39°C
Target criteria Proof of superiority of the active drug confirmed by a change in the BSS
Results
An improvement in the BSS of 5.9 (active drug) vs. 3.2 (placebo)
(p < 0.0001) was recorded by day 7.
Tolerability
96.1% of patients assessed the tolerability of
EPs® 7630 as “very good” or “good”.
Study of acute bronchitis in adults
The objective of the trial by Matthys
et al. was to evaluate the efficacy and
safety of the Pelargonium sidoides extract
EPs® 7630 compared to placebo in
patients with acute bronchitis. The
primary outcome measure (change in
the BSS by day 7) was assessed in 468
adults suffering from acute bronchitis
(present ≤ 48 hours) with a Bronchitis
Severity Score (BSS) ≥ 5.
By day 7, the BSS had decreased in
patients treated with EPs® 7630 to a
significantly greater degree than in
those treated with placebo (p <0.0001;
Fig. 21a). In addition, the duration of
the illness was significantly shorter
for patients treated with EPs® 7630
(p <0.001) the ability to work was
higher (p < 0.0001; Fig. 21b) and they
were able to return to work two
days sooner than patients treated with
placebo (p <0.0001). Adverse events
occurred in only 7.7% of all patients
during the trial and were all assessed
as non-serious. No adverse event was
considered to have a probable relationship
with EPs® 7630 treatment.
Changes in the Bronchitis Severity Score (BSS) ITT analysis (n = 468)
10
9
8
7
6
5
4
3
2
1
0
Bro nchitis Severit y Score
(mean and 95% CI)
Day
0 3-5 7
Figure 21a: Decrease in bronchitis symptoms with EPs® 7630
Placebo EPs® 7630
Figure 21b: Recovery and ability to work by day 7
16%
84%
Ability to work (n=468)
57%
43%
EPs® 7630 Placebo
Able to work Unable to work
*p < 0.0001
6. Clinical efficacy and safety studies
p < 0.0001
29
Author Chuchalin et al. 2005
Study design
Multicentre, prospective, randomised, double-blind,
placebo-controlled study
Investigational medicinal product EPs® 7630 vs. placebo
No. of patients 124
Duration of treatment 7 days
Dosage
3 x 30 drops/day, optional 500 mg paracetamol p.o.
when body temperature rises to ≥ 39°C
Target criteria Proof of superiority of the active drug confirmed by a change in the BSS
Results
An improvement in the BSS of 7.2 (active drug) vs. 4.9 (placebo)
(p < 0.0001) was recorded by day 7. More rapid recovery with EPs® 7630
by day 7 (90.6% vs. 41.7% with placebo. p<0.0001)
Tolerability
98.4% of patients assessed the tolerability of EPs® 7630
as “very good” or “good”.
Study of acute bronchitis in adults
This trial was also designed to evaluate
the efficacy and safety of EPs® 7630 vs.
placebo in adults with acute bronchitis.
As in the previous study, the change in
the BSS by day 7 was assessed in patients
suffering from acute bronchitis (present
≤ 48 hours) with a Bronchitis Severity
Score (BSS) ≥ 5.
Again, the BSS had decreased in patients
treated with EPs® 7630 to a significantly
greater degree by day 7 than in those
treated with placebo (p <0.0001; Fig. 22a).
Recovery in patients treated with
EPs®7630 was much more rapid than
in patients treated with placebo and the
onset of treatment effect was observed
sooner (p <0.0002). By day 7, nearly
80% of patients treated with EPs® 7630
were able to pursue their usual daily
activities again (Fig. 22b). EPs® 7630 was
well tolerated, with no serious adverse
events during the trial.
Figure 22b: Ability to pursue usual activities again by day 7
65%
35%
EPs® 7630 Placebo
Usual activities (n=124)
22%
78%
Changes in the Bronchitis Severity Score (BSS) ITT analysis (n = 124)
10
9
8
7
6
5
4
3
2
1
0
Bro nchitis Severit y Score
(mean and 95% CI)
Day
0 3-5 7
Figure 22a: Decrease in bronchitis symptoms with EPs® 7630 vs. placebo
Placebo EPs® 7630
Able Unable
6. Clinical efficacy and safety studies
*p < 0.0001
30
Author Matthys, Funk 2008
Study design
Multicentre, prospective, randomised, double-blind,
placebo-controlled study
Investigational medicinal product EPs® 7630 vs. placebo
No. of patients 217
Duration of treatment 7 days
Dosage
3 x 30 drops/day, optional 500 mg paracetamol p.o.
when body temperature rises to ≥ 39°C
Target criteria Proof of superiority of the active drug confirmed by a change in the BSS
Results
A decrease in the BSS of 7.6 (active drug) vs. 5.3 (placebo)
(p < 0.0001) was recorded by day 7.
Tolerability Tolerability was comparable with placebo. None of the AEs was serious.
Study of acute bronchitis in adults
Acute bronchitis represents a considerable
economic burden – not only for the
health-care system but also in terms of
work productivity. The objective of this
study was to analyse previously published
data in combination with new findings in
order to focus on the major features of
acute bronchitis and the economic
impact of EPs® 7630 treatment compared
to placebo in adults suffering from acute
bronchitis (present ≤ 48 hours) with a
Bronchitis Severity Score (BSS) ≥ 5.
Overall, treatment with EPs® 7630 resulted
in faster remission of bronchitis-related
symptoms and an earlier return to work,
thus lowering the economic burden of
the illness. The decrease in the BSS was
significantly greater with EPs® 7630 than
with placebo (p < 0.0001 - see Fig. 23a)
and a clinically relevant effect of the
active treatment could already be seen
after 3 to 5 days (see Fig. 23b regarding
cough). The findings for all secondary
efficacy endpoints were similar. All these
clinical benefits translate into a better
pharmaco-economic profile for the patients
treated with EPs® 7630. The medication
was also well-tolerated and no serious
adverse events were observed.
100
90
80
70
60
50
40
30
20
10
0
patie nts (%)
Figure 23b: Presence of cough
Cough (n = 217)
Day 0 Day 3-5 Day 7
EPs® 7630 (n=108) Placebo (n=109)
Changes in the Bronchitis Severity Score (BSS) ITT analysis (n = 217)
10
9
8
7
6
5
4
3
2
1
0
Bro nchitis Severit y Score
(mean and 95% CI)
Day
0 3-5 7
Placebo *p < 0.0001
Figure 23a: Decrease of bronchitis symptoms with EPs® 7630 vs. placebo
EPs® 7630
6. Clinical efficacy and safety studies
31
Author Matthys et al. 2010
Study design
Multicentre, prospective, randomised, double-blind,
placebo-controlled dose-finding study
Investigational medicinal product EPs® 7630 vs. placebo
No. of patients 406
Duration of treatment 7 days
Dosage
Group A: placebo
Group B: 3 x 10 mg tablets/day
Group C: 3 x 20 mg tablets/day
Group D: 3 x 30 mg tablets/day
Target criteria Proof of superiority of the active drug confirmed by a change in the BSS
Results
A decrease in the BSS of 2.7 (placebo), 4.3 (30-mg group), 6.1 (60-mg group)
and 6.3 (90-mg group) (p < 0.0001 each statistically significant compared to
placebo) was recorded by day 7.
The results indicate that a daily dose of 60 mg EPs® 7630 constitutes the
optimal dose with respect to the risk-benefit ratio.
Tolerability
All dosages of EPs® 7630 were well tolerated. Gastrointestinal disturbances
were the most frequent AEs, their occurrence increasing dose-dependently.
None of the AEs was serious.
Study of acute bronchitis in adults
Figur 24a: Changes in BSS score between day 0 and day 7 with different dosages
Figure 24b: Faster recovery with EPs® 7630
CHANGE OF THE BSS TOTAL SCORE
BETWEEN DAY 0 AND DAY 7 (POINTS)
*statistically significant (p<0.0001)
compared to placebo
6. Clinical efficacy and safety studies
*statistically significant (p<0.0001)
compared to placebo
This trial investigated the efficacy and
tolerability of treatment with EPs® 7630
tablets at three different dosages in adults
suffering from acute bronchitis outside
the strict indication for antibiotics.
The treatment of adults suffering from
acute bronchitis (present ≤ 48 hours and
a Bronchitis Severity Score (BSS) ≥ 5)
with EPs® 7630 tablets showed that
the improvement in the BSS score
(primary outcome parameter) from day
0 to day 7 was significantly better than
with placebo (p < 0.0001 in each case)
and clinically relevant in all active
treatment groups (Fig.24a). Recovery
was faster with EPs® 7630 tablets and
patients were able to return to work
sooner (Fig. 24b). A model calculation
suggests that as much as €20 billion in
indirect costs per year could be saved in
Germany by treatment with EPs® 7630
tablets.
Taking both efficacy and safety into
account, the results indicate that 60 mg
EPs® 7630/day is the optimal dose with
respect to risk-benefit ratio of the tablets.
The tablets were well-tolerated and no
serious adverse events were observed.
32
Author Matthys et al. 2007
Study design Multicentre, prospective, open observational study
Investigational medicinal product EPs® 7630
No. of patients
2,099 patients aged 0-93
127 patients > 6 – 12 years
241 patients ≤ 6 years
Duration of treatment 14 days
Dosage
Adults and children > 12 years of age: 3 x 30 drops/day
Children > 6 to 12 years of age: 3 x 20 drops/day
Children 6 years of age or less: 3 x 10 drops/day
Target criteria Change in the BSS
Results
The mean BSS of all patients decreased from 7.1 ± 2.9 at baseline
to 1.0 ± 1.9 at the final visit.
Subgroup analysis for children (patients < 18 years, n = 498):
the mean BSS decreased from 6.3 ± 2.8 to 0.9 ± 1.8 at the final visit.
Subgroup analysis for infants (patients < 3 years, n = 78):
the mean BSS decreased from 5.2 ± 2.5 to 1.2 ± 2.1 at the final visit.
Tolerability
The tolerability of EPs® 7630 was very good. Adverse events occurred in
only 1.2% of the patients. None of the AEs was serious.
Study of acute bronchitis in children and adults
Figure 25a: BSS changes during the study period in children and infants
Figure 25b: Remission rates in all patients
10
9
8
7
6
5
4
3
2
1
0
Bro nchitis Severit y Score
(mean and sta ndard deviatio n)
baseline 1st follow-up 2nd follow-up 3rd follow-up
Changes in the Bronchitis Severity Score (BSS)
100
90
80
70
60
50
40
30
20
10
0
Patie nts (%) with remissio n at
last individual visit
Cough Sputum Rales/
Rhonchi
Chest pain
on coughing
Dyspnoea
Freedom from bronchitis symptoms (n = 2,099)
all children (n = 498) all infants (n = 78)
This study was one of the first to be
performed with children as well as adults
suffering from acute bronchitis. The trial
was designed to investigate the efficacy
and safety of treatment with EPs® 7630
in patients presenting with productive
cough that had been present for less than
six days and no indication for antibiotics.
Sub-group analyses were performed with
498 patients below the age of 18 and 78
infants younger than three.
The mean value of the BSS of all patients
decreased over the 14-day study period
with a responder rate, defined as a
decrease in BSS of at least five points by
the last follow-up, of 68.0%. The mean
decreases in the BSS for the sub-groups
of children and infants are given in
Fig. 25a and show a clear improvement
between baseline and the last
examination. Remission of over 80% was
found for the majority of all bronchitisspecific
symptoms (Fig. 25b). The adverse
event rate was extremely low (1.2%) and
no serious adverse events were reported.
EPs® 7630 was found to be an effective
and well-tolerated treatment of acute
bronchitis in both children and adults
without the indication for antibiotic
treatment.
6. Clinical efficacy and safety studies
Following the promising results of previous trials, this
study aimed to further investigate the effects of EPs® 7630
in young patients (1 - 18 years old) with acute bronchitis
but no indication for antibiotic treatment.
A continuous decrease in mean BSS total score between
baseline and day 7 was observed, with a significantly
greater change in the EPs® 7630 group than in the placebo
group (Fig. 26a; p < 0.0001, ANCO VA). Response rates
were considerably higher in the EPs®7630 group than
in the placebo group, as can be seen clearly in Fig. 26b
(responders defined by a BSS total score of < 3 points
by day 7; p < 0.0001, two-tailed chi² test), and the onset
of treatment effect was much earlier in the EPs® 7630
group (p < 0.0001, two-tailed Mantel - Haenszel chi² test).
Tolerability of EPs® 7630 was good with no serious
adverse events. A causal relationship with the study
medication was assessed as “unlikely” for 8 adverse
events, all others were considered as “not related”.
Author Kamin et al. 2010
Study design Multicentre, randomised, double-blind, placebo-controlled study
Investigational medicinal product EPs® 7630 vs. placebo
No. of patients 200 from 1 - 18 years
Duration of treatment 7 days
Dosage
Patients ≤ 6 years of age: 3 x 10 drops/day
Patients > 6 to 12 years of age: 3 x 20 drops/day
Patients > 12 years of age: 3 x 30 drops/day
Target criteria Proof of superiority of the active drug confirmed by a change in the BSS
Results
A decrease in the mean BSS of 3.4 (active drug) vs. 1.2 (placebo)
(p < 0.0001) was recorded by day 7.
Tolerability Tolerability was comparable with placebo. None of the AEs was serious.
Study of acute bronchitis in children and adolescents
Figure 26a: Decrease in bronchitis symptoms with EPs® 7630
Changes in the Bronchitis Severity Score (BSS) ITT analysis (n = 200)
6
5
4
3
2
1
0
Bro nchitis Severit y Score
(mean and 95% CI)
Day
0 3-5 7
Figure 26b: Responders based on the
BSS total score < 3 points by day 7
80
70
60
50
40
30
20
10
0
Respo nders (%)
Response rate (n = 200)
*
Placebo
EPs® 7630
EPs® 7630
Placebo
*p < 0.0001 *statistically significant (p < 0.0001)
6. Clinical efficacy and safety studies 33
Author Kamin et al. 2010
Study design Multicentre, randomised, double-blind, placebo-controlled dose-finding study
Investigational medicinal product EPs® 7630 vs. placebo
No. of patients 400 from 6 - 18 years
Duration of treatment 7 days
Dosage
Group A: placebo
Group B: 3 x 10 mg tablets/day
Group C: 3 x 20 mg tablets/day
Group D: 3 x 30 mg tablets/day
Target criteria Change in the BSS
Results
The results indicate that a daily dose of 60 mg EPs® 7630
constitutes the optimal dose with respect to the risk-benefit ratio.
Tolerability Tolerability was comparable with placebo in all treatment groups.
Study of acute bronchitis in children and adolescents
Figure 27a: Decrease in bronchitis symptoms with EPs® 7630
8
6
4
2
0
bss total score
( mean and 95% ci)
Changes in the Bronchitis Severity Score (BSS) (n = 399)
Treatment day
0 3-5 7
Figure 27b: Investigators‘ assessment of the efficacy of EPs® 7630 by day 7
80
60
40
20
0
patie nts (%)
Clinical Outcome (IMOS) (n = 399)
Combination of the categories
“completely recovered“ and “major improvement“
*p < 0.05
The primary objective of this study was
to demonstrate the efficacy and to
evaluate the safety and tolerability of 3
doses o f EPs® 7630 (30mg, 60mg, 90mg)
administered as film-coated tablets for
the treatment of acute bronchitis in 6
to 18-year-olds. Once again the results
clearly showed that treatment with
EPs® 7630 at the 3 different doses was
significantly better than with placebo. The
decrease in mean BSS is demonstrated
in Fig. 27a. Pairwise comparisons of the
active treatment with placebo showed
statistically significant differences in
the decrease in the BSS total score for
the EPs®7630 60mg and 90mg groups
(p = 0.0004 and p < 0.001, respectively,
two-tailed ANCO VA). The onset of the
therapeutic effect was again earlier in the
EPs® 7630 groups and the final treatment
response was higher in the active
treatment groups than in the placebo
group. Fig. 27b illustrates the combination
of the categories “complete recovery” and
“major improvement” for patients in the
different treatment groups. The frequency
of adverse events in the active treatment
groups was similar to that in the placebo
group and no serious adverse events
were reported.
Placebo 30 mg 60 mg 90 mg
EPs® 7630
Placebo 30 mg 60 mg 90 mg
EPs® 7630
34 6. Clinical efficacy and safety studies
35
Author Kamin et al. 2012
Study design
Multicentre, prospective, randomised, double-blind,
placebo-controlled study
Investigational medicinal product EPs® 7630 vs. placebo
No. of patients 220
Duration of treatment 7 days
Dosage
Patients < 6 years of age: 3 x 10 drops/day
Patients ≥ 6 to 12 years of age: 3 x 20 drops/day
Patients > 12 years of age: 3 x 30 drops/day
Target criteria Proof of superiority of the active drug confirmed by a change in the BSS
Results
A decrease in the mean BSS of 4.4 (active drug) vs. 2.9 (placebo)
(p < 0.0001) was recorded by day 7.
Tolerability Adverse events occurred in only 1.8% of the patients. None of the AEs was serious.
Study of acute bronchitis in children and adolescents
Figure 28a: Decrease in bronchitis symptoms with EPs® 7630
8
6
4
2
0
Bro nchitis severit y score
(MEAN AND 95 % CONFIDENCE INTERVAL)
Changes in the Bronchitis Severity Score (BSS) (n = 220)
Treatment day
0 3-5 7
Figure 28b: Recovery occurred earlier with EPs® 7630
60
50
40
30
20
10
0
patie nts (%)
Onset of treatment effect (n = 220)
Day 1-2 Day 3-4 Day 5-7 Not at all
Placebo EPs® 7630 *p < 0.0001
Placebo EPs® 7630 p < 0.0001
6. Clinical efficacy and safety studies
The patients enrolled in this study were
between 1 and 18 years of age and were
suffering from acute bronchitis as assessed
by bronchitis-specific symptoms (BSS).
The mean BSS total score decreased by
4.4 ± 1.6 points in the EPs®7630 group
compared to 2.9 ± 1.4 points in the placebo
group. This difference was statistically
significant (Fig. 28a, p < 0.0001, two-tailed
ANCO VA). Recovery also occurred earlier
in the EPs® 7630 group (see Fig. 28b) and
the percentage of responders (as defined
by a BSS score of < 3 points by day 7) was
higher in the active treatment group than
in the placebo group. Adverse events were
extremely infrequent (1.8%), not classified
as serious and were unrelated to the study
medication. These results demonstrate
once more the efficacy, tolerability and
safety of EPs® 7630 solution in children
and adolescents suffering from acute
bronchitis. After the 7-day treatment
with EPs® 7630 almost 60% of patients
could return to kindergarten, school or
work, whereas recovery in the placebo
group was only around 17%.
36
Acute sinusitis is generally virally-induced. Antibiotics are
indicated only if bacterial presence has been proven by
means of a swab. Indiscriminate use of antibiotics poses
a high risk of bacterial resistance. In addition, the use
of antibiotics often results in gastrointestinal disorders
and other unpleasant adverse events. EPs® 7630 has
already been shown to be a safe, well-tolerated, and
effective treatment in the indication acute bronchitis
and was therefore investigated as an option for acute
sinusitis.
The efficacy and safety of EPs® 7630 in the management
of acute sinusitis was investigated in both adults and
children. The primary test criterion was the change
in the severity of objective and subjective symptoms
including headache, maxillary pain on bending, maxillary
pressure, blocked nose, prulent nasal secretion and
purulent post-nasal discharge, assessed on a five-point
scale (Sinusitis Severity Score – SSS). In the trials, the
diagnosis of acute sinusitis was confirmed by x-ray
imaging or sonography. The positive trial findings are
given in detail below.
Acute sinusitis
6. Clinical efficacy and safety studies
37
Figure 29a: Decrease in sinusitis symptoms with EPs® 7630
Changes in the Sinusitis Severity Score (SSS) ITT analysis (n = 103)
16
14
12
10
8
6
4
2
0
Sinusitis Severit y Score
(mean and 95% CI)
Day
0 7 14 21
Figure 29b: Improvement in all individual symptoms with EPs® 7630
100
90
80
70
60
50
40
30
20
10
0
% patie nts who improved /
were symptom -free
Headache Maxillary
pain on
bending
Maxillary
pressure
Blocked nose Purulent
post-nasal
discharge
Purulent
nasal
secretion
Improvement in sinusitis symptoms (n=103)
Placebo EPs® 7630 *p < 0.0001
Placebo (n = 52) EPs® 7630 (n = 51)
Author Bachert et al. 2009
Study design
Multicentre, prospective, randomised, double-blind,
placebo-controlled study
Investigational medicinal product EPs® 7630 vs. placebo
No. of patients 103
Duration of treatment 21 days
Dosage 3 x 60 drops/day
Target criteria Proof of superiority of the active drug confirmed by a change in the SSS
Results
A mean decrease in SSS of 5.5 points (EPs® 7630) vs. 2.5 points (placebo)
was recorded for the primary outcome measure by day 7 (confirmatory
comparison: p < 0.00001).
Study of acute maxillary sinusitis in adults
The primary objective of this study was to
evaluate the efficacy and safety of
EPs® 7630 compared to placebo in
patients with acute rhinosinusitis (ARS
present for at least 7 days and confirmed
clinically and radiographically). Fig. 29a
shows clearly that a statistically significant
difference in the mean decrease in the
Sinusitis Severity Score (SSS) was found
as early as day 7 of treatment. This
difference became more pronounced with
continued treatment and by day 21 had
more than doubled (mean SSS of patients
treated with EPs® 7630 < 2 points; placebo
> 8 points). EPs® 7630 was also statistically
and clinically superior to placebo on all
the secondary outcome parameters
(illustrated in Fig. 29b for individual
sinusitis symtoms). The safety assessment
showed no clinically relevant change in any
laboratory parameters and a low adverse
event (AE) rate (7.8%). AEs were mostly
classified as mild and none was reported
to be serious. The study demonstrated
a statistically significant and clinically
relevant superiority of EPs®7630 over
placebo and confirmed that EPs® 7630 is
well tolerated and safe.
6. Clinical efficacy and safety studies
38
Author Schapowal, Heger 2007
Study design Open outcomes study
Investigational medicinal product EPs® 7630
No. of patients 361 with 41 children below 12 years
Duration of treatment 4 weeks / 12 weeks
Dosage
Acute sinusitis:
Adults: 30 drops/hour (max. 12 x per day) for 1-2 days
Thereafter 3 x 30 drops/day
Children: 20 drops/hour (max. 12 x per day) for 1-2 days
Thereafter 3 x 20 drops/day
Recurrence prophylaxis of chronic sinusitis:
Adults: 2 x 30 drops/day ; Children: 2 x 20 drops/day
Target criteria
Changes in 7 objective and subjective symptoms of sinusitis on a 5-point scale
(minimum score = 0, maximum attainable score = 28)
Results
The mean total clinical score decreased from 15.2 ± 4.6 (median: 15.0) to 2.4 ±3.2
(median: 1.0) by day 28. After only 7 days 55.9% of the physicians and 56.2% of the
patients reported an absence of symptoms or a distinct improvement in the illness.
Tolerability
94.2% of patients and 95.8% of doctors assessed the tolerability of
EPs® 7630 as “very good” or “good”.
Study of acute sinusitis / acute exacerbation of chronic sinusitis in children and adults
Changes in the Sinusitis Severity Score (SSS)
20
15
10
5
0
total SYMPTOM Score
Time of examination (days)
Figure 30a: Decrease in mean sinusitis symptom score with EPs® 7630
0
(n = 361)
7
(n = 351)
14
(n = 311)
28
(n = 240)
56
(n = 153)
84
(n = 121)
Tolerability (n = 361)
Figure 30b: Tolerabiliy rating by patients and by physicians
Physicians Patients
all other categories
4,2%
very good or good
95,8%
all other categories
5,8%
very good or good
94,2%
The objective of this study was to
investigate the tolerability of EPs® 7630
and to monitor the changes in seven
individual sinusitis symptoms summarised
as a mean total symptom score (Fig. 30a).
The diagnosis of sinusitis was confirmed
by rhinoscopy plus either x-ray imaging or
sonography. Fig. 30a shows clearly that
the mean total sinusitis symptom score
decreased rapidly over the first 7 days of
treatment. Positive outcomes in terms of
remission or improvement were found in
more than 90% of patients within the first
four weeks. The results of a sub-group
analysis of children showed a decrease
from a median 13.5 points at baseline to
a median of 6.0 after 28 days, thus
reflecting the general findings of the
study. Physicians rated the tolerability of
treatment with EPs® 7630 as very good or
good in 95.8% of cases; the patients
themselves in 94.2% of cases (Fig. 30b).
Adverse events only ocurred in 15.5% of
patients and the causal relationship with the
study medication was considered “unlikely”
in the majority of cases. Two serious events
were reported but these were not related
to the medication. These findings are
especially interesting given the high
dosage of EPs® 7630 used in this study.
In conclusion the risk-benefit profile of
the therapy can be regarded as very good.
39
Tonsillitis and tonsillopharyngitis mainly affect children,
adolescents and young adults. Acute tonsillitis or
tonsillopharyngitis is usually caused by viral infection
and normally disappears within 1 - 2 weeks. Serious
complications such as superinfection with ß-haemolytic
streptococci require antibiotic treatment, but are rare.
Especially in children, antibiotics should not be used at
an early stage, as they have serious side effects and pose
a high risk of bacterial resistance development. Early
studies have provided positive results of the benefit of
EPs® 7630 in children and adults with tonsillopharyngitis,
suggesting that EPs® 7630 may be used as a first-line
treatment in this indication. The findings of a confirmatory
trial (Bereznoj et al. 2003) are given below.
In a further study, Bereznoj et al. confirmed the superiority
of EPs® 7630 compared to placebo in children with acute
tonsillitis. Furthermore, the risk of exacerbation in patients
with chronic or recurrent tonsillitis could be reduced.
Tonsillitis / tonsillopharyngitis
6. Clinical efficacy and safety studies
40
Author Bereznoj et al. 2003
Study design Multicentre, randomised, double-blind, placebo-controlled study
Investigational medicinal product EPs® 7630 vs. placebo
No. of patients 143 children between 6 and 10 years of age
Duration of treatment 6 days
Dosage
3 x 20 drops/day
Paracetamol suppositories (500 mg) when body
temperature rises to ≥ 38.5°C (day 0 to day 4)
Target criteria Proof of superiority of the active drug confirmed by a change in TSS
Results
A decrease in TSS of 7.1 ± 2.1 points (active drug) vs. 2.5 ±3.6 points
(placebo) (p < 0.0001) was recorded by day 4.
Tolerability
97.2% of patients and 97.3% of doctors assessed the tolerability of
EPs® 7630 as “very good” or “good”.
Study of acute non-GABHS tonsillopharyngitis in children
Changes in the Tonsilloharyngitis Severity Score (TSS) ITT analysis (n = 143)
12
10
8
6
4
2
0
Tonsillophar yngitis Severit y Score
(mean and 95% CI)
Day
0 2 4 6
Figure 31a: Decrease in tonsillitis symptoms with EPs® 7630
Placebo EPs® 7630
Freedom from typical tonsillitis symptoms on day 4 (n = 143)
100
90
80
70
60
50
40
30
20
10
0
PATIENTS WITH REMISSION (%)
Figure 31b: Remission rates for individual tonsillitis symptoms
Difficulties
in
swallowing
Sore throat Saliva flow Redness
of mouth
and throat
Fever Headache
Placebo EPs® 7630
6. Clinical efficacy and safety studies
The main objective of this study was to
confirm that treatment with EPs® 7630
is superior to placebo in the treatment of
non-group A ß-haemolytic streptococcus
(non-GA BHS) tonsillopharyngitis in
children. Fig. 31a shows clearly that a
major difference in the decrease in the
Tonsillopharyngitis Severity Score (TSS)
was found between patients treated
with EPs® 7630 and those treated with
placebo, which already reached statistical
significance by day 2 of treatment
(p < 0.0001). This difference became more
pronounced with continued treatment
and by day 6 the TSS in the children
treated with EPs® 7630 had dropped to
around 1. Fig. 31b shows the results for
the individual symptoms on day 4. In
terms of duration of illness, approx.
half of the patients treated with EPs® 7630
no longer needed to stay in bed after day 2
and over 80.0% were able to go back to
school by day 6 (placebo around 21.0%).
The tolerability and safety assessment
showed that no adverse events were
serious or related to the investigational
medication. The risk of adverse events
was actually higher in the placebo group
and mostly involved complications of the
original illness. The study demonstrated
that EPs® 7630 was more effective than
placebo, reduced the severity of symptoms,
shortened the duration of illness by
at least 2 days and protected patients
from complications.
*p < 0.0001
41
Author Bereznoj et al. 2009
Study design Multicentre, prospective, open-label outcomes study
Investigational medicinal product EPs® 7630
No. of patients 1,000 (aged 2–35)
Duration of treatment 7 days / 35 days
Dosage
Patients 2 - 6 years: 3 x 10 drops/day
Patients > 6 to 12 years of age: 3 x 20 drops/day
Patients > 12 years of age: 3 x 30 drops/day
Target criteria Change in the ATS (angina tonsillaris symptoms)
Results A decrease of 10.5 ± 4.7 points in the mean total ATS was recorded by day 7.
Tolerability
Adverse events occurred in only 1.8% of the patients.
None of the AEs was serious.
Study of acute tonsillitis / acute exacerbation of chronic tonsillitis in children and adults
Figure 32a: Decrease in tonsillitis symptoms with EPs® 7630
14
12
10
8
6
4
2
0
total score ats
(MEAN AND 95% CI)
Changes in the Angina Tonsillaris Symptoms (ATS)
Day of treatment (No. patients)
Day 0
(1000)
Day 3-5
(996)
Day 7
(991)
Day 21
(359)
Day 35
(357)
Figure 32b: Investigators‘ assessment of the efficacy of EPs® 7630 by day 7
100
90
80
70
60
50
40
30
20
10
0
patie nts (%)
Difficulty
swallowing
Treatment success rate ITT analysis ( n =1000)
Sore
throat
Salivation Redness Coating
left
Coating
right
Fever
Improvement Remission
The trial investigated the objective and
subjective treatment effects of EPs® 7630
in adults and children with acute tonsillitis
(angina tonsillaris) or acute exacerbation of
chronic recurrent tonsillitis as monitored
by means of the change in mean total
score of angina tonsillaris symptoms
(AT S). Assessment of the tolerability of
EPs® 7630 was made on the basis of the
number of adverse events reported and
subjective tolerability by means of a 4-
point verbal rating scale. The primary
outcome criterion for the assessment of
the success of treatment was the change
in mean total AT S score by day 7 in
patients with acute tonsillitis, or day 35 in
patients with chronic/recurrent tonsillitis
(see Fig. 32a). The AT S score dropped
by a mean of 10.5 ± 4.7 points by the 7th
day of treatment and a response rate
of 88.2% (defined as a drop below 4
points in the total score) was found for the
whole population within the first week of
the study. The success rate (remission and
improvement) for the individual symptoms
is demonstrated in Fig. 32b, which shows
values of the order of 95 - 98%. Only 18
patients (1.8%) reported adverse events,
mostly concomitant infections, none of
which was serious. Subjective tolerability
was rated as “good” or “very good” in
around 99% of cases by both physicians
and patients. The findings of the study
confirm that acute tonsillitis or acute
exacerbation of chronic recurrent tonsillitis
can be quickly, successfully and safely
treated with EPs® 7630.
6. Clinical efficacy and safety studies
42
The common cold is a viral infection with symptoms
such as sneezing, sore throat and running nose. It is one
of the most prevalent illnesses in the world. Although
human rhinoviruses are known to be the major causative
agents in the adult common cold, antibiotics are
often prescribed unnecessarily. This injudicious use of
antibiotics may be responsible for the increase in
antibiotic-resistant strains of bacteria. Several recent
surveys have confirmed that the rates of antibacterial
resistance among common respiratory pathogens, e.g.
Streptococcus pneumonia and Haemophilus influenzae, have
risen significantly over the past decade (see Lizogub et
al. 2007). Over-the-counter treatments for the common
cold alleviate symptoms but have so far not been
associated with shortening the duration of the illness.
Treatment by EPs® 7630 has, however, been successful,
including faster recovery, in the indications acute
bronchitis, acute rhinosinusitis and acute tonsillitis.
This has been demonstrated in placebo-controlled trials
and several observational studies with both adults and
children. In all the controlled clinical trials, treatment with
EPs® 7630 was better than placebo, with a significant
reduction in disease-specific symptoms and good
tolerability. The multicentre, prospective, randomised,
double-blind, parallel-group, placebo-controlled clinical
trial of adaptive group-sequential design described
below therefore aimed to evaluate the efficacy
and safety of EPs® 7630 compared with placebo in
adult patients suffering from the common cold
(Lizogub et al. 2007).
Common cold
6. Clinical efficacy and safety studies
43
Author Lizogub et al. 2007
Study design
Multicentre, prospective, randomised, double-blind,
placebo-controlled study
Investigational medicinal product EPs® 7630 vs. placebo
No. of patients 103
Duration of treatment 10 days
Dosage 3 x 30 drops/day
Target criteria Proof of superiority of the active drug confirmed by a change in the CIS
Results A decrease in the CIS of 10.4 (active drug) vs. 5.6 (placebo) was recorded by day 5.
Tolerability
No serious adverse events were reported. On day 5, over 90% of patients assessed
the tolerability of EPs® 7630 as “very good” or “good”.
Study of common cold in adults
The trial was designed to evaluate the
efficacy and safety of EPs® 7630 compared
with placebo in adult patients suffering from
the common cold by assessing the sum
of symptom intensity differences (SSID)
of the cold intensity score (CIS) as well as
adverse event rates and tolerability. The
study reports the results of low-dose
treatment with EPs® 7630 or placebo.
The primary outcome criterion for the
assessment of the success of treatment
was the change in SSID of the CIS from day
0 to day 5. Fig. 33a shows the decrease in
the CIS over the period of treatment. The
SSID on day five was calculated on the
basis of the assessments of total CIS on days
one, three and five. The improvement in the
SSID in the EPs® 7630 group by day 5 was
significantly greater than in the placebo
group (p < 0.0001). Over the treatment
period, the mean alleviation of all individual
symptoms was noticeably greater in the
EPs® 7630 group than in the placebo
group (Fig. 33b), responder rate was higher
and recovery and return to work more rapid.
Only 2.9% of patients experienced adverse
events, none of which was serious. On day
10, all 52 patients (100%) in the EPs® 7630
group assessed the tolerability of the active
treatment as “good” or “very good”. These
findings once again demonstrate clearly
that EPs® 7630 is an effective and safe
therapy – in this case significantly reducing
suffering from the common cold and
leading to faster recovery.
Changes in the Cold Intensity Score (CIS) ITT analysis (n = 103)
20
18
16
14
12
10
8
6
4
2
0
Cold Intensity Score
(mean and 95% CI)
Day
0 3 5 10
Placebo EPs® 7630
Figure 33a: Decrease in common cold symptoms with EPs® 7630
-1,8
-1,6
-1,4
-1,2
-1,0
-0,8
-0,6
-0,4
-0,2
-0,0
0,2
Changes in individual symptoms
of the CIS (points )
Figure 33b: Changes in individual common cold symptoms with EPs® 7630
Nasal
drainage
Sore
throat
Nasal
congestion
Sneezing
Scratchy
throat
Hoarseness
Cough Headache
Muscle
aches
Fever
[°C]
Improvement in common cold symptoms (n = 103)
*statistically significant (p < 0.0001)
6. Clinical efficacy and safety studies
Placebo EPs® 7630
44
6.2 Additional clinical studies
Chronic obstructive pulmonary disease (CO PD) is
characterised by airflow limitation that is not fully
reversible, usually progressive and associated with an
abnormal inflammatory response of the lung to
noxious particles or gases (Matthys et al. 2013).
Chronic bronchitis is one form of CO PD. Effective
control of CO PD involves assessment and monitoring
of the illness, reducing risk factors and managing
stable disease. The standardised baseline therapy for
patients with moderate to severe CO PD is treatment
with bronchodilators (e.g. ipratropium bromide/fenoteol).
Acute exacerbation is one of the major risks of CO PD.
Exacerbations contribute to the morbidity and mortality
associated with the disease. Prevention and management
of acute exacerbations is therefore a main objective
of any alternative or add-on therapy. In view of former
clinical findings in the treatment of acute bronchitis and
other respiratory tract infections (RT Is), EPs® 7630
would appear to be a promising therapeutic option as
add-on treatment in CO PD. The study described below
presents the results of a 6-month trial in adults with
this indication.
COPD - Chronic obstructive pulmonary disease
6. Clinical efficacy and safety studies
45
Author Matthys et al. 2013
Study design Multicentre, prospective, randomised, double-blind, placebo-controlled study
Investigational medicinal product EPs® 7630 vs. placebo
No. of patients 200
Duration of treatment 24 weeks
Dosage Add-on therapy to standard COPD treatment: 3 x 30 drops/day
Target criteria The primary efficacy variable was time to first exacerbation of COPD.
Results
Median time to exacerbation was significantly longer in the EPs® 7630 group
compared to placebo (57 versus 43 days, p = 0.005).
Tolerability
Gastrointestinal disorders were the most frequently reported AEs. None of the AEs
was serious. A causal relationship ot AEs with the study medication was assessed
as unlikely. EPs® 7630 showed a good long-term safety profile.
Study of moderate to severe (II–III) COPD in adults
Figure 34a: EPs® 7630 prolongs median time to exacerbation
Time to first exacerbation
10 20 30 40 50
Days
EPs®
7630
(n = 98)
Placebo
(n = 101)
Figure 34b: EPs® 7630 significantly
reduces antibiotic use during reported
exacerbation
100
90
80
70
60
50
40
30
20
10
0
Antibiotic use (%)
Antibiotic use
Placebo
(n = 101)
EPs® 7630
(n = 98)
73,3%
37,8%
EPs® 7630 Placebo p < 0.0001
57
43
The trial was designed to investigate whether EPs® 7630
can delay acute exacerbation of CO PD (primary efficacy
variable) and reduce exacerbation frequency compared
with placebo as an add-on therapy in adult patients
suffering from moderate to severe CO PD (Stage II/III).
The results demonstrated clearly that EPs® 7630 can
delay the time to a first exacerbation in CO PD (Fig. 34a).
Fewer patients suffered from exacerbations compared to
placebo and the time to first exacerbation was prolonged
(p = 0.005, one-tailed, centre-stratified log-rank test).
The add-on treatment with EPs® 7630 also significantly
reduced the use of antibiotics compared to placebo
(p <0.0001, two-tailed chi² test) (Fig. 34b) and the
duration of antibiotic treatment was shorter (p = 0.0466,
two-tailed t-test). The safety profile of EPs® 7630 over
the approx. 6-month treatment period was good. The
results show a statistically significant and clinically
relevant superiority of add-on treatment with EPs® 7630
over placebo and good long-term tolerability in the
treatment of moderate to severe CO PD in adults.
6. Clinical efficacy and safety studies
46
Asthma
Asthma is a chronic disease characterised by inflammation
of the respiratory tract, episodic symptoms and airflow
obstruction. The chronic inflammation observed in asthma
may result in an abnormal increase in airflow restriction
after exposure to a non-allergic stimulus such as exercise.
Asthma exacerbations are common and mostly related
to viral infections. Bronchial inflammation is typical for
exacerbations and may differ in type depending on whether
the causal factors are infective or allergic in nature. One of
the major objectives in asthma management is therefore
the development of novel prophylactic or treatment
strategies. As the majority of exacerbations are thought
to be of viral origin, EPs® 7630, which has been shown to
be effective in the treatment of many virally-induced
acute respiratory tract infections, represents a potentially
effective therapy. Particularly for children, this could be
a beneficial treatment in the prevention of acute
asthma attacks. The study by Tahan and Yaman (2013)
reported below portrays the efficacy of such treatment.
6. Clinical efficacy and safety studies
47
The trial investigated whether EPs® 7630 is effective in
preventing asthma attacks during viral infections of the
upper respiratory tract in children. Supportive treatment
(paracetamol) was given as required. Additional treatment
with EPs® 7630 was associated with a significant reduction
in nasal symptoms and cough frequency compared
to supportive therapy only (p < 0.05, Chi² test) as shown
in Fig. 35a. The frequency of asthma attacks was also
significantly reduced under treatment with EPs® 7630
(p < 0.05, Chi² test) as shown in Fig. 35b. The study
demonstrated conclusively that EPs® 7630 is able to
prevent asthma attacks in children during upper
respiratory tract infections of viral origin.
Author Tahan, Yaman 2013
Study design Prospective, randomised study
Investigational medicinal product EPs® 7630 + supportive therapy vs. supportive therapy
No. of patients 61 from 1 to 14 years
Duration of treatment 5 days
Dosage
Add-on therapy to supportive treatment
Patients from 1 - 5 years of age: 3 x 10 drops/day
Patients from 6 - 12 years of age: 3 x 20 drops/day
Patients > 12 years of age: 3 x 30 drops/day
Target criteria Number of asthma attacks during RTI
Results
EPs® 7630 significantly reduced the asthma attack frequency compared to
supportive treatment only (20% versus 48%, p = 0.05).
Study of prevention of asthma attacks during upper RTI in children with mild asthma
100
90
80
70
60
50
40
30
20
10
0
(%)
Figure 35a: Primary endpoints on day 5
Nasal symptoms and cough
Nasal symptoms Cough
EPs® 7630 (n = 30) No EPs® 7630 (n = 30) p < 0.05
100
90
80
70
60
50
40
30
20
10
0
(%)
Figure 35b: Secondary
endpoints on day 5
Asthma attack frequency
Asthma attacks
20%
48%
p < 0.05
EPs® 7630 (n = 30) No EPs® 7630 (n = 30)
43%
74%
56%
90%
6. Clinical efficacy and safety studies
48
6.3 Meta-analyses
In meta-analyses, data are pooled with a view to drawing
on great numbers of patients to obtain more accurate
information on the efficacy of a particular therapy.
A: EPs® 7630 in acute respiratory tract infections
The fi ndings o f t he Cochrane Collaboration, a n
independent panel that assesses the current state of
research on the use of medicinal products in their
therapeutic indications, are summarised below [Timmer
et al. 2008].
In 2008 two m eta-analyses w ere published on the u se
of Pelargonium sidoides extract EPs® 7630 in the treatment
of acute respiratory tract infections (AR Is) and acute
bronchitis, respectively.
Data source
Research for relevant studies was performed in the
Cochrane Central Register of Controlled Trials (CENTRA L)
(The Cochrane L ibrary 2007, issue 4) which includes
the Cochrane Acute Respiratory I nfections Group’s
Specialised Register; MEDLINE (1966 to November
2007); EMBASE (1974 to December 2007); and other
electronic databases.
Selection criteria
Randomised controlled trials (RCT s) examining the
efficacy of Pelargonium sidoides preparations in AR Is
compared to placebo, no treatment or any other
treatment.
Data analysed
In total, 8 placebo-controlled studies with EPs® 7630
in acute bronchitis, acute sinusitis and the common
cold were evaluated. These studies involved more than
1,750 patients, almost half (46%) of whom were
children from age one year upwards.
Primary outcomes
• Time to complete resolution of all symptoms (in days);
• Time to complete resolution of key symptoms (in days);
• Proportion of participants with continuing symptoms
at day 7 (day 21 in the subset of sinusitis studies).
Secondary outcomes included reduction in severity
of symptoms, need for antibiotics at follow up, quality
of life measures, days off work or days off school,
and side effects.
Results:
Both the adults and the children suffering from acute
bronchitis experienced a beneficial reduction in symptoms
after taking EPs® 7630. In acute rhinosinusitis, EPs® 7630
showed “significant treatment effects for resolution of all
symptoms including resolution of headaches and nasal
discharge.” In the common cold, well known as the most
prevalent upper respiratory tract infection, EPs® 7630
showed “a significant reduction in days off work”.
“The available data from clinical trials with short-term therapies
and results from uncontrolled post-marketing studies do not
show an elevated risk of serious adverse events.”
Conclusion
EPs® 7 630 “may b e e ffective i n r elieving s ymptoms
in acute bronchitis in adults and children” and it “may
(also) be effective in alleviating symptoms of acute
rhinosinusitis and the common cold in adults.”
Pelargonium sidoides extract for acute respiratory tract
infections(Review)
TimmerA,GüntherJ,RückerG,MotschallE,AntesG,KernWV
“In the light of inappropriate antibiotic use and increasing
drug resistance rates worldwide, the need for an alternative,
effective remedy for these medical conditions is crucial.“
Pelargonium sidoides extract for acute respiratory
tract infections (Review)
Timmer A, Günther J, Rücker G, Motschall E, Antes G, Kern WV
6. Clinical efficacy and safety studies
49
B: EPs® 7630 in acute bronchitis
A meta-analysis published in 2008 looked in great
detail into the clinical evidence on the treatment of
acute b ronchitis w ith E Ps® 7630 [ Agbabiaka 2008].
The aim of this systematic review was to assess
available evidence from rigorous clinical trials on the
efficacy o f Pelargonium sidoides e xtract EPs® 7630 i n
the treatment of acute bronchitis.
Data sources
Systematic literature searches were performed in 5
electronic d atabases: (MEDLINE ( 1950 - July 2007),
AMED (1985 - July 2007), EMBASE (1974 - July 2007),
CINAH L (1982 - July 2007), and The Cochrane Library
(Issue 3, 2007) without language restrictions. Reference
lists of retrieved articles were searched and
manufacturers contacted for published and unpublished
materials.
Selection criteria
Randomised clinical trials (RCT s) testing Pelargonium
sidoides extract against placebo or standard treatment
in patients with acute bronchitis and assessing clinically
relevant outcomes were included.
Data analysed
Six RCT s met the inclusion criteria, of which 4 were
suitable for statistical pooling. The methodological
quality of most of the trials was good. One study
compared EPs® 7630 with conventional non-antibiotic
treatment (acetylcysteine); the other five tested
EPs® 7630 against placebo.
Results
All the RCT s reported findings suggesting effectiviness
of Pelargonium sidoides in the t reatment o f acute
bronchitis.
The meta-analysis indicated that EPs® 7630 “significantly
reduced bronchitis symptom scores in patients with
acute bronchitis by day 7”.
No serious adverse events were reported.
Conclusion
“There is encouraging evidence from currently available
data that Pelargonium sidoides extract EPs® 7630 is
effective compared to placebo in patients with acute
bronchitis.”
6. Clinical efficacy and safety studies
50
51
7. EPs® 7630 -
frequently a sked questions
Interactions
No interactions with other medicinal products have been
reported to date.
Special patient groups
• D iabetics
EPs® 7630 is suitable for diabetics. The amount of
sugar absorbed in the daily dose is diabetologically
irrelevant and need not be taken into account in
the daily sugar intake.
• C oeliac disease (gluten enteropathy)
EPs® 7630 does not contain gluten and can be
administered to patients with coeliac disease
(gluten enteropathy).
• Pregnancy/lactation
T here is insufficient experience to date on the use
of EPs® 7630 during pregnancy and lactation. For
this reason, EPs® 7630 should not be used during
pregnancy and lactation except on medical advice.
• A utoimmune diseases
EPs® 7630 has an immunomodulatory as opposed
to an immunostimulatory effect, i.e. it boosts the
immune system only in the event of infection.
Consequently, there should be no problems with
autoimmune processes during administration.
However, to date there are no scientific data on
the use of EPs® 7630 in patients with autoimmune
diseases.
• C hildren under 1 year of age
C hildren under 1 year of age should not be treated
with EPs® 7630 in view of the insufficient experience
with this medicinal product in this age group.
• A lcoholics
In general, alcohol-containing medicinal products
such as EPs® 7630 solution should not be
administered to alcoholics.
• A lcohol content of EPs® 7630
H erbal remedies in a liquid form such as EPs®7630
frequently contain alcohol. This is used as an
extraction agent, natural stabilising agent and
absorption-enhancing agent and dispenses with
the need for chemical preservatives.
T he natural blood alcohol level in humans is
0.03‰. This is altered only slightly by the intake of
a small quantity of alcohol such as that contained
in EPs®7630 because such small quantities are
broken down within minutes.
Many foodstuffs consumed in normal quantities
contain as much as or even more alcohol than that
contained in a daily dose of EPs® 7630.
Similarly, there is no risk to children. A glass (0.2 l)
of apple juice contains more than three times as
much pure alcohol (0.76ml) as does the maximum
paediatric dose of 60 drops of EPs® 7630. In any
case, the product can be administered in a small
glass of warm tea or juice. A large proportion of the
alcohol evaporates and the taste is also lost.
52
53
8. summary
Respiratory tract infections such as acute bronchitis are
the most common reason for seeking medical advice or
visiting a pharmacy.
These diseases, which are caused by viruses in 95%
of cases, cause considerable suffering particularly in
children, who, because their immune system is not
fully developed, often suffer 8 to 12 infections per year.
In addition, they generate primary (e.g. medicines,
medical consultations) and secondary (e.g. absences from
work) costs amounting to several hundred million euros in
Germany alone each year. Respiratory tract infections are
therefore of considerable individual and socioeconomic
relevance.
Studies of prescription trends have shown that
antibiotics are prescribed for most respiratory tract
infections despite the fact that the therapeutic benefit of
such medication for viral infections is nonexistent or at
most marginal.
Various meta-analyses undertaken by the Cochrane
Institute failed to reveal any statistically significant or
clinically relevant effects of antibiotics versus placebo in
uncomplicated respiratory tract infections. On the other
hand, almost all studies revealed a significantly higher
incidence of side effects with antibiotic therapy. It is
particularly important to note that bacterial resistance to
antibiotics develops very rapidly. This resistance has now
reached shockingly high proportions around the world.
The frequency of occurrence of resistant bacterial strains
is positively correlated with the frequency of antibiotic
administration. Moreover, even a single dose of antibiotic
can result in considerable bacterial resistance, as a clinical
study published in The Lancet in 2007 confirmed.
Administration of antivirally active substances such
as the neuraminidase inhibitors, which are approved
exclusively for use in the treatment of influenza (and
moreover are only effective in the treatment of influenza),
is not a therapeutic option. Many viral strains have
already become resistant to antiviral substances as a
result of misuse.
There is therefore a pressing need for substances that
(a) are effective and well tolerated in the treatment of
viral respiratory tract infections and (b) do not induce
resistance.
One such product is EPs® 7630, a special root extract
of Pelargonium sidoides. Extensive scientific studies have
shown that this extract possesses cytoprotective and
potent antiviral properties. This fact is of extreme
therapeutic relevance given that respiratory tract
infections such as acute bronchitis are almost exclusively
of viral aetiology.
The proven antibacterial and secretomotor properties
also make crucial contributions to the excellent efficacy
of this herbal remedy.
The efficacy and safety of EPs® 7630 have been
confirmed in an extensive study programme involving
over 10,000 patients, more than 4,000 of whom
have taken part in placebo-controlled clinical studies
involving adults and children of 1 year and over. These
facts are further corroborated by the use of this product
by 30 million patients in many countries across the globe.
54
55
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EPs® 7630
First choice. Fast recovery.
Dr. Willmar Schwabe GmbH & Co. KG
Willmar-Schwabe-Straße 4
76227 Karlsruhe
GERMANY
Phone +49 (0) 721 40 05 0
Fax +49 (0) 721 40 05 202
www.schwabepharma.com
IM-EPSP M400-0214

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