Microsoft word - auswertung_eucarbon_ungarn-marokko1 0_eng.doc

Final evaluation of the
postmarketing study of
„Eucarbon®“

Client:
F. TRENKA Chemisch-Pharmazeutische Fabrik GES.M B H.
A-1040 Vienna
Goldeggasse 5
Statistical evaluation:
Dr. Robert Heinz & Partner Medical Consulting
A-1070 Vienna
Kaiserstraße 84/9
Tel.: (1) 524 61 78 Fax: (1) 524 61 78/22
E-mail: [email protected]
DR. ROBERT HEINZ & PARTNER Medical

Table of contents

Aim of the postmarketing study
Annex: Software output of the statistical evaluation
Tables

TABLE 1: DESCRIPTION OF COLLECTIVES: SEX, AGE, HEIGHT AND WEIGHT OF PATIENTS
TABLE 2: CONDITION OF PATIENTS OVER TIME: BL, WEEK 6 AND WEEK 12 TABLE 3: MEDICAL FINDINGS OF THE ABDOMINAL EXAMINATION AT BASELINE VISIT AND AT WEEK 12 TABLE 4: SEVERITY OF THE PATIENTS' ILLNESS OVER TIME: BL, WEEK 6 AND WEEK 12 TABLE 5: DOSE OF EUCARBON® OVER TIME: BL, WEEK 6 AND WEEK 12 TABLE 6: EFFICACY OF EUCARBON® EVALUATED AT WEEK 12 TABLE 7: TOLERABILITY OF EUCARBON® EVALUATED AT BL, WEEK 6 AND WEEK 12 Aim of the postmarketing study

The aim of the this postmarketing study (PMS) was to determine efficacy and tolerability of
Eucarbon® tablets in patients suffering from gastrointestinal disorders or Irritable Bowel
Syndrome (IBS). In addition to the already known therapeutical effect, this study shall provide
further findings on efficacy. This final evaluation presents the results of all patients from
Hungary and Morocco (hereinafter referred to as total collective). In addition to the total
collective, the target parameters for the subgroup of all patients from Morocco have also been
evaluated statistically.

Statistical methods

The statistical evaluation was carried out with the program REPORT/TESTIMATE of the
company idv - Datenanalyse und Versuchsplanung (IDV), Gauting/Munich. All program parts
are validated, Heinz & Partner work according to the SOPs developed by IDV. For data
description, primarily descriptive methods have been used. For categorial characteristics, the
number of patients is calculated as absolute frequency and as percentage (compared to the total
number of surveyed patients). As to important quantitative parameters, classical statistical
characteristics (sample size, mean and median resp., standard deviation, minimum and
maximum) were used for data description. The modifications over time under therapy with
Eucarbon® tablets (baseline compared with follow-up visits after 6 and 12 weeks) were analysed
exploratively by non-parametric tests for combined samples (Wilcoxon-Mann-Whitney). For all
statistical calculations a two-sided p-value of < 0.05 is used as significance treshold. The table
below shows the p-values along with the Mann-Whitney characteristics (MWC) serving for
clinical interpretation of the results. The Mann-Whitney characteristics can take values situated
between 0 and 1, where 0,5 stands for equality. The more the value differs from 0,5, the more
importance is attached to the difference. For example a value beyond 0,64 is referred to as
medium superiority, a value beyond 0,71 as large superiority. For values beyond 0,64 (medium
superiority) the difference is referred to as being relevant. For inferiority the following tresholds
apply: values below 0,36 represent medium inferiority, below 0,29 large inferiority. For values
beyond 0.36 (medium inferiority) the difference is referred to as being relevant.
Interpretation of results Mann-Whitney characteristics
Large superiority
Baseline characteristics and demography

The baseline characteristics and patient data were collected at the admission examination before
starting the treatment. As to demographic characteristics, age and sex of the patients were
evaluated. The following characteristics were collected at the baseline examination: body weight
(kg), height (cm) and diagnosis of IBS. At the end of the PMS the patients’ weight is again
checked and evaluated. A total of 748 patients participated in the twelve-week PMS. As to 742
patients, data on sex is available. There were nearly twice as many women as men who
participated in the study. The average age of patients was 45,9 ± 16,83 years. As shown in the
evaluation, not only adults but also children participated in the PMS, a fact which is reflected in
the wide range of figures. The collective of Morocco is composed of 349 patients. As to 344
patients, data on sex is available. There were nearly three times as many female as male
participants. 340 patients documented their age. Regarding the age, there is no relevant difference
beween the collectives. For more information see table 1.
SEX N (%)
Age years
cases n =
Age

TABLE 1: DESCRIPTION OF COLLECTIVES: Sex, age, body height and weight of patients
In 93 % (n=696) of the patients IBS is diagnosed. The rest of the patients suffers from another
disease. In 59 % of the patients, who suffer from IBS, “constipation” is predominant, in 12 % of
the patients “diarrhea” is predominant, in almost 20 % diarrhea alternates with constipation and 9
% suffer neither often from diarrhea nor from constipation. In about 95 % of the patients of
Morocco, IBS is diagnosed (in about 58 % of the patients “constipation” is predominant, in only
3 % of the patients “diarrhea” is predominant, in approx. 25 % diarrhea alternates with
constipation and almost 14 % suffer neither often from diarrhea nor from constipation).

Change of body weight

549 patients of the total collective provide information about their weight at the end of the PMS
which – compared to the baseline – slightly changed (68,3±16,84 kg). 177 of the Moroccan
patients provide information about their weight after week 12 (65,3±11,03 kg). In this group, the
modification compared to the baseline is more pronounced, coming up to an average reduction
during treatment of 2,9 kg.

Anamnesis
277 patients (37 %) of the total collective provide information about the duration of IBS. On
average, the illness is evident since 32,92 ± 46,49 months. During anamnesis, it is determined if
IBS has been treated during the last three months or not. For 119 Moroccan patients, data about
the duration of IBS is available. The medium duration of the illness was 10,41 months. This
corresponds to a medium difference of duration of 22,51 months between the collectives. More
than ¼ of all patients (26 %) in the total collective and 27 % of Morocco report that IBS has been
pretreated. All active substances which have been used during the last 3 months for treatment of
IBS, such as espumisan, meteospasmin, coordinax and their respective dose, are listed in the
annex. The patients of Morocco were often prescribed antispasmodics and laxatives.

Other intestinal diseases
All other intestinal diseases, of which the patient suffered in the past, are recorded at the baseline
visit. These diseases such as ulcus duodeni, ulcus ventriculi, GERD (Gastroesophageal Reflux
Disease), gallstones and cholecystitis are listed in the annex.

Concomitant diseases and medication
In the annex, all concomitant diseases and medications are listed per patient. The most frequently
documented diseases were hypertension and/or coronary heart disease (CHD) as well as
depression. Likewise, the corresponding medications such as Norvasc, Enalapril and Citalopram
are listed. The patients of Morocco were often prescribed Proctolog as concomitant medication.


Diet
About 40 % of all patients in the total collective report to follow a diet. Primarily the diet consists
of a high-fiber, carbohydrate-rich and low-fat nutrition. Great importance is also attached to a
high fluid intake. 29 % of the patients of Morocco indicate to follow a diet. Often the doctors
recommended to avoid flatulent food and carbonated beverages. In the annex all dietary measures
are listed per patient.

Smoking behavior
22 % of all patients in the total collective and 12 % of the Moroccan sub-collective were smoking
during the PMS. On average, the patients of the total collective smoked 14,9 ± 7,3 cigarettes per
day and the Moroccan patients smoked 14,7± 5,91.

Alcohol consumption
About 13 % of the patients of the total collective and only 3 % of the Moroccan patients
confirmed to regularly consume alcohol. As to the type of alcohol consumed, there are entries
such as „occasional alcohol consumption“, „beer“ and „wine“ but also “hard liquor” i.e. spirits.
In the annex all additional data regarding alcohol consumption is listed per patient.

Blood in the stool
In approx. 70 % of all patients no blood was found in the stool and only in 17 patients (2,43 %)
blood was found in the stool. In approx. 27 % of patients no test was carried out in this respect.
202 patients of Morocco (62 %) had a negative result. In two patients (0,62 %) the result was
positive, in 120 patients no test was carried out in this respect.

Patients’ condition
The actual condition and the actual complaints respectively were investigated at the baseline
examination, at check-up 1 after 6 weeks and at check-up 2 after 12 weeks. Table 2 shows how
the actual complaints of the patients changed during therapy with Eucarbon® in both collectives.
In both collectives not only a statistically highly significant (p<0,0001) but also a clinically
relevant improvement was achieved during treatment compared to the initial situation before the
PMS (baseline). The following complaints improved:
constipation hard stool abdominal press abrupt impulse to defecate sense of incomplete defecation flatulences abdominal distension and Using pain as an example, there was a significant difference (p<0,0001) for the total collective, i.e. a statistically highly significant superiority for week 6 and week 12 respectively. The Mann-Whitney characteristics for the improvement of pain frequency from baseline to week 6 comes up to 0,8318. This value clearly falls within the group “large superiority” of week 6, i.e. significantly less pain at week 6. The difference is clearly to be referred to as clinically relevant difference. In spite of the lower number of patients of the Moroccan sub-collective, the tendency of the results is repeated. Here, even more importance is attached to the clinically relevant difference (0,9247). In fact, there are statistically significant improvements (p<0,05) in respect to diarrhea and liquid stool at week 6 in both collectives but they are clinically not relevant. The same applies to liquid stool at week 12 for the patients of the total collective. On the other hand, the improvement of liquid stool at week 12 in the Moroccan patients has neither a statistical significance nor a clinical relevance. There is no difference due to treatment regarding soft stool in the total collective. With respect to soft stool, a statistical significance but no clinical relevance was observed in the Moroccan collective. For more information see table 2. Stool frequency:
BASELINE WEEK 6
BASELINE WEEK 6
diarrhea N (%)
non-existent
m oderate
Number of cases n =
Constipation N (%)
non-existent
moderate
Number of cases n =
Modified stool frequency: Hard stool N (%)
non-existent
moderate
Number of cases n =
Soft stool N (%)

non-existent
moderate
Number of cases
n =
P=; MWC=
Liquid stool N (%)
non-existent
moderate
Number of cases
Modified bowel movement: Abdominal press N (%)
non-existent
moderate
Number of cases
n =
P=; MWC=
Abrupt impulse to defecate N (%)
non-existent
moderate
Number of cases
Sense of incomplete defecation N (%)
non-existent
moderate
Number of cases
n =
P=; MWC=
Flatulences N (%)
non-existent
moderate
Number of cases
n =
P=; MWC=
Abdominal distension N (%)
non-existent
moderate
Number of cases
n =
P=; MWC=
Pain N (%)
non-existent
moderate
Number of cases n
=
P=; MWC=

TABLE 2: CONDITION OF PATIENTS OVER TIME: BL, WEEK 6 AND WEEK 12
Examination of the abdomen
In 80 patients (11 %) there were no pathological findings during examination of the abdomen at
the baseline visit. In almost 88 % there was a positive finding at the baseline whereas only in 46
% after week 12. In the Moroccan patients, 83 % had a positive finding at the baseline and only
10 patients (4,65 %) after week 12. The following table shows the results of the patients’
examinations at the beginning and at the end of the PMS. Multiple answers were allowed.

FINDINGS N (%)
BASELINE WEEK 12 BASELINE WEEK 12
Pain at percussion
Increased peristalsis
Tymp. percussion
Pain at percussion + increased peristalsis
Pain at percussion + tymp. percussion
Pain at percussion + other
Pain at percussion + increased peristalsis +
tymp. percussion
Pain at percussion + increased peristalsis +
Pain at percussion + tymp. Percussion +
Increased peristalsis + other
Increased peristalsis + tymp. percussion
Tymp. percussion + other
Pain at percussion + increased peristalsis +

percussion + other
TABLE 3: Results of the abdominal examination at the baseline visit and after week 12
„Other“ often stands for a soft palpable abdominal wall as well as a negative finding/status. For
more information see annex.

Severity of illness
At each visit or check-up of the patients the doctor makes a snap-shot of the severity of illness.
The following table shows that the clinical picture of the patients improves in both collectives in
a highly significant and clinically relevant manner from baseline to week 6 and 12 respectively.

Severity N
BASELINE WEEK 6
BASELINE WEEK 6
mildly ill
319 (48,26) 217 (36,29) 89 (28,80) 133 (48,54) 35 (16,13) moderately ill 367
severely ill
number of
cases n =
P=; MWC=

TABLE 4: SEVERITY OF THE PATIENTS' ILLNESS OVER TIME: BL, WEEK 6 AND WEEK 12

Dosage of Eucarbon®
In case of missing dosage data, the last dose indicated by the participant was carried forward
(Last observation carried forward, LOCF). In the total collective, the patients took on average
3,7 ±1,68 tablets Eucarbon® at the baseline visit. At week 6, almost 33 % of the doctors report a
dosage change of Eucarbon® tablets. On average, the number of tablets is 3,2±1,49. At week 12,
almost 17 % of the patients changed the dose. According to the doctors, the average number of
tablets was 3,0 ± 1,39. The patients of Morocco received a higher average dose of Eucarbon® at
the baseline, week 6 and week 12 examination. 41 % of the patients received a new dose at week
6 and about 31 % at week 12. For more information see table 5.
BASELINE WEEK 6 WEEK 12 BASELINE WEEK 6 WEEK 12
Mean value ±
standard deviation
Number of cases n = 614 615 615 244 244 244

TABLE 5: DOSE OF EUCARBON® OVER TIME: BL, WEEK 6 AND WEEK 12

Termination of treatment
At the first check-up visit after week 6, 50 patients (7,49 %) of the total collective terminated the
treatment with Eucarbon®, 80 doctors didn’t report on that subject. At the end of the PMS at
week 12, 51 patients (8,57 %) terminated and 153 doctors didn’t provide information in this
regard. In the Moroccan collective, 38 patients (13 %) terminated at week 6 and 34 patients (15,6
%) at week 12. The reasons are listed in the annex. In both collectives patients primarily
discontinued taking Eucarbon® due to “freedom from symptoms”. At times, adverse reactions
such as stomach pain or similar were reported.
Efficacy of Eucarbon®
The efficacy of Eucarbon® was assessed at week 12 not only by the doctors but also by the
patients themselves. The following table shows the efficacy of Eucarbon® such as rated by the
collectives.

Patients
Patients
235 (37,96) 209 (33,76) 139 (59,66) 111 (47,64)
TABLE 6: Efficacy of Eucarbon® assessed at week 12:

Table 6 clearly shows that doctors and patients gave similar notes regarding the efficacy of
Eucarbon®, which was rated as „very good“, „good“, „medium“ or „ineffective“. About 78 % of
all doctors and patients of the total collective rated efficacy as”very good” and “good”
respectively. The assessment of efficacy by the doctors in Morocco resulted in about 96 % good
to very good results. 94,42 % of the patients of Morocco rated efficacy as „very good“/“good“,
4,29 % as „medium” and 1,29 % as “ineffective”.

Tolerability of Eucarbon®
Also the tolerability of Eucarbon® was rated at week 12 not only by the doctors but also by the
patients themselves. The following table shows how tolerability of Eucarbon® was rated by the
doctors and the patients.

Patients
Patients
222 (35,86) 206 (33,28) 130 (55,79) 110 (47,21)
TABLE 7: Tolerability of Eucarbon® evaluated at week 12
Table 7 also shows that doctors and patients have a very similar assessment regarding tolerability
of Eucarbon®. 89 % of the doctors and almost 88 % of the patients of the total collective rated
the tolerability of the treatment with Eucarbon® as „very good“ and „good“ respectively. 2,1 %
of the patients poorly tolerated the therapy. The evaluation according to the rating of the doctors
and patients of Morocco resulted in a “good” to “very good” tolerability of the therapy. Thus,
even approx. 97 % of the doctors and 93 % of the patients rated the tolerability of Eucarbon® as
“very good” and “good” respectively at the end of the treatment. Only 2.15 % of the patients
poorly tolerated the therapy.

Adverse reactions – AR
There were no serious adverse reactions reported during the course of the postmarketing study.
In the total collective, 19 adverse reactions were reported, corresponding to an incidence of
adverse reactions amounting to 2,5 %. There was one AR per patient. Only for 13 patients (5
from Hungary and 8 from Morocco) detailed information is available about the adverse reaction.
The following AR during the PMS were reported from Hungary: 2 x headaches, 2 x diarrhea, 1 x
heartburn and bloated feeling and eructation. In the Moroccan patients, totally 8 adverse
reactions were reported. 2x „diarrhea“, 1 x „diarrhea and abdominal pain”, 1 x “diarrhea and
liquid stool”, 1 x “liquid stool”, 2 x “stomach cramp” as well as 1 x “hemorrhoids”.

Annex: Software output of the statistical evaluation

Source: http://www.trenka.at/PDF/PMS/Final%20evaluation%20of%20the%20PMS%20Eucarbon%20in%20Hungary%20and%20Morocco%209_2008.pdf