Microsoft word - auswertung_eucarbon_ungarn-marokko1 0_eng.doc
Final evaluation of the postmarketing study of
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
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.
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.
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.
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
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