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Phlogenzym® in the Model of an Experimentally Induced Hematoma (MU-697403)
 Dose-Response Study
Study No.: MU-697403
Randomised double-blind study phase II with four parallel dosing groups including placebo according to the guidelines of good clinical practice (GOP)
Integrated biometric-medical final report according to ICH E3 guidelines
Primary Investigator: Michael-W. Kleine M. D, Egenhofenstrasse 18, D-82152 Planegg, Germany
Evaluation and Report by: PharmaScript, Primelweg 2 D-82538 Geretsried, Germany
Synopsis

Name of Sponsor/Company:
MUCOS Pharma GmbH & Co.
Malvenweg 2, D-82538 Geretsried

Individual Study Table Referring to Part at the Dossier

Name of Finished Product: Phlogenzym®

Name of Active Ingredient(s): Trypsin, Bromelin, Rutosid 

Title of Study:
Phlogenzym® in the Model of an Experimentally Induced Hematoma - Dose-Response Study

Investigator(s):
Michael-W. Kleine, M.D., Doris Ertl, M.D., Egenhofenstrasse 18, D-82152 Planegg, Germany

Study centre(s):

Publication (reference/s):

Studied period (mo/years): 9 days
(date of first enrolment) April 05th, 1997
(date of last completed) April 14th, 1997

Phase of development:
Phase II

Objectives:
Efficacy and tolerance of different doses of Phlogenzym® in the model of an experimentally induced hematoma.

Methodology:
Measurement of threshold of pain (using a special tonometer) on the forearm. The arm with an experimentally induced hematoma is compared to the sound arm of the same patient. The difference between the hematoma-carrying arm and the sound arm is calculated. The sum of these differences over 9 days is computed as main criterion.

Number of patients (planned and analysed):
planned 96 (4 x 24)
analyzed 96 (4 x 24)

Diagnosis and main criteria for inclusion:
Healthy volunteers

Test product, dose and mode of administration, batch number:
Phlogenzym® (48mg trypsin, 90mg bromelin, 100mg rutosid); oral intake
group I: 12 tablets/day;
group II: 6 tablets/day;
group III: 2 tablets/day;
group IV: placebo.
Batch-number of active drug: 951184

Duration of treatment: 9 days

Reference therapy, dose and mode of administration, batch number.
Placebo tablets. Batch-number 750398

 

Name of Sponsor/Company:
MUCOS Pharma GmbH & Co.
Malvenweg 2, D-82538 Geretsried

Individual Study Table Referring to Part at the Dossier

(For National Authority Use Only)

Name of Finished Product:
Phlogenzym®

Volume:

 

Name of Active Ingredient(s):
Trypsin, Bromelin, Rutosid

Page:

 

Criteria for evaluation
Efficacy: Main endpoint was the sum of the differences of the thresholds of pain on the hematoma-carrying and the sound arm from day 1 through day 8
Safety: Global judgement of tolerance (by physician and subjects); laboratory parameters; adverse events

Statistical methods:
To test comparability of groups: Kruskal-Wallis analysis;
to test difference between groups: 1. Mann-Whitney 2. AOV and Scheffe F-value for multiple comparison;
to test difference in number of adverse events: Kruskal-Wallis analysis.

SUMMARY - CONCLUSIONS
EFFICACY RESULTS:
The main criterion was statistically significantly (p < 0.001 ) better under high dose and normal dose Phlogenzym (12 tbl./day vs. placebo, 6 tbl./day vs. placebo 12 tbl./day vs. 2 tbl./day, and 6 tbl./day vs. 2 tbl./day). There were no significant differences between 12 and 6 enzyme tablets/day and between 2 tablets/day and placebo. The existing differences are clinically relevant with a "big difference according to the Mann-Whitney test statistics P(X<Y) + 0.5·P(X=Y): 0.9705, 0.9141, 0.9314 and 0.8594 (all > 0.71).
SAFETY RESULTS:
No significant differences between the enzyme groups and the placebo group. Changes in laboratory parameters are only minor.
The test drug is safe and well tolerated in all dosing groups.
CONCLUSIONS:
The dosis of 6 tablets/day of Phlogenzym® is as effective as the dosis of 12 tablets/day, and significantly better than 2 tablets/day or placebo.

Date of the report: September 17th, 1997
Summary
In a randomised double-blind experimental clinical trial phase II (acc. to German Drug Law) with four parallel groups, the efficacy and tolerance of the enzyme preparation Phlogenzym® in reducing pain under pressure was tested in three dosing and one placebo group in subjects with an experimentally induced hematoma on the flexor side of the forearm.
96 healthy volunteers of either sex were recruited and taken into this study. 24 subjects received 4 tablets t.i.d. (i.e. 12 tablets per day) of the enzyme preparation Phlogenzym® ("high dose group"), 24 subjects got 2 tablets t.i.d. (i.e. 6 tablets/day) enzymes plus the same amount of placebo tablets ("normal dose group"), 24 subjects got 2 tablets h.s. (i.e. 2 tablets/day) enzymes, filled up with placebo tablets to a daily total of 12 tablets ("low dose group"), and 24 subjects received placebo only (12 tablets/day; "placebo group"). The data of all subjects was evaluable.
The principal investigator was Michael-W. Kleine, M.D., Egenhofenstrasse 18, D-82152 Planegg.
Each subject received 96 tablets over 9 days (day 0: 4 tablets h.s., days 1 to 7: 4 tablets t.i.d., day 8: 4 tablets b.i.d.).
At baseline the subjects were comparable with regard to age, sex, weight and height (p > 0.05, Kruskal-Wallis analysis).
As main endpoint for statistical evaluation the sum of pain under pressure from day 0 through day 8 was evaluated. The pain under pressure was defined as difference between the measured values for the threshold of pain from the arm with hematoma and the sound arm. This difference was chosen to compensate inter-individual variations. Each subject served as its own control. The sum was calculated by summarizing these differences of all days.
The main criterion "sum of pain under pressure over 9 days" was statistically significantly lower (p < 0.001 ) in the high dose and normal dose groups vs. the low dose and the placebo groups. The difference was "big" according to the Mann-Whitney statistics. There was no difference (p > 0.05) in the efficacy between the high dose and the normal dose groups, and between the low dose and the placebo groups, resp.
The efficacy of the drugs was judged by the physician as 1.2 ("very good") in the high dose group, as 1.6 ("very good" to "good") in the normal dose group, as 4.7 ("unsatisfactory" to "poor") in the low dose and in the placebo group. Judgement by the subjects was 1.2 ("very good") in the high dose group, 1.4 ("very good" to "good") in the normal dose group, 4.7 ("unsatisfactory" to "poor") in the low dose group, and 4.6 ("unsatisfactory" to "poor") in the placebo group. There were significant differences between the high and normal dose groups on one side as compared with the low dose and placebo groups (p < 0.0001 ).
The tolerance of the drugs was judged globally by the physician and by the subjects, and by changes of the laboratory parameters from baseline to day 8.
There were only minor laboratory changes in all groups, the tested enzyme preparation can be judged as safe in all dosing groups.
The global judgement of tolerance by the physician and by the subjects was 1.0 to 1.2 ("very good") in all enzyme groups and in the placebo group.
Adverse events were documented in one subject in the high dose group (nausea), and in one subject in the low dose group (nausea and diarrhea). They started after 6.0 days in the high dose group, and after 3.0 days in the low dose group. The duration was 4.0 days in the high dose group, and 2.0 days in the low dose group. They were judged as "moderate" in the high dose group, and as "mild" in the low dose group. In all cases the subject's outcome was a complete restitution without change of the test therapy. With regard to the frequencies of adverse events there was no difference between the groups (p = 0.5680, Kruskal-Wallis analysis).