Phlogenzym® in the Treatment of a Monoarticular Gonarthritis

Efficacy and Tolerance
Study No.: MU-695 414
Randomised double-blind, clinical study phase III with parallel groups vs. diclofenac according to the guidelines of good clinical practice (GCP)
Integrated biometric-medical report according to ICH E3 guidelines

Primary Investigator: Univ.-Doc. Franz Singer, M.D.

Rehabilitation Center Tiergartenstrasse 3 c, A-2381 Laab im Walde, Austria

Evaluation by: MUCOS Pharma GmbH & Co, Clinical Research Dpt., Malvenweg 2, D-82538 Geretsried, Germany

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 (For National Authority Use Only)
Name of Finished Product:
Phlogenzym®		 Volume:  
Name of Active Ingredient(s):
Trypsin, Bromelin, Rutosid		 Page:  
Title of Study:
Phlogenzym in the Treatment of a Monoarticular Gonarthritis
Investigator(s):
Univ.-Doz. Franz Singer, M.D., Rehabilitation Center, Tiergartenstrasse 3 c, A-2381 Laab im Walde, Austria
Study centre(s):
Univ.-Doz. Franz Singer, M.D., Rehabilitation Center, Tiergartenstrasse 3 c, A-2381 Laab im Walde, Austria
Publication (reference/s):
Studied period (mo/years): 17 months
(date of first enrolment) Sept. 15th, 1995
(date of last completed) Febr. 14th, 1997		 Phase of development:
Phase III
Objectives:
To test efficacy and tolerance of Phlogenzym as compared with the NSAID diclofenac
Methodology:
Double-blind, randomised, clinical study with two parallel groups.
Measurements of clinical signs and symptoms.
Number of patients (planned and analysed):
68 planned, 63 evaluated.
Diagnosis and main criteria for inclusion:
Monoarticular gonarthritis; Lesquesne index > 10.
Test product, dose and mode of administration, batch number:
Phlogenzym: 90 mg bromelin, 48 mg trypsin, 100 mg rutosid X 3 H20,
2 tablets orally t.i.d. (i.e., 6 tbl. per day), batch no.: 950126;
Placebo tablets, batch no.: 750397
Duration of treatment:
3 weeks
Reference therapy, dose and mode of administration, batch number.
Diclofenac 50 mg, 1 tablet t.i.d. (i.e., 3 tbl. per day) during first week, 1 tbl. b.i.d. (i.e., 2 tbl.
per day) during second and third week; batch no.: 5KZ02;
diclofenac placebo tablets, batch no.: 000.4795
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 Lesquesne index and the sum score of pain and restricted movement 4 weeks after end of therapy; secondary endpoints single pain symptoms, global judgement.
Safety: Global judgement of tolerance (by physician and patients); adverse events
Statistical methods:
To test comparability of groups: Wilcoxon-Mann-Whitney (two-tailed);
to test equivalence of groups: Wilcoxon-Mann-Whitney (one-sided); MW statistics with 95% CI, lower bound to test difference in number of adverse events: Fisher's exact test (two-tailed).
SUMMARY - CONCLUSIONS

EFFICACY RESULTS:
Equivalence of both groups is proven: MW statistics 95% LB = 0.5780 (> 0.44);
following test on superiority: p = 0.0165, MW statistics = 0.6933 (> 0.64 = moderate superiority for Phlogenzym), 95% CI LB = 0.5454 (< 0.56, for proven superiority).

SAFETY RESULTS:
No significant differences between the groups in the global judgement of tolerance nor in the frequency of adverse events.

CONCLUSIONS
The enzyme preparation Phlogenzym has statistically proven to be at least equivalent to diclofenac. Tendency was even seen for superiority of Phlogenzym over diclofenac.
The tolerance of both test drugs was equally good, as the study design was chosen in a manner that the side-ffects of diclofenac were minimized.

Date of the report: July 17th, 1997

1. Summary

A double-blind clinical study was performed to prove efficacy and tolerance of Phlogenzym® for equivalence to the non-steroidal anti-inflammatory drug diclofenac in monoarticular gonarthritis.
68 patients were planned, 63 patients with monoarticular gonarthritis were included and randomised into two groups: 31 patients received the enzyme preparation Phlogenzym® (enzyme group), and 32 patients diclofenac (diclofenac group). The data of all patients was evaluable.

The principal investigator of this center was Univ.-Doz. Franz Singer, M.D., rehabilitation center, Tiergartenstrasse 3 c, A-2381 Laab im Walde, Austria.

To make the compared drugs suitable for the double blind design, the study material had to be prepared following the "double dummy" method: all patients received 2 tablets t.i.d. (i.e. 6 tablets per day) of the "enzyme tablets" and in the 1s week 1 tablet t.i.d. (i.e. 3 tablets per day) diclofenac, in the 2nd and 3rd week 1 tablet b.i.d. (i.e. 2 tablets per day). In one group (enzyme group) the patients received active enzyme and placebo diclofenac tablets, in the other group enzyme placebos and active diclofenac.

At baseline the patients were comparable with regard to age, sex, weight, height and duration of complaints (p > 0.05, Wilcoxon-Mann-Whitney-U-test).

As main endpoints for statistical evaluation on equivalence of both drugs the Lesquesne index and the sum score of the symptoms (rest pain, pain on movement, restricted movement) by the patients using the "visual analog scale" (Huskisson score) 4 weeks after end of therapy was defined.

As secondary criteria the self judgement by the patients, the result of the therapy, the motility of the knee without pain, the circumference (cm) of the knee and the global judgements by the physician and by the patients were evaluated descriptively.

The main endpoints Lesquesne index and sum score have proven for at least equivalence of Phlogenzym® to diclofenac: Lesquesne index - MannWhitney statistics, 95% CI LB = 0.5780; sum score - 95% CI LB = 0.5363 Each value is above 0.44, the limit for equivalence. The following test on difference failed to prove statistically for superiority of Phlogenzym, but a distinct tendency was seen: MW statistics 0.6933; LB 95% = 0.5454 (< 0.56) for lesquesne index; MW statistics 0.6528; LB 95% = 0.5032 (< 0.56) for sum score.

The secondary criteria showed no significant differences (p > 0.05). The pain on movement improved more in the enzyme group (p = 0.0118).

The efficacy of the drug was judged in the enzyme group by the physician as 2.2 ("good") and by the patients as 2.1 ("good"). In the diclofenac group the physician judged the efficacy of the drug as 2.3 ("good" to "moderate") and the patients as 2.4 ("good" to "moderate").

The tolerance of the drugs was judged by the physician and by the patients in the enzyme group as 1.3 ("very good" to "good"), and in the diclofenac group as 1.4 ("very good" to "good") by the physician and as 1.3 ("very good" to "good") by the patients.

Adverse events were documented in 15 patients in the enzyme group and in 18 patients in the diclofenac group. They started on average after 7.7 days in the enzyme group and after 13.1 days in the diclofenac group. The duration was on average 7.1 days in the enzyme group and 3.7 days in the diclofenac group. They were judged as "mild" to "moderate". In the enzyme group they were without sequelae and in the diclofenac group the adverse events were in 16 patients without sequelae, in two patients with mild sequelae and in two patients the sequelae were in need of ambulatory treatment.