Phlogenzym® in the Treatment of a Monoarticular Gonarthritis

Efficacy and Tolerance Study No.: MU-696 401
Randomised double-blind study phase III with parallel groups vs. diclofenac according to the guidelines of good clinical practice (GCP)
Integrated final report according to ICH E3 guidelines

Primary Investigator: Univ.-Prof. Gert Klein, M.D.

Rehabilitation Center of Rheumatic Diseases and Diseases of the Cardiovascular System Thorerstrasse 26, A-5760 Saalfelden, 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):
Prim. Prof. Gert Klein, M.D., Rehabilitation Center for Rheumatic Diseases and Diseases of the Cardiovascular System, Thorerstrasse 26, A-5760 Saalfelden, Austria
Study centre(s):
Prim. Prof. Gert Klein, M.D., Rehabilitation Center for Rheumatic Diseases and Diseases of the Cardiovascular System, Thorerstrasse 26, A-5760 Saalfelden, Austria
Publication (reference/s):
Studied period (mo/years): 1 year
(date of first enrolment) June 18th, 1996
(date of last completed) July 21st, 1997 		Phase of development:
Phase III
Objectives:
To test efficacy and tolerance of Phlogenzym as compared with the NSAID diclofenac for equivalence.
Methodology:
Double-blind, randomized study with two parallel groups.
Measurements of clinical signs and symptoms.
Number of patients (planned and analysed):
72 planned, 73 included, 73 evaluated.
Diagnosis and main criteria for inclusion:
Monoarticular activated, painful gonarthritis; Lesquesne index > 10.0.
Test product, dose and mode of administration, batch number:
Phlogenzym® (48mg trypsin, 90mg bromelin, 100mg rutosid x 3 H2O,
2 tablets orally t.i.d. (i.e., 6 tbl. per day), batch no.: 951184;
Placebo tablets, batch no.: 750398
Duration of treatment:
3 weeks; follow-up 4 weeks later
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.: 960591;
diclofenac placebo tablets, batch no.: 967806
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 were single pain symptoms, global judgement.
Safety: Global judgement of tolerance (by physician and patients); laboratory parameters; adverse events
Statistical methods:
To test comparability of groups: Wilcoxon-Mann-Whitney (two-tailed);
to test equivalence of the groups: Wilcoxon-Mann-Whitney (one-tailed);
to test difference in number of adverse events: Fisher's exact test (two-tailed).

SUMMARY - CONCLUSIONS

EFFICACY RESULTS:
The main endpoint Lesquesne index 4 weeks after end of therapy has shown proven equivalence between the two treatment arms. The Mann-Whitney statistic (0.5459) and the lower bound of the 95% confidence interval (0.4568) were above the limit for equivalence (0.44). Also if tested at end of therapy, both groups were equivalent (statistics: 0.5308, LB of 95%-Cl: 0.4458). The areas under the curve were both equivalent, until 4 weeks after end of therapy and until end of therapy (LB 95%-CI: 0.4664, and 0.4610, resp.).
The second main endpoint, the sum score of symptoms 4 weeks after end of therapy, also proved significantly for equivalence: the LB of the 95%-CI was with 0.4608 above the limit (0.44).

SAFETY RESULTS:
No differences between the groups in the global judgement of tolerance nor in the frequency of adverse events. No relevant changes in any laboratory parameter.

CONCLUSIONS:
The results have proven confirmatively the equivalent effect of Phlogenzym® and the NSAID diclofenac. Because of the better benefit/risk-ratio, Phlogenzym is a real and good alternative to NSAIDs in the treatment of an activated gonarthritis.

Date of the report: September 25th, 1997

1. Summary

A double-blind clinical study to prove efficacy and tolerance of Phlogenzym® for equivalence with the nonsteroidal anti-inflammatory drug diclofenac in monoarticular gonarthritis was performed.
72 patients were planned, 73 patients with monoarticular gonarthritis were included and randomised into two groups: 36 patients received the enzyme preparation Phlogenzym® (enzyme group), and 37 patients diclofenac (diclofenac group). The data of all patients was evaluable.

The principal investigator of this center was Prim. Univ.-Prof. Gert Klein, M.D., rehabilitation center of rheumatic diseases and diseases of the cardiovascular system, Ludwig Boltzmann-Institut, Thorerstrasse 26, A-5760 Saalfelden, 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 first week 1 tablet t.i.d. (i.e. 3 tablets) diclofenac, in the second and third week 1 tablet b.i.d. (i.e. 2 tablets). In the enzyme group the patients received active enzyme and placebo diclofenac tablets, in the diclofenac 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 the Lesquesne index and the sum score of the self-judgement (rest pain, pain on movement, restricted movement) by the patients using a "visual analog scale" (Huskisson score) 4 weeks after the 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 endpoint "Lesquesne index 4 weeks after end of therapy" has proven for equivalence of both groups: the Mann-Whitney statistics yielded a value of 0.5459 with a lower limit of the 95% confidence interval of 0.4568, which is above 0.44, the limit for proven equivalence.

The second main endpoint, the sum score of the symptoms, also proved for equivalence: the lower bound of the 95% confidence interval was with 0.4608 above the limit (0.44).

The efficacy of the drug was judged in the enzyme group by the physician and by the patients as 1.5 ("very good" to "good"). In the diclofenac group the physician judged the efficacy of the drug as 1.3 ("very good" to "good") and the patients as 1.4 ("very good" to "good"). The tolerance of the drugs was judged in the enzyme group by the physician and by the patients as 1.2 ("very good") and in the diclofenac group as 1.3 ("very good" to "good"). There were no differences between the groups (p > 0.05).

Adverse events were documented in two patients in the enzyme group (headache, diarrhea) and in three patients in the diclofenac group (sinus bradycardia, pain in the stomach due to a duodenal ulcer, nausea). They started on average after 6.5 days in the enzyme group and after 9.3 days in the diclofenac group. The duration was on average 5.5 days in the enzyme group and 3.0 days in the diclofenac group. They were all judged as "moderate". In the enzyme group they were without sequelae and in the diclofenac group the adverse events were in two patients without sequelae, the patient with the ulcer was in need of ambulatory treatment.