Systémová enzymoterapie pro odborníky

Enzyme Therapy of Patients with Acute Hemorrhagic Cystitis

Randomized, Placebo controlled, Clinical, Double-blind, Multicenter Study of Phase III
According to the European Standard of Good Clinical Practice (GCP)
(Protocol: MU-695 416, Final Version of 25.03.96)

Prof. Dr. med. J. Sökeland, Dortmund, Germany

Title:	Enzyme Therapy of Patients with Acute Hemorrhagic Cystitis Randomized, Placebo-controlled, Clinical, Double-blind Multicenter Study of Phase III According to the European Standard of Good Clinical Practice (GOP)
Name of test medication:	Phlogenzym® (Bromelain, Trypsin, Rutosid)
Indication studied:	acute hemorrhagic cystitis
Design:	randomized, placebo-controlled, clinical, double-blind multicenter study, two parallel groups
Name of the sponsor:	MUCOS Pharma GmbH & Co Alpenstr.29 D-82538 Geretsried, Germany
Protocol:	MU-695 416, final version, dated 25.03.1996
Phase of development:	III
Studied Period:	March 1996 - January 1997
Principal Investigator:	Prof. Dr.med. J. Sökeland specialist for urology, former director of the urological clinic of the Städt. Kliniken Westfalendamm, institute for occupational physiology and ergonomics (Institut fur Arbeitsphysiologie - Ergonomie) Ardeystr. 67 44139 Dortmund, Germany
Name of sponsor signatory:	H.G. Wenning, Prakt.Arzt, MUCOS Pharma GmbH & Co, Abt. Klinische Forschung, Alpenstr. 29 D-82538 Geretsried, Deutschland

This study was performed according to the principles of the current edition of the Declaration of Helsinki, according to the German drug law (AMG), and according to Good Clinical Practice (GOP), including the archiving of essential documents.

Date of report: 01.10.1997

Note: There are no earlier reports!

SUMMARY - CONCLUSION

EFFICACY RESULTS:

It can be seen that in both treatment groups (Phlogenzym® + antibiotics vs. placebo + antiobitics) the sumscores decreased considerably from a similar baseline level (data set: ITT):

Phlogenzym® :	8.8 (SD: 3.41) on day 1	->	1.4 (SD: 1.79) on day 7
placebo:	9.2 (SD: 2.77) on day 1	->	2.2 (SD: 2.10) on day 7

The Phlogenzym® treatment group attained a larger change from baseline (day 1 minus day 7) than the placebo group (data set: ITT):

Phlogenzym® :	7.4 (SD: 3.83)
placebo:	6.8 (SD: 3.89)

General results
The one-sided Wilcoxon-Mann-Whitney-U-test of the sum-score on day 7 (change from baseline) gave no hints for group differences (P = 0.2101 ), a small trend to superiority of Phlogenzym® (MW = 0.5440; Cl_95%: 0.4382 to 0.6498) was found, however, for the ITT data set. The second primary criterion of the protocol, time-to-freedom of 3 complaints, resulted in a "significant" P = 0.0030 (Peto-Wilcoxon). A new analysis with the appropriate percentage change values of index values resulted in a definite hint for superiority of the test drug. The Wilcoxon results were P_1-sided= 0.0096 and MW = 0.6253 (Cl_95%: 0.5223 to 0.7283).
The results of the centers were inconsistent (data set: ITT): Lücke (inferiority); Schult, Gebauer, and Timpe (superiority of Phlogenzym®) Ahn (inferiority: sum-score; superiority: time-to-freedom).

Subgroup analysis
A stratified analysis was run with two strata with range [0 to 7] and [8 and more] of the baseline sum-scores. For index-values on day 7 there is a good benefit resulting from the test preparation for patients with scores 0 to 7 (sum-score: P = 0.0071, OR = 1.7542); for patients with higher baseline values there is little effect (sum-score: P = 0.1761, OR = 1.2413). For time-to-freedom of complaints, there is, however, a definite advantage in both strata (range 0-7: P = 0.0283, OR = 2.4677; range 8 to 15: P = 0.0190, OR = 1.9320), whatever the baseline.

SAFETY RESULTS:

During the 14 days observation period 5 adverse events were reported in 4/58 (6.9%%) Phlogenzym®-patients and 14 adverse events in 9/58 (15.5%) placebo-patients. No serious adverse event occurred. The tolerability was rated by the investigator as "very good" or "good" for 50/54 (92.6%) Phlogenzym® -patients and for 45/50 (90.0%) placebo-patients.
Phlogenzym® was well tolerated according to the ratings of the investigator and the patients.

CONCLUSION:
Phlogenzym® plus antibiotics had a "medium" superiority in comparison with placebo plus antibiotics in patients with acute cystitis. Phlogenzym® was well tolerated.