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Wobenzym® and Wobe-Mugos® in the Treatment of Multiple Sclerosis

Krejcová, Hana. Wobenzym® and Wobe-Mugos® in the Treatment of Multiple Sclerosis.  PharmaScript, Kathi-Kobus-Steig 1, D-82515 Wolfratshausen, Germany.

Summary: In this open randomised clinical phase III trial (acc. to German Drug Law) with two parallel groups, efficacy and tolerance of two enzyme drugs were tested in patients with multiple sclerosis: during acute attacks, Wobenzym® tablets (high dose) and Wobe-Mugos® ampoules were used, in the interval low dose Wobenzym® tablets. This was compared with a treatment with ACTH/corticosteroids during attacks and - in patients with worse prognosis and in advanced stages if necessary cyclophosphamid in the interval.
40 patients with established multiple sclerosis (clinical follow-up, liquor diagnosis, MRI, CT and/or VEP, optional SPECT) were taken into this study. 20 patients received the enzyme preparations and 20 ACTH/corticosteroids. The data of all patients were evaluable.
The study was conducted under the direction of Prof. MUDr. Hana Krejcová, DrSc., Neurologická klinika, Pediatrická Fakulta, Universita Karlova, FN Motol, V úvalu 84, 15012 Praha 5, Czech Republic.
In any case the therapy in the enzyme group started with high dose enzymes: during the first week the patients received 1 ampoule Wobe-Mugos® pro inj. and 30 tablets of Wobenzym®daily. In the second week the patients got 1 ampoule Wobe-Mugos® every other day and 30 tablets of Wobenzym® daily. From the third week the patients received a maintenance dose of 9 tablets Wobenzym® each day. The patients in the comparative group received throughout an attack either a pulsed therapy of high dose corticosteroids (3 days 1000 mg/die methylprednisolone i.v., 2 days pause, 3 days tapering off), an oral therapy with corticosteroids (60 - 80 mg/die methylprednisolone orally 2 to 4 weeks, last week tapering off) or a therapy with ACTH (100 1.E. ACTH daily during 2 weeks, last week tapering off). During intervals patients with worse prognosis and/or advanced stages got daily if necessary 3 mg/kg body weight oral cyclophosphamide. Patients with good prognosis and in early stage received no interval therapy.
The patients were comparable at baseline with regard to age, sex, family case history, classification of multiple sclerosis by Poser, kind of disease, parameters of the functional system, of the performance system and of the social environment (Wilcoxon-Mann-Whitney- U-Test: p > .05).The main endpoint for statistical evaluation was the extended Kurtzke disability scale (EDSS).
Despite randomisation, the patients had a significantly different mean value at baseline (enzyme group: 3.3 - corticosteroid group: 4.5 - p = .015). After adjusting the baseline values of either group to 100%, a statistically significant difference in favor of the enzymes was demonstrated from the sixth month (p < .01 ), an even highly significant difference at end of therapy (p < .001 ).
If the difference at baseline is judged as clinically so relevant that a direct comparison during the course of the therapy is not acceptable, there is nevertheless a difference in favor of the enzymes in the change of the Kurtzke scale: whereas the value improved until the last available vaIue in the enzyme group by 24.2% (from 3.3 to 2.5), it worsened in the corticosteroid group by (-)2.2% from 4.5 to 4.6.
As secondary criteria the parameters of the functional system, of the performance system and of the social environment, the serodiagnosis, the diagnosis of the liquor, and the subjective judgement of efficacy and tolerance were evaluated statistically.

The parameters of the functional system (the findings of the pyramidal tract, cerebellum, sensorium, vesicorectal function, index of the gait pattern, sum score), of the performance system (dress and undress, personal hygiene, fatigability,) and of the social environment (work, sumscore) showed statistically significant (p < .05) differences at end of therapy in favor of the enzymes. The data of the parameter"walking" and of the parameters of the social envorinment showed significant advantages in the corticosteroid group.There were other statistically significant differences in favor of the enzyme treatment for the number of hospitalisation and for the number and duration of multiple sclerosis attacks: there was a total of 15 hospitalisations necessary in the enzyme group (mean 0.8 hospitalisations per patient) and 35 hospitalisations in the corticosteroid group (mean 1.8 - p = .038). The mean duration of hospitalisation (enzymes: 25.7 days, corticosteroids: 60.7 days) just missed significance (p = .055). 15 attacks were documented in the enzyme group (mean 0.8 attacks per patient) with a mean duration of 28.7 days, 37 attacks in the corticosteroid group (mean 1.9 - p - .019) with a mean duration of 58.2 days (p = .02). There were no differences in progression and severity of the attacks between the groups (p > .05).
The result of the therapy was judged by the physician and by the patients at end of therapy as 3.1 ("slight improvement") in the enzyme group and as 4.1 ("unchanged") in the corticosteroid group. The groups differed statistically significantly in favor of the enzyme treatment (p < .05).

The judgement of efficacy by the physician was 2.0 ("good') and by the patients 2.1 ("good") in the enzyme treated group and 3.1 ("moderate") in the corticosteroid group. The difference was statisticalIy significant in favor of the enzymes (p < .05).
The tolerance of the treatment was judged by the physician and by the patients as 1.4 ("very good" to "good") in either group.
The duration of treatment was comparable in both groups. The average duration was 19.4 months in the enzyme group and 23.0 months in the corticosteroid group. The difference was not significant (p > .05)

The parameters of the functional system (the findings of the pyramidal tract, cerebellum, sensorium, vesicorectal function, index of the gait pattern, sum score), of the performance system (dress and undress, personal hygiene, fatigability,) and of the social environment (work, sumscore) showed statistically significant (p < .05) differences at end of therapy in favor of the enzymes. The data of the parameter"walking" and of the parameters of the social envorinment showed significant advantages in the corticosteroid group.There were other statistically significant differences in favor of the enzyme treatment for the number of hospitalisation and for the number and duration of multiple sclerosis attacks: there was a total of 15 hospitalisations necessary in the enzyme group (mean 0.8 hospitalisations per patient) and 35 hospitalisations in the corticosteroid group (mean 1.8 - p = .038). The mean duration of hospitalisation (enzymes: 25.7 days, corticosteroids: 60.7 days) just missed significance (p = .055). 15 attacks were documented in the enzyme group (mean 0.8 attacks per patient) with a mean duration of 28.7 days, 37 attacks in the corticosteroid group (mean 1.9 - p - .019) with a mean duration of 58.2 days (p = .02). There were no differences in progression and severity of the attacks between the groups (p > .05).
The result of the therapy was judged by the physician and by the patients at end of therapy as 3.1 ("slight improvement") in the enzyme group and as 4.1 ("unchanged") in the corticosteroid group. The groups differed statistically significantly in favor of the enzyme treatment (p < .05).

Three "moderate" adverse events in two patients (gastro-intestinal symptoms and cholecystitis, transient increase of transaminases) were documented in the enzyme group. The gastro-intestinal symptoms started during the 12th month, the cholecystitis during the 15th month, but they were "certainly not" caused by the enzymes. The increase of transaminases started during the tenth month. As there was not found any causa, the relationship to the enzyme therapy was judged as "probably". The enzymes were discontinued in the first patient after the second adverse event, in the second patient immediately. No sequelae were documented.There were no adverse events noted in the corticosteroid group. The difference was not significant (p = .605).