DEFINING SMALL DIFFERENCES IN EFFICACY BETWEEN ANTI-PARKINSONIAN AGENTS USING GAIT ANALYSIS - A COMPARISON OF 2 CONTROLLED RELEASE FORMULATIONS OF LEVODOPA DECARBOXYLASE INHIBITOR

1 Stride length is highly relevant to mobility and is sensitive to the effects of levodopa in Parkinsonism. Its selection as the primary outcome criterion allowed comparison of two levodopa/decarboxylase inhibitor formulations using a small number of subjects. 2 It is also desirable to improve stability. An instrumental method, based on infrared telemetry, has been developed which obtains both distance/time measures of gait and broadness of base, as measured by foot separation at mid-swing. The latter was used as a subsidiary outcome criterion. 3 Nine patients (aged 57 to 77 years) then receiving maintenance therapy for idiopathic Parkinsonism with Sinemet CR alone, but who had previously experienced end of dose effect within 4 h of receiving a dose of a conventional formulation of levodopa/decarboxylase inhibitor, were studied. 4 They received, in random order and at least 4 days apart, single doses of one tablet of Sinemet CR (200 mg levodopa/50 mg carbidopa) and of two capsules of Madopar CR (each 100 mg levodopa/25 mg benserazide), with placebo balance, at 10.00 h. Gait analysis was carried out immediately before and half-hourly for 7 h after a challenge. No routine doses of Sinemet CR were taken between 22.00 h on the night before and 17.00 h on the day of a challenge. 5 Analysis of variance showed a highly significant difference in mean stride length (P < 0.001) and in mean foot separation (P = 0.01) between serial time points, irrespective of the nature of treatment. There appeared to be a useful therapeutic response to both challenges. 6 There was a significant overall difference in stride length (P = 0.04) between the challenges containing active Madopar CR and active Sinemet CR, stride length being, on average, 49 mm (congruent-to 5% of the grand mean, 1034 mm) greater for the latter. The difference was best seen 2 h post challenge, when it reached 184 mm (congruent-to 18% of corresponding mean, 1013 mm). There was no significant overall difference with respect to foot separation. 7 This methodology makes direct titration of developmental modifications in formulation against a relevant dynamic end point practical. It avoids making erroneous assumptions about performance from the pharmacokinetic profile, and the need to recruit larger numbers of subjects in order to make decisions on the basis of clinical assessments.