Objective: To assess how the efficacy of tozadenant differed by region in a randomized, double-blind, placebo-controlled trial of Parkinson’s disease patients with motor fluctuations.

Background: Clinical trials often utilize sites in diverse geographical regions in order to recruit a sufficient number of subjects within a reasonable period of time. There is concern, however, that patient selection and other unknown factors lead to regional differences in clinical data. Typically this information is not disclosed publicly.

Methods: We analyzed regional differences in a Phase 2b multicenter study of tozadenant in fluctuating Parkinson patients (Hauser et al. 2014). We focused on the primary endpoint of the study, OFF time, which was collected at baseline, Week 2, 6, and 12 for placebo and four active treatment arms.

Results: A total of 420 subjects were randomized from 76 study sites in Argentina, Canada, Chile, Romania, Ukraine, and the USA. Overall, the mean (SD) age was 63.3 (8.3) years; the mean PD duration was 8.7 (4.7) years; and mean daily off-time was 6.1 (2.2) hours/day. Across all regions a statistically significant reduction in mean daily OFF time vs. placebo was observed for tozadenant 120 mg BID (−1.1 h; raw and adjusted p=0.0039) and 180 mg BID (−1.2 h; raw p=0.0024, adjusted p=0.0039) but not 60 mg BID (−0.6 h; raw and adjusted p=0.0881) or 240 mg BID (−0.9 h; raw p=0.0262, adjusted p=0.0881). An overall risk/benefit assessment favored tozadenant 120 mg BID. Among regions, mean (SD) change in OFF time at Week 12 was compared between placebo and tozadenant 120 mg BID. For North American subjects, placebo changed by -0.83 (2.34) hours/day while tozadenant 120 mg BID changed -2.46 (2.52) hours/day. Subjects from South America demonstrated a larger placebo effect -1.70 (3.38) hours/day and a similar change to tozadenant 120 mg BID: -1.75 (2.14) hours/day. For European subjects, placebo changed by -0.65 (2.38) hours/day while tozadenant 120 mg BID changed by -0.87 (2.97) hours/day.

Conclusions: Regional analyses of this Phase 2b study of tozadenant indicate that North American subjects experienced a more robust improvement in efficacy between placebo and active treatment compared to other regions. Such differences should be understood as they may impact development costs and timelines by making it more difficult to detect an efficacy signal.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/regional-differences-in-the-results-of-a-phase-2b-study-of-tozadenant-in-parkinsons-disease-patients-with-motor-fluctuations/