Objective: To evaluate variation in Phase 2 and 3 Parkinson’s disease (PD) neuroprotective trial designs and identify key trial design features in Phase 2 studies that successfully met their primary endpoint.

Background: Despite many agents showing pre-clinical promise, none has been shown to be protective in clinical trials. This failure in translation may result from limitations of trial design. We were interested to identify (1) current variation in Phase 2 and 3 neuroprotective design and (2) key trial design features in Phase 2 studies that successfully met their primary endpoint.

Methods: ClinicalTrials.gov and PD Trial Tracker (PDTrialTracker.info) were searched to identify Phase 2 and Phase 3 neuroprotective PD trials currently recruiting or published in the last 5 years. Trials of symptomatic therapies were excluded. Key variables in study design were recorded.

Results: 216 trials were identified after removal of duplicates; 178 were excluded; 38 trials were included in the evaluation – 29 Phase 2 (6 reported, 23 unreported) and 9 Phase 3 (3 reported, 6 unreported). There was marked variability in all aspects of trial design with low levels of consensus between studies. 17% of studies stipulated the same disease duration for ‘Early PD’ (within 3 years of diagnosis); the highest level of agreement in primary outcome measure was between 28% of Phase 2 studies (MDS-UPDRS Part III) and 44% of Phase 3 studies (MDS-UPDRS Parts I-III). Phase 2 studies that reported successfully meeting their endpoints (n=4) used: efficacy outcomes (50%); safety and tolerability outcomes (25%); and mechanistic outcomes (25%). The phase 2 studies that were unsuccessful in meeting their endpoints (n=2) used efficacy outcomes. Treatment durations across studies were variable (0.5 – 60 months). Phase 2 studies that used efficacy outcomes had longer treatment durations than studies using mechanistic outcomes (p<.05).

Conclusions: There was marked variability in trial design across studies. Phase 2 studies having an efficacy primary outcome measure had a greater risk of not successfully meeting their endpoints. Efficacy outcomes require lengthier treatment durations which increases cost and potential for patient attrition. Achieving consensus on design parameters may lead to improved comparability of findings between trials, and improved neuroprotective trial designs in the future.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/what-makes-a-successful-phase-2-study-an-evaluation-of-parkinsons-neuroprotective-trial-design-over-the-last-5-years/