Objective: To describe the study design and timeline of a platform interventional study in Neuronal α-Synuclein Disease (NSD).

Background: The recent description of the biological definition and staging anchors of NSD enable the design of studies to test potential disease modifying agents before traditional clinical diagnosis. These participants were previously defined as ‘prodromal’. The interventional study is “nested” within the observational PPMI, sponsored by the MJFF.

Method: P2P is a platform, Phase 2 randomized double blind multi-center, multi-regimen trial with a single Master Protocol dictating the conduct of the trial, supplemented by regimen specific subprotocols outlining intervention specific aspects.  Qualified participants will be recruited from active participants in PPMI, using NSD Stage 2B criteria (Figure 1).

The study’s Multiple Primary Endpoints include 1) DAT imaging as measured by the rate of progression in the mean striatum Specific Binding Ratio and 2) rate of progression in the MDS-UPDRS part III score. Secondary endpoints include safety, tolerability and feasibility. The study will have exploratory clinical (including digital) and biomarker measures. Participants will first be randomized to one of the eligible regimen-specific sub-protocols (N=125 per arm), and then within the regimen to an active arm or placebo, in a K:1 ratio with K denoting the number of active interventions (Figure 2). Intervention duration will be at least 24 months and up to 36 months, or until 24 months since the randomization of the last participant, whichever comes first. The study is 85% powered to detect treatment effects when both of the endpoints achieve 40% slowing of progression, respectively.

Results: The P2P master protocol has been finalized and reviewed by FDA. Interventions are being selected from 20 industry submitted applications, with a targeted start in 2026.  Study prelaunch activities and sites selection are on-going.

Conclusion: We report the design of the first platform study targeting NSD Stage 2B population. Innovative recruitment into PPMI will enable this study.

Figure 1 Study Synopsis

Figure 2A P2P study design

Figure 2B. Participants randomization

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MDS Abstracts - https://www.mdsabstracts.org/abstract/p2p-therapeutics-platform-trial-in-stage-2b-neuronal-alpha-synuclein-disease-study-design-and-statistical-considerations/