Statistical design of Path to Prevention platform trial in early neuronal alpha-synuclein disease
Year: 2026
Type: preprint
Study design: Study Protocol
Abstract: The Path to Prevention (P2P) platform trial is a first-in-class, phase 2A, randomized, double-blind, placebo-controlled learning study. Its design expedites the assessment of investigational therapies for the treatment of early-stage Neuronal a-Synuclein Disease (NSD), a biological disease continuum that encompasses and often precedes clinically manifest Parkinson's Disease. P2P is embedded within the Parkinson's Precision Medicine Initiative (PPMI), a robust observational longitudinal cohort study on Parkinson's disease progression and a trial-facilitating enrollment framework. A regimen, comprised of an active investigational therapy and a matched placebo control, evaluates a therapeutic candidate within the P2P perpetual platform framework. Multiple regimens can be enrolled, enabling efficient testing of multiple therapeutics. A two-stage randomization scheme determines regimen sample size with 125 participants assigned to a regimen's active therapy and a variable number to placebo control. The treated follow up period is a minimum of 96 weeks and a maximum of 144 weeks, with the last randomized participant followed for 96 weeks. As a pioneering interventional trial in early-stage NSD, P2P endpoint selection was critically informed by modeling and analysis of available PPMI data. In P2P, regimens will be evaluated for efficacy using two primary endpoints: 1) a biomarker outcome of Dopamine Transporter Single-Photon Emission Computed Tomography (DAT SPECT) imaging measured by the bilateral putamen Specific Binding Ratio (SBR) and 2) a clinical outcome measured by the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. Each endpoint will be assessed separately using a longitudinal Bayesian mixed effects model, which compares the active treatment group to the shared placebo control group. The model uses regimen-specific controls at full weight and dynamically discounts controls from other regimens. Additionally, placebo control estimates are supplemented by non-randomized control data from the PPMI cohort. Clinical trial simulations, informed by longitudinal data from 275 P2P-eligible PPMI study participants (Age 60-81, 35% Female, 65% Male), were conducted to evaluate the design. Each regimen is well-powered to detect a 40% slowing in progression for both the clinical and biomarker primary endpoints when comparing active treatment to randomized control data. Supplementing the control estimation with non-randomized, P2P-eligible registry participant data increases power in the explored scenarios up to 4% for each endpoint. The embedded P2P platform trial is a powerful learning study that leverages statistical efficiencies from the platform trial design and established PPMI infrastructure and is poised to advance treatment development in early-stage NSD.
Source: medRxiv
Authors: Barbara Wendelberger, Cora Allen-Savietta, Amy Crawford, Michael C Brumm, Seung Ho Choi, Catherine M Kopil, Ruth B Schneider, Maggie M Kuhl, David-Erick Lafontant, Dixie Ecklund, Kimberly Fabrizio, Tatiana Foroud, Frederic S Goldstein, Cornelia Kamp, Karl Kieburtz, Danielle N Larson, Nijee Luthra, Nicola Pavese, Andrew Siderowf, Craig E Stanley, Caroline M Tanner, Thomas F Tropea, Tawny Willson, Sohini Chowdhury, Kenneth Marek, Tanya Simuni, Christopher S Coffey
Institutions: Berry Consultants, LLC (United States), University of Iowa, Michael J. Fox Foundation, University of Rochester Medicine, University of Rochester, Institute for Neurodegenerative Disorders, Indiana University Indianapolis, Indiana University School of Medicine, Northwestern University, University of California, San Francisco, Newcastle University, University of Pennsylvania
Language: English
Subfield: Statistics and Probability
Field: Mathematics
Domain: Physical Sciences
Open Access status: green
Funders: Michael J. Fox Foundation for Parkinson's Research, Bristol-Myers Squibb, Eli Lilly and Company, Sanofi, Patient-Centered Outcomes Research Institute, Regeneron Pharmaceuticals, Ionis Pharmaceuticals, ACADIA Pharmaceuticals, Voyager Therapeutics, Weston Family Foundation, H. Lundbeck A/S, National Institutes of Health, Genentech
OpenAlex ID: W7225427343