Statistical design of Path to Prevention platform trial in early neuronal alpha-synuclein disease
- 1Berry Consultants, LLC, Austin, Texas 78746, United States
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.
Related
- Path to Prevention Platform Trial in Early-Stage Neuronal Alpha-Synuclein Disease: Study Design
- Visualizing α‐synuclein pathology in live brain: A new platform for Parkinson's disease research
- Reproducible cerebrospinal fluid proteomic signatures across early neuronal α-synuclein disease stages in PPMI
- Cognitive Performance in Prodromal Neuronal α Synuclein Disease
- CD38 inhibition increases neuronal survival and reduces α-synuclein in vitro, elevates brain NAD+, and reduces motor deficits in a Parkinson’s disease model
BibTeX
@misc{wendelberger2026statistical,
title = {{Statistical design of Path to Prevention platform trial in early neuronal alpha-synuclein disease}},
author = {B. Wendelberger and C. Allen-Savietta and A. Crawford and M. C. Brumm and S. H. Choi and C. M. Kopil and R. B. Schneider and M. M. Kuhl and D.-E. Lafontant and D. Ecklund and K. Fabrizio and T. Foroud and F. S. Goldstein and C. Kamp and K. Kieburtz and D. N. Larson and N. Luthra and N. Pavese and A. Siderowf and C. E. Stanley and C. M. Tanner and T. F. Tropea and T. Willson and S. Chowdhury and K. Marek and T. Simuni and C. S. Coffey},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.04.26367306},
url = {https://www.medrxiv.org/content/10.64898/2026.11.04.26367306v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Statistical design of Path to Prevention platform trial in early neuronal alpha-synuclein disease
AU - B. Wendelberger
AU - C. Allen-Savietta
AU - A. Crawford
AU - M. C. Brumm
AU - S. H. Choi
AU - C. M. Kopil
AU - R. B. Schneider
AU - M. M. Kuhl
AU - D.-E. Lafontant
AU - D. Ecklund
AU - K. Fabrizio
AU - T. Foroud
AU - F. S. Goldstein
AU - C. Kamp
AU - K. Kieburtz
AU - D. N. Larson
AU - N. Luthra
AU - N. Pavese
AU - A. Siderowf
AU - C. E. Stanley
AU - C. M. Tanner
AU - T. F. Tropea
AU - T. Willson
AU - S. Chowdhury
AU - K. Marek
AU - T. Simuni
AU - C. S. Coffey
PY - 2026
DA - 2026/11/04
PB - medRxiv
DO - 10.64898/2026.11.04.26367306
UR - https://www.medrxiv.org/content/10.64898/2026.11.04.26367306v1
AB - 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.
ER -