{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Berry Consultants, LLC, Austin, Texas 78746, United States"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 27,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "B. Wendelberger"
    },
    {
      "name": "C. Allen-Savietta"
    },
    {
      "name": "A. Crawford"
    },
    {
      "name": "M. C. Brumm"
    },
    {
      "name": "S. H. Choi"
    },
    {
      "name": "C. M. Kopil"
    },
    {
      "name": "R. B. Schneider"
    },
    {
      "name": "M. M. Kuhl"
    },
    {
      "name": "D.-E. Lafontant"
    },
    {
      "name": "D. Ecklund"
    },
    {
      "name": "K. Fabrizio"
    },
    {
      "name": "T. Foroud"
    },
    {
      "name": "F. S. Goldstein"
    },
    {
      "name": "C. Kamp"
    },
    {
      "name": "K. Kieburtz"
    },
    {
      "name": "D. N. Larson"
    },
    {
      "name": "N. Luthra"
    },
    {
      "name": "N. Pavese"
    },
    {
      "name": "A. Siderowf"
    },
    {
      "name": "C. E. Stanley"
    },
    {
      "name": "C. M. Tanner"
    },
    {
      "name": "T. F. Tropea"
    },
    {
      "name": "T. Willson"
    },
    {
      "name": "S. Chowdhury"
    },
    {
      "name": "K. Marek"
    },
    {
      "name": "T. Simuni"
    },
    {
      "name": "C. S. Coffey"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7pnh01h11kmhb.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.04.26367306",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.11.04.26367306v1.full",
  "id": "7pnh01h11kmhb",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.11.04.26367306v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "neurology"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.11.04.26367306v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7pnh01h11kmhb.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T00:20:58Z",
      "native_id": "10.64898/2026.11.04.26367306",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.11.04.26367306v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:neurology",
      "subfield": "neurology"
    }
  ],
  "title": "Statistical design of Path to Prevention platform trial in early neuronal alpha-synuclein disease",
  "title_text": "Statistical design of Path to Prevention platform trial in early neuronal alpha-synuclein disease",
  "type": "preprint",
  "updated_at": "2026-11-08T00:20:58Z",
  "url": "https://research.draconitic.com/paper/7pnh01h11kmhb",
  "venue": "medRxiv",
  "versions": []
}