Objective: Develop a quantitative tool to optimize the definition of entry criteria, enrichment strategies and stratification approaches, and submit for formal regulatory endorsement at FDA (through the Fit-For-Purpose Initiative), and EMA (through Qualification of Novel Methodologies).

Background: The Critical Path for Parkinson’s (CPP) Consortium is based on the value of sharing patient-level data from cohorts and clinical trials in Parkinson’s disease (PD), and transforming those data into generalizable and applicable knowledge for PD therapeutics. Development of a comprehensive PD progression model, intended as a model-based clinical trial enrichment tool for Phase II and III studies is a key goal.

Methods: A non-linear mixed-effects model is being proposed to model disease progression, where the harmonized parts II and III of the Unified Parkinson’s Disease Rating Scale (UPDRS) and MDS-UPDRS will be the primary endpoint. Baseline covariates will include disease severity, disease duration, specific candidate genes (e.g., LRRK2) status, age, gender and DAT imaging if available. The Clinical Data Interchange Standards Consortium (CDISC) standards was used to integrate data from the defined cohorts including Parkinson’s Progression Markers Initiative (PPMI) and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT). Additional data planned for integration include Oxford PD Centre (OPDC) Discovery Cohort; the Cambridgeshire Parkinson’s Incidence from GP to Neurologist cohort (CamPaIGN); Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation – PD (ICICLE-PD) and Tracking Parkinson’s (the Proband study).

Results: Analysis of integrated data from PRECEPT (n=191) and PPMI (n=481) demonstrates that subjects defined as SWEDD (scans without evidence of dopamine deficiency) have a >50% reduction of the rate of motor worsening compared to subjects with DAT deficit. The present work will provide a comprehensive evaluation of the findings in the presence of additional covariates and studies, accounting for potential non-linearity in disease progression.

Conclusions: Developing the quantitative drug development tools for PD through collaborative effort and regulatory review will enable optimized study design for trials targeting early stage PD.

« Back to 2017 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/the-critical-path-for-parkinsons-consortium-understanding-motor-disease-progression-through-quantitative-medicine/