Modeling of Parkinson’s Disease Progression and Implications for Detection of Disease Modification in Treatment Trials

Author:

Ribba Benjamin1,Simuni Tanya2,Marek Kenneth3,Siderowf Andrew4,Diack Cheikh1,Pierrillas Philippe Bernard1,Monnet Annabelle5,Ricci Benedicte1,Nikolcheva Tania5,Pagano Gennaro16

Affiliation:

1. Roche Pharma Research and Early Development (pRED), Roche Innovation Center, F. Hoffmann-La Roche Ltd., Basel, Switzerland

2. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

3. Institute for Neurodegenerative Disorders, New Haven, CT, USA

4. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

5. Roche Product Development, F. Hoffmann La Roche Ltd., Basel, Switzerland

6. University of Exeter Medical School, London, UK

Abstract

Background: Objectively measuring Parkinson’s disease (PD) signs and symptoms over time is critical for the successful development of treatments aimed at halting the disease progression of people with PD. Objective: To create a clinical trial simulation tool that characterizes the natural history of PD progression and enables a data-driven design of randomized controlled studies testing potential disease-modifying treatments (DMT) in early-stage PD. Methods: Data from the Parkinson’s Progression Markers Initiative (PPMI) were analyzed with nonlinear mixed-effect modeling techniques to characterize the progression of MDS-UPDRS part I (non-motor aspects of experiences of daily living), part II (motor aspects of experiences of daily living), and part III (motor signs). A clinical trial simulation tool was built from these disease models and used to predict probability of success as a function of trial design. Results: MDS-UPDRS part III progresses approximately 3 times faster than MDS-UPDRS part II and I, with an increase of 3 versus 1 points/year. Higher amounts of symptomatic therapy is associated with slower progression of MDS-UPDRS part II and III. The modeling framework predicts that a DMT effect on MDS-UPDRS part III could precede effect on part II by approximately 2 to 3 years. Conclusions: Our clinical trial simulation tool predicted that in a two-year randomized controlled trial, MDS-UPDRS part III could be used to evaluate a potential novel DMT, while part II would require longer trials of a minimum duration of 3 to 5 years underscoring the need for innovative trial design approaches including novel patient-centric measures.

Publisher

IOS Press

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