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February 16, 2009

“Disease-modification” trials in Parkinson disease: Target populations, endpoints and study design

February 17, 2009 issue
72 (7_supplement_2) S51-S58


“Neuroprotective” compounds that block dopamine cell death are expected to slow the progression of the neurologic symptoms of Parkinson disease (PD) and therefore “modify” the disease course. However, presently, no fully satisfying efficacy “disease-modification” study design exists, and no drug has yet been approved for that indication. This is inherent to the slow progression of PD with respect to the limited time for patient follow-up and exposure to placebo, the modest effects of investigated drugs, and the confounding effects of symptomatic medications used to treat patients with PD. Disease-modification trials assessing drug efficacy on PD progression are currently prospective, randomized, parallel-group, placebo-controlled, long-term (1–3 year) studies. Untreated patients with early PD represent the main target population because more neurons remain for protection, PD may progress faster, and symptomatic medications are not needed at this stage. “Long lasting” prevention/postponement of disability is a relevant objective for such trials and two main types of outcome and analysis are proposed: slopes analysis of cardinal clinical feature progression (Unified PD Rating Scale, UPDRS) or survival curve analysis of “time to emergence” of clinically relevant milestones (time to dopaminergic therapy, Hoehn and Yahr stage III, etc.). The use of biomarkers remains investigational. Wash-out and delayed-start designs have been proposed to disentangle symptomatic and neuroprotective mechanisms, although this clarification might not be so important practically, as long as the effect on disability is large and long-lasting. To observe clinically relevant changes, several years of follow-up is required, and controlled, randomized, pragmatic trials should be considered when establishing clinical development plans.

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Information & Authors


Published In

Volume 72Number 7_supplement_2February 17, 2009
Pages: S51-S58
PubMed: 19221315

Publication History

Published online: February 16, 2009
Published in print: February 17, 2009


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Affiliations & Disclosures

Olivier Rascol, MD, PhD
From the University Hospital of Toulouse, Clinical Investigation Center, Departments of Neurosciences and Clinical Pharmacology, INSERM UMR 825, Toulouse, France.


Address correspondence and reprint requests to Olivier Rascol, MD, PhD, University Hospital of Toulouse, Clinical Investigation Center, Departments of Neurosciences and Clinical Pharmacology, INSERM UMR 825, Toulouse, France [email protected]

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