Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial

Anthony H V Schapira, Michael P McDermott, Paolo Barone, Cynthia L Comella, Stefan Albrecht, Helen H Hsu, Daniel H Massey, Yoshikuni Mizuno, Werner Poewe, Olivier Rascol, Kenneth Marek, Anthony H V Schapira, Michael P McDermott, Paolo Barone, Cynthia L Comella, Stefan Albrecht, Helen H Hsu, Daniel H Massey, Yoshikuni Mizuno, Werner Poewe, Olivier Rascol, Kenneth Marek

Abstract

Background: In models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson's disease (PD).

Methods: Between May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30-79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1·5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson's disease rating scale (UPDRS). This trial is registered with ClinicalTrials.gov, number NCT00321854.

Findings: Of 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (-0·4 points, 95% CI -2·2 to 1·4, p=0·65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal (123)I-FP-CIT binding was -15·1% (SE 2·1) for early and -14·6% (2·0) for delayed pramipexole (difference -0·5 percentage points, 95% CI -5·4 to 4·4, p=0·84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole group and 17 (8%) in the delayed pramipexole group had serious events, two of which (hallucinations and orthostatic hypotension) were deemed related to study drug.

Interpretation: By clinical and neuroimaging measures, pramipexole showed little evidence differentiating 15-month usage from usage delayed for 6-9 months. The results do not support the hypothesis that pramipexole has disease-modifying effects.

Funding: Boehringer Ingelheim GmbH.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile PD=Parkinson's disease.
Figure 2
Figure 2
15-month time course of UPDRS total score (study investigators' ratings; period 2 full-analysis set) UPDRS total score was the sum of parts I. II, and III; means were adjusted for country and baseline. 95% CIs are shown at every timepoint. UPDRS=unified Parkinson's disease rating scale. *n=210 at all timepoints, one patient was excluded because of missing baseline data. †n=200 at all timepoints with the exception of month 3 (n=198).

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