title: Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Boehringer Ingelheim GmbH.
authors.affiliation: Department of Clinical Neurosciences, University College London Institute of Neurology, London, UK. a.schapira@ucl.ac.uk
authors.forename: Anthony H V
authors.initials: AH
authors.lastname: Schapira
authors.forename: Michael P
authors.initials: MP
authors.lastname: McDermott
authors.forename: Paolo
authors.initials: P
authors.lastname: Barone
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Comella
authors.forename: Stefan
authors.initials: S
authors.lastname: Albrecht
authors.forename: Helen H
authors.initials: HH
authors.lastname: Hsu
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Massey
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.forename: Olivier
authors.initials: O
authors.lastname: Rascol
authors.forename: Kenneth
authors.initials: K
authors.lastname: Marek
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D052160:Benzothiazoles / Q000627:therapeutic use*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000523:psychology; D000077487:Pramipexole; D011788:Quality of Life; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D000978:Antiparkinson Agents; D052160:Benzothiazoles; D000077487:Pramipexole