title: Opicapone as Adjunct to Levodopa Therapy in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial.
abstract: OBJECTIVE
  Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects.
  
  
  OBJECTIVE
  To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations.
  
  
  METHODS
  This phase 3 international, multicenter outpatient study evaluated a 25- and a 50-mg/d dosage of opicapone in a randomized, double-blind, 14- to 15-week, placebo-controlled clinical trial, followed by a 1-year open-label phase during which all patients received active treatment with opicapone. Patients with PD who experienced signs of end-of-dose deterioration and had a mean total awake off-time (state of akinesia or decreased mobility) of at least 1.5 hours, not including morning akinesia, were enrolled. Data were collected from March 18, 2011, through June 25, 2013. Data from the evaluable population were analyzed from July 31, 2013, to July 31, 2014.
  
  
  METHODS
  The primary efficacy outcome of the double-blind phase was the change from baseline in absolute off-time vs placebo based on patient diaries. The open-label phase focused on maintenance of treatment effect in off-time.
  
  
  RESULTS
  A total of 427 patients (258 men [60.4%] and 169 women [39.6%]; mean [SD] age, 63.1 [8.8] years) were randomized to a 25-mg/d (n = 129) or a 50-mg/d (n = 154) dosage of opicapone or to placebo (n = 144). Of these, 376 patients completed the double-blind phase and entered the open-label phase, of whom 286 completed 1 year of open-label treatment. At the end of the double-blind phase, the least squares mean change (SE) in off-time was -64.5 (14.4) minutes for the placebo group, -101.7 (14.9) minutes for the 25-mg/d opicapone group, and -118.8 (13.8) minutes for the 50-mg/d opicapone group. The adjusted treatment difference vs placebo was significant for the 50-mg/d opicapone group (treatment effect, -54.3 [95% CI, -96.2 to -12.4] minutes; P = .008), but not for the 25-mg/d opicapone group (treatment effect, -37.2 [95% CI, -80.8 to 6.4] minutes; P = .11). The off-time reduction was sustained throughout the open-label phase (-126.3 minutes at 1-year open-label end point). The most common adverse events in the opicapone vs placebo groups were dyskinesia, constipation, and dry mouth. Fifty-one patients (11.9%) discontinued from the study during the double-blind phase.
  
  
  CONCLUSIONS
  Treatment with a 50-mg once-daily dose of opicapone was associated with a significant reduction in mean daily off-time in levodopa-treated patients with PD and motor fluctuations, and this effect is maintained for at least 1 year. Opicapone was safe and well tolerated.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01227655.
authors.affiliation: Reta Lila Weston Institute, University College London, London, England.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lees
authors.affiliation: Centro de Estudos Egas Moniz, Hospital de Santa Maria, Lisbon, Portugal.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Ferreira
authors.affiliation: Department of Clinical Pharmacology, Institut National de la Santé et de la Recherche Medicale (INSERM) and University Hospital of Toulouse, Toulouse, France4Department of Neurosciences, INSERM and University Hospital of Toulouse, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rascol
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.affiliation: Department of Research and Development, BIAL-Portela & Ca SA, Sao Mamede do Coronado, Portugal.
authors.forename: José-Francisco
authors.initials: JF
authors.lastname: Rocha
authors.affiliation: Quintiles, Dublin, Ireland.
authors.forename: Michelle
authors.initials: M
authors.lastname: McCrory
authors.affiliation: Department of Research and Development, BIAL-Portela & Ca SA, Sao Mamede do Coronado, Portugal8Department of Pharmacology and Therapeutics, University Porto, Porto, Portugal.
authors.forename: Patricio
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007391:International Cooperation; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects*; D010069:Oxadiazoles / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology; D012720:Severity of Illness Index
chemical_list: D000978:Antiparkinson Agents; D010069:Oxadiazoles; D007980:Levodopa; C549349:opicapone