title: Randomized clinical trial of fipamezole for dyskinesia in Parkinson disease (FJORD study).
abstract: OBJECTIVE
  Fipamezole, a selective α2-adrenergic receptor antagonist, reduced levodopa-induced dyskinesias (LID) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. In 10 dyskinetic subjects with Parkinson disease (PD), a proof-of-concept study showed beneficial effects at single doses of 60 and 90 mg. The primary study objective was to assess suppression of LID by fipamezole at day 28, as measured by the levodopa-induced dyskinesia scale (LIDS), a modification of the abnormal involuntary movement scale.
  
  
  METHODS
  This was a double-blind, randomized, placebo-controlled, dose-escalating 28-day study in levodopa-treated patients with PD experiencing LID, conducted at 25 centers in the United States (115 subjects) and 7 centers in India (64 subjects). Dyskinesias were evaluated 3 times after subjects became "on" from levodopa. Outcome assessment was performed with analysis of variance, which evaluated fipamezole dose-effects in a hierarchical stepwise manner and the Jonckheere test for dose responsiveness.
  
  
  RESULTS
  The total study population showed no statistically significant primary endpoint difference. However, because of inhomogeneity recognized between U.S. and Indian study populations, a prespecified subgroup analysis of U.S. subjects was conducted, showing fipamezole at 90 mg reduced LID (mean, 95% CI, LID rating improvement vs placebo -1.9 [0.0 to -3.8; p = 0.047]). Dose responsiveness was demonstrated (p = 0.014 for placebo, 30, 60, and 90 mg fipamezole). Fipamezole induced mild, transient blood pressure elevation and was associated with an acceptable profile of adverse effects.
  
  
  CONCLUSIONS
  The evidence of efficacy in the US subgroup suggested that fipamezole at 90 mg TID may be useful to treat LID in PD without exacerbating parkinsonism.
  
  
  METHODS
  This study provides Class III evidence that fipamezole is well-tolerated and, in the US subpopulation, lessens LID at 90 mg TID.
authors: Departments of Neurology, Henry Ford Hospital, Detroit, MI, USA. plewitt1@hfhs.org
authors: Peter A
authors: PA
authors: Lewitt
authors: Robert A
authors: RA
authors: Hauser
authors: Mei
authors: M
authors: Lu
authors: Anthony P
authors: AP
authors: Nicholas
authors: William
authors: W
authors: Weiner
authors: Nicholas
authors: N
authors: Coppard
authors: Mika
authors: M
authors: Leinonen
authors: Juha-Matti
authors: JM
authors: Savola
mesh_terms: D000368:Aged; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D007189:Indans / Q000008:administration & dosage*; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy*; D010919:Placebos; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D007093:Imidazoles; D007189:Indans; D010919:Placebos; D007980:Levodopa; C480818:fipamezole