title: Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial.
abstract: BACKGROUND
  IPX066 is an oral, extended-release, capsule formulation of carbidopa-levodopa. We aimed to assess this extended-release formulation versus immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations.
  
  
  METHODS
  We did a phase 3, randomised, double-blind, double-dummy study at 68 academic and clinical centres in North America and Europe. Patients with Parkinson's disease who had at least 2·5 h per day of off-time underwent 3 weeks of open-label immediate-release carbidopa-levodopa dose adjustment followed by 6 weeks of open-label extended-release carbidopa-levodopa dose conversion. These patients were then randomly allocated (1:1), by use of an interactive web-response system, to 13 weeks of double-blind treatment with extended-release or immediate-release carbidopa-levodopa plus matched placebos. The primary efficacy measure was off-time as a percentage of waking hours in all patients randomly allocated to treatment groups, adjusted for baseline value. This study is registered with ClinicalTrials.gov, number NCT00974974.
  
  
  RESULTS
  Between Sept 29, 2009, and Aug 16, 2010, we enrolled 471 participants, of whom 393 (83%) were randomly allocated in the double-blind maintenance period and were included in the main efficacy analyses. As a percentage of waking hours, 201 patients treated double-blind with extended-release carbidopa-levodopa (mean 3·6 doses per day [SD 0·7]) had greater reductions in off-time than did 192 patients treated double-blind with immediate-release carbidopa-levodopa (mean 5·0 doses per day [1·2]). Covariate-adjusted end-of-study means were 23·82% (SD 14·91) for extended-release carbidopa-levodopa and 29·79% (15·81) for immediate-release carbidopa-levodopa (mean difference -5·97, 95% CI -9·05 to -2·89; p<0·0001). Extended-release carbidopa-levodopa reduced daily off-time by, on average, an extra -1·17 h (95% CI -1·69 to -0·66; p<0·0001) compared with immediate-release carbidopa-levodopa. During dose conversion with extended-release carbidopa-levodopa, 23 (5%) of 450 patients withdrew because of adverse events and 13 (3%) withdrew because of a lack of efficacy. In the maintenance period, the most common adverse events were insomnia (seven [3%] of 201 patients allocated extended-release carbidopa-levodopa vs two [1%] of 192 patients allocated immediate-release carbidopa-levodopa), nausea (six [3%] vs three [2%]), and falls (six [3%] vs four [2%]).
  
  
  CONCLUSIONS
  Extended-release carbidopa-levodopa might be a useful treatment for patients with Parkinson's disease who have motor fluctuations, with potential benefits including decreased off-time and reduced levodopa dosing frequency.
  
  
  BACKGROUND
  Impax Laboratories.
authors.affiliation: University of South Florida, Tampa, FL, USA. rhauser@health.usf.edu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hauser
authors.forename: Ann
authors.initials: A
authors.lastname: Hsu
authors.forename: Sherron
authors.initials: S
authors.lastname: Kell
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Espay
authors.forename: Kapil
authors.initials: K
authors.lastname: Sethi
authors.forename: Mark
authors.initials: M
authors.lastname: Stacy
authors.forename: William
authors.initials: W
authors.lastname: Ondo
authors.forename: Martin
authors.initials: M
authors.lastname: O'Connell
authors.forename: Suneel
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000368:Aged; D002230:Carbidopa / Q000008:administration & dosage*; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D019957:Motor Skills Disorders / Q000188:drug therapy* / Q000453:epidemiology*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000453:epidemiology*; D016896:Treatment Outcome
chemical_list: D003692:Delayed-Action Preparations; D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002230:Carbidopa