title: TCH346 as a neuroprotective drug in Parkinson's disease: a double-blind, randomised, controlled trial.
abstract: BACKGROUND
  There is an important unmet medical need in Parkinson's disease for a neuroprotective treatment that slows or stops disease progression. TCH346 is a potent anti-apoptotic drug that protects against loss of dopaminergic neurons in laboratory models. Our aim was to assess TCH346 as a neuroprotective drug in patients with Parkinson's disease.
  
  
  METHODS
  Patients presenting at 45 international movement disorder clinics with early untreated Parkinson's disease were assessed as part of this parallel-group, double-blind, randomised controlled trial. 301 eligible patients were randomly assigned 12-18 months' treatment with TCH346 at a daily dose of 0.5 mg (n=78), 2.5 mg (n=79), or 10 mg (n=73), or placebo (n=71), followed by a 4 week washout period. The primary outcome measure was time to development of a disability requiring dopaminergic treatment. Secondary outcome measures were the annual rate of change in the unified Parkinson's disease rating scale (UPDRS) and the PDQ-39, a measure of quality of life. Analyses were by intention-to-treat. This study is pending registration with .
  
  
  RESULTS
  255 patients completed the study. TCH346 did not differ from placebo for any of the study outcomes. Treatment was needed in 26 (34%) patients in the TCH346 0.5 mg group, 30 (38%) in the TCH346 2.5 mg group, 24 (33%) in the TCH346 10 mg group, and 23 (32%) in the placebo group. There were no significant differences between groups. There were no differences between groups in the annual change in the UPDRS or PDQ-39 either. Few patients withdrew because of adverse events and none was judged to be related to the study intervention.
  
  
  CONCLUSIONS
  TCH346 did not show evidence of a neuroprotective effect. The discrepancy between the preclinical promise of TCH346 and the clinical outcome could have arisen because of the use of laboratory models that do not accurately reflect the pathogenesis of Parkinson's disease, the doses of study drug used, insensitive clinical endpoints, and the patient population selected for study.
authors.affiliation: Department of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA. warren.olanow@mssm.edu
authors.forename: C Warren
authors.initials: CW
authors.lastname: Olanow
authors.forename: Anthony H V
authors.initials: AH
authors.lastname: Schapira
authors.forename: Peter A
authors.initials: PA
authors.lastname: LeWitt
authors.forename: Karl
authors.initials: K
authors.lastname: Kieburtz
authors.forename: Dirk
authors.initials: D
authors.lastname: Sauer
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Olivieri
authors.forename: Harald
authors.initials: H
authors.lastname: Pohlmann
authors.forename: Jean
authors.initials: J
authors.lastname: Hubble
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010082:Oxepins / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy*; D011788:Quality of Life; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D010082:Oxepins; C111178:dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine