Abstract
ObjectiveBromocriptine mesylate (BRC), a dopamine D2 receptor agonist has been shown to confer neuroprotection, sustained motor function and slowed disease progression in mouse models of amyotrophic lateral sclerosis (ALS) Here we report a first in human trial in ALS.DesignA multicenter, Riluzole add-on, randomized, double-blind, placebo controlled 102-week extension BRC clinical trial.MethodsThe trial was conducted between January 2009 and March 2012 on 36 Japanese ALS patients. A 12-week treatment with Riluzole observational period was followed by combined treatment (Riluzole + BRC; n = 29 or Riluzole + placebo; n = 7). The dosing commenced at 1.25 mg/day increasing in steps at two weeks intervals to a maximum of 15 mg/day. The efficacy of BRC was evaluated by comparing BRC and placebo groups upon completion of stepwise dosing at 14 weeks 2 points (1st endpoint) and upon completion or discontinuation of the study (2nd endpoint) of the dosing.ResultsStatistics analyses revealed a marginal BRC treatment efficacy with P≦20%to placebo by 1st and 2nd endpoint analysis. In the 1st endpoint analysis, BRC group was significantly effective on the scores of ALSAQ40-communicaton (P = 1.2%), eating and drinking (P = 2.2%), ALSFRS-R total (P = 17.6%), grip strength (P = 19.8%) compared to the placebo group. In the 2nd endpoint analysis, differences between the scores of Limb Norris Scale (P = 18.3%), ALSAQ40-communication (P = 11.9%), eating and drinking (P = 13.6%), and neck forward-bent test (P = 15.4%) of BRC group were detected between the two groups. There was no significant difference between the treatment groups for adverse events or serious drug reactions incidence.ConclusionsBRC sustains motoneuronal function at least in part through BRC treatment. Further analysis involving a Phase 2b or 3 clinical trial is required but BRC currently shows promise for ALS treatment.Trial RegistrationUMIN Clinical Trials UMIN000008527
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that preferentially targets motor neurons controlling muscle movement and is usually fatal
The efficacy of bromocriptine methylate (BRC) was evaluated by comparing BRC and placebo groups upon completion of stepwise dosing at 14 weeks 2 points (1st endpoint) and upon completion or discontinuation of the study (2nd endpoint) of the dosing
In the 2nd endpoint analysis, differences between the scores of Limb Norris Scale (P = 18.3%), ALSAQ40-communication (P = 11.9%), eating and drinking (P = 13.6%), and neck forward-bent test (P = 15.4%) of BRC group were detected between the two groups
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that preferentially targets motor neurons controlling muscle movement and is usually fatal. NAIP is a founding member of anti-apoptosis IAP family [10] and selectively suppresses oxidative stress-induced cell death. Both upregulation and exogenous over expression of NAIP protects neuronal cells against oxidative stress in vivo and in vitro [11,12,13]. Using this system, we have identified several compounds that transiently upregulate NAIP, including bromocriptine methylate (BRC) [9,13]. BRC confered protection against oxidative stress-induced cell death [14,15]. The present study is designed to evaluate both the efficacy of BRC in the presence of Riluzole on motor function and quality of life (QOL) as well as safety in Japanese patients with solitary ALS
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