Phase III CONCERT Trial of Latrepirdine
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TRIAL REPORT
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Phase III CONCERT Trial of Latrepirdine Negative Results Mel Sweetlove Adis, Auckland, New Zealand
Abstract
CONCERT: a Phase III multicentre randomized, placebo-controlled, double-blind 12-month safety and efficacy study evaluating dimebon in patients with mild-to-moderate Alzheimer’s disease on donepezil. This trial investigated the efficacy and tolerability of adjunctive therapy with latrepirdine at 15 or 60 mg/day in patients with mild-to-moderate Alzheimer’s disease receiving stable treatment with donepezil. The coprimary outcomes were Alzheimer’s Disease Assessment Scale-cognitive subscale or Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory scores. Trial results showed that latrepirdine failed to improve either of the primary endpoints compared with placebo, leading to discontinuation of latrepirdine development for all indications.
Discussion The CONCERT trial, investigating the efficacy of latrepirdine (Dimebon) 15 or 60 mg/day as add-on therapy to donepezil in patients with Alzheimer’s disease, reported negative results in January 2012, leading to discontinuation of development of latrepirdine for all indications. The analysis showed no effect of latrepirdine on the co-primary endpoints of the Alzheimer’s Disease Assessment Scale-cognitive subscale or the Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory scores at 12 months compared with placebo,[1] a result that echoed those of a previously reported phase III trial of latrepirdine as monotherapy in patients with mild-to-moderate Alzheimer’s disease (the CONNECTION trial).[2] Results of the CONCERT trial were reported briefly in a media release, with full results expected to be presented at an upcoming scientific conference. Latrepirdine was previously approved in Russia as a nonselective antihistamine for the treatment of allergic conditions and was removed from the market for commercial reasons when selective antihistamines became available.[3] Subsequently, additional mechanisms of action were identified for latrepirdine, including weak inhibition of butyrylcholinesterase, acetylcholinesterease and N-methyl-D-aspartate (NMDA) receptor signalling, and inhibition of mitochondrial permeability transition pore opening. Based on these modes of action, latrepirdine was studied in preclinical models of Alzheimer’s disease, demonstrating consistent neuroprotective effects.[3-5]
The mechanism behind lartepirdine’s neuroprotective effect is not entirely clear. However, studies in rat models have shown that it is unlikely to be related to inhibition of cholinesterase or Trial summarya Study details Status
Completed
Outcome
Negative – primary endpoint not met
Study dates
Initiation date:
1 Mar 2009 (planned), 1 Mar 2009 (actual)
End date:
1 Dec 2011 (planned), 17 Jan 2012 (actual)
Design:
Double-blind, multicentre, parallel, prospective, randomized
Control:
Drug dosage comparison, placebo comparison
Phase:
III
Location:
Aust
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