Abstract
BackgroundSymptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg.MethodsThis was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10–24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data.ResultsAt the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment).ConclusionsSAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT6 receptor antagonists.Trial registrationClinicaltrials.gov, NCT01712074. Registered 19 October 2012.
Highlights
Symptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials
The trial was terminated after the interim analysis was conducted when 163 subjects had completed the week 12 posttreatment visit; the analysis revealed the criteria for futility had been met
The Bayesian predictive probability for success on the ADAS-cog13 endpoint at study end was shown to be less than 1%, meaning that even if the trial had been continued to completion (n = 342) there was essentially no chance to demonstrate a benefit of SAM-760 over placebo on the primary endpoint
Summary
Symptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials. The discrepant results between trials of 5-HT6 antagonist monotherapy and those assessing utility as an add-on therapy have been postulated to be due to the potentially synergistic mechanisms of potentiating acetylcholine release through 5-HT6 blockade while promoting synaptic neurotransmitter durability via cholinesterase inhibition [12]. Despite these inconsistent findings, the available data suggest that 5-HT6 antagonists may represent a viable additive treatment strategy to address symptoms of AD
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