A disease progression model adequately described the natural decline of ADAS-cog observed in Alzheimer's Disease Neuroimaging Initiative. Baseline severity is an important covariate to predict a curvilinear rate of disease progression in normal elderly, mild cognitive impairment, and AD patients. Age, APOE ɛ4 genotype, and gender also influence the rate of disease progression.

Baseline ADAS-cog is a significant covariate affecting the rate of disease progression, and it describes or at least explains the different rates of deterioration evident in early or late stages of the disease. There was no significant impact of publication year in the model, suggesting that disease progression has not slowed in more recent trials.

Varenicline is a novel selective alpha4beta2 nicotinic acetylcholine partial agonist developed for smoking cessation. This study investigated the single- and multiple-dose pharmacokinetics, safety, and tolerability of varenicline in elderly (> or = 65 years) smokers. Twenty-four elderly smokers with normal renal function for their age (estimated creatinine clearance > or = 70 mL/min) received varenicline 1 mg once daily (n = 8) or placebo (n = 4) for 7 days, or 1 mg twice daily (n = 8) or placebo (n = 4) for 6 days with a single dose on day 7 in a double-blind, parallel group and placebo-controlled design. There was no evidence of concentration- or time-dependent changes in varenicline pharmacokinetics upon repeat dosing. Once- and twice-daily dosing was associated with an approximate 2-fold and 3-fold increase, respectively, in systemic exposure to varenicline. Varenicline was well tolerated; all adverse events reported were mild to moderate in intensity. Thus, no dose adjustment is necessary based on age alone.

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.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0368-9) contains supplementary material, which is available to authorized users.

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