Terence Fullerton

Disease progression meta-analysis model in Alzheimer's disease

Various authors have evaluated disease progression in Alzheimers disease (AD), using patient data from individual clinical studies or pooled data across various trials. We conducted a systematic review of public data sources from 1990 to 2008 for all available AChE inhibitor studies, as well as clinical studies that evaluated the rate of deterioration in AD patients. Unique to this analysis, we developed a model based on literature data to describe the longitudinal response in the Alzheimers Disease Assessment Scale‐Cognitive (ADAS‐cog) (change from baseline) in mild to moderate severity AD patients. The model was used to estimate disease progression for both placebo‐treated patients and acetylcholinesterase (AChE)‐inhibitor treated patients, and factors that affected disease progression.

Disease progression model for cognitive deterioration from Alzheimer's Disease Neuroimaging Initiative database

A mathematical model was developed to describe the longitudinal response in Alzheimers Disease Assessment Scale‐cognitive (ADAS‐cog) obtained from the Alzheimers Disease Neuroimaging Initiative.

Pharmacokinetics, Safety, and Tolerability After Single and Multiple Oral Doses of Varenicline in Elderly Smokers

Varenicline is a novel selective α4β2 nicotinic acetylcholine partial agonist developed for smoking cessation. This study investigated the single‐ and multiple‐dose pharmacokinetics, safety, and tolerability of varenicline in elderly (≥ 65 years) smokers. Twenty‐four elderly smokers with normal renal function for their age (estimated creatinine clearance ≥ 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.

Pharmacokinetics, Safety, and Tolerability Following Multiple Oral Doses of Varenicline Under Various Titration Schedules in Elderly Nonsmokers

This study was designed to investigate the multiple‐dose pharmacokinetics, safety, and tolerability of the selective α4β2 nicotinic acetylcholine partial agonist, varenicline, in elderly (65–85 years old) nonsmokers. Fifty male and female subjects with normal renal function for their age were randomized to receive varenicline or placebo once or twice daily for 3 weeks in an investigator‐ and subject‐blinded parallel‐group design. Treatment regimens included weekly titration (n = 14; days 1–7, 0.5 mg once daily; days 8–14, 0.5 mg twice daily; days 15–21, 1 mg twice daily); 2‐week twice‐daily titration (n = 13; days 1–14, 0.5 mg once daily; days 15–21, 0.5 mg twice daily); 2‐week once‐daily titration (n = 13; days 1–14, 0.5 mg once daily; days 15–21, 1 mg once daily); and placebo (n = 10). Approximate dose‐proportional increases in systemic exposure of varenicline at steady state, based on maximum concentration and area under the plasma concentration‐time curve over the 24‐hour period at steady state, were observed across the dose range of 0.5 to 2 mg/d. Median time to maximum concentration was 3 hours. Mean elimination half‐life was estimated to be approximately 24 to 32 hours and independent of dose. Varenicline was considered to be safe and well tolerated in this elderly nonsmoking population.

A disease progression meta-analysis model for cognitive deterioration in patients with Alzheimer's disease

Background: Previously, efforts have been made by various authors to evaluate disease progression in Alzheimer’s disease (AD), utilizing patient data from individual clinical studies or pooled patient data across studies. In this analysis, we conducted a systematic review of public data sources from 1990 to 2008 of all available studies of acetylcholinesterase (AChE) inhibitors, as well as clinical studies evaluating the rate of deterioration in AD patients (e.g. Vitamin E study). The unique aspect of this analysis is that we have developed a model to describe the longitudinal response in ADAS-cog (change from baseline) in patients with mild-to-moderate AD and estimate disease progression in both placebo-treated and AChE inhibitor-treated patients. Methods: A total of 52 trials, with data from 19,972 patients and 84,441 individual observations, were identified. From these, we obtained 576 mean change in ADAS-cog scores from baseline values, spanning 12 weeks to 3 years of treatment. The model described the rate of disease progression, the placebo effect observed, and the symptomatic effect of AChE inhibitors. Baseline ADAS-cog, MMSE, age and publication year were tested as covariates. Results: Disease progression in patients with mild-to-moderate AD across all available and relevant literature sources was estimated as 5.5 points per year (95% CI: 4.96.1) with baseline ADAS-cog of 25. An Emax-over time model best described the symptomatic drug effect for AChE inhibitors. Baseline ADAS-cog was a significant covariate on disease progression in that greater baseline impairment was associated with faster cognitive decline. The model was not able to describe any effect of baseline age, likely due to the narrow distribution of mean age (literature-level analysis). There was no significant impact of publication year in the model. Conclusions: Baseline ADAS-cog was a significant covariate on disease progression, and describes, or at least explains, the different rates of deterioration observed in mild versus moderate stages of AD. There was no significant impact of publication year in the model, suggesting a slower rate of disease progression has not been observed in more recent trials. Differences from various previous analyses may be due to differences in underlying disease severity in the datasets used.

A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer’s disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil

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.