Effect of circadian rhythm on cognition testing in a Phase 2b mild/moderate Alzheimer's disease (AD) study (CTAD 2015) - Nov 5, 2015 - Abstract #P1-41; P2b, N=409; NCT01073228; Sponsor: FORUM Pharmaceuticals Inc; "The 1.8 mg/d Encenicline group [n=100 vs n=104 placebo] showed the largest treatment effect on the ADAS-Cog-13 [cohen’s d ES at 6 months vs placebo of d=0.39, p=0.019 after multiplicity correction]....Patients in the 1.8 mg Encenicline treatment group whose ADAS-Cog-13 at 6 months was administrated at the same time of day (+ one hour) (n= 46, 1.8 mg Encenicline, n=40, placebo) at 6 months as compared to baseline had a treatment effect of d=0.5, p=0.039 vs those who did not: d=0.16, p=0.708 (n=37, 1.8 mg Encenicline, n=48, placebo)."
P2b data • Alzheimer's Disease
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8th Clinical Trials Conference on Alzheimer's Disease, 5-7 Nov 2015, Barcelona, Spain.
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Background: Cognition is affected by a variety of factors including circadian fluctuations over the course of the day. Most people have optimal cognition early in the day with variation, typically a decrease in cognition, as the day and evening progress. Additionally, patients with AD may have sleep disturbances or other alterations of their circadian rhythms. These factors may contribute to variation and challenges for signal detection in assessing cognition in patients with AD. Methods: We examined the impact of time-of-day cognition testing in a large (n=409) multinational (US and Eastern Europe) placebo-controlled Phase 2b mild/moderate 6-month AD study. The primary cognition measure in the study was the ADAS-Cog-13. Overall, 409 patients with mild/moderate AD (MMSE 14-24 and CDR-SB >2) were enrolled and treated with placebo or Encenicline 0.27, 0.9, or 1.8 mg/day. Results: The 1.8 mg/d Encenicline group [n=100 vs n=104 placebo] showed the largest treatment effect on the ADAS-Cog-13 [cohen’s d ES at 6 months vs placebo of d=0.39, p=0.019 after multiplicity correction]. In order to assess the effect of variation in time-of-day cognition testing performance, patients who completed the 24 week study were analyzed according to the consistency of time-of-day ADAS-Cog-13 cognition testing. Patients in the 1.8 mg Encenicline treatment group whose ADAS-Cog-13 at 6 months was administrated at the same time of day (+ one hour) (n= 46, 1.8 mg Encenicline, n=40, placebo) at 6 months as compared to baseline had a treatment effect of d=0.5, p=0.039 vs those who did not: d=0.16, p=0.708 (n=37, 1.8 mg Encenicline, n=48, placebo). Conclusion: These results suggest that circadian rhythm effects on the assessment of cognition are a significant source of variability in interventional mild/moderate AD clinical trials. Taking this factor into consideration by assuring that cognition testing occurs in each specific patient at the same time of day (+ one hour) may decrease variability, enhance the ability to detect a procognitive signal, and more accurately measure the procognitive effects of a drug.
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