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O4–05–06: Effect of sample size re‐estimation in adaptive clinical trials for Alzheimer's disease and mild cognitive impairment
Author(s) -
Kennedy Richard,
Wang Guoqiao,
Cutter Gary,
Schneider Lon
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.04.363
Subject(s) - sample size determination , clinical trial , placebo , medicine , clinical study design , statistics , mathematics , pathology , alternative medicine
of the pooled HY and AD data evaluated whether the drug action of MK8931 on brain biomarker production was altered by disease and explored the influence of the oligomer and plaque pool in AD on beta-amyloid monomer kinetics.Methods:Mild-to-moderate AD patients (n1⁄46-8 per arm) received 7 daily doses of placebo, 12, 40 or 60 mg MK-8931 with serial CSF sampling to determine drug, Ab40, Ab42, and sAPPb concentrations. Data were analyzed by fitting simultaneously to the timecourses of 3 biomarkers using a mechanistic amyloid pathway model including terms for amyloid brain production and distribution to lumbar CSF. Drug effect on brain production was tested for altered maximal response (Emax) and in vivo potency (IC 50) between HYand AD.Results:Data from all 3 biomarkers in HYand AD were well represented by a model with separate Emax values for each biomarker / population, but joint IC 50 value across all biomarkers that varied slightly by population. The ratio (AD/HY) of median IC 50 (90% CI) was 1.17 (0.91, 1.56) indicating little alteration in potency in AD vs HY. Emax was reduced in AD vs HY (A b 40 0.96 a 0.93; A b 42 0.96 a 0.90; sAPP b 0.98 a 0.96). These Emax alterations suggest that a portion of CSF amyloid is not derived from de novo production, but rather comes from other sources such as the oligomer / plaque pool. This indirect evidence of reversibility of higher order amyloid forms to monomer suggests that BACE inhibition may act to reduce these pools as well as monomer. Conclusions: MK-8931 has consistent drug effects on brain amyloid production in AD and HY, supporting use of HY studies for dosing guidance. MK-8931 is predicted to reduce median CSF Ab40 by 67.4%, 83.8%, and 86.8% at steady-state 12, 40, and 60 mg daily in AD. These potent inhibition effects provide a unique opportunity to test the amyloid hypothesis. Ref 1: Forman et al. 2012 AAIC abstract.