Oral Sessions: O4-05: Therapeutics: Clinical Trials III P691

of the pooled HY and AD data evaluated whether the drug action of MK-

8931 on brain biomarker production was altered by disease and explored

the influence of the oligomer and plaque pool in AD on beta-amyloid mono-

mer kinetics.Methods:Mild-to-moderate AD patients (n¼6-8 per arm) re-

ceived 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 pro-

duction 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 var-

ied 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 evi-

dence 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 pro-

duction 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.

O4-05-06 EFFECT OF SAMPLE SIZE RE-ESTIMATION IN

ADAPTIVE CLINICALTRIALS FOR

ALZHEIMER’S DISEASE AND MILD COGNITIVE

IMPAIRMENT

Richard Kennedy1, Guoqiao Wang1, Gary Cutter1, Lon Schneider2,1University of Alabama at Birmingham, Birmingham, Alabama, United

States; 2University of Southern California, Los Angeles, California, United

States. Contact e-mail: rekenned@mail.ad.uab.edu

Background: Clinical trials of drugs to modify disease progression and

longer-term trials in AD have not shown efficacy, which may be due to

smaller observed effects than planned, and consequently inadequate

power. Adaptive trial designs that prospectively allow for modifications

in design after the start of the trial have been proposed as a potential rem-

edy. Planned sample size re-estimation (SSR) can increase the sample size

and improve power based on initial data collected during the course of

a trial. We investigated utility of SSR in AD clinical trials using a series

of simulation studies with an adaptive design reflecting current clinical tri-

als methods and proposed adaptive designs. Methods:We used a metada-

tabase of 18 ADCS studies and ADNI to simulate clinical trial

scenarios similar to current clinical trials. We included 1,418 subjects

with mild AD and 1,192 subjects with MCI. We randomly resampled

the database for initial samples of 50 to 400 for each "drug" and "pla-

cebo" group in 12-, 18-, and 24-month trials with a range of effect

sizes. A single SSR was conducted based on observed 6-month trial

data, with analysis of the augmented sample to determine power to de-

tect a significant treatment effect. A second set of simulations evaluated

a single SSR based on observed 12-month data. Results: SSR based on

6-month data was highly variable. Approximately 25% of trials required

doubling of sample size, regardless of initial sample sizes, while 50% of

trials with initial sample size of 50 subjects per group projected, no in-

crease in sample size was necessary. SSR yielded variable increases in

power, and gains were typically less than 5%. SSR based on 12-month

data showed greater gains in power but were still highly variable, ranging

from 0% to 44%, with no clear increase in power with larger initial sample

sizes. Conclusions: Variability in individual outcomes in AD trials may

limit the utility of adaptive trials designs using SSR, and particularly for

smaller trials and trials using SSR based on 6- and 12-month data. Further

work on SSR in longitudinal trial design is needed to effectively imple-

ment this strategy in AD clinical trials.