Effect of sample size re-estimation in adaptive clinical trials for Alzheimer's disease and mild...
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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 HY and AD. Results: Data from all 3 biomarkers in HY and 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 CLINICAL TRIALS FOR ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT Richard Kennedy 1 , Guoqiao Wang 1 , Gary Cutter 1 , Lon Schneider 2 , 1 University of Alabama at Birmingham, Birmingham, Alabama, United States; 2 University of Southern California, Los Angeles, California, United States. Contact e-mail: [email protected] 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. Oral Sessions: O4-05: Therapeutics: Clinical Trials III P691
Transcript of Effect of sample size re-estimation in adaptive clinical trials for Alzheimer's disease and mild...
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: [email protected]
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.
