Over 200 publications, including the composite endpoints regulators now recognize. We publish our methodology in the open so reviewers meet it before your submission does.
Alzheimer's Association International Conference (AAIC) · 2024:Poster Tue-17 · Hendrix, Dickson et al.
Companies recently identified clinical study sites engaging in fraudulent practices, reducing success in Alzheimer's disease (AD) clinical trials. Successful trials are reliable…
When the sample size a conventional design demands is larger than the trial you can run, a Global Statistical Test lets the clinical-endpoint hypotheses be tested anyway. The paper sets out when GST applies, how it is pre-specified, and how it has been received in review.
5 publications
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2016 · J Prev Alzheimers Dis
Brown, Bruce · Hendrix, Suzanne
Background: Tramiprosate is an oral amyloid anti-aggregation agent that reduces amyloid oligomer toxicity in preclinical studies and was evaluated in two 78-week trials in North America and Western Europe that enrolled 2,025 patients with Mild to Moderate Alzheimer's Disease. The completed North American study did not achieve its efficacy objectives, but a pre-specified subgroup analysis suggested potential efficacy in apolipoprotein E4 (APOE4) carriers. To further explore this observation, we analyzed tramiprosate Phase 3 clinical data based on the number of APOE4 alleles. Objectives: To analyze tramiprosate efficacy, safety, and occurrence of vasogenic edema in the three APOE4 subgroups: homozygous, heterozygous and non-carriers. Design: Randomized, double-blind, placebo-controlled parallel-arm multi-center studies. Setting: Academic Alzheimer's disease and dementia centers, community-based dementia and memory clinics, and neuropsychiatric clinical research sites. Participants: Subjects included 2,025 patients, 50 years of age or older, with approximately 60% having APOE4 carrier status (10-15% homozygotes and 45-50% heterozygotes), and mild to moderate disease. All subjects were on stable symptomatic drugs. Intervention: Randomized subjects received placebo, 100 mg BID, or 150 mg BID of tramiprosate. Measurements: Co-primary outcomes in both studies were change from baseline in the ADAS-cog11 and CDR-SB assessment scales. Results: Highest efficacy was observed in APOE4/4 homozygotes receiving 150 mg BID of tramiprosate, showing statistically significant effects on ADAS-cog and positive trends on CDR-SB (respectively, 40-66% and 25-45% benefit compared to placebo). APOE4 heterozygotes showed intermediate efficacy, and non-carriers showed no benefit. In 426 patients with MRI scans, no cases of treatment-emergent vasogenic edema were observed. In the three subgroups, the most common adverse events were nausea, vomiting, and decreased weight. Conclusions: The "APOE4 Gene-Dose effect" is likely explained by the high prevalence of amyloid pathology in symptomatic APOE4 carriers. In APOE4/4 Alzheimer's disease patients, the high dose of tramiprosate showed favorable safety and clinically meaningful efficacy in addition to standard of care.
2011 · Alzheimer's & Dementia
Background: We have proposed an Alzheimer's Prevention Initiative (API) to relate a presymptomatic Alzheimer's disease (AD) treatment's biomarker effects to clinical outcome in cognitively normal people at the highest imminent risk to develop AD, including the world's largest kindred of early-onset AD (EOAD) causing mutation carriers (mean age at clinical onset=45), from Antioquia, Colombia. Here, we used longitudinal data from cognitively normal E280A Presenilin 1 (PS1) mutation carriers and non-carriers over age 35 to 1) characterize the combination of cognitive tests most sensitive to cognitive decline, 2) estimate the number of mutation carriers needed in randomized clinical trial (RCTs) to detect AD-slowing treatment effect on the composite cognitive endpoint, and 3) estimate the treatment effect that could be detected in 75 PS1 mutation carriers with 80% power and p=0.05. Methods: A battery of 19 cognitive tests, acquired every 2-5 years between 1995 and 2010 by the Neuroscience group at the University of Antioquia, was used to calculate the mean-to-standard-deviation ratios (MSDR) for each combination of one to six measurements. Measurements were adjusted for aging/practice effects using data from no carriers. The best combination was used to estimate statistical power in 24-60 month presymptomatic AD RCTs. Results: After practice/aging correction, the optimal combination to predict cognitive decline included CERAD word list delayed recall, category verbal fluency, MMSE Orientation and Time, Constructional Praxis and Ravens progressive matrices. (A similar pattern was observed in cognitively normal older APOE4 carriers [Langbaum et al, ICAD abstract 2011]). We estimate the need for 215/79 PS1 mutation carriers per group over the age of 35, respectively, to detect a 25% treatment effect in a 24/60-month RCT. We estimate that 75 carriers per group would permit us to detect 43/26% treatment effects, respectively in a 24/60-month RCT. Conclusions: We have identified a combination of cognitive tests to evaluate presymptomatic AD treatments in cognitive normal people at highest imminent risk for EOAD. We have found a similar combination in those at highest risk for late-onset AD. We will continue to develop this approach in preparation for the presymptomatic AD/surrogate marker development trials proposed in the API.
2011 · Alzheimer's & Dementia
Background: We have proposed an Alzheimer's Prevention Initiative (API) to relate a pre-symptomatic Alzheimer's disease (AD) treatment's biomarker effects to clinical outcome in cognitively normal people who, based on age and genetic background, are at highest imminent risk of symptomatic AD. Here, we used longitudinal data from two cohort studies at the Rush Alzheimer's Disease Center to identify a new cognitive composite score that is sensitive to cognitive decline associated with pre-symptomatic AD to inform on the design of a randomized clinical trial (RCT) in apolipoprotein E (APOE) e4 carriers. Methods: Using a battery of 19-21 cognitive tests, the annualized mean-to-standard-deviation ratios (MSDR) of the change over time were calculated for the un-weighted sum of every combination of two to six tests for those who developed cognitive impairment (MCI or AD) in the five years prior to diagnosis. Measurements were adjusted for aging/practice effects using data from participants who remained cognitively normal. The best combinations were evaluated for construct validity. This optimal test combination was then examined in APOE4 carriers. Results: The optimal combination of measurements that was selected to sensitively measure cognitive decline over time included Logical Memory-delayed recall, CERAD word list-delayed recall, category fluency, Ravens progressive matrices, and MMSE (annual MSDR =0.182847). A similar composite test was independently developed using data from a longitudinal cohort of cognitively normal PS1 E280A mutation carriers (Ayutyanont et al, ICAD abstract 2011). This composite score was also shown to be sensitive to decline in APOE4 carriers relative to non-carriers between the ages of 70 and 85. Using this composite cognitive endpoint, we estimate that 4,360/1,100 APOE4 carriers per group would permit us to detect a 30% treatment effect in a 24/60-month RCT, respectively. Conclusions: In this first phase of the process, we have identified a combination of cognitive tests to evaluate pre-symptomatic AD treatments in cognitive normal people at high imminent risk for late-onset AD, and have shown that a similar combination performs well in individuals at highest risk for early-onset AD. We will continue to develop and refine this approach in preparation for the pre-symptomatic AD/surrogate marker development trials proposed in the API.
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