RESUMO
BACKGROUND: There is a critical need for novel primary endpoints designed to detect early and subtle changes in cognition in clinical trials targeting the asymptomatic (preclinical) phase of Alzheimer's disease (AD). The Alzheimer's Prevention Initiative (API) Generation Program, conducted in cognitively unimpaired individuals at risk of developing AD (e.g., enriched by the apolipoprotein E (APOE) genotype), used a novel dual primary endpoints approach, whereby demonstration of treatment effect in one of the two endpoints is sufficient for trial success. The two primary endpoints were (1) time to event (TTE)-with an event defined as a diagnosis of mild cognitive impairment (MCI) due to AD and/or dementia due to AD-and (2) change from baseline to month 60 in the API Preclinical Composite Cognitive (APCC) test score. METHODS: Historical observational data from three sources were used to fit models to describe the TTE and the longitudinal APCC decline, both in people who do and do not progress to MCI or dementia due to AD. Clinical endpoints were simulated based on the TTE and APCC models to assess the performance of the dual endpoints versus each of the two single endpoints, with the selected treatment effect ranging from a hazard ratio (HR) of 0.60 (40% risk reduction) to 1 (no effect). RESULTS: A Weibull model was selected for TTE, and power and linear models were selected to describe the APCC score for progressors and non-progressors, respectively. Derived effect sizes in terms of reduction of the APCC change from baseline to year 5 were low (0.186 for HR = 0.67). The power for the APCC alone was consistently lower compared to the power of TTE alone (58% [APCC] vs 84% [TTE] for HR = 0.67). Also, the overall power was higher for the 80%/20% distribution (82%) of the family-wise type 1 error rate (alpha) between TTE and APCC compared to 20%/80% (74%). CONCLUSIONS: Dual endpoints including TTE and a measure of cognitive decline perform better than the cognitive decline measure as a single primary endpoint in a cognitively unimpaired population at risk of AD (based on the APOE genotype). Clinical trials in this population, however, need to be large, include older age, and have a long follow-up period of at least 5 years to be able to detect treatment effects.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Apolipoproteínas E/genética , Cognição , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/genética , Fatores de RiscoRESUMO
The rise of targeted therapy and immunotherapy has challenged the conventional more-is-better phase I trial design paradigm that focuses on finding the MTD. In this article, we propose a novel model-assisted phase I/II design, called checkerboard design, that considers both toxicity and efficacy. As an extension of the keyboard design, the checkerboard design models the joint distribution of toxicity and efficacy, and divides toxicity and efficacy domain into a series of equal-width intervals or keys. In light of interim data, the checkerboard design continuously updates the posterior distribution of toxicity and efficacy, and adaptively determine the optimal dose for treating the next cohort of patients based on the posterior probability of toxicity and efficacy keys. As a model-assisted design, one important advantage of the checkerboard design is that its decision rule can be pretabulated, greatly simplifying its implementation. We also extend the checkerboard design to handle continuous efficacy endpoint. Simulations study shows that the checkerboard design yields competitive performance comparable to existing model-based phase I/II designs, but is simpler and easier to implement in real applications.