Abstract
BackgroundThe COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made.MethodsWe identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trials using existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes. Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined.ResultsTruncating both symptomatic and disease modification trials led to underpowered trials. By contrast, adapting the trials by extending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned.DiscussionThese analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies and that adaptations can be made that maintain the trials’ validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect the original effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.
Highlights
The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity
Simulations and statistical modeling were conducted with data from past therapeutic trials conducted by the Alzheimer’s Disease Cooperative Study (ADCS) and adjusted for patterns of enrollment, follow-up, and dropouts that occurred in those trials
The impact of trial modifications made under each scenario is presented below
Summary
The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. The unexpected COVID-19 pandemic substantially disrupted ongoing randomized clinical trials for Alzheimer disease (AD), including seven trials being. Investigators and sponsors were challenged to make these changes while maintaining trial validity and clinical meaningfulness by mitigating the risks of introducing bias or loss of statistical power to detect a potential therapeutic effect. To better understand the effects of exigent trial modifications due to disruptions caused by the COVID-19 pandemic, we developed several scenarios with different potential trial modifications and simulated the impact of making these modifications on the power to detect a specified treatment effect. Our goal was to show the potential effects of various trial modifications that might have been taken in reaction to disruptions caused by COVID-19 to inform both current trials and future trial planning
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