Practical Considerations for a Two-Stage Confirmatory Adaptive Clinical Trial Design and Its Implementation: ADVENT Trial

Abstract

In this chapter, we provide the details of an innovative two-stage, seamless adaptive clinical trial called ADVENT. This trial was conducted as a ``final phase 3'' clinical trial to establish the safety and efficacy of a first-in-class antidiarrheal agent, crofelemer, for the symptomatic relief of diarrhea in HIV patients receiving anti-retroviral therapy. Given that this was a trial with two-stage design that included a dose selection, it was necessary to demonstrate the strong control of Type 1 error. This was accomplished with a close testing procedure applied to combination tests that utilized the inverse normal combination function. We developed a one-sided significance testing procedure that ensures strong control of the Type 1 error at level 0.025. Using appropriate statistical methodology for combining the results from the two stages, a statistically significant outcome was obtained for the primary efficacy endpoint and crofelemer received marketing approval based on the ADVENT trial. While the authors acknowledge the importance of statistical methodology required to analyze the data from the ADVENT trial, this chapter also provides significant details on the clinical and regulatory challenges that were demanded for the conduct of this innovative, two-stage, adaptive clinical trial.