C8 The ALS platform trial: design considerations and statistical efficiencies

27-11-2019

MNDA SYMPOSIUM PERTH DEC19 PRESENTATIONS

Session 2B Clinical trials

Healey and AMG Center for ALS at Mass General, Boston, MA, USA

Background: Given the urgent clinical need for new ALS therapeutics and the large number of candidate therapies awaiting testing, there is a great need for innovative clinical trial designs that can accelerate the drug development process. One potential solution is an adaptive platform trial in which multiple drugs are both simultaneously and serially evaluated under a single master protocol.

Objectives: To design an ALS platform trial that can simultaneously and perpetually evaluate multiple drugs under a single master protocol, with sharing of placebo participants across treatment regimens, and frequent interim analyses to allow early stopping for success or futility of individual treatment regimens.

Methods: The design of the Healey Center ALS Platform Trial incorporates several statistical innovations:
1) Increased power through the use of sharing of placebo participants across treatment regimens:
2) Staggered entry of treatment regimens into the ongoing platform trial;
3) Frequent interim analyses for success and futility of individual treatment regimens;
4) A Bayesian primary analysis model for proportional slowing of disease progression as measured by ALSFRS-R total score over 24 weeks;
5) Innovative statistical modeling to account for effects of time and administration in placebo participants; and
6) Inclusion of biomarkers and novel outcome measures to improve understanding of disease progression.

Results: Participants will be randomized in two stages; first to a treatment regimen, where a regimen is defined as both an active treatment and the corresponding randomized placebo, followed by 3:1 randomization to either the active treatment or placebo within each regimen. Interim analyses will be conducted every 3 months to allow early stopping for success or futility, with a minimum of 40 patients and a maximum of 120 patients within each regimen (90 active treatment and 30 placebo).

Simulation studies are used to assess the performance of the design, including statistical power, average sample sizes, probability of early stopping, and Type I error, and to calibrate the adaptive decision criteria. In addition, the inclusion of novel outcome measures in a trial setting may lead to more efficient measures of disease progression.

Discussion and conclusions: The Healey Center ALS Platform Trial is an adaptive platform trial that provides the innovation needed to accelerate the drug development process. Compared to traditional drug development, we estimate that the ALS Platform Trial will find an effective therapy more quickly (average 3.4 vs. 8.5 years), with fewer total participants (average 880 vs. 1400), and fewer participants on placebo (average 220 vs. 700).

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