Design and Statistical Innovations in a Platform Trial for Amyotrophic Lateral Sclerosis

Author:

Quintana Melanie1,Saville Benjamin R.12,Vestrucci Matteo1,Detry Michelle A.1,Chibnik Lori34,Shefner Jeremy5,Berry James D.67,Chase Marianne67,Andrews Jinsy8,Sherman Alexander V.67,Yu Hong67,Drake Kristin67,Cudkowicz Merit67ORCID,Paganoni Sabrina679,Macklin Eric A.45,

Affiliation:

1. Berry Consultants Austin Texas USA

2. Department of Biostatistics Vanderbilt University Medical Center Nashville Tennessee USA

3. Biostatistics Center Massachusetts General Hospital Boston Massachusetts USA

4. Department of Medicine Harvard Medical School Boston Massachusetts USA

5. Department of Neurology Barrow Neurological Institute Phoenix Arizona USA

6. Sean M. Healey & AMG Center for ALS at Mass General, Department of Neurology Massachusetts General Hospital Boston Massachusetts USA

7. Department of Neurology Harvard Medical School Boston Massachusetts USA

8. Neurological Institute of New York Columbia University New York New York USA

9. Department of Physical Medicine and Rehabilitation Spaulding Rehabilitation Hospital Boston Massachusetts USA

Abstract

Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products in parallel and sequentially in persons with amyotrophic lateral sclerosis (ALS) with the goal of rapidly identifying novel treatments to slow disease progression. Platform trials have considerable operational and statistical efficiencies compared with typical randomized controlled trials due to their use of shared infrastructure and shared control data. We describe the statistical approaches required to achieve the objectives of a platform trial in the context of ALS. This includes following regulatory guidance for the disease area of interest and accounting for potential differences in outcomes of participants within the shared control (potentially due to differences in time of randomization, mode of administration, and eligibility criteria). Within the HEALEY ALS Platform Trial, the complex statistical objectives are met using a Bayesian shared parameter analysis of function and survival. This analysis serves to provide a common integrated estimate of treatment benefit, overall slowing in disease progression, as measured by function and survival while accounting for potential differences in the shared control group using Bayesian hierarchical modeling. Clinical trial simulation is used to provide a better understanding of this novel analysis method and complex design. ANN NEUROL 2023;94:547–560

Funder

ALS Association

Muscular Dystrophy Association

Publisher

Wiley

Subject

Neurology (clinical),Neurology

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