Statistical Considerations for an Adaptive Design for a Serious Rare Disease

Abstract

Background:

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, disabling autoimmune disorder of the central nervous system. Clinical trials in NMOSD present unique design and statistical challenges to adequately determine treatment effect and to minimize risk.

Methods:

The N-MOmentum trial (NCT02200770) is evaluating the efficacy and safety of MEDI-551, an anti-CD 19 B-cell depleting monoclonal antibody, in patients with NMOSD and employs a number of unique design features. Patients are randomized (3:1) to receive MEDI-551 or placebo for up to 197 days. NMOSD attacks are evaluated by the investigator and confirmed by an independent adjudication committee. The primary endpoint is time to first relapse as determined by adjudication committee. Sample size re-estimation and futility analyses are planned interim analyses. Novel multiplicity adjustment methods are developed to control the study-wise type I error. Methods for assessing inter- and intrarater reliability are proposed.

Conclusions:

The N-MOmentum study minimizes exposure to placebo for individual patients. The application of several statistical methods in the N-MOmentum trial is novel in NMOSD and aims to achieve a balance between minimizing risk and maintaining scientific integrity.