Randomized Controlled Trials for Neuromyelitis Optica Spectrum Disorder: A Review of Trial Architecture

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing inflammatory disease that primarily affects the optic nerves and the spinal cord. Randomized controlled trials (RCTs) assessing treatments for NMOSD have only been performed in the past decade, and to date, there are 3 drugs approved by the US Food and Drug Administration (FDA) for antiaquaporin-4 immunoglobulin G seropositive NMOSD. This review assesses the characteristics and challenges of RCTs when evaluating treatments for NMOSD.

We conducted a review using the terms ("neuromyelitis optica" OR "NMO" OR "NMOSD") AND "clinical trial" in any language on March 28, 2021. Seven RCTs were included, and the trials' architecture was analyzed and synthesized. Overall, 794 subjects were randomized [monoclonal antibody intervention group, n= 493 (62.1%), placebo, n=196 (24.7%), and active control, n=105 (13.2%)]; 709 (89.3%) were females; and 658 (82.9%) were aquaporin-4 (AQP4) antibody seropositive. The primary outcome was time to relapse in 6/7 of the trials, and annualized relapse rate in the remaining one. Four RCTs used placebo in their design. Among the seven published RCTs, the trial design differed by the criteria used to define NMOSD relapse, selection of subjects, proportion of AQP4 immunoglobulin G seronegative patients, and baseline characteristics indicating NMO disease severity.

Ethical considerations for the use of placebo should change in light of the approval of 3 therapies for seropositive NMOSD. Remaining challenges for clinical trials in NMOSD include the assessment of long-term safety and efficacy, standardization of trial design and endpoints, and head-to-head study designs.