DMT54
A Phase 3 Efficacy and Safety Study of Ravulizumab in Adult Patients with Neuromyelitis Optica Spectrum Disorder: Study Design and Methodology
Eculizumab is a first-generation complement component 5 (C5) inhibitor approved for the treatment of adults with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab, which binds the same C5 epitope, has a longer half-life than eculizumab, enabling an extended dosing interval providing patients with a therapy that reduces treatment burden by decreasing infusion frequency relative to eculizumab (every 8 weeks vs every 2 weeks). In view of the evolving treatment landscape in this rare disease patient population, we designed an innovative phase 3 trial with no concurrent placebo exposure to assess the efficacy and safety of ravulizumab in adults with AQP4+ NMOSD.
Objectives:
To present the design and rationale for the development of the phase 3 trial ALXN1210-NMO-307 (NCT04201262).
Methods:
Described in Results.
Results:
ALXN1210-NMO-307 was designed as an open-label, multicenter, single-arm study using the placebo group from the PREVENT trial (eculizumab vs placebo in NMOSD; 2014– 2018) as an external comparator. To ensure scientific validity, constancy with PREVENT will be maintained, including similar patient populations, adjudication procedures, and endpoints. Sensitivity analyses using propensity scores are prespecified to account for differences in patient characteristics that may confound the treatment effect. To characterize the amount of confounding that would eliminate the treatment effect, an E-value (Vanderweele and Ding, 2017) will be calculated for the primary endpoint (time-to-first adjudicated on-trial relapse).
Several factors informed this study design. Given the serious long-term impact of NMOSD attacks, eculizumab approval precluded the use of a concurrent placebo comparator for ethical reasons, as it would require assigning patients to placebo when effective treatments exist. A non-inferiority efficacy trial against existing treatments was also considered but recruiting the very large sample size required to adequately power the study was not a viable option in this ultra-rare disease. Thus, a standard randomized clinical trial design was deemed unfeasible.
The trial enrolled 58 adults with Expanded Disability Status Scale score ≤ 7 to receive an intravenous infusion of ravulizumab every 8 weeks after the loading dose. The ongoing primary treatment period will end when the last enrolled patient reaches week 50 unless a predefined number of patients have an adjudicated on-trial relapse by that time.
The entire treatment period will last up to ~4.5 years.
Conclusions:
ALXN1210-NMO-307 is an ongoing, open-label, multicenter phase 3 study using the placebo arm of PREVENT as an external comparator to assess the efficacy and safety of the C5 inhibitor ravulizumab in patients with AQP4+ NMOSD. The study is designed to be consistent with PREVENT and robust statistical methods will address the potential impact of an external comparator.