Placebo-controlled study in neuromyelitis optica—Ethical and design considerations

Abstract

Background:To date, no treatment for neuromyelitis optica (NMO) has been granted regulatory approval, and no controlled clinical studies have been reported.Objective:To design a placebo-controlled study in NMO that appropriately balances patient safety and clinical–scientific integrity.Methods:We assessed the “standard of care” for NMO to establish the ethical framework for a placebo-controlled trial. We implemented measures that balance the need for scientific robustness while mitigating the risks associated with a placebo-controlled study. The medical or scientific community, patient organizations, and regulatory authorities were engaged early in discussions on this placebo-controlled study, and their input contributed to the final study design.Results:The N-MOmentum study (NCT02200770) is a clinical trial that randomizes NMO patients to receive MEDI-551, a monoclonal antibody that depletes CD19+ B-cells, or placebo. The study design has received regulatory, ethical, clinical, and patient approval in over 100 clinical sites in more than 20 countries worldwide.Conclusion:The approach we took in the design of the N-MOmentum trial might serve as a roadmap for other rare severe diseases when there is no proven therapy and no established clinical development path.

Review: Recent advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorder

“…The therapeutic monoclonal IgG eculizumab that neutralizes the complement protein C5 appears to be well tolerated, reduces the frequency of attack and improves neurological disability when used to treat intractable cases . Moreover, recent evidence highlights the role for B‐cell‐mediated humoral immunity in the pathogenesis of NMO; this finding led to the usage of rituximab (an antibody against the CD20) or an antibody against the CD19 antigen expressed on B cells that profoundly depletes B cells and decreases the frequency and severity of NMO attacks . However, long‐term treatment with anti‐CD20 drugs is associated with the risk of hypo‐IgG, and thus caution must be exercised when prescribing rituximab as a first‐line therapy .…”

NMO-Spektrum-Erkrankungen

“…Verschiedene Mechanismen, z. B. asymmetrische Randomisierung zugunsten der Studienmedikation, Definition des ersten Schubereignisses als klinischer Endpunkt oder enge zeitliche Limitation der Studienmedikation, wurden zur Risikominimierung ergriffen [72]. Mit Ausnahme von Mitoxantron, Rituximab und Azathioprin sind die meisten aus der MS-Therapie bekannten Medikamente entweder wirkungslos (z.…”

Practice Current: How do you treat neuromyelitis optica?

“…While there are unknowns, there are 3 phase III worldwide trials of different strategies in NMO that will shed light on appropriate treatments of NMO, including second-line immunotherapy options. This includes the following: (1) an anti-CD19 monoclonal antibody, MEDI-551 (N-Momentum study, NCT02200770) 31 ; (2) eculizumab, a complement inhibitor approved for hemolytic anemias (Prevention of Recurrent Venous Thromboembolism [PREVENT] study, NCT01892345) 32 ; and (3) an anti-IL6 monoclonal antibody, SA237 (NCT02073279), 33 a long-acting form of tocilizumab. Duration of immunotherapy What we know about NMO is that the disease will return if treatment is ever stopped.…”