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

Bruce Ac Cree, Jeffrey L Bennett, Mark Sheehan, Jeffrey Cohen, Hans-Peter Hartung, Orhan Aktas, Ho Jin Kim, Friedemann Paul, Sean Pittock, Brian Weinshenker, Dean Wingerchuk, Kazuo Fujihara, Gary Cutter, Kaushik Patra, Armando Flor, Gerard Barron, Soraya Madani, John N Ratchford, Eliezer Katz, Bruce Ac Cree, Jeffrey L Bennett, Mark Sheehan, Jeffrey Cohen, Hans-Peter Hartung, Orhan Aktas, Ho Jin Kim, Friedemann Paul, Sean Pittock, Brian Weinshenker, Dean Wingerchuk, Kazuo Fujihara, Gary Cutter, Kaushik Patra, Armando Flor, Gerard Barron, Soraya Madani, John N Ratchford, Eliezer Katz

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.

Keywords: MEDI-551; Neuromyelitis optica; anti-CD19 monoclonal antibody; ethics; trial design.

Conflict of interest statement

Conflict of interest: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: O. Aktas has served as a consultant for MedImmune and as a speaker for Bayer, Biogen, Genzyme, Merck Serono, Novartis, and Teva, and his institution has received research funding and grants from Bayer, Biogen, the German Research Foundation, and Novartis. JL Bennett holds patents for compositions, including blocking monoclonal therapy, and treatment methods for neuromyelitis optica; has served as a consultant for AbbVie, Alnylam Pharmaceuticals, Chugai Pharma, EMD Serono, Genentech, Genzyme, MedImmune, and Novartis; has received research support from the Guth-Jackson Foundation, the NIH, Novartis, and Questcor Pharmaceuticals; holds stock in Apsara Therapeutics; and receives royalties from Aquaporumab. J. Cohen has served as a consultant for Novartis and his institution has received research support from Genzyme, Novartis, Receptos, Synthon, and Teva. B. Cree has served as a consultant and has developed educational presentations for MedImmune. G. Cutter has served as a consultant, speaker, and advisory board member for the Consortium of MS Centers, D3 (Drug Discovery and Development), EMD Serono, Genzyme, Genentech, Jannsen Pharma-ceuticals, Klein-Buendel Incorporated, MedImmune, Novartis, Opexa Therapeutics, Receptos, Roche, Spiniflex Pharmaceuticals, Somahlution, Teva, and Transparency Life Sciences; he has also participated on Data and Safety Monitoring Boards for Apotek, Biogen-Idec, Cleveland Clinic, GlaxoSmithKline, Gilead, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Merck/Pfizer, the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, the National Institute of Child Health and Human Development, Neuren, Sanofi-Aventis, and Teva. K. Fujihara has served as a consultant and developed educational presentations for MedImmune, and his institution has received research support and payment for lectures from MedImmune. H-P Hartung has served as a consultant for Apexa, Biogen GmbH, GeNeuro, Merck Serono, Novartis, and Octapharma. HJ Kim has served as a consultant, speaker, and advisory board member for MedImmune, and has received research funding and paid travel and accommodations from MedImmune. F. Paul has received research funding and grants from various pharmaceutical companies, government agencies, and private bodies; serves on the editorial board of Neurology; and his institution has received consultancy fees from Alexion Pharmaceuticals, MedImmune, and Novartis. S. Pittock has served as a consultant for Alexion Pharmaceuticals, Chugai Pharma, and MedImmune; has received a research grant from the National Institutes of Health and research funding from Alexion Pharmaceuticals; and holds several patents. M. Sheehan’s institution has received consultancy fees and research funding from MedImmune. B. Weinshenker has served as a consultant for Chord Therapeutics, Chugai Pharma, and Novartis; received a grant from the Guthy Jackson Charitable Foundation; holds a patent with Mayo Medical Ventures and receives royalties from RSR and Oxford University; has received paid travel and accommodations from Alexion Pharmaceuticals; has participated on Data and Safety Monitoring Boards for Biogen-Idec, Mitsubishi, and Novartis; and has served on an adjudication committee for a clinical trial for MedImmune. D. Wingerchuk’s institution has received consultancy fees from Alexion Pharmaceuticals and MedImmune and has received research funding from Alexion Pharmaceuticals and Terumo BCT. E. Katz, S Madani, G. Barron, A. Flor, J. Ratchford, and K. Patra are employees of MedImmune and own stock in AstraZeneca. No author received an honorarium or other form of payment for the preparation of this manuscript.

© The Author(s), 2015.

Figures

Figure 1.
Figure 1.
N-MOmentum study design scheme.

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