Sensitivity analysis of the primary endpoint from the N-MOmentum study of inebilizumab in NMOSD

Abstract

Background: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo.

Objective: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses.

Methods: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and post hoc analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints.

Results: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, p < 0.05). Analyses of secondary endpoints showed similar trends.

Conclusion: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy.The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.

Keywords: Attack risk; Devic’s disease; clinical trial; inebilizumab; neuromyelitis optica; neuromyelitis optica spectrum disorder; patient demographics; sensitivity analyses.

Conflict of interest statement

Declaration of Conflicting Interest: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: B.A.C. Cree reports personal fees for consulting from Akili, Alexion, Autobahn, EMD Serono, Novartis, Sanofi, TG Therapeutics, and Therini. J.L. Bennett reports payment for study design/consultation from MedImmune/Viela Bio; personal fees from AbbVie, Alexion, Chugai, Clene Nanomedicine, Genentech, Genzyme, Mitsubishi-Tanabe, Reistone Bio, and Roche; grants and personal fees from EMD Serono and Novartis; grants from the Guthy–Jackson Charitable Foundation, Mallinckrodt, and the National Institutes of Health; and has a patent for Aquaporumab issued. H.J. Kim has received a grant from the National Research Foundation of Korea; consultancy/speaker fees or research support from Alexion, Aprilbio, Celltrion, Eisai, HanAll BioPharma, MDimune, Merck Serono, Novartis, Sanofi Genzyme, Teva-Handok, and Viela Bio; serves on a steering committee for MedImmune/Viela Bio and is a coeditor for the Multiple Sclerosis Journal and an associate editor for the Journal of Clinical Neurology. B.G. Weinshenker receives payments for serving as chair of attack adjudication committees for clinical trials in NMOSD for Alexion, MedImmune, and Viela Bio; has consulted with Chugai, Genentech, Roche Pharmaceuticals, and Mitsubishi Tanabe Pharma regarding clinical trial design for NMOSD; and has a patent for NMO-IgG for diagnosis of neuromyelitis optica, with royalties paid by Hospices Civils de Lyon, MVZ Labor PD Dr. Volkmann und Kollegen GbR, Oxford University, and RSR. S.J. Pittock reports grants, personal fees, and non-financial support from Alexion Pharmaceuticals, Inc.; grants from Autoimmune Encephalitis Alliance, Grifols; grants, personal fees, non-financial support, and other from MedImmune and Viela Bio; consulting support from Astellas; personal fees for consulting services from UCB; and has a patent # 9,891,219 (Application#12-573942) “Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive.” D. Wingerchuk reports personal fees from Arcus Medica, Biogen, Celgene, Genentech, MedImmune, Novartis, Reistone Biopharma, TG Therapeutics, and Third Rock Ventures; research support paid to the Mayo Clinic by Alexion and Terumo BCT; and serves on a clinical trial adjudication committee for MedImmune and Viela Bio. K. Fujihara serves on scientific advisory boards for Alexion, Bayer Schering, Biogen Idec, Chugai, MedImmune, Merck Serono, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Novartis, Ono, and Viela Bio; has received funding for travel and speaker honoraria from Asahi Kasei Medical, Astellas, Bayer Schering, Biogen Idec, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Novartis, and Takeda; and research support from Asahi Kasei Medical, Bayer Schering, Biogen Idec, Chemo-Sero-Therapeutic Research Institute, Chugai, Genzyme Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Ministry of Health, Welfare and Labor of Japan, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Ono, Teijin, and Teva. G.R. Cutter has received personal fees for participation on Data and Safety Monitoring Boards from AstraZeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Orphazyme, Sanofi-Aventis, Reata Pharmaceuticals, Teva pharmaceuticals, Viela Bio Inc., Vivus, NHLBI (Protocol Review Committee) and NICHD (OPRU oversight committee); personal fees for consulting or advisory board partici-pation from Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Medimmune, Medday, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche and TG Therapeutics. Dr Cutter is employed by the University of Alabama at Birmingham and is President of Pythagoras, Inc., a private consulting company based in Birmingham, AL, USA. F. Paul has received research support, speaker fees, and travel reimbursement from Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and Teva; is supported by the German Competence Network for Multiple Sclerosis and the German Research Council (DFG Exc 257); has received travel reimbursement from the Guthy–Jackson Charitable Foundation; and serves on the steering committee of the OCTIMS study sponsored by Novartis. R. Marignier serves on scientific advisory boards for MedImmune and Viela Bio; and has received funding for travel and fees from Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, Teva, and Viela Bio. A.J. Green reports grants from the Conrad N. Hilton Foundation and the Tom Sherak MS Hope Foundation; other financial relationships (for activities as expert witness, associate editor, advisory board/steering committee participation, and endpoint adjudication) with Bionure, Inception Sciences, JAMA Neurology, MedImmune/Viela Bio, Mylan, Synthon, and Trims Pharma; and personal fees from and other financial relationships with Pipeline Therapeutics. O. Aktas reports grants from the German Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); grants and personal fees from Bayer HealthCare, Biogen, Genzyme, Novartis, Teva, and Viela Bio; and personal fees from Almirall, MedImmune, Merck Serono, and Roche. H.-P. Hartung has received fees for consulting, speaking, and serving on steering committees from Bayer HealthCare, Biogen Idec, Celgene Receptos, CSL Behring, GeNeuro, Genzyme, MedDay, MedImmune, Merck Serono, Novartis, Roche, Sanofi, TG Therapeutics, and Viela Bio with approval by the Rector of Heinrich Heine University Düsseldorf. I.M. Williams is an employee of Oxford PharmaGenesis. J. Drappa, D. She, D. Cimbora, W. Rees, J.N. Ratchford, and E. Katz are employees of Viela Bio.

Figures

Figure 1.

N-MOmentum study design. IDMC: Independent Data Monitoring Committee; NMOSD: neuromyelitis optica spectrum disorder; RCP: randomized controlled period. N-MOmentum was a double-blind, placebo-controlled study at 99 medical centers in 25 countries, with a time-to-event design. End of RCP was defined as 67 NMOSD attacks, or when 252 participants had been randomized and had received study drug, whichever happened first. Enrollment was stopped early at 231 participants and 43 attacks owing to proven efficacy as determined by the IDMC. No background immunotherapy was permitted. The primary endpoint was the time to an NMOSD adjudicated attack within the RCP. aParticipants eligible for the open-label period at the end of the RCP or after an adjudicated attack.

Figure 2.

CONSORT flow diagram. CONSORT: Consolidated Standards of Reporting Trials; i.v.: intravenous; RCP: randomized controlled period.

Figure 3.

Sensitivity analyses for primary endpoint (time to adjudicated attack; overall population). AC: adjudication committee; CI: confidence interval; EDSS: Expanded Disability Status Scale; HR: hazard ratio; NMOSD: neuromyelitis optica spectrum disorder. Based on Cox regression method, with placebo as the reference group.

Figure 4.

Sensitivity analyses for primary endpoint (time to adjudicated attack; AQP4-IgG seropositive population). AC: adjudication committee; AQP4-IgG: aquaporin-4 immunoglobulin G; CI: confidence interval; EDSS: Expanded Disability Status Scale; HR: hazard ratio; NMOSD: neuromyelitis optica spectrum disorder. Based on Cox regression method, with placebo as the reference group.

Figure 5.

Primary endpoint by demographic and baseline characteristic subgroup (time to adjudicated attack; overall population). CI: confidence interval; EDSS: Expanded Disability Status Scale; HR: hazard ratio; NMOSD: neuromyelitis optica spectrum disorder. Based on Cox regression method, with placebo as the reference group.