Jacqueline Palace1, Dean M Wingerchuk2, Kazuo Fujihara3, Achim Berthele4, Celia Oreja-Guevara5, Ho Jin Kim6, Ichiro Nakashima7, Michael Levy8, Murat Terzi9, Natalia Totolyan10, Shanthi Viswanathan11, Kai-Chen Wang12, Amy Pace13, Marcus Yountz14, Larisa Miller15, Róisín Armstrong16, Sean Pittock17. 1. Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford, OX3 9DU, UK. Electronic address: jacqueline.palace@ndcn.ox.ac.uk. 2. Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA. Electronic address: wingerchuk.dean@mayo.edu. 3. Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan; Department of Multiple Sclerosis Therapeutics, Fukushima Medical University, Fukushima City, 960-1295, Japan; Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience (STRINS), Koriyama, 963-8563, Japan. Electronic address: fujikazu@med.tohoku.ac.jp. 4. Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Neuro-Kopf-Zentrum, Ismaninger Str. 22, 81675 Munich, Germany. Electronic address: achim.berthele@tum.de. 5. Hospital Universitario Clínico San Carlos, Calle del Profesor Martín Lagos, 28040 Madrid; Departamento de Medicina, Universidad Complutense de Madrid (UCM); IdISSC, 28040 Madrid, Spain. Electronic address: orejacbn@gmail.com. 6. Department of Neurology, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, South Korea. Electronic address: hojinkim@ncc.re.kr. 7. Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan; Division of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan. Electronic address: nakashima@tohoku-mpu.ac.jp. 8. Department of Neurology, Johns Hopkins University, 1800 Orleans Street, Baltimore, MD 21287, USA. Electronic address: mlevy11@mgh.harvard.edu. 9. Department of Neurology, Ondokuz Mayıs University, Samsun, Turkey. Electronic address: mterzi@omu.edu.tr. 10. Department of Neurology, First Pavlov State Medical University of St Petersburg, 6/8, Lva Tolstogo str., 197022, St Petersburg, Russia. Electronic address: ntotolyan@mail.ru. 11. Department of Neurology, Kuala Lumpur Hospital, Jalan Pahang, Kuala Lumpur, 50560, Malaysia. Electronic address: shivenda70@yahoo.com. 12. Cheng-Hsin General Hospital, 45 Zhenxing Street, Beitou District, Taipei, Taiwan 112; School of Medicine, National Yang Ming University, 155, Section 2, Linong St, Beitou District, Taipei C, Taiwan 112. Electronic address: kcwangtpe@gmail.com. 13. Alexion Pharmaceuticals, Boston, 121 Seaport Boulevard, Boston, MA 02210, USA. Electronic address: Amy.Pace@alexion.com. 14. Alexion Pharmaceuticals, Boston, 121 Seaport Boulevard, Boston, MA 02210, USA. Electronic address: Marcus.Yountz@alexion.com. 15. Alexion Pharmaceuticals, Boston, 121 Seaport Boulevard, Boston, MA 02210, USA. Electronic address: Larisa.Miller@alexion.com. 16. Alexion Pharmaceuticals, Boston, 121 Seaport Boulevard, Boston, MA 02210, USA. Electronic address: armstrongraf@yahoo.com. 17. Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address: Pittock.Sean@mayo.edu.
Abstract
BACKGROUND: Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulinG-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. METHODS: In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults receivedeculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. RESULTS: The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. CONCLUSION: Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. TRIAL REGISTRATION: NCT01892345 (ClinicalTrials.gov).
RCT Entities:
BACKGROUND: Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. METHODS: In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. RESULTS: The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. CONCLUSION: Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. TRIAL REGISTRATION: NCT01892345 (ClinicalTrials.gov).
Authors: Dean M Wingerchuk; Kazuo Fujihara; Jacqueline Palace; Achim Berthele; Michael Levy; Ho Jin Kim; Ichiro Nakashima; Celia Oreja-Guevara; Kai-Chen Wang; Larisa Miller; Shulian Shang; Guido Sabatella; Marcus Yountz; Sean J Pittock Journal: Ann Neurol Date: 2021-02-27 Impact factor: 10.422
Authors: Dean M Wingerchuk; Ina Zhang; Adrian Kielhorn; Minying Royston; Michael Levy; Kazuo Fujihara; Ichiro Nakashima; Imran Tanvir; Friedemann Paul; Sean J Pittock Journal: Neurol Ther Date: 2022-07-02