Richard J Nowak1, Christopher S Coffey2, Jonathan M Goldstein3, Mazen M Dimachkie4, Michael Benatar5, John T Kissel6, Gil I Wolfe7, Ted M Burns8, Miriam L Freimer6, Sharon Nations9, Volkan Granit10,5, A Gordon Smith11, David P Richman12, Emma Ciafaloni13, Muhammad T Al-Lozi14, Laura Ann Sams15, Dianna Quan16, Eroboghene Ubogu17, Brenda Pearson2, Aditi Sharma18,19, Jon W Yankey2, Liz Uribe2, Michael Shy20, Anthony A Amato21, Robin Conwit22, Kevin C O'Connor18, David A Hafler18, Merit E Cudkowicz23, Richard J Barohn4,24. 1. Department of Neurology, Yale University School of Medicine, New Haven, CT richard.nowak@yale.edu. 2. Clinical Trials Statistical & Data Management Center, University of Iowa, Iowa City, IA. 3. Department of Neurology, Hospital for Special Surgery, New York, NY. 4. Department of Neurology, Kansas University School of Medicine, Kansas City, KS. 5. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL. 6. Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH. 7. Department of Neurology, University at Buffalo Jacobs School of Medicine & Biomedical Sciences, Buffalo, NY. 8. Department of Neurology, University of Virginia School of Medicine, Charlottesville, VA. 9. Department of Neurology, University of Texas Southwestern Medical School, Dallas, TX. 10. Department of Neurology, Albert Einstein College of Medicine, Bronx, NY. 11. Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT. 12. Department of Neurology, University of California Davis School of Medicine, Sacramento, CA. 13. Department of Neurology, University of Rochester School of Medicine & Dentistry, Rochester, NY. 14. Department of Neurology, Washington University School of Medicine, St. Louis, MO. 15. Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH. 16. Department of Neurology, University of Colorado School of Medicine, Aurora, CO. 17. Department of Neurology, The University of Alabama at Birmingham School of Medicine, Birmingham, AL. 18. Department of Neurology, Yale University School of Medicine, New Haven, CT. 19. Department of Neurology, University of Iowa, Iowa City, IA. 20. Department of Neurology, University of Iowa, Carver College of Medicine, Iowa City, IA. 21. Department of Neurology, Brigham and Women's Hospital, Boston, MA. 22. Division of Clinical Research, National Institute of Neurological Disorders and Stroke, Rockville, MD. 23. Department of Neurology, Massachusetts General Hospital, Boston, MA. 24. Department of Neurology, University of Missouri, Columbia, MO.
Abstract
OBJECTIVE: To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG). METHODS: The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks. RESULTS: Of the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified. CONCLUSIONS: While rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02110706.
OBJECTIVE: To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG). METHODS: The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks. RESULTS: Of the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified. CONCLUSIONS: While rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02110706.
Authors: J Díaz-Manera; E Martínez-Hernández; L Querol; R Klooster; R Rojas-García; X Suárez-Calvet; J L Muñoz-Blanco; C Mazia; K R Straasheijm; E Gallardo; C Juárez; J J Verschuuren; I Illa Journal: Neurology Date: 2012-01-04 Impact factor: 9.910
Authors: Jonathan C W Edwards; Leszek Szczepanski; Jacek Szechinski; Anna Filipowicz-Sosnowska; Paul Emery; David R Close; Randall M Stevens; Tim Shaw Journal: N Engl J Med Date: 2004-06-17 Impact factor: 91.245
Authors: D B Sanders; I K Hart; R Mantegazza; S S Shukla; Z A Siddiqi; M H V De Baets; A Melms; M W Nicolle; N Solomons; D P Richman Journal: Neurology Date: 2008-04-23 Impact factor: 9.910
Authors: Fredrik Piehl; Ann Eriksson-Dufva; Anna Budzianowska; Amalia Feresiadou; William Hansson; Max Albert Hietala; Irene Håkansson; Rune Johansson; Daniel Jons; Ivan Kmezic; Christopher Lindberg; Jonas Lindh; Fredrik Lundin; Ingela Nygren; Anna Rostedt Punga; Rayomand Press; Kristin Samuelsson; Peter Sundström; Oskar Wickberg; Susanna Brauner; Thomas Frisell Journal: JAMA Neurol Date: 2022-09-19 Impact factor: 29.907
Authors: Abeer H Obaid; Chryssa Zografou; Douangsone D Vadysirisack; Bailey Munro-Sheldon; Miriam L Fichtner; Bhaskar Roy; William M Philbrick; Jeffrey L Bennett; Richard J Nowak; Kevin C O'Connor Journal: Neurol Neuroimmunol Neuroinflamm Date: 2022-04-26