Abstract
Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II–IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference −11·7, 95% CI −24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.
Original language | English (US) |
---|---|
Pages (from-to) | 976-986 |
Number of pages | 11 |
Journal | The Lancet Neurology |
Volume | 16 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2017 |
ASJC Scopus subject areas
- Clinical Neurology
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN)
T2 - a phase 3, randomised, double-blind, placebo-controlled, multicentre study
AU - REGAIN Study Group
AU - Howard, James F.
AU - Utsugisawa, Kimiaki
AU - Benatar, Michael
AU - Murai, Hiroyuki
AU - Barohn, Richard J.
AU - Illa, Isabel
AU - Jacob, Saiju
AU - Vissing, John
AU - Burns, Ted M.
AU - Kissel, John T.
AU - Muppidi, Srikanth
AU - Nowak, Richard J.
AU - O'Brien, Fanny
AU - Wang, Jing Jing
AU - Mantegazza, Renato
AU - Mazia, Claudio Gabriel
AU - Wilken, Miguel
AU - Ortea, Carolina
AU - Saba, Juliet
AU - Rugiero, Marcelo
AU - Bettini, Mariela
AU - Vidal, Gonzalo
AU - Garcia, Alejandra Dalila
AU - Lamont, Phillipa
AU - Leong, Wai Kuen
AU - Boterhoven, Heidi
AU - Fyfe, Beverly
AU - Roberts, Leslie
AU - Jasinarachchi, Mahi
AU - Willlems, Natasha
AU - Wanschitz, Julia
AU - Löscher, Wolfgang
AU - De Bleecker, Jan
AU - Van den Abeele, Guy
AU - de Koning, Kathy
AU - De Mey, Katrien
AU - Mercelis, Rudy
AU - Wagemaekers, Linda
AU - Mahieu, Delphine
AU - Van Damme, Philip
AU - Smetcoren, Charlotte
AU - Stevens, Olivier
AU - Verjans, Sarah
AU - D'Hondt, Ann
AU - Tilkin, Petra
AU - Alves de Siqueira Carvalho, Alzira
AU - Hasan, Rosa
AU - Dias Brockhausen, Igor
AU - Nations, Sharon
AU - Trivedi, Jaya
N1 - Funding Information: In this phase 3 study, the mean-ranked difference in change in MG-ADL between eculizumab and placebo was not statistically significant. Inhibition of terminal complement activation is a biologically rational approach to prevent damage at the neuromuscular junction in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. REGAIN was designed to compare eculizumab, a terminal complement inhibitor, with placebo in these patients. However, the worst-rank approach we used was a statistical method that enabled patients who needed temporary rescue medication to be included in the efficacy analysis by treating rescue medication use or discontinuation for any reason as a negative outcome. The derived use of ranks rather than actual change scores in the worst-rank analysis makes it difficult to translate the implications of the study results into clinical practice. To provide a comprehensive clinical picture of treatment effect that reflects both the physicians' and patients' perspectives, we included prespecified sensitivity and secondary analytical approaches in the analysis plan. The sensitivity analyses of changes in the MG-ADL, QMG, and MG-QOL15 scores showed improvements with eculizumab compared with placebo, and results for the MGC were consistent with those for MG-ADL (the change from baseline to week 26, as measured by the worst-rank analysis, were not statistically significant for both the MG-ADL and the MGC, but in all other analyses a benefit of eculizumab compared with placebo was observed in both measures). An emphasis on the proportion of patients who exceed established clinically meaningful differences is especially important in a rare disease. Using thresholds above the established clinically important differences, defined as the threshold value that patients and clinicians perceived as clinically meaningful ( appendix ) for the responder analyses of MG-ADL and QMG, 33,34 as well as progressively increasing stricter thresholds, two to three times as many patients improved with eculizumab treatment compared with placebo. A portion of patients in the placebo group also achieved a clinically meaningful change in both MG-ADL and QMG scores. This might reflect the well known effect of placebo responsiveness in patients with neurological disorders participating in clinical trials, and could account for some of the response seen in the placebo group during this study in which patients were followed up more frequently than in clinical practice. 35 Alternatively, this observation might partly reflect the known variability of myasthenic symptoms over short periods of time or greater potential for variability when baseline scores are higher (as expected in patients with refractory disease). Patients in REGAIN were maintained on stable immunosuppressive therapies throughout the study and, even with concomitant immunosuppressive therapy, those in the eculizumab group had larger improvements than those in the placebo group, as shown by responder and repeated-measures analyses. The prespecified repeated-measures sensitivity analyses were specifically done to determine if background immunosuppressive therapy use confounded interpretation of study results; it was shown that with or without controlling for their use, there was a separation between treatment arms favouring eculizumab over placebo. Using the repeated-measures analyses, the benefit of eculizumab compared with placebo occurred within the first 4 weeks of treatment, with most of the effect achieved by 12 weeks. Commonly used steroid-sparing agents might require 6 months or longer 36–38 to achieve clinical benefit, although the extent and rate of steroid reduction that constitutes steroid sparing has not been defined. Overall, eculizumab was well tolerated, and the safety profile was consistent with its known safety profile in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome 25–27 and post-marketing experience in these indications over 10 years. No increase occurred in serious infections or reports of meningococcal infections, and no new safety concerns were identified in this patient population. Numerically fewer myasthenia gravis exacerbations, reduced use of rescue medication, and fewer admissions to hospital occurred in the eculizumab group compared with the placebo group, all of which contribute to overall disease burden. The strengths of this study included a rigorous randomised, placebo-controlled study design and use of several validated outcome measures, including physician-reported and patient-reported outcomes, as well as multiple analytical approaches. However, this study highlights an important limitation in the use of a worst-rank analytic approach. Because discontinuation from a clinical study could be viewed as a negative outcome, the prespecified worst-rank analyses assigned all patients who discontinued the study to the poor-outcome group, regardless of the reason for discontinuation or myasthenia gravis status at the time of discontinuation. The results of the post-hoc analysis illustrate the importance of differentiating patients with poor myasthenia gravis outcomes (myasthenia gravis crisis or clinical worsening with or without rescue therapy) from patients with poor outcomes unrelated to myasthenia gravis when applying the worst-rank analytical approach. The sample size used in this study might not have been adequate to allow for the informative use of the worst-rank analytical approach. This study offered the opportunity to characterise patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis, adding to the scarce characterisation of such patients in the literature. 1 Maximum disease worsening in myasthenia gravis has been reported in the first 2–3 years after diagnosis, 39 but has never been described for refractory disease. In this study, patients were on background immunosuppressive therapy; however, patients continued to be at risk of exacerbations and hospital admissions before the start of REGAIN, despite a mean disease duration of 10 years. After 26 weeks of treatment, the numbers of exacerbations and hospital visits for patients receiving eculizumab were half those for patients receiving placebo, suggesting that over-activation of the complement system might contribute to the risk of disease exacerbation. Effective therapies to treat patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis are crucially needed. This was the first phase 3 clinical study specifically targeting this patient population that is difficult to treat and has a substantial disease burden. The primary endpoint did not achieve statistical significance. Interpretation of any trial, however, should consider all evidence from the study. 40 The preplanned analyses and outcomes from REGAIN suggest a potential benefit of eculizumab treatment in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. These results should stimulate further research into the role of complement in this disease. Contributors JFH Jr, KU, MB, HM, RJB, TMB, JTK, FO'B, J-JW, and RM contributed to the concept or design of the study. JFH Jr, KU, MB, HM, II, SJ, JV, JTK, SM, RJN, FO'B, J-JW, and RM contributed to acquisition, analysis, or interpretation of the data. All authors contributed to drafting the report or revised it critically for important intellectual content. Declaration of interests JFH Jr received research support and grants from Alexion Pharmaceuticals, research support from the Centers for Disease Control and Prevention (CDC), grants from the National Institutes of Health (NIH; National Institute of Neurological Disorders and Stroke [NINDS] National Institute of Arthritis and Musculoskeletal and Skin Diseases, Environmental Medicine, Asthma and Lung Biology), grants from UCB Biosciences, research support from the Muscular Dystrophy Association, and non-financial support from Alexion Pharmaceuticals, Alnylam Pharmaceuticals, Argenx BVBA, RA Pharmaceuticals, and Toleranzia AB. KU has received honoraria for consultancies from Alexion Pharmaceuticals. MB received research support from NIH (NINDS, National Center for Advancing Translational Sciences), CDC, the Food and Drug Administration Orphan Products Development Program, US Department of Defense, ALS Association, Muscular Dystrophy Association, and Eli Lilly and Company. KU is also the site investigator for Alexion Pharmaceuticals, Cytokinetics, and Neuraltus, and has consultantships with Alnylam Pharmaceuticals, RA Pharmaceuticals, Voyager Therapeutics, UCB Pharma, Denali, and Mitsubishi-Tanabe Pharmaceuticals. HM received fees from Alexion Pharmaceuticals, Biogen, Novartis, Bayer, Mitsubishi-Tanabe, and the Japan Blood Products Organization. RJB received personal fees from NuFactor, Plan 365, and Option Care, and research support from Novartis, Sanofi/Genzyme, Biomarin, IONIS, Teva, Cytogenetics, and Eli Lilly and Company. SJ is an advisory board member for Alnylam Pharmaceuticals and a member of International Advisory Board for Alexion Pharmaceuticals. JV received research and travel support, speaker honoraria from Sanofi/Genzyme, Ultragenyx Pharmaceuticals, Santhera Pharmaceuticals and aTyr Pharma, and has served as consultant on advisory boards for Sanofi/Genzyme, aTyr Pharma, Ultragenyx Pharmaceuticals, Santhera Pharmaceuticals, Sarepta Therapeutics, Novo Nordisk, Alexion Pharmaceuticals, and Stealth Biotherapeutics within the past 3 years. JTK received research and travel support from Alexion Pharmaceuticals, NIH (NINDS), aTyr Pharma, Cytokinetics, and AveXis. SM has been an advisory board member for Alnylam Pharmaceuticals, and a consultant for Alexion Pharmaceuticals, Alnylam Pharmaceutical, and Lundbeck Pharmaceuticals. RJN received research support from the NIH (NINDS and NIADS), Alexion Pharmaceuticals, Genentech, Grifols, and Myasthenia Gravis Foundation of America, and has consultantships with Alexion Pharmaceuticals, RA Pharma, Shire, and Grifols. RM received funding for research and congress participation from Sanofi-Genzyme, Teva, Bayer, and BioMarin, and has participated in scientific advisory boards for BioMarin, Alexion Pharmaceuticals, and Argenx BVBA. FO'B and J-JW are employed by and own stocks in Alexion Pharmaceuticals. II and TMB declare no competing interests. Acknowledgments This study was funded by Alexion Pharmaceuticals (New Haven, CT, USA). We thank the patients who took part and their families as well as the REGAIN principal investigators, subinvestigators, and study coordinators ( appendix ). We also thank Gary Cutter (UAB School of Public Health, New Haven, Connecticut, USA) for his expert advice early in the study, Laura Herbelin (University of Kansas Medical Center, KA, USA) for providing standardised training and certification of the MG-ADL, QMG, and MGC scales, Angela Kaya (Alexion Pharmaceuticals) for medical writing support, Róisín Armstrong, Kenji Fujita, and Gus Khursigara (Alexion Pharmaceuticals) for critical review of the manuscript, Cindy Lane (Alexion Pharmaceuticals) for clinical study oversight, and Charlotte Cookson and Ruth Gandolfo (Oxford PharmaGenesis, Oxford, UK) who provided editorial assistance in the production of the manuscript (funded by Alexion Pharmaceuticals). Publisher Copyright: © 2017 Elsevier Ltd
PY - 2017/12
Y1 - 2017/12
N2 - Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II–IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference −11·7, 95% CI −24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.
AB - Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II–IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference −11·7, 95% CI −24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.
UR - http://www.scopus.com/inward/record.url?scp=85035019720&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85035019720&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(17)30369-1
DO - 10.1016/S1474-4422(17)30369-1
M3 - Article
C2 - 29066163
AN - SCOPUS:85035019720
VL - 16
SP - 976
EP - 986
JO - The Lancet Neurology
JF - The Lancet Neurology
SN - 1474-4422
IS - 12
ER -