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.

摘要

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapiesudspecifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complementudinhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positiveudrefractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patientudpopulation in a phase 3 trial.udMethods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitalsudand specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients wereudaged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, MyastheniaudGravis Foundation of America (MGFA) class II–IV disease, vaccination against Neisseria meningitides, and previousudtreatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenousudimmunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma orudthymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasmaudexchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. Weudrandomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks.udDosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given everyudsecond week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or webresponseudsystem with patients stratified to one of four groups based on MGFA disease classification. Where possible,udpatients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the studyudphysician’s discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. Theudprimary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rankudANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who receivedudat least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADLudassessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trialudis registered with ClinicalTrials.gov, number NCT01997229.udFindings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumabudand 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (leastsquaresudmean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference −11·7, 95% CI −24·3 to 0·96;udp=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverseudevents in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumabudgroup and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patientsudin the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%)udin the placebo group required rescue therapy.udInterpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, asudmeasured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approachudproved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistentudwith the primary endpoint resu further research into the role of complement is needed.