Efficacy and Safety of Rituximab for New-Onset Generalized Myasthenia Gravis: The RINOMAX Randomized Clinical Trial

Abstract

Importance: Rituximab is a third-line option for refractory generalized myasthenia gravis (MG) based on empirical evidence, but its effect in new-onset disease is unknown.

Objective: To investigate the efficacy and safety of rituximab compared with placebo as an add-on to standard of care for MG.

Design, setting, and participants: This randomized, double-blind, placebo-controlled study took place throughout 48 weeks at 7 regional clinics in Sweden. Key inclusion criteria were age older than 18 years, onset of generalized symptoms within 12 months or less, and a Quantitative Myasthenia Gravis (QMG) score of 6 or more. Patients were screened from October 20, 2016, to March 2, 2020. Key exclusion criteria included pure ocular MG, suspected thymoma, previous thymectomy, and prior noncorticosteroid immunosuppressants or high doses of corticosteroids.

Interventions: Participants were randomized 1:1 without stratification to a single intravenous infusion of 500 mg of rituximab or matching placebo.

Main outcomes and measures: Minimal disease manifestations at 16 weeks defined as a QMG score of 4 or less with prednisolone, 10 mg or less daily, and no rescue treatment.

Results: Of 87 potentially eligible patients, 25 were randomized to rituximab (mean [SD] age, 67.4 [13.4] years; 7 [28%] female) and 22 to placebo (mean [SD] age, 58 [18.6] years; 7 [32%] female). Compared with placebo, a greater proportion with rituximab met the primary end point; 71% (17 of 24) in the rituximab group vs 29% (6 of 21) in the placebo group (Fisher exact test P = .007; probability ratio, 2.48 [95% CI, 1.20-5.11]). Secondary end points, comparing changes in Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Quality of Life at 16 weeks with QMG at 24 weeks did not differ between groups with censoring for rescue treatment (per-protocol analysis) but were in favor of active treatment when rescue treatment was taken into account by worst rank imputation (post hoc analysis). Rescue treatments were also more frequent in the placebo arm (rituximab: 1 [4%]; placebo, 8 [36%]). One patient in the placebo arm had a myocardial infarction with cardiac arrest and 1 patient in the active arm experienced a fatal cardiac event.

Conclusions and relevance: A single dose of 500 mg of rituximab was associated with greater probability of minimal MG manifestations and reduced need of rescue medications compared with placebo. Further studies are needed to address long-term benefit-risk balance with this treatment.

Trial registration: ClinicalTrials.gov Identifier: NCT02950155.

Figure 1.. Study Flowchart

ALS indicates amyotrophic lateral sclerosis; ITT, intention-to-treat.

Figure 2.. Proportion With Minimal Disease Manifestation and No Rescue Treatment Over Time

A, Proportion with minimal disease manifestations at each study visit defined as Quantitative Myasthenia Gravis score ≤4 and a dose of prednisolone, ≤10 mg, without protocol-defined rescue treatment. Proportions at week 16 was the primary end point of the study, with other time points analyzed as tertiary end points. B, Kaplan-Meier estimates of the proportion with no rescue therapy and number of patients remaining at risk by week since randomization, for each treatment group. Shaded areas are 95% pointwise CIs. This was a post hoc analysis. HR indicates hazard ratio; Rtx, rituximab. ^aP = .007. ^bP = .04.