RINOMAX
(2022)Objective
To investigate the efficacy and safety of a single low-dose rituximab infusion compared with placebo as add-on to standard of care for new-onset generalized myasthenia gravis
Study Summary
• Rescue treatment was needed in only 4% with rituximab vs 36% with placebo (P = .008)
• No hospitalizations for MG exacerbation with rituximab vs 3 with placebo
Intervention
Single intravenous infusion of 500 mg rituximab vs matching placebo
Inclusion Criteria
Adults >=18 years with new-onset generalized MG (<=12 months), QMG score >=6, MGFA class II-IV, diagnosis confirmed by AChR antibodies, electrophysiology, or AChEI response
Study Design
Arms: Rituximab 500 mg IV single dose, Placebo
Patients per Arm: 25 (rituximab), 22 (placebo)
Outcome
• Rescue therapy by 24 weeks: 4% vs 36%, PR 0.11, P = .008
• Secondary endpoints (per-protocol) not significant due to differential censoring; post hoc worst rank analysis favored rituximab
Bottom Line
A single 500 mg infusion of rituximab significantly increased the proportion of patients achieving minimal disease manifestations (71% vs 29%) at 16 weeks and substantially reduced the need for rescue therapies (4% vs 36%), supporting early rituximab use in new-onset generalized MG.
Major Points
- Primary endpoint achieved: 71% (17/24) with rituximab vs 29% (6/21) with placebo met minimal disease manifestations at 16 weeks (PR 2.48, P = .007)
- Rituximab dramatically reduced need for rescue treatment: 4% vs 36% (P = .008)
- No hospitalizations for MG exacerbation in rituximab group vs 3 in placebo group (including 1 requiring mechanical ventilation)
- Secondary endpoints showed no difference with per-protocol analysis due to differential censoring, but post hoc worst rank analysis favored rituximab
- Low-dose single infusion protocol (500 mg) was used, similar to Swedish MS protocols
- All but 2 patients were AChR+; the 2 seronegative patients were MuSK-
- One fatal cardiac event occurred in rituximab arm in patient with preexisting ischemic heart disease
- One patient randomized to rituximab was later diagnosed with ALS (initial MG diagnosis was incorrect)
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind: patients, investigators, and all study personnel were blinded. Central pharmacy prepared and shipped blinded study drug in identical containers
- Sample Size
- 47
- Follow-up
- 48 weeks
- Centers
- 7
- Countries
- Sweden
Primary Outcome
Definition: Minimal disease manifestations at week 16 defined as QMG score <=4, daily prednisolone dose <=10 mg, and no rescue treatment during weeks 9-16
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 6/21 (29%) | 17/24 (71%) | - (1.20 to 5.11 (probability ratio)) | .007 |
Limitations & Criticisms
- Small sample size (n=47) limits generalizability and statistical power
- Baseline imbalances between groups: placebo group was younger, had higher AChR titers, lower proportion on prednisolone, and more MGFA class III disease
- Randomization was done without stratification, contributing to baseline imbalances
- Secondary endpoints failed to show significance due to differential censoring from rescue treatment (disproportionately affected placebo arm)
- One participant in rituximab arm was later diagnosed with ALS (misdiagnosed as MG initially)
- One thymoma was discovered post-enrollment in placebo arm despite exclusion criteria
- Low-dose rituximab protocol (500 mg) may not be optimal; higher doses might show greater efficacy
- Long-term benefit-risk balance not established from this 48-week study
- Predominantly late-onset MG population (92% in rituximab arm) limits applicability to early-onset MG
- Only 2 MuSK+ patients enrolled, preventing subgroup analysis for this population
- Fatal cardiac event in rituximab arm occurred in patient with preexisting ischemic heart disease
Citation
JAMA Neurol. 2022;79(11):1105-1112