RIN-1
(2020)Objective
To evaluate the efficacy and safety of rituximab compared with placebo in preventing relapses in patients with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder
Study Summary
• No patient in rituximab group relapsed; 7 of 19 placebo patients relapsed
• EDSS worsening significantly less in rituximab group
• CD19+ B cells depleted to <1% in rituximab group
Intervention
Rituximab 375 mg/m² IV weekly × 4 at baseline then single infusion at weeks 24 and 48, versus placebo infusions on same schedule, for 72 weeks
Inclusion Criteria
Age 18-70 years; AQP4-IgG seropositive NMOSD per 2015 IPND criteria; ≥1 relapse in preceding 2 years or ≥2 relapses in preceding 4 years; EDSS 0-7.0
Study Design
Arms: Array
Patients per Arm: Rituximab: 19; Placebo: 19
Outcome
• Relapse-free: 100% vs 63%
• EDSS change: improved in rituximab, worsened in placebo
• Infusion reactions: 26% rituximab vs 5% placebo; no serious infections
Bottom Line
Rituximab completely prevented relapses over 72 weeks (0% vs 37% placebo, P=0.0058) in AQP4-positive NMOSD patients, providing the first randomized controlled trial evidence supporting rituximab use in this condition, which had previously relied on observational data alone.
Major Points
- First double-blind, placebo-controlled RCT of rituximab in NMOSD
- 38 AQP4-IgG seropositive NMOSD patients randomized 1:1 to rituximab or placebo
- Zero relapses in rituximab group vs 7 relapses in 19 placebo patients (37%) over 72 weeks, P=0.0058
- Study stopped early by the data safety monitoring board due to overwhelming efficacy
- CD19+ B cells depleted to <1% within 2 weeks and maintained throughout in rituximab group
- EDSS improved in rituximab group (mean change −0.2) vs worsened in placebo group (mean change +0.8)
- No serious infections or unexpected safety signals in the rituximab group
- Supports rituximab as a cost-effective alternative to newer biologics (inebilizumab, satralizumab, eculizumab) in NMOSD
Study Design
- Study Type
- Multicenter, double-blind, placebo-controlled, phase II/III randomized controlled trial
- Randomization
- Yes
- Blinding
- Double-blind; identical placebo infusions; independent relapse adjudication committee blinded to treatment
- Sample Size
- 38
- Follow-up
- 72 weeks
- Centers
- 7
- Countries
- Japan
Primary Outcome
Definition: Time to first relapse over 72 weeks
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 37% relapsed (7/19) | 0% relapsed (0/19) | - | 0.0058 |
Limitations & Criticisms
- Very small sample size (N=38) limits generalizability and detection of rare adverse events
- Conducted exclusively in Japan — ethnic/genetic homogeneity may not represent global NMOSD populations
- Short follow-up (72 weeks) does not assess long-term efficacy, hypogammaglobulinemia risk, or sustained remission after discontinuation
- Study stopped early, which can overestimate treatment effects
- No active comparator — standard of care (azathioprine, mycophenolate) not tested
- Concomitant low-dose corticosteroids allowed in both groups, potentially confounding results
Citation
Lancet Neurol 2020;19:298-306