← Back
NeuroTrials.ai
Neurology Clinical Trial Database

MEDEN

Comparative Evaluation of Rituximab Versus Approved Therapies in Aquaporin-4-IgG-Positive Neuromyelitis Optica Spectrum Disorder: A Systematic Review and Network Meta-analysis

Share Share Copied! Compare

Year of Publication: 2026

Authors: Barzegar M, Samadzadeh S, Audoin B, et al.; MEDEN study group

Journal: Neurology and Therapy

Citation: Neurol Ther (2026). https://doi.org/10.1007/s40120-026-00989-x

Link: https://doi.org/10.1007/s40120-026-00989-x

Bottom Line

In this network meta-analysis of 8 trials, hazard ratio point estimates for time to first relapse numerically favored eculizumab and ravulizumab over rituximab, but all pairwise comparisons were non-significant with extremely wide, overlapping confidence intervals — no therapy could be shown to be clearly superior, and rituximab likely remains a cornerstone globally because of its lower cost and wider accessibility.

Major Points

  • First NMA to include rituximab in a direct network alongside all approved monoclonal antibody therapies (eculizumab, ravulizumab, inebilizumab, satralizumab) for AQP4-IgG-positive NMOSD.
  • Eight trials met eligibility from 6,337 screened records: RIN-1 and Nikoo et al. (rituximab), PREVENT (eculizumab), CHAMPION-NMOSD (ravulizumab), N-MOmentum (inebilizumab), SAkuraSky and SAkuraStar (satralizumab), and TANGO (tocilizumab).
  • Primary NMA (combination ± monotherapy): rituximab vs ravulizumab HR 5.00 (95% CI 0.25–101.01); vs eculizumab HR 1.17 (95% CI 0.12–10.89); vs satralizumab HR 0.29 (95% CI 0.04–2.23) — all crossed the null.
  • Monotherapy NMA: rituximab vs ravulizumab HR 3.33 (0.13–83.16); vs eculizumab HR 1.59 (0.05–50.17); vs inebilizumab HR 0.31 (0.04–2.31); vs satralizumab HR 0.27 (0.03–2.21) — none statistically significant.
  • P-score treatment rankings for time to first relapse (combination±monotherapy): ravulizumab (0.927) > eculizumab (0.667) > rituximab (0.618) > satralizumab (0.287); monotherapy rankings were ravulizumab (0.868) > eculizumab (0.736) > rituximab (0.677) > inebilizumab (0.38) > satralizumab (0.334).
  • Substantial between-trial heterogeneity in baseline relapse activity (ARR 1.4–1.5 in rituximab/satralizumab trials vs 1.9 in eculizumab/ravulizumab trials), ethnicity, relapse definitions, adjudication (centrally adjudicated vs investigator-assessed in RIN-1), and use of concomitant immunosuppression makes indirect comparisons unreliable.
  • Continuity correction (0.5 to all cells) was applied because several trials had zero relapses in one arm, which introduces bias and inflates uncertainty in HR estimates.
  • Authors emphasize the findings are hypothesis-generating only and should NOT be used to select therapy; head-to-head trials or real-world registry studies are needed to determine relative efficacy.

Design

Study Type: Systematic Review and Frequentist Network Meta-analysis

Randomization:

Blinding: N/A (systematic review of published trials)

Enrollment Period: Databases searched through October 31, 2024, updated November 1, 2025

Follow-up Duration: Variable across included trials (RIN-1: 72 weeks; PREVENT: to 23 relapses; CHAMPION-NMOSD: ≥50 weeks in ravulizumab arm; other trials varied)

Countries: International — pooled from trials conducted globally (Japan, US, Europe, China, others)

Sample Size: 8

Analysis: Frequentist NMA using netmeta package in R v4.5.1; random-effects model; P-scores for treatment ranking; continuity correction 0.5 for zero-event arms; PRISMA-compliant; registered on OSF (identifier UW5MQ)

Inclusion Criteria

  • Population: patients who are AQP4-IgG-positive with neuromyelitis optica spectrum disorder (NMOSD)
  • Intervention: rituximab, eculizumab, inebilizumab, ravulizumab, satralizumab, or tocilizumab
  • Comparator: placebo or any other active intervention
  • Outcome: primary outcome was time to first relapse; secondary outcomes were any outcome reported in rituximab trials also reported in other trials (EDSS, ARR, QOSI, steroid reduction, AQP4 titers, lymphocyte subsets)
  • Study type: randomized clinical trials (RCTs) or open-label trials
  • Peer-reviewed publications

Exclusion Criteria

  • Observational studies (cohort, case-control, cross-sectional, case series, case reports)
  • Studies that did not compare a medication with placebo or another active medication
  • Reviews, animal studies, hypothesis papers, in vitro studies, and books
  • Systematic reviews, meta-analyses, and other network meta-analyses
  • Non-peer-reviewed articles
  • Qualitative studies
  • AQP4-IgG-negative NMOSD patients were excluded from the NMA analyses

Baseline Characteristics

CharacteristicRIN-1 (rituximab)PREVENT (eculizumab)CHAMPION-NMOSD (ravulizumab)SAkuraSky (satralizumab)SAkuraStar (satralizumab)N-MOmentum (inebilizumab)TANGO (tocilizumab)Nikoo et al. (rituximab)
Sample Size38 (19 rituximab, 19 placebo)143105
PopulationJapanese AQP4-IgG-positive NMOSD
Baseline ARR (prior 24 months)~1.4–1.51.91.9
Prior relapse requirementNone≥2 relapses in prior 12 months or ≥3 in prior 24 months≥1 relapse in previous 12 months≥2 relapses≥1 relapse in previous 12 months≥1 relapse in previous 12 months
Concomitant ISTTapered prednisolone 2–5 mg/day maintainedPermittedMonotherapyCombination therapy (with baseline IST)MonotherapyMonotherapy; prednisone 20 mg/day days 1–14 then tapered by day 21IST allowed for up to 12 weeks after enrollment
Follow-up72 weeks
DesignOpen-label; used PREVENT placebo group as external comparator
Baseline ARR~1.4–1.5
ComparatorAzathioprine (excluded from NMA)Azathioprine (excluded from primary NMA)
Primary OutcomeARR (time to relapse not reported)

Arms

FieldRituximabEculizumabRavulizumabInebilizumabSatralizumabControl
InterventionAnti-CD20 monoclonal antibody (off-label)Terminal complement C5 inhibitorLong-acting terminal complement C5 inhibitorAnti-CD19 monoclonal antibodyAnti-IL-6 receptor monoclonal antibodyPlacebo (used in most included trials)
DurationVariable (72 weeks in RIN-1)Trial-dependent≥50 weeks in CHAMPION-NMOSDTrial-dependentTrial-dependentTrial-dependent

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Time to first relapse — Rituximab vs comparators (Combination therapy ± Monotherapy NMA, hazard ratios; HR>1 indicates higher hazard with rituximab)PrimaryRituximab vs Ravulizumab ± IST: HR 5.00, 95% CI 0.25–101.01 (non-significant) · Rituximab vs Eculizumab ± IST: HR 1.17, 95% CI 0.12–10.89 (non-significant) · Rituximab vs Satralizumab ± IST: HR 0.29, 95% CI 0.04–2.23 (non-significant; point estimate favors rituximab) · P-score Rankings (combination±monotherapy): Ravulizumab 0.927 > Eculizumab 0.667 > Rituximab 0.618 > Satralizumab 0.287 · Statistical significance: All pairwise comparisons non-significant; wide overlapping CIs crossing HR=1
Time to first relapse — Monotherapy NMA: Rituximab vs RavulizumabSecondaryHR 3.33Non-significant
Time to first relapse — Monotherapy NMA: Rituximab vs EculizumabSecondaryHR 1.59Non-significant
Time to first relapse — Monotherapy NMA: Rituximab vs InebilizumabSecondaryHR 0.31Non-significant
Time to first relapse — Monotherapy NMA: Rituximab vs SatralizumabSecondaryHR 0.27Non-significant
Monotherapy P-score rankingsSecondaryRavulizumab 0.868 > Eculizumab 0.736 > Rituximab 0.677 > Inebilizumab 0.38 > Satralizumab 0.334
Absolute relapse events in monotherapy rituximab (RIN-1)Secondary0 relapses among 19 rituximab-treated vs 7 relapses among 19 placebo (RIN-1, 72 weeks)
EDSS change, ARR, QOSI, steroid reduction, AQP4 titers, HACA/JCV antibodies, lymphocyte subsetsSecondaryNot analyzed in NMA due to non-uniform reporting across included trials
Not assessedAdverseSafety comparisons were beyond the scope of this NMA — authors state that meaningful safety comparisons would require observational and real-world data. This is acknowledged as a limitation.

Subgroup Analysis

Two analyses conducted: (1) combination therapy ± monotherapy (5 studies: RIN-1, PREVENT, CHAMPION-NMOSD, SAkuraSky, SAkuraStar); (2) monotherapy only (6 studies: same plus N-MOmentum). TANGO and Nikoo et al. excluded from both due to azathioprine comparator and lack of time-to-relapse reporting.

Criticisms

  • Extremely small sample size for rituximab (only 19 patients in RIN-1) drives enormous confidence interval widths (CIs spanning HR 0.04 to 101) — all pairwise comparisons were statistically non-significant.
  • Substantial between-trial heterogeneity in baseline relapse activity (ARR 1.4–1.5 in rituximab/satralizumab trials vs 1.9 in eculizumab/ravulizumab trials) violates the transitivity assumption critical for NMA validity.
  • RIN-1 enrolled exclusively Japanese patients, a population associated with better clinical outcomes; other trials had diverse international populations — ethnicity is a known effect modifier.
  • Marked differences in relapse definitions and adjudication (investigator-assessed in RIN-1 vs central blinded committees in other trials; MRI-supported in RIN-1 and N-MOmentum vs clinical-only in others).
  • Variation in required prior relapse history (none required in RIN-1 vs ≥2–3 in PREVENT) means trial populations were not comparable.
  • Zero-event arms required a continuity correction (adding 0.5 to all cells) which introduces bias and inflates uncertainty.
  • CHAMPION-NMOSD was open-label and used the PREVENT placebo arm as an external comparator, further complicating direct comparability.
  • Only one trial per therapy (except satralizumab with two), no direct head-to-head comparisons, and no inclusion of trial extension phases.
  • Time to first relapse alone does not capture long-term disease control, relapse severity, or cumulative disability; annualized relapse rate and EDSS could not be pooled due to inconsistent reporting.
  • Safety data were not analyzed — no comparative adverse event information provided.

Funding

No funding or sponsorship was received for the publication of this article. Multiple authors report speaker/advisory fees from companies marketing NMOSD therapies (Alexion, Roche, Argenx, UCB, Novartis, Sanofi, others); one author (MB) is an Advisory Board member of Neurology and Therapy.

Based on: MEDEN (Neurology and Therapy, 2026)

Authors: Barzegar M, Samadzadeh S, Audoin B, et al.; MEDEN study group

Citation: Neurol Ther (2026). https://doi.org/10.1007/s40120-026-00989-x

Content summarized and formatted by NeuroTrials.ai.