PDF: PREVENT
(2019)Objective
To evaluate the efficacy and safety of eculizumab, a terminal complement inhibitor, in reducing relapse risk in patients with AQP4-IgG-positive neuromyelitis optica spectrum disorder
Study Summary
• Adjudicated ARR: 0.02 vs 0.35 (rate ratio 0.04, p<0.001)
• No significant difference in EDSS change (-0.18 vs +0.12); trial stopped after 23/24 prespecified relapses
Intervention
Eculizumab 900 mg IV weekly x 4 weeks, then 1200 mg IV every 2 weeks vs placebo; 76% continued stable-dose immunosuppressive therapy
Inclusion Criteria
Age ≥18 years, NMO/NMOSD diagnosis (2006/2007 criteria), AQP4-IgG seropositive, ≥2 relapses in prior 12 months or ≥3 in prior 24 months with ≥1 in past 12 months, EDSS ≤7, meningococcal vaccination
Study Design
Arms: Eculizumab IV (n=96) vs Placebo IV (n=47); 2:1 randomization
Patients per Arm: 96 (eculizumab), 47 (placebo)
Outcome
• Adjudicated ARR: 0.02 vs 0.35 (rate ratio 0.04; 95% CI 0.01-0.15; p<0.001)
• EDSS change: -0.18 vs +0.12 (difference -0.29; 95% CI -0.59 to 0.01; not significant)
• One death (pulmonary empyema) in eculizumab group; no meningococcal infections
Bottom Line
In this phase 3, randomized, double-blind, placebo-controlled trial, eculizumab dramatically reduced the risk of adjudicated relapse by 94% compared with placebo (3% vs 43%, HR 0.06, p<0.001) in patients with AQP4-IgG-positive NMOSD. The adjudicated annualized relapse rate was 0.02 with eculizumab vs 0.35 with placebo. However, there was no significant between-group difference in EDSS disability change. The trial was stopped early after 23 of 24 prespecified relapses. Eculizumab was generally well tolerated; one patient died from pulmonary empyema, but no meningococcal infections occurred despite this known risk. This trial led to FDA approval of eculizumab for AQP4-IgG-positive NMOSD.
Major Points
- First phase 3, randomized, placebo-controlled trial of complement inhibition in NMOSD
- Dramatic 94% reduction in adjudicated relapse risk with eculizumab (HR 0.06; 95% CI 0.02-0.20; p<0.001)
- Only 3/96 (3%) patients on eculizumab had adjudicated relapse vs 20/47 (43%) on placebo
- Adjudicated ARR: 0.02 (eculizumab) vs 0.35 (placebo); rate ratio 0.04 (p<0.001)
- 76% of patients continued stable-dose immunosuppressive therapy during trial
- Efficacy maintained in subgroup not receiving concomitant immunosuppressive therapy (0% vs 54% relapse)
- No significant difference in EDSS change (-0.18 vs +0.12; 95% CI crossed zero) - hierarchical testing failed here
- Trial stopped early after 23/24 prespecified adjudicated relapses due to uncertainty in timing of final event
- Physician-determined relapses higher than adjudicated (sensitivity analysis: 15% vs 62%, HR 0.18, p<0.001)
- One death from pulmonary empyema (S. intermedius and P. micros; organisms not associated with complement deficiency)
- No meningococcal infections despite this being a known risk of complement inhibition
- Led to FDA approval of eculizumab (Soliris) for AQP4-IgG-positive NMOSD
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled, time-to-event trial
- Randomization
- Yes
- Blinding
- Double-blind. Patients, site staff, and sponsor representatives were unaware of trial-group assignments. Trial agents and treatment kits appeared identical. EDSS raters were separate from treating physicians and also blinded. Independent relapse adjudication committee (3 members) blinded to treatment assignment.
- Sample Size
- 143
- Follow-up
- Time-to-event design; median not specified; trial terminated after 23/24 prespecified adjudicated relapses
- Centers
- 70
- Countries
- 18 countries
Primary Outcome
Definition: First adjudicated relapse. Relapse defined as: new onset or worsening of neurologic symptoms with objective change on examination persisting >24 hours, attributable to NMOSD rather than other causes, onset preceded by at least 30 days of clinical stability. Independent relapse adjudication committee (2 neurologists, 1 neuro-ophthalmologist) reviewed all physician-determined relapses.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 20/47 (43%) | 3/96 (3%) | 0.06 (0.02-0.20) | <0.001 |
Limitations & Criticisms
- Only AQP4-IgG-positive patients included - results cannot be extrapolated to seronegative NMOSD or MOG-antibody disease
- No significant between-group difference in EDSS change (hierarchical testing failed here) - long-term disability effects uncertain
- Trial design precluded follow-up beyond 6 weeks after single relapse - cannot assess sustained disability impact
- Trial stopped after 23/24 prespecified relapses, though retained >80% power
- Discordance between physician-determined and adjudicated relapses (53% agreement) - concern that adjudication was too strict
- Placebo control ethically questionable given known disease severity, though 76% received concomitant immunosuppressive therapy
- Rituximab excluded as concomitant therapy due to mechanistic incompatibility - cannot assess eculizumab vs rituximab
- High previous rituximab use (32%) may have affected baseline characteristics
- Higher withdrawal rate in eculizumab group (17% vs 6%) for reasons other than adverse events
- One death from pulmonary empyema in eculizumab group (though organisms not complement-related)
- Cost of eculizumab (~$500,000-700,000/year) limits accessibility - not addressed in trial
- 46 patients (32%) previously received rituximab but not within 3 months - potential carryover effects
Citation
N Engl J Med 2019;381:614-625