PRISMS
Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis
Clinical Question
Does subcutaneous interferon β-1a reduce relapse rate, delay disability progression, and improve MRI outcomes in relapsing-remitting MS compared to placebo, and is there a dose-response relationship?
Study Overview
Objective
To investigate the effects of subcutaneous interferon β-1a on relapse rate, disability progression, and MRI outcomes in relapsing-remitting multiple sclerosis
Study Summary
- IFN-β-1a 44 μg TIW reduced relapse rate by 33% vs placebo (p<0.005)
- Both doses significantly delayed time to confirmed disability progression
- T2 lesion burden decreased 3.8% with high dose vs 10.9% increase with placebo
Intervention
Subcutaneous interferon β-1a (Rebif) 22 μg or 44 μg three times weekly vs placebo
Patients per Arm
Placebo: 187, IFN-β-1a 22 μg: 189, IFN-β-1a 44 μg: 184
Bottom Line
Subcutaneous IFN-β-1a at both 22 μg and 44 μg TIW significantly reduced relapse rates by 27-33%, delayed disability progression, and reduced MRI lesion burden compared to placebo, with evidence of dose-response favoring the higher dose.
Major Points
- 33% reduction in relapse rate with 44 μg dose vs placebo (27% with 22 μg)
- Time to first relapse prolonged by 3 months (22 μg) and 5 months (44 μg)
- Significant delay in confirmed disability progression at both doses
- T2 lesion burden decreased with treatment vs 10.9% increase with placebo
- 67-78% reduction in T2 active lesions on MRI
- Dose-response relationship demonstrated for most clinical and MRI outcomes
- Neutralizing antibodies less frequent at higher dose (12.5% vs 23.8%)
- Treatment well tolerated with expected interferon side effects
Design
Study Type: Phase 3, randomized, double-blind, placebo-controlled trial
Randomization: 1
Blinding: Double-blind; treating neurologist separate from assessing neurologist; injection sites covered during examinations; MRI analyzed centrally by blinded researchers
Enrollment Period: May 1994 to February 1995
Follow-up Duration: 2 years
Centers: 22
Countries: Australia, Belgium, Canada, Finland, Germany, Netherlands, Sweden, Switzerland, UK
Sample Size: 560
Analysis: Intention-to-treat; GLM with log link for relapse count; Cox proportional hazards for time-to-event; logistic regression for binary outcomes; ANOVA on rank data for continuous endpoints
Inclusion Criteria
- Clinically definite or laboratory-supported definite MS
- Relapsing-remitting course
- Disease duration ≥1 year
- ≥2 relapses in previous 2 years
- EDSS score 0-5.0
Exclusion Criteria
- Previous systemic treatment with interferons
- Previous lymphoid irradiation
- Previous cyclophosphamide treatment
- Other immunomodulatory or immunosuppressive treatments in preceding 12 months
Arms
| Field | Control | IFN-β-1a 22 μg | IFN-β-1a 44 μg |
|---|---|---|---|
| Intervention | Placebo subcutaneous injection 0.5 mL three times weekly | Interferon β-1a (Rebif) 22 μg subcutaneously three times weekly with dose escalation over 4-8 weeks | Interferon β-1a (Rebif) 44 μg subcutaneously three times weekly with dose escalation over 4-8 weeks |
| Duration | 2 years | 2 years | 2 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Mean number of relapses per patient over 2 years | Primary | 2.56 | <0.005 for both doses vs placebo | ||
| Time to confirmed disability progression (1 point sustained 3 months) | Intervention 22 μg: 18.5 months; Intervention 44 μg: 21.3 months | Secondary | 11.9 months to 25th percentile | Risk ratio 0.68 (95% CI 0.48-0.98) for 22 μg; 0.62 (0.43-0.91) for 44 μg | ≤0.05 | |
| Proportion relapse-free at 2 years | Intervention 22 μg: 27%; Intervention 44 μg: 32% | Secondary | 16% | OR (none vs any relapses) 2.01 (95% CI 1.21-3.35) for 22 μg; 2.57 (1.56-4.25) for 44 μg | <0.05 | |
| Median change in T2 burden of disease | Intervention 22 μg: -1.2%; Intervention 44 μg: -3.8% | Secondary | +10.9% | <0.0001 | ||
| T2 active lesions reduction vs placebo | Intervention 22 μg: 67% reduction; Intervention 44 μg: 78% reduction | Secondary | Reference | <0.0001; dose effect p=0.0003 | ||
| Mean EDSS change from baseline | Intervention 22 μg: 0.23; Intervention 44 μg: 0.24 | Secondary | 0.48 | <0.05 | ||
| Injection site reactions (3 months) | Adverse | 21.9% | Intervention 22 μg: 60.8%; Intervention 44 μg: 61.9% | ≤0.05 | |
| Lymphopenia (3 months) | Adverse | 3.7% | Intervention 22 μg: 4.7%; Intervention 44 μg: 13.0% | ≤0.05 for 44 μg | |
| Elevated ALT (3 months) | Adverse | 1.1% | Intervention 22 μg: 4.8%; Intervention 44 μg: 6.5% | ≤0.05 for 44 μg | |
| Depression (2 years) | Adverse | 28% | Intervention 22 μg: 21%; Intervention 44 μg: 24% | NS | |
| Neutralizing antibodies | Adverse | N/A | Intervention 22 μg: 23.8%; Intervention 44 μg: 12.5% |
Subgroup Analysis
In patients with baseline EDSS >3.5 (more disabled), only the 44 μg dose significantly delayed disability progression compared to placebo (Risk ratio 0.42, 95% CI 0.18-0.99, p≤0.05); the 22 μg dose showed a non-significant trend (Risk ratio 0.75, 95% CI 0.35-1.56).
Criticisms
- Treatment allocation may have been revealed due to characteristic interferon side effects
- EDSS changes at lower scale scores have not been validated as surrogates for longer-term disability outcomes
- Disability scores may be affected by acute relapses despite 3-month confirmation requirement
- Short 2-year duration limits conclusions about long-term disability prevention
- Arm-function index showed no significant change due to relative insensitivity of measure
Funding
Ares-Serono International SA (Geneva, Switzerland)
Based on: PRISMS (The Lancet, 1998)
Authors: PRISMS Study Group, George C Ebers
Citation: Lancet 1998;352:1498-1504
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