IFNB MS Study
(1993)Objective
To evaluate the efficacy and safety of recombinant interferon beta-1b (IFN-β-1b) in reducing relapse rate and MRI disease activity in patients with relapsing-remitting multiple sclerosis
Study Summary
• Relapse-free at 2 yr: 36% high-dose vs 18% placebo
• MRI disease burden reduced by 17.3% in high-dose vs 3.6% increase in placebo group
• First disease-modifying therapy approved for MS (FDA 1993)
Intervention
Interferon beta-1b (Betaseron) 8 MIU or 1.6 MIU subcutaneous every other day for up to 5 years
Inclusion Criteria
Age 18-50 years; clinically definite or laboratory-supported definite relapsing-remitting MS; EDSS 0-5.5; ≥2 exacerbations in preceding 2 years; ambulatory
Study Design
Arms: Array
Patients per Arm: High-dose (8 MIU): 124; Low-dose (1.6 MIU): 125; Placebo: 123
Outcome
• Relapse-free at 2 yr: 36% vs 18% (placebo)
• MRI burden: −17.3% high-dose vs +3.6% placebo
• Flu-like symptoms: 76% high-dose; injection site reactions: 85% high-dose
Bottom Line
Interferon beta-1b 8 MIU subcutaneous every other day significantly reduced the annual relapse rate by 34% (0.84 vs 1.27, P=0.0001) and MRI disease burden compared with placebo in RRMS patients, becoming the first FDA-approved disease-modifying therapy for multiple sclerosis.
Major Points
- Landmark phase III trial — first disease-modifying therapy proven effective in MS and first to receive FDA approval (1993)
- 372 RRMS patients randomized to 3 arms: high-dose IFN-β-1b (8 MIU), low-dose (1.6 MIU), or placebo
- Annual relapse rate significantly reduced: 0.84 high-dose vs 1.12 low-dose vs 1.27 placebo (P=0.0001 for high-dose)
- 36% of high-dose patients relapse-free at 2 years vs 18% placebo
- MRI disease burden decreased 17.3% in high-dose group vs 3.6% increase in placebo group
- No significant effect on disability progression (EDSS) — a limitation addressed in subsequent extension studies
- Dose-response relationship evident across both clinical and MRI endpoints
- Flu-like symptoms (76%) and injection site reactions (85%) were common but manageable
Study Design
- Study Type
- Multicenter, double-blind, placebo-controlled, phase III randomized controlled trial
- Randomization
- Yes
- Blinding
- Double-blind with matching placebo injections; MRI readers blinded to treatment assignment
- Sample Size
- 372
- Follow-up
- 2-5 years (median 3 years)
- Centers
- 11
- Countries
- United States, Canada
Primary Outcome
Definition: Annual exacerbation rate
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 1.27 | 0.84 (high-dose); 1.12 (low-dose) | - | 0.0001 (high-dose vs placebo) |
Limitations & Criticisms
- No significant effect on disability progression — relapse reduction did not translate to EDSS improvement in the initial study period
- Injection site necrosis occurred in 5% of high-dose patients — a unique safety concern for IFN-β-1b
- High rate of neutralizing antibody formation (45% in high-dose group) which may attenuate long-term efficacy
- Variable follow-up duration (2-5 years) makes long-term comparisons difficult
- Unblinding risk due to flu-like symptoms and injection site reactions
Citation
Neurology 1993;43:655-661