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PRISMS

Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis

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Year of Publication: 1998

Authors: PRISMS Study Group, George C Ebers

Journal: The Lancet

Citation: Lancet 1998;352:1498-1504

Link: https://doi.org/10.1016/S0140-6736(98)03334-0

PDF: https://www.thelancet.com/journals/lance...3334-0/abstract

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?

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

Baseline Characteristics

Placebo:

  • N: 187
  • Age - Median (IQR): 34.6 (28.8-40.4)
  • Sex - Female: 75%
  • MS Duration - Median years (IQR): 4.3 (2.4-8.4)
  • Relapses in prior 2 years - Mean (SD): 3.0 (1.3)
  • EDSS - Mean (SD): 2.4 (1.2)

IFN-β-1a 22 μg:

  • N: 189
  • Age - Median (IQR): 34.8 (29.3-39.8)
  • Sex - Female: 67%
  • MS Duration - Median years (IQR): 5.4 (3.0-11.2)
  • Relapses in prior 2 years - Mean (SD): 3.0 (1.1)
  • EDSS - Mean (SD): 2.5 (1.2)

IFN-β-1a 44 μg:

  • N: 184
  • Age - Median (IQR): 35.6 (28.4-41.0)
  • Sex - Female: 66%
  • MS Duration - Median years (IQR): 6.4 (2.9-10.3)
  • Relapses in prior 2 years - Mean (SD): 3.0 (1.1)
  • EDSS - Mean (SD): 2.5 (1.3)

Arms

FieldControlIFN-β-1a 22 μgIFN-β-1a 44 μg
InterventionPlacebo subcutaneous injection 0.5 mL three times weeklyInterferon β-1a (Rebif) 22 μg subcutaneously three times weekly with dose escalation over 4-8 weeksInterferon β-1a (Rebif) 44 μg subcutaneously three times weekly with dose escalation over 4-8 weeks
Duration2 years2 years2 years

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Mean number of relapses per patient over 2 yearsPrimary2.56<0.005 for both doses vs placebo
Time to confirmed disability progression (1 point sustained 3 months)Secondary11.9 months to 25th percentile0.68 (22 μg), 0.62 (44 μg)≤0.05
Proportion relapse-free at 2 yearsSecondary16%OR 2.01 (22 μg), 2.57 (44 μg)<0.05
Median change in T2 burden of diseaseSecondary+10.9%<0.0001
T2 active lesions reduction vs placeboSecondaryReference<0.0001; dose effect p=0.0003
Mean EDSS change from baselineSecondary0.48<0.05
Injection site reactions (3 months)Adverse21.9%≤0.05
Lymphopenia (3 months)Adverse3.7%≤0.05 for 44 μg
Elevated ALT (3 months)Adverse1.1%≤0.05 for 44 μg
Depression (2 years)Adverse28%NS
Neutralizing antibodiesAdverseN/A

Subgroup Analysis

In patients with baseline EDSS >3.5 (more disabled), only the 44 μg dose significantly delayed disability progression compared to placebo (HR 0.42, 95% CI 0.18-0.99, p≤0.05); the 22 μg dose showed a non-significant trend (HR 0.75).

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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