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Copolymer-1 Pivotal Trial

Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial

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Year of Publication: 1995

Authors: Johnson KP, Brooks BR, Cohen JA, ..., for the Copolymer 1 Multiple Sclerosis Study Group

Journal: Neurology

Citation: Neurology 1995;45:1268-1276

Link: https://www.neurology.org/doi/10.1212/WNL.45.7.1268

Clinical Question

Does glatiramer acetate (Copolymer-1) 20 mg subcutaneous daily reduce relapse rates and disability progression compared with placebo in relapsing-remitting multiple sclerosis?

Bottom Line

Glatiramer acetate 20 mg SC daily significantly reduced the 2-year relapse rate by 29% (1.19 vs 1.68, P=0.007) and improved EDSS scores compared with placebo in RRMS patients, establishing it as an effective injectable disease-modifying therapy with a favorable safety profile dominated by injection site reactions.

Major Points

  • Phase III, multicenter, double-blind, placebo-controlled trial of 251 RRMS patients across 11 US centers
  • Mean 2-year relapse rate significantly lower with glatiramer acetate: 1.19 vs 1.68 (29% reduction, P=0.007)
  • EDSS improved by 0.05 in glatiramer group vs worsened by 0.21 in placebo group (P=0.023)
  • 33.6% of glatiramer patients were relapse-free at 2 years vs 27.0% of placebo patients
  • Injection site reactions occurred in 90% of glatiramer patients but were generally mild and self-limiting
  • 15% of glatiramer patients experienced transient systemic post-injection reaction (flushing, chest tightness, dyspnea)
  • Led to FDA approval of glatiramer acetate (Copaxone) in 1996 for relapsing-remitting MS

Design

Study Type: Multicenter, double-blind, placebo-controlled, phase III randomized controlled trial

Randomization: 1

Blinding: Double-blind with matching placebo injections

Enrollment Period: 1991-1993

Follow-up Duration: 2 years

Centers: 11

Countries: United States

Sample Size: 251

Analysis: Intention-to-treat; Poisson regression for relapse rates; Wilcoxon rank-sum for EDSS change

Inclusion Criteria

  • Age 18-45 years
  • Clinically definite relapsing-remitting MS (Poser criteria)
  • EDSS score 0-5.0
  • ≥2 exacerbations in the preceding 2 years
  • Disease duration ≥1 year
  • Ambulatory

Exclusion Criteria

  • Progressive forms of MS
  • Prior treatment with immunosuppressive agents within 6 months
  • Prior treatment with glatiramer acetate
  • Pregnancy or lactation
  • Significant systemic disease

Arms

FieldGlatiramer acetateControl
InterventionGlatiramer acetate 20 mg subcutaneous dailyMatching placebo subcutaneous daily
Duration2 years2 years

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Mean 2-year relapse ratePrimary1.681.1929% reduction in relapse rate0.007
Change in EDSS from baselineSecondary+0.21-0.050.023
Proportion relapse-free at 2 yearsSecondary27.0%33.6%NS
Time to first relapseSecondaryShorterLonger0.014
Proportion with sustained EDSS worsening ≥1.5 stepsSecondary14.3%8.0%NS
Injection site reactionsAdverse37%90%<0.001
Post-injection systemic reactionAdverse3%15%<0.001
Transient chest tightnessAdverse1%13%<0.001

Subgroup Analysis

Benefit observed across subgroups regardless of baseline EDSS or relapse history; greater benefit in patients with higher baseline relapse rates

Criticisms

  • Relatively small sample size (N=251) by modern standards
  • No MRI outcomes included in this trial (addressed in later extension study)
  • 2-year duration may not capture long-term disability outcomes
  • Injection site reactions may have partially unblinded participants
  • No active comparator — placebo-controlled only

Funding

Teva Pharmaceutical Industries

Based on: Copolymer-1 Pivotal Trial (Neurology, 1995)

Authors: Johnson KP, Brooks BR, Cohen JA, ..., for the Copolymer 1 Multiple Sclerosis Study Group

Citation: Neurology 1995;45:1268-1276

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