← Back
NeuroTrials.ai
Neurology Clinical Trial Database

Copolymer 1

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

Share Share Copied! Compare

Year of Publication: 1995

Authors: K.P. Johnson, B.R. Brooks, J.A. Cohen, ..., and the Copolymer 1 Multiple Sclerosis Study Group

Journal: Neurology

Citation: Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: Results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology 1995;45:1268-1276

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

Clinical Question

Does daily subcutaneous administration of copolymer 1 (20 mg) reduce the relapse rate and improve disability in patients with relapsing-remitting multiple sclerosis compared to placebo over 2 years?

Bottom Line

Copolymer 1 treatment significantly reduced the MS relapse rate by 29% and favorably affected neurologic disability with good patient tolerance and minimal side effects in relapsing-remitting MS patients

Major Points

  • This phase III multicenter trial confirmed findings from an earlier pilot study showing efficacy of copolymer 1 in relapsing-remitting MS
  • The 2-year relapse rate was significantly reduced with copolymer 1 (1.19 vs 1.68, p=0.007), representing a 29% reduction
  • Disability measured by EDSS showed significant benefit with more patients improving and fewer worsening in the copolymer 1 group (p=0.037)
  • Treatment was well tolerated with injection-site reactions being the most common adverse event (90% vs 59%)
  • A transient self-limited systemic reaction occurred in 15.2% of copolymer 1 patients, characterized by flushing, chest tightness, palpitations, or dyspnea lasting 30 seconds to 30 minutes
  • Therapeutic effect appeared most pronounced in patients with lowest EDSS scores at entry (0-2)
  • This represents the second treatment (after interferon beta-1b) proven to alter the natural course of relapsing-remitting MS

Design

Study Type: Phase III multicenter, randomized, double-blind, placebo-controlled trial

Randomization: 1

Blinding: Double-blind using two-neurologist protocol (examining neurologist and treating neurologist both blinded to treatment assignment)

Enrollment Period: October 1991 to May 1992

Follow-up Duration: 24 months (2 years)

Centers: 11

Countries: United States

Sample Size: 251

Analysis: Intention-to-treat analysis as primary; ANCOVA for mean relapse rate with covariates including sex, duration of disease, prior 2-year relapse rate, and baseline EDSS; logistic regression for proportions; Weibull regression for time to first relapse; repeated-measures ANCOVA for disability changes

Inclusion Criteria

  • Clinically definite MS or laboratory-supported definite MS
  • Age 18-45 years
  • Ambulatory with EDSS score 0-5.0
  • History of at least 2 clearly identified and documented relapses in the 2 years prior to entry
  • Onset of first relapse at least 1 year before randomization
  • Period of neurologic stability and freedom from corticosteroid therapy of at least 30 days prior to entry

Exclusion Criteria

  • Prior treatment with copolymer 1
  • Previous immunosuppressive therapy with cytotoxic chemotherapy (azathioprine, cyclophosphamide, or cyclosporine) or lymphoid irradiation
  • Pregnancy or lactation
  • Insulin-dependent diabetes mellitus
  • Positive HIV or HTLV-I serology
  • Evidence of Lyme disease
  • Required use of aspirin or chronic nonsteroidal anti-inflammatory drugs during the trial

Arms

FieldCopolymer 1Control
Intervention20 mg of copolymer 1 by daily subcutaneous self-injectionPlacebo by daily subcutaneous self-injection
Duration24 months24 months

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Mean number of MS relapses over 24 months (covariate adjusted mean). Relapse defined as appearance or reappearance of neurologic abnormalities persisting ≥48 hours, preceded by stable or improving state of ≥30 days, confirmed by objective neurologic changesPrimary1.68 (annualized rate 0.84)1.19 (annualized rate 0.59)0.007
Proportion of relapse-free patientsSecondary27.0%33.6%0.098
Median time to first relapse (days)Secondary1982870.097
Categorical change in EDSS (improved/unchanged/worsened by ≥1 step) from baseline to 24 months - ImprovedSecondary15.2%24.8%0.037
Categorical change in EDSS - No changeSecondary56.0%54.4%0.037
Categorical change in EDSS - WorsenedSecondary28.8%20.8%0.037
Mean EDSS change from baseline (repeated measures)Secondary0.21 ± 0.99-0.05 ± 1.130.023
Proportion of progression-free patients (increase ≥1 EDSS step sustained >90 days)Secondary75.4%78.4%NS
Mean ambulation index changeSecondary0.28 ± 0.930.27 ± 0.94NS
Injection-site reactions (at least once)Adverse59%90%
Injection-site painAdverse36.51%64.00%
Injection-site erythemaAdverse12.70%56.80%
Transient self-limited systemic reactionAdverse3.2%15.2%
Withdrawal due to adverse eventsAdverse1 (protocol non-compliance 2)2 serious AEs (generalized lymphadenopathy, prolonged systemic reaction), 3 for brief systemic reactions
Total withdrawalsAdverse17 (13.5%)19 (15.2%)NS

Subgroup Analysis

Patients with lower EDSS scores at baseline (0-2) had fewer relapses during the trial and showed the most pronounced therapeutic effect (33% difference in relapse rate favoring copolymer 1). Patients with higher baseline EDSS had more relapses regardless of treatment group, though copolymer 1 still showed benefit.

Criticisms

  • The difference in mean relapse rate, though highly significant, was less pronounced than in the earlier pilot study (29% vs greater reduction in pilot), possibly due to differences in patient populations
  • The study population had lower pre-study relapse frequency and proportionally fewer patients at low end of EDSS scale compared to pilot study
  • Sustained progression (defined as EDSS increase ≥1 step for >90 days) did not differ significantly between groups, though this may reflect the relatively early disease stage of enrolled patients
  • Ambulation index changes were not significantly different between groups
  • The two-neurologist protocol, while maintaining blinding, added complexity to trial conduct
  • MRI and neuropsychological testing results were not included in this publication
  • The mechanism of action of copolymer 1, though studied extensively in vitro and in EAE models, remains incompletely understood in human MS

Funding

Federal Food and Drug Administration Orphan Drug Program no. FD-R000559-01, National Multiple Sclerosis Society no. RG 2202-A-6, and Teva Pharmaceutical Industries, Ltd., Petah Tiqva, Israel

Based on: Copolymer 1 (Neurology, 1995)

Authors: K.P. Johnson, B.R. Brooks, J.A. Cohen, ..., and the Copolymer 1 Multiple Sclerosis Study Group

Citation: Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: Results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology 1995;45:1268-1276

Content summarized and formatted by NeuroTrials.ai.