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
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
| Field | Copolymer 1 | Control |
|---|---|---|
| Intervention | 20 mg of copolymer 1 by daily subcutaneous self-injection | Placebo by daily subcutaneous self-injection |
| Duration | 24 months | 24 months |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-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 changes | Primary | 1.68 (annualized rate 0.84) | 1.19 (annualized rate 0.59) | 0.007 | |
| Proportion of relapse-free patients | Secondary | 27.0% | 33.6% | 0.098 | |
| Median time to first relapse (days) | Secondary | 198 | 287 | 0.097 | |
| Categorical change in EDSS (improved/unchanged/worsened by ≥1 step) from baseline to 24 months - Improved | Secondary | 15.2% | 24.8% | 0.037 | |
| Categorical change in EDSS - No change | Secondary | 56.0% | 54.4% | 0.037 | |
| Categorical change in EDSS - Worsened | Secondary | 28.8% | 20.8% | 0.037 | |
| Mean EDSS change from baseline (repeated measures) | Secondary | 0.21 ± 0.99 | -0.05 ± 1.13 | 0.023 | |
| Proportion of progression-free patients (increase ≥1 EDSS step sustained >90 days) | Secondary | 75.4% | 78.4% | NS | |
| Mean ambulation index change | Secondary | 0.28 ± 0.93 | 0.27 ± 0.94 | NS | |
| Injection-site reactions (at least once) | Adverse | 59% | 90% | ||
| Injection-site pain | Adverse | 36.51% | 64.00% | ||
| Injection-site erythema | Adverse | 12.70% | 56.80% | ||
| Transient self-limited systemic reaction | Adverse | 3.2% | 15.2% | ||
| Withdrawal due to adverse events | Adverse | 1 (protocol non-compliance 2) | 2 serious AEs (generalized lymphadenopathy, prolonged systemic reaction), 3 for brief systemic reactions | ||
| Total withdrawals | Adverse | 17 (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
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