Copolymer 1 reduced relapse rate and improved disability in multiple sclerosis
ACP J Club. 1996 Jan-Feb;124:2. doi:10.7326/ACPJC-1996-124-1-002
Johnson KP, Brooks BR, Cohen JA, et al. and the Copolymer 1 Multiple Sclerosis Study Group. 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 Jul;45:1268-76.
To evaluate the effectiveness and safety of copolymer 1 in reducing the relapse rate and alleviating disability in patients with relapsing-remitting multiple sclerosis (MS).
Randomized, double-blind, placebo-controlled trial with 2-year follow-up.
11 universities with active MS centers in the United States.
251 patients between the ages of 18 and 45 years (mean age 34 y, 73% women) with definite MS who were ambulatory, had a mean Expanded Disability Status Scale (EDSS) score between 0 and 5, had had ≥ 2 relapses in the previous 2 years, and had had neurologic stability and no corticosteroid therapy for ≥ 30 days before study entry. Exclusion criteria were previous copolymer 1 or immunosuppressive therapy with cytotoxic chemotherapy or lymphoid irradiation; pregnancy or lactation; insulin-dependent diabetes mellitus; positive human immunodeficiency virus or human T-cell lymphotrophic virus type 1 serology; Lyme disease; or required use of aspirin or chronic nonsteroidal anti-inflammatory therapy during the study.
125 patients were allocated to copolymer 1, 20 mg/d subcutaneously for 2 years, and 126 patients were allocated to placebo.
Main Outcome Measures
Relapse (defined as the appearance or reappearance of ≥ 1 neurologic abnormality lasting ≥ 48 h preceded by a stable or improving neurologic state for ≥ 30 d), median time to relapse, EDSS score, and adverse effects.
During the 2-year follow-up period, patients in the copolymer 1 group had 161 confirmed relapses compared with 210 confirmed relapses in patients in the placebo group. The mean 2-year relapse rate was 1.19 in the copolymer 1 group and 1.68 in the placebo group, a 29% reduction (P = 0.007). The median time to first relapse was 287 days for the copolymer 1 group and 198 days for the placebo group (P = 0.09). 42 patients (33.6%) were relapse-free in the copolymer 1 group compared with 34 patients (27.0%) in the placebo group (P = 0.098). More patients in the copolymer 1 group had improved EDSS scores at 2 years, whereas more patients in the placebo group were worse by ≥ 1 EDSS step (P = 0.037). Copolymer 1 therapy was well tolerated.
Copolymer 1 reduced the relapse rate and improved disability in patients with relapsing-remitting multiple sclerosis.
Sources of funding: Federal Food and Drug Administration Orphan Drug Program; the National Multiple Sclerosis Society; Teva Pharmaceutical Industries, Ltd.
For article reprint: Dr. K.P. Johnson, Department of Neurology, N4W46, University of Maryland Hospital, 22 South Greene Street, Baltimore, MD 21201, USA. FAX 410-328-5899.
Both of these studies found statistically significant reductions in relapse rates for patients with relapsing-remitting MS. The copolymer 1 study showed a significant reduction in disability among treated patients, whereas the IFNB study did not. The IFNB study documents a highly significant reduction in the progression of "lesion burden" measured on MRIs from baseline and annually for 4 years. The copolymer 1 trial did not report data for MRI lesion area. The authors of the copolymer 1 study concluded that there are now 2 drugs that change the natural history of relapsing-remitting MS, copolymer 1 and IFNB, but they caution that direct comparison of the 2 treatments will require further study.
Both studies are rigorous trials that adhered to strict protocols designed to minimize the inevitable complexities of evaluating disease progression in this patient population. Relapse rates, within- and between-patient differences in disease progression, baseline disability, sex, and duration of disease are only a few of the variables that may confound studies of MS therapies. The copolymer 1 study investigators address many of these potential confounders by statistically controlling for the covariate effects that they may have exerted on primary outcome measures.
The high quality of the data analysis is supported by an example from the IFNB study, in which the dropouts from the placebo arm had a more aggressive course of MS compared with the completers in the placebo arm. This finding raises the possibility that treatment-related reductions in lesion area progression may have been blunted by the high dropout rate in the placebo group of the patients with the most aggressive MS. The authors address this concern by confirming that the dropout rate from baseline to year 1 was negligible for both the placebo group and the high-dose IFNB group, but a pronounced improvement still occurred in lesion area progression for treated patients. The intention-to-treat analysis further assures us that this potential confounding variable, severity of disease, is unlikely to have biased the results. The dropout of the most severely affected patients from the placebo group, however, may have precluded the confirmation of benefit of IFNB on disability.
These 2 studies have direct relevance to physicians who treat patients who have relapsing-remitting MS. The beneficial effect of both drugs on the relapse rate is clinically important, and copolymer 1 was effective at reducing disability. Although the benefit of IFNB on disability was not statistically significant, the lack of progression of lesion burden and the significant correlation (r = 0.20, P < 0.001) between lesion-burden progression and relapse rate are sufficiently promising to pursue further trials to determine whether IFNB reduces the disability caused by MS.
Physicians are advised to consider the use of IFNB in their patients with relapsing-remitting MS, to consider copolymer 1 when it becomes available for use, and to monitor the literature for further evidence about the effectiveness and clinical use of these promising agents for the treatment of relapsing-remitting MS.
John R. Absher, MD
Bowman Gray School of MedicineWinston-Salem, North Carolina, USA