Interferon β-1b reduced exacerbations in multiple sclerosis
ACP J Club. 1996 Jan-Feb;124:3. doi:10.7326/ACPJC-1996-124-1-003
The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995 Jul; 45:1277-85.
To compare the effectiveness and safety of 2 doses of interferon β-1b (IFNB) with placebo in reducing exacerbations in patients with relapsing-remitting multiple sclerosis (MS).
Randomized, double-blind, placebo-controlled trial with a median 46-month follow-up.
11 medical centers in the United States and Canada.
372 patients (mean age 36 y, mean duration of disease 4.4 y, 70% women) with clinically definite or laboratory-supported definite MS. Patients were ambulatory with Expanded Disability Status Scale (EDSS) scores between 0 and 5.5, had had ≥ 2 acute exacerbations in the previous 2 years, had been clinically stable for ≥ 30 days, had not received adrenocorticotropic hormone or prednisone in the previous 30 days, and had never received azathioprine or cyclophosphamide.
125 patients were allocated to 1.6 million international units (MIU) of IFNB, 124 were allocated to 8 MIU of IFNB, and 123 were allocated to placebo. All treatments were self-administered subcutaneously every other day.
Main Outcome Measures
Annual rate of exacerbations (defined as the appearance and worsening of MS symptoms that were accompanied by a new neurologic abnormality, that existed for ≥ 24 h without fever, and that were preceded by stability or improvement in the previous 30 days) and disease burden and activity as measured by magnetic resonance imaging (MRI).
Pooled annual exacerbation rates for the entire study were 1.12 (95% CI 1.02 to 1.23) for the placebo group, 0.96 (CI 0.87 to 1.06) for the 1.6-MIU group, and 0.78 (CI 0.70 to 0.88) for the 8-MIU group (P < 0.01 for both comparisons of active drug with placebo). In the first year of follow-up, a 33% reduction occurred in the exacerbation rate in the 8-MIU group compared with the placebo group (P < 0.001). An increase occurred in MRI lesion burden each year, compared with baseline, in the placebo group and, with the exception of year 5, in the 1.6-MIU group (at 4 y P ≤ 0.001). In contrast, no increase occurred in lesion burden in the 8-MIU group (at 4 y P = 0.92). 35% of patients in the 8-MIU group satisfied the criteria for disease progression compared with 46% of patients in the placebo group (P = 0.096). Laboratory abnormalities were slightly more common in the 8-MIU group than in the placebo group, but were infrequent in both groups after 3 months.
Interferon β-1b was well tolerated and reduced the rate of exacerbations and progression of lesion burden on magnetic resonance imaging in patients with relapsing-remitting multiple sclerosis.
Sources of funding: Triton Biosciences and Berlex Laboratories.
For article reprint: Dr. W.A. Sibley, University Hospital, Tucson, AZ 85724, USA. FAX 520-626-4903.
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