INTERFERON BETA-1B IN THE TREATMENT OF MULTIPLE-SCLEROSIS - FINAL OUTCOME OF THE RANDOMIZED CONTROLLED TRIAL

Our previously reported multicenter, blinded, randomized, controlled s tudy of two doses of interferon beta-1b (IFNB) in 372 patients demonst rated a reduction in relapse frequency and severity and in MRI activit y. mie now report the results of the continuation of that study. The m edian time on study was 46.0 months for the placebo arm, 45.0 months f or 1.6 million international units (MIU), and 48.0 months for 8 MIU. I FNB had a persistent beneficial effect on exacerbation rate and MRI bu rden of disease and was relatively free of long-term side effects. The re was a one-third reduction in exacerbation rate in the 8-MIU treatme nt arm, compared with placebo, in each of 5 years. Serial annual MRI w as done in all patients, and 217 of the patients had either a fourth- or fifth-year scan. There was no significant progression of lesion bur den in the 8-MIU arm in each successive year compared with baseline (a t 4 years, p = 0.917), whereas a highly significant increase in lesion area occurred in the placebo arm (p = 0.0001). Among the 154 noncompl eters, there was no systematic bias recognized that favored either tre atment arm for the outcome measures of exacerbation rate, disability, or MRI activity. Dropouts in the placebo group had higher exacerbation rates and accumulation of MRI lesion burden than did dropouts in the other treatment arms, which probably reduced the power of the study to demonstrate treatment effects on these measures in the later years of the trial. Neutralizing antibodies to IFNB were detectable in 38% of patients by the third year and were associated with a significant atte nuation of treatment effect on exacerbation rate. However, the reducti on in exacerbation rate approached 50% in the antibody-negative 8-MIU group. For all patients, both baseline and end point lesion burden sig nificantly correlated with disability. Increase in MRI lesion area was also significantly correlated with increase in disability over the co urse of the study, validating serial MRI as an outcome measure with cl inical relevance. Since the 8-MIU treatment arm had significantly less lesion accumulation by MRI, a reasonable expectation is that IFNB wil l limit progression of disability. Confirmed disease progression occur red in fewer patients in the high-dose treatment arm (35%) than in the placebo arm (46%) (p = 0.096). These results support but do not estab lish an effect of IFNB in limiting progression of disability. This stu dy was not originally powered to demonstrate a treatment effect on dis ease progression. At these levels of disability, more patients or long er follow-up, or both, would be required. Accordingly, additional clin ical trials will be necessary to evaluate the role of IFNB in preventi ng disability.