The PRISMS Study Group; and the University
of British Columbia MS/MRI Analysis Group
Once the diagnosis of multiple sclerosis (MS) is made, the ultimate goal is to slow the progression of the disease and reduce subsequent disability. Previous clinical studies have demonstrated the efficacy of interferon (IFN)-beta in the treatment of relapsing-remitting multiple sclerosis (RRMS). IFN-beta is a type I interferon with multiple immunomodulatory actions. The results of the Prevention of Relapses and Disability by Interferon-beta-1a Subcutaneously in Multiple Sclerosis-2 (PRISMS-2) study supported the effectiveness of IFN-beta-1a in RRMS, with a trend toward superior outcomes with the higher dose. In PRISMS-2, the patients were randomized to receive placebo, 22 mcg or 44 mcg of IFN-beta-1a subcutaneously (sc), 3 times a week (tiw). Significant clinical and MRI benefit was seen at 2 years for patients who received IFN-beta-1a at dosages of 22 and 44 mcg tiw compared with patients who received placebo. In regard to a number of benefits seen with magnetic resonance imaging (MRI) (including MRI activity and burden), a significant dose-response effect was seen with the 44 mcg dose compared with 22 mcg. As an extension of the previous trial, the PRISMS-4 study was conducted to evaluate (1) the long-term efficacy of the therapy, (2) the presence of dose-response relationship over an extended period, (3) the comparison of early vs late treatment effects, and (4) the treatment effect in the crossover group (placebo patients re-randomized to 1 of the 2 doses of IFN-beta-1a).
In the PRISMS-2 trial, 560 patients were enrolled from 22 centers in Europe, Canada, and Australia. The participants had an Expanded Disability Status Scale (EDSS) score of 0 to 5.0 with at least 2 relapses in the previous 2 years. Before the first patient had reached the end of year 2, the placebo patients were randomized to blinded IFN-beta-1a, 22 or 44 mcg tiw (n = 172; crossover group) while the patients receiving active treatment continued the same blinded dose (22 mcg [n = 167] and 44 mcg [n = 167]). Even when patients stopped the treatment prematurely, they were followed (with consent) until the end of the prespecified study period and these data were included in the analyses. Immunosuppressive therapy was not allowed during the study period. Acetaminophen was recommended for IFN side effects; steroids were limited to treating acute exacerbations of MS (1.0 g/day intravenous methylprednisolone for 3 consecutive days). All of the patients had 3- to 6-month clinical and annual MRI assessments. The patients were tested twice a year for neutralizing antibodies (NAb) to IFN-beta. The primary outcome was the relapse count per patient over 4 years. MRI results were determined by comparing the baseline scan to the annual scans from years 1 through 4. MRI activity was assessed in terms of the number of new T2 lesions and percentage of scans demonstrating such lesions.
Ninety percent (506/560) of the patients who were originally randomized in PRISMS-2 were enrolled in PRISMS-4. An extended clinical and MRI benefit was seen with both doses of IFN-beta-1a for up to 4 years, with evidence of a dose response. The relapse rates for the 4 years were 1.02 (crossover), 0.80 (22 mcg, P < .001), and 0.72 (44 mcg, P < .001). Notably, the results of the crossover group showed reductions in the relapse count, MRI activity, and lesion-burden accumulation with IFN-beta-1a compared with the results after the placebo period (P < .001 for both doses). Treatment with 44 mcg prolonged the time to sustained disability progression by 18 months when compared with the crossover group (P = .047). MRI benefit (reduction in new T2-lesion number and burden) was seen with both doses of IFN-beta-1a compared with the crossover group (P < .001). Notably, the 44-mcg dosage was found to be superior to 22 mcg on several clinical and MRI outcomes.
Persistent neutralizing antibodies (NAb present at a patient's final evaluation) were detected in 14.3% of the patients treated with 44 mcg IFN-beta-1a and in 23.7% of those treated with 22 mcg. Transient antibodies developed in an additional 5.9% of the 22-mcg group and 4.9% of the 44-mcg group. The analysis of the 4-year efficacy data by NAb status showed a reduction in clinical (in years 3 and 4) and MRI efficacy for patients who were NAb positive. The results of the study appear to support the efficacy and sustained clinical benefit of treatment with 44 mcg IFN-beta-1a for RRMS. The early initiation of therapy seems to provide a greater benefit over delayed treatment.