Tolerability and safety profile of 12- to 28-week treatment with interferon beta-1b 250 and 500 μg QOD in patients with relapsing-remitting multiple sclerosis:: A multicenter, randomized, double-blind, parallel-group pilot study

Background: It is not known whether the currently available treatment regimen of interferon beta-1b (IFN beta-1b) 250 mu g provides the maximum benefit possible in the treatment of relapsing-remitting multiple sclerosis (RRMS), or whether higher doses of IFN beta-1b will prove to be more beneficial. Objective: The objective of the present study was to evaluate the tolerability and safety profile of IFN beta-1b 500 mu g compared with the currently approved 250-mu g dose. Methods: A multicenter, randomized, double-blind, parallel-group pilot study was carried out to compare IFN beta-1b 250 mu g with IFN beta-1b 500 mu g, both self-administered SC QOD for >= 12 weeks in patients with RRMS. Patients in both groups started with 25% (0.25 mL) of their final dose and were scheduled to increase the dose by 0.25 mL every 2 weeks, so that the full dose (1.0 mL, 250 mu g or 500 mu g) would be reached by week 7. The primary outcome measure was the percentage of patients experiencing each of the following adverse events (AEs): influenza-like symptoms (general term used to code the presence of >1 symptom typical of influenza), fever, myalgia, asthenia, headache, injection-site reactions, injection-site pain, or liver or hematologic abnormalities. All patients underwent a priori magnetic resonance imaging (MRI) with 0.1 mmol/kg gadolinium (Gd-)diethylenetriaminepentaacetic acid as contrast medium at screening and at week 12. MRI evaluation was included as a safety measure to monitor for excessive new disease not visible through clinical symptoms. Results: Seventy-seven patients were assessed for inclusion in the study. Of these, 6 patients were screening failures and the remaining 71 were randomized to treatment (38-250 and 33-500 mu g IFN beta-1b). The uneven numbers in the groups were a consequence of the randomization process. Two patients in the 250-mu g group (withdrawal of consent) and 1 in the 500-mu g group (not completing follow-up visit) prematurely discontinued medication. The demographic characteristics were not significantly different between the 250-mu g (n = 38; mean [SD] age, 37.9 [8.3] years; weight, 83.5 [19.0] kg; height, 168.4 [9.3] cm) and 500-mu g (n = 33; mean [SD] age, 37.8 [7.7] years; weight, 82.3 [19.5] kg; height, 169.9 [10.5] cm) treatment groups. The patients in both groups were mostly white (87% and 73%, respectively). Baseline Expanded Disability Status Scale scores also were not significantly different between the 2 groups (mean [SD] score, 2.8 [1.4] vs 2.0 [1.4], respectively). In the IFN beta-1b 250-mu g group, 97% of the patients titrated to the full dose at some point during the course of the study, compared with 91% of the 500-mu g group (P = NS). A dose-response effect was observed in some of the more frequent AEs (no. [%]) that included influenza-like syndrome (250-mu g group, 13 [34] vs 500-mu g group, 16 [48]), asthenia (13 [34] vs 16 [48], respectively), headache (12 [32] vs 12 [36]), myalgia (10 [26] vs 13 [39]), hypesthesia (10 [26] vs 11 [33]), nausea (6 [16] vs 8 [24]), paresthesia (6 [16] vs 8 [24]), myasthenia (4 [11] vs 8 [24]), chills (3 [8] vs 6 [18]), depression (3 [8] vs 5 [15]), back pain (2 [5] vs 5 [15]), increased liver enzymes (4 [11] vs 6 [18]), lymphopenia (4 [11] vs 3 [9]), fever (2 [5] vs 4 [12]), and pain in extremities (1 [3] vs 4 [12]). The between-group incidence of injection-site reactions was not significantly different. No new or unexpected AEs were recorded. Changes in MRI parameters between screening and 12 weeks were not significantly different between dose groups; these included median T2 lesion volume, median Gd-enhanced lesion volume, median Gd-enhanced lesion number, and mean number of newly active lesions. Conclusions: IFN beta-1b 500 mu g administered SC QOD was generally well tolerated in these patients with RRMS. Large, randomized controlled studies are needed to determine if there are significant differences in MRI end points between the 250- and 500-mu g doses.