Full results of the evidence of interferon dose-response-European north American comparative efficacy (EVIDENCE) study:: A multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon β-1a for relapsing multiple sclerosis

Background: Interferon (IFN)-beta therapy represents an important advance in the management of relapsing multiple sclerosis (MS), but information about the relative benefits and risks of available preparations is limited. Objective: This report describes the full results of the Evidence of Interferon Dose-response-European North American Comparative Efficacy (EVIDENCE) study, combining analyses that were previously reported in separate publications for different phases of the study. Methods: The EVIDENCE study was a multicenter, randomized, assessor- blinded comparison of 2 IFN-beta dosing regimens. In the study, patients with relapsing MS were randomly assigned to SC IFN-beta 1 a 44 mu g TIW (Rebif (R), Serono Inc., Geneva, Switzerland) or IM IFN-beta 1a 30 mu g QW (Avonex (R), Blogen Idec, Cambridge, Massachusetts) for 1 to 2 years. The primary clinical end point during the comparative phase was the proportion of patients who remained free from relapses; secondary and tertiary clinical end points included the annualized relapse rate and time to first relapse, respectively. All clinical and magnetic resonance imaging (MRI) evaluations were performed by blinded assessors. In the crossover phase of the study, patients who were originally randomized to low-dose QW treatment switched to the high-close TIW treatment for an additional 8 months. Adverse events were determined by spontaneous reporting and monthly laboratory testing during the comparative phase. Results: A total of 677 patients were enrolled in the study and evenly randomized to treatment; 605 patients completed the comparative phase and 439 completed the crossover phase. During the comparative phase, a significantly higher proportion of patients in the highdose TIW treatment group remained free from relapses when compared with patients in the low-dose QW treatment group (adjusted odds ratio, 1.5; 95% CI, 1.1-2.0; P = 0.023). The high-dose TIW regimen was also assoclated with a significant reduction in the annualized relapse rate (47%; P = 0.033) and a prolonged time to first relapse (hazard ratio, 0.70; P = 0.002). MRI measures of disease activity were significantly reduced in the high-dose TIW group compared with the low-dose QW treatment. During the crossover phase, a 50% reduction in mean relapse rates was observed in patients who converted from low-dose QW treatment to high-dose TIW treatment (P < 0.001), with significant concomitant recluctions in MRI activity. Injection-site reactions were significantly more common with high-dose TIW treatment than with low-dose QW treatment (85% vs 33%; P < 0.001). Neutralizing antibody formation was more common with high-dose TIW treatment than with lowdose QW treatment (26% vs 3%; P < 0.001). Conclusions: The comparative phase of the EVIDENCE study found that treatment of MS with SC IFN-beta 1a 44 mu g TIW was associated with a significant reduction in clinical and imaging measures of disease activity over 1 to 2 years, when compared with IM IFN-beta 1a 30 mu g QW treatment. The crossover phase found that patients who changed from low-dose QW treatment to high-dose TIW treatment experienced enhanced benefits of treatment without a substantial increase in adverse events.