PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS.

BACKGROUND: The PRISMS study demonstrated significant clinical and MRI benefit at 2 years for interferon-beta-1a, 22 and 44 mcg thrice weekly (tiw), compared with placebo in relapsing-remitting MS. Years 3 and 4 extension study results are reported. METHODS: Patients initially receiving placebo were randomized to blinded interferon-beta-1a, 22 or 44 mcg tiw (n = 172; crossover group); others continued blinded treatment with their originally assigned dose, 22 mcg (Rx22 group) or 44 mcg (Rx44 group) tiw (n = 167 per group). Patients had 3- to 6-month clinical and annual MRI assessments. RESULTS: Relapse rates for 4 years were 1.02 (crossover), 0.80 (Rx22, p < 0.001), and 0.72 (Rx44, p < 0.001); the dose effect approached significance (p = 0.069; risk ratio, 0.88; 95% CI, 0.76-1.01). Crossover groups showed reductions in relapse count, MRI activity, and lesion-burden accumulation with interferon-beta-1a compared with their placebo period (p < 0.001 both doses). Time to sustained disability progression was prolonged by 18 months in the Rx44 group compared with the crossover group (p = 0.047). Rx22 and Rx44 reduced new T2 lesion number and lesion burden compared with crossover (p < 0.001); Rx44 was superior to Rx22 on several clinical and MRI outcomes. Persistent neutralizing antibodies developed in 14.3% (Rx44) and 23.7% (Rx22) of patients and were associated with reduced efficacy. CONCLUSIONS: Clinical and MRI benefit continued for both doses up to 4 years, with evidence of dose response. Outcomes were consistently better for patients treated for 4 years than for patients in crossover groups. Efficacy decreased with neutralizing antibody formation.