Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS

Objective: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNβ-1a) combined with methotrexate (MTX), IV methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNβ-1a monotherapy. Methods: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0–5.5, and ≥1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNβ-1a monotherapy. Participants continued weekly IFNβ-1a 30 μg IM and were randomized in a 2 × 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center. Results: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNβ-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNβ neutralizing antibody titers. Conclusions: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis. ACT = Avonex Combination Trial; BPF = brain parenchymal fraction; DEXA = dual energy X-ray absorptiometry; EDSS = Expanded Disability Status Scale; GdE = gadolinium-enhancing; IFNβ-1a = interferon beta-1a; IVMP = IV methylprednisolone; MSFC = MS Functional Composite; MTX = methotrexate; N/E = new or enlarged; NAb = neutralizing antibody; OR = odds ratio; RRMS = relapsing-remitting multiple sclerosis; SENTINEL = Safety and Efficacy of Natalizumab in Combination with Interferon β-1a in Patients with Relapsing-Remitting MS.