Avonex Combination Trial in relapsing-remitting MS: Rationale, design and baseline data

Objective: To review the rationale, design and baseline data of the Avonex Combination Trial (ACT), an investigator-run study of intramuscular interferon beta-1a (IM IFNβ-1a) combined with methotrexate (MTX) and/or IV methylprednisolone (IVMP) in relapsing-remitting multiple sclerosis (RRMS) patients with continued disease activity on IM 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 while on IM IFNβ-1a monotherapy. Subjects continued IFNβ-1a 30 mcg IM weekly and were randomized in a 2 × 2 factorial design to adjunctive weekly placebo or MTX 20mg PO, with or without IVMP 1000mg/day for three days every other month. ACT was industry-supported, and collaboratively designed and governed by an Investigator Steering Committee with independent Advisory and Data Safety Monitoring Committees. Study operations, MRI analysis and aggregated data were managed by the Cleveland Clinic MS Academic Coordinating Center. Results: In total 313 subjects were enrolled with clinical and MRI characteristics typical of RRMS. Most subjects (86.9%) qualified with a clinical relapse, with or without an enhancing MRI lesion, in the preceding year. At baseline, 21.4% had enhancing lesions, and 5.1% had anti-IFNβ neutralizing antibodies. ACT's management and operational structures functioned well. Conclusion: This study provides an innovative model for academic-industry collaborative MS research and will enhance understanding of the utility of combination therapy for RRMS patients with continued disease activity on an established first-line treatment.