Background: Patients with relapsing-remitting multiple sclerosis (RRMS) may experience acute relapses that are nonresponsive (20-35%) to high-dose corticosteroids. Repository corticotropin injection (RCI; Acthar® Gel) is approved by the US FDA for the treatment of MS relapses. RCI is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides that has anti-inflammatory and immunomodulatory effects by engaging melanocortin receptors. Objectives: The multicenter, randomized, double-blind, placebo-controlled, parallel-group OPTIONS trial assessed the efficacy and safety of RCI in patients with RRMS experiencing an acute relapse and inadequate response to high-dose corticosteroids (NCT03126760). Methods: Patients experiencing a relapse received 3 to 5 days of intravenous or oral methylprednisolone (1 g/d) or oral prednisone (1250 mg/d) within 28 days of relapse onset. Patients without a ?1-point improvement in ?1 function of the Functional Systems Score (FSS) at 14 days after steroid initiation were randomized (1:1) to subcutaneous RCI 1 mL (80 U) or matching placebo (PBO) daily for 14 days. Responses were evaluated up to 42 days after randomization using the Expanded Disability Status Scale (EDSS), Clinical Global Impression of Improvement (CGI-I) scale, 29-item MS Impact Scale (MSIS-29), and adverse events (AEs). The primary efficacy endpoint was EDSS response rate at day 42, defined as the percentage of patients with an EDSS score improvement of ?1.0 point (if ?5.5 at baseline) or ?0.5 point (if >5.5 at baseline). Results: Thirty-five patients completed the study: 77.1% women and 85.7% White. A greater proportion (with 90% confidence intervals) of EDSS responders were observed in the RCI group on days 42 (primary endpoint; RCI, 61.1% [42.0, 77.3]; PBO, 11.1% [4.0, 30.1]); 21 (RCI, 38.9% [22.7, 58.0]; PBO, 23.5% [11.0, 43.3]), and 7 (RCI, 38.9% [22.7, 58.0]; PBO, 11.8% [4.0, 30.1]). Qualitative CGI-I analyses showed that 88.9% of patients receiving RCI vs 70.6% receiving placebo were very much or much improved by day 42. No significant treatment differences were observed for MSIS-29. Incidence of treatment-emergent AEs was similar between RCI (77.8%) and placebo (70.6%) groups, with no serious AEs or deaths in the RCI group. Conclusions: These results support RCI as a safe and highly effective treatment for MS relapse in patients with an inadequate response to high-dose corticosteroids.