Abstracts

Rationale: Infantile spasms (IS) involve sudden, rapid contractions of the trunk and limbs of varied intensity that last 5-10 seconds. Delayed diagnosis and treatment of IS can lead to long-term neurobehavioral issues. Repository corticotropin injection (RCI), a naturally sourced complex mixture of purified adrenocorticotropic hormone analogs (ACTH1-39) and other pituitary peptides, is approved by the US Food and Drug Administration for first-line treatment of IS. Although data from individual randomized controlled trials (RCTs) suggest RCI and synthetic ACTH may differ in their efficacy, there are no head-to-head RCTs or meta-analyses of efficacy in patients with IS. We conducted a systematic literature review and meta-analysis of RCTs to compare the efficacy of RCI and synthetic ACTH in patients with IS. Methods: This systematic review and analysis complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. PubMed/Medline, EMBASE, and Cochrane databases were searched through 02/28/2019. RCTs were selected if comparators included RCI, synthetic ACTH1-24, or synthetic ACTH1-39 with other drugs and if they reported ≥1 endpoint with a common comparator arm (e.g., steroids). Literature review and data extraction were performed by two independent reviewers. The methodological quality of trials was assessed using Jadad scoring (low [0] to high [5] quality) and Cochrane’s risk of bias tool. A Bayesian indirect network meta-analysis using the fixed-effects model was used to estimate treatment effects. Separate analyses were conducted to compare RCI with synthetic ACTH1-24 or synthetic ACTH1-39.  Results: Of 465 studies screened, six RCTs were included in the quantitative analysis after exclusion of those not meeting prespecified criteria. All RCTs reported randomization methods and withdrawals had a Jadad quality score of 3 and included prednisolone as a comparator. Efficacy outcomes included cessation of spasms and resolution of hypsarrhythmia, separately and as a combined outcome. RCI demonstrated greater efficacy on all outcomes compared to synthetic ACTH1-24, synthetic ACTH1-39, and steroids (Figure). RCI had 5-8 times greater odds of achieving efficacy outcomes than synthetic ACTH1-24 and 14-16 times greater odds of achieving efficacy outcomes than synthetic ACTH1-39. The odds of achieving efficacy outcomes were 9-12 times greater for RCI than for steroids. RCI reduced the risk of spasms and/or hypsarrhythmia by 10%-14% versus synthetic ACTH1-24 and by 40%-50% versus synthetic ACTH1-39. The adjusted number needed to treat, defined as improved efficacy outcomes in 1 additional patient, for RCI versus synthetic ACTH1-24, synthetic ACTH1-39, and steroids was 4-5, 2, and 3, respectively. Conclusions: RCI was significantly better than synthetic ACTH at improving efficacy outcomes in patients with IS. Our findings are consistent with literature reporting significantly better outcomes with RCI versus steroids and no significant difference in the cessation of spasms with synthetic ACTH1-24 versus prednisone. Non-RCT studies were not included to reduce the risk of biased effect estimation.  Funding: Mallinckrodt Pharmaceuticals funded the study and editorial services (by MedLogix Communications, LLC).