Sickle Cell Disease Treatment with Arginine Therapy (STArT): study protocol for a phase 3 randomized controlled trial

• Type of Material: Article
• Authors: Christopher Rees, Emory University; David C. Brousseau, Thomas Jefferson University; Daniel M. Cohen, Nationwide Childrens Hospital; Anthony Villella, Nationwide Childrens Hospital; Carlton Dampier, Emory University; Kathleen Brown, George Washington University; Andrew E. Campbell, George Washington University; Corrie E. Chumpitazi, Texas Childrens Hospital; Gladstone Airewele, Texas Childrens Hospital; Todd Chang, University of Southern California; Christopher Denton, University of Southern California; Angela Ellison, Childrens Hospital of Philadelphia; Alexis Thompson, Childrens Hospital of Philadelphia; Fahd Ahmad, Washington University in St. Louis; Nitya Bakshi, Emory University; Keli D. Coleman, Childrens Wisconsin; Sara Leibovich, University of California San Francisco; Deborah Leake, Childrens Healthcare Atlanta; Dunia Hatabah, Emory University; Hagar Wilkinson, Childrens Healthcare Atlanta; Michelle Robinson, University of Utah; T. Charles Casper, University of Utah; Elliott R. Vichinsky, University of California San Francisco; Claudia Morris, Emory University
• Language: English
• Date: 2023-08-17
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © BioMed Central Ltd., part of Springer Nature 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13063-023-07538-z
• Title of Journal or Parent Work: TRIALS
• Volume: 24
• Issue: 1
• Start Page: 538
• End Page: 538
• Grant/Funding Information: This study was supported by the NIH/NHLBI under Award Number 5UH3HL148560 (to CRM), and in part by NIH/NCCIH K24AT009893 (to CRM) and the Pediatric Emergency Care Applied Research Network (PECARN), supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS), in the Maternal and Child Health Bureau (MCHB), under the Emergency Medical Services for Children (EMSC) program through the following cooperative agreements: DCC-University of Utah, GLEMSCRN-Nationwide Children’s Hospital, HOMERUN-Cincinnati Children’s Hospital Medical Center, PEMNEWS-Columbia University Medical Center, PRIME-University of California at Davis Medical Center, CHaMP node-State University of New York at Buffalo, WPEMR-Seattle Children's Hospital, and SPARC-Rhode Island Hospital/Hasbro Children’s Hospital. NB received funding from the NIH/NHLBI under award number 1K23HL140142 and 1K23HL140142-03S1, from the Doris Duke Charitable Foundation COVID19 Fund to Retain Clinical Scientists-PeRSEVERE Program at Emory University School of Medicine, and the Georgia Clinical and Translational Science Alliance under award UL1-TR002378. The funders had no role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, or the preparation, review, approval of the manuscript, or decision to submit the manuscript for publication.
• Keywords: Life Sciences & Biomedicine; INTRAVENOUS MAGNESIUM; CHILDREN; NITRIC-OXIDE PRODUCTION; Science & Technology; MANAGEMENT; PLACEBO; Arginine; PAIN CRISIS; VASOOCCLUSIVE CRISIS; Randomized controlled trial; GUIDELINES; GROWTH-HORMONE; Sickle cell disease; RATIONALE; Research & Experimental Medicine; Medicine, Research & Experimental; Vaso-occlusive pain
• Research Categories: Health Sciences, Rehabilitation and Therapy; Biology, Cell

Abstract

Background: Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults. Methods: STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 sites in the USA through the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 and will continue for 5 years. Within 12 h of receiving their first dose of intravenous opioids, enrolled participants are randomized 1:1 to receive either (1) a one-time loading dose of L-arginine (200 mg/kg with a maximum of 20 g) administered intravenously followed by a standard dose of 100 mg/kg (maximum 10 g) three times a day or (2) a one-time placebo loading dose of normal saline followed by normal saline three times per day at equivalent volumes and duration as the study drug. Participants, research staff, and investigators are blinded to the participant’s randomization. All clinical care is provided in accordance with the institution-specific standard of care for SCD-VOE based on the 2014 National Heart, Lung, and Blood Institute guidelines. The primary outcome is time to SCD-VOE pain crisis resolution, defined as the time (in hours) from study drug delivery to the last dose of parenteral opioid delivery. Secondary outcomes include total parental opioid use and patient-reported outcomes. In addition, the trial will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD-VOE. Discussion: Building on the foundation of established relationships between emergency medicine providers and hematologists in a multicenter research network to ensure adequate participant accrual, the STArT Trial will provide definitive information about the efficacy of intravenous arginine for the treatment of SCD-VOE for children. Trial registration: The STArT Trial was registered in ClinicalTrials.gov on April 9, 2021, and enrollment began on June 21, 2021 (NCT04839354).