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

Chris A. Rees, Department of Pediatrics, Division of Pediatric Emergency Medicine, Emory University School of Medicine, 1760 Haygood Drive NE, Atlanta, GA, W45830322, USA.
David C. Brousseau, Department of Pediatrics, Nemours Children's Health Delaware and the Sidney Kimmel Medical College, Thomas Jefferson University, Wilmington, DE, USA.
Daniel M. Cohen, Nationwide Children's Hospital, Columbus, OH, USA.
Anthony Villella, Nationwide Children's Hospital, Columbus, OH, USA.
Carlton Dampier, Department of Pediatrics, Division of Pediatric Emergency Medicine, Emory University School of Medicine, 1760 Haygood Drive NE, Atlanta, GA, W45830322, USA.
Kathleen Brown, Children's National Hospital, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Andrew Campbell, Children's National Hospital, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Corrie E. Chumpitazi, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA.
Gladstone Airewele, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA.
Todd Chang, Children's Hospital Los Angeles and Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
Christopher Denton, Children's Hospital Los Angeles and Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
Angela Ellison, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Alexis Thompson, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Fahd Ahmad, Washington University in St. Louis, St. Louis, MO, USA.
Nitya Bakshi, Division of Pediatric Hematology/Oncology/BMT, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
Keli D. Coleman, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI, USA.
Sara Leibovich, University of California, San Francisco, CA, USA.
Deborah Leake, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Dunia Hatabah, Department of Pediatrics, Division of Pediatric Emergency Medicine, Emory University School of Medicine, 1760 Haygood Drive NE, Atlanta, GA, W45830322, USA.
Hagar Wilkinson, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Michelle Robinson, University of Utah School of Medicine, Salt Lake City, UT, USA.
T Charles Casper, University of Utah School of Medicine, Salt Lake City, UT, USA.
Elliott Vichinsky, Center for Maternal-Fetal Precision Medicine, University of California, San Francisco, CA, USA.
Claudia R. Morris, Department of Pediatrics, Division of Pediatric Emergency Medicine, Emory University School of Medicine, 1760 Haygood Drive NE, Atlanta, GA, W45830322, USA. claudia.r.morris@emory.edu.

Document Type

Journal Article

Publication Date

8-17-2023

Journal

Trials

Volume

24

Issue

1

DOI

10.1186/s13063-023-07538-z

Keywords

Arginine; Randomized controlled trial; Sickle cell disease; Vaso-occlusive pain

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).

Department

Pediatrics

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