Safety of Intravenous Arginine Therapy in Children with Sickle Cell Disease Hospitalized for Vaso-occlusive Pain: A Randomized Placebo-controlled Trial in Progress

Background: Sickle cell disease (SCD) is the most common hemoglobinopathy in the United States. Vaso-occlusive episodes (VOE) are the leading cause of hospitalizations and emergency department (ED) visits in SCD. Therapeutic management of VOEs is largely symptomatic with frequent use of parenteral hydration and analgesics.
Arginine is a conditionally essential amino acid and low arginine bioavailability contributes to sickle cell vasculopathy, pain severity, and early mortality, and predicts the need for pediatric hospitalization. Arginine is also a precursor of the endogenous analgesic dipeptide, kyotorphin, and has been effective as an opioid sparing agent to decrease pain scores in children hospitalized with SCD-VOE in 2 placebo-controlled randomized control trials (RCT).
IV arginine has an excellent safety profile and has been used in the management of mitochondrial diseases and sepsis with few side effects. Reported adverse events (AE) include headaches, vomiting, dyspnea and dose-dependent effects on blood pressure and serum electrolytes. We present the safety of IV arginine therapy in an ongoing phase 2 RCT evaluating 2 IV arginine dosing regimens at Emory University and Children’s Healthcare of Atlanta (CHOA).

Methods: This is a single-center, prospective, double-blind, RCT studying the effect of IV arginine in children 3-21 years with SCD (any genotype), hospitalized for VOE and requiring parenteral opioids. It is approved by Emory University and CHOA Institutional Review Boards and utilizes an active Investigational New Drug (#66943; sponsor-C.R.Morris). Patients with significant hepato-renal dysfunction, new SCD or NO therapy in the last month or with hemoglobin <5g/dL are excluded from study participation. Subjects are randomized into one of three IV arginine treatment arms: 1) standard dose (SD) (100 mg/kg/dose TID), 2) loading dose (200 mg/kg/dose) followed by SD or 3) placebo (IV normal saline 1-2 mL/kg TID). The primary outcome measure is total parenteral opioid use between study arms.

Results: The Figure summarizes the screening and randomization to date. The patient population is comprised mostly of adolescents of African American race and HbSS genotype. The table includes a summary of the cumulative 360 AEs in 90 unique patients and 27 serious AEs in 18 unique patients, classified by system and per treatment arm. There was a median of 2 AEs in patients who experienced AEs. Headache, abdominal pain, nausea and vomiting were the most commonly reported symptoms, however there were no significant differences across treatment arms. Across all treatment arms, there were mild derangements in liver function tests, but these were not clinically significant. There were no significant electrolyte derangements.

Conclusion: In this study of patients hospitalized with SCD-VOE, IV arginine was generally well tolerated, with no new clinical or biochemical AEs compared to other studies. This study provides further support for the safety of IV Arginine therapy in children with SCD.