2/2: Sickle Cell Disease Treatment with Arginine Therapy (STArT) trial

Project Summary/Abstract
Vaso-occlusive painful episodes (VOE) in sickle cell disease (SCD) are the leading cause of hospitalizations,
emergency room (ED) visits, and missed school, and are associated with an increased mortality rate. There are
no current therapies to relieve vaso-occlusion, with interventions limited to hydration and analgesia. Nitric oxide
(NO), produced by the 5-electron oxidation of L-arginine, is a potent vasodilator and exerts pleiotropic effects on
vascular and circulating blood cells, including the inhibition of platelet aggregation, down-regulation of adhesion
molecules, and modulation of ischemia-reperfusion injury, all pathways adversely affected during VOE. We have
found that pediatric SCD patients admitted with VOE have depleted plasma L-arginine levels. Additionally, we
have now completed a single-center randomized, double-blinded, placebo-controlled trial of arginine therapy in
54 children with VOE requiring hospitalization. We observed a reduction in total opioid use (mg/kg) by 54% and
significantly lower pain scores at discharge in children who received 5 days IV L-arginine therapy every 8 hours
compared to placebo, as well as a clinically relevant trend in reduced length of hospital stay of approximately
17 hours. In pharmacokinetic studies, we found that IV arginine induced a dose-dependent improvement in
mitochondrial function in children with SCD hospitalized for pain. We now propose to extend these results to a
pivotal phase 3 trial of L-arginine for VOE. We hypothesize that arginine is a safe intervention with narcotic-sparing
effects in pediatric SCD patients with VOE that will decrease the time children experience severe pain. Aim 1 of
this study will determine the efficacy of IV arginine therapy on the primary endpoint, time-to-crisis resolution, as
well as total parenteral opioid use (mg/kg) and pain scores in children with SCD and VOE compared to placebo
(Efficacy). Aim 2 will monitor for safety of IV L-arginine (Safety). Aim 3 will characterize alterations in the
arginine metabolome and mitochondrial function in children with SCD and VOE, and evaluate how it is impacted
by IV arginine therapy (Exploratory). This proposal will provide essential data for product development and FDA
regulatory approval for use of arginine in SCD. Acute care of patients with SCD and pain in the ED is a neglected
area of research. The results of this study may ultimately lead to change in clinical practice for children with SCD
in both the ED and inpatient hospital wards. ED-based studies and novel therapies that target mechanisms of
vaso-occlusion and pain are needed in SCD.

Grant Number: 5U24HL148563-06
NIH Institute/Center: NIH
Principal Investigator: Theron Casper