Vaso-occlusive painful episodes (VOE) in sickle cell disease (SCD) are the leading cause of hospitalizations, emergency room (ED) visits, missed school, & 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 & exerts pleiotropic effects on vascular & circulating blood cells, including the inhibition of platelet aggregation, down-regulation of adhesion molecules, & 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 randomize, 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 & 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, while also creating a valuable biorepository of SCD-VOE blood samples for future mechanism studies (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 & 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 & inpatient hospital wards. ED-based studies and novel therapies that target mechanisms of vaso-occlusion and pain are needed in SCD.
Pain is the hallmark of sickle cell disease (SCD), and is the leading cause of hospitalizations, emergency room visits, missed school, and is associated with an increased death rate. We found that patients with SCD and pain had low levels of the amino acid arginine in their blood, and we also demonstrated that arginine supplementation during acute pain events signi?cantly reduced the amount of narcotics needed to treat sickle cell pain in children and dramatically improved pain scores at discharge compared to placebo. We propose to investigate the bene?ts and safety of arginine for the treatment of patients with SCD and pain in a phase 3 randomized, placebo-controlled clinical trial where neither the patient nor the clinical team know which therapy the patient is receiving, since Arginine is a promising new therapy that could change the way we treat acute pain in SCD.
