# 1/2 Sickel Cell Disease Treatment with Arginine Therapy (STArT Trial)

> **NIH NIH UH3** · EMORY UNIVERSITY · 2021 · $1,542,812

## Abstract

Project Summary/Abstract
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.

## Key facts

- **NIH application ID:** 10274834
- **Project number:** 4UH3HL148560-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Claudia R Morris
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,542,812
- **Award type:** 4N
- **Project period:** 2020-09-20 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10274834

## Citation

> US National Institutes of Health, RePORTER application 10274834, 1/2 Sickel Cell Disease Treatment with Arginine Therapy (STArT Trial) (4UH3HL148560-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10274834. Licensed CC0.

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