Sickle Cell Disease Treatment With Arginine Therapy (STArT) Trial

NCT04839354 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: STUDY00002344PECARN Protocol Number 050UG3HL148560
• Study Type: interventional
• Target: 271
• Locations: 1 country
• Sites: 10

Brief Summary

The trial is designed to test intravenous (IV) arginine therapy in children with sickle cell disease (SCD) and vaso-occlusive painful episodes (VOE) to further knowledge on efficacy and safety of this orphan drug.

Conditions

Sickle Cell Disease

Keywords

Arginine Therapy; Pain management

Outcome Measures

Primary Outcomes (1)

• Time-to-crisis Resolution

  The time-to-crisis resolution is defined as the time in hours from the date and time of the first study drug delivery to time of the last dose of parenteral opioid delivery.

  From study drug delivery to last IV opioid treatment (up to 1,724.1 hours)

Secondary Outcomes (5)

• Total Parenteral Opioid Use

  From the time of IV placement throughout opioid treatment (up to 1,724.1 hours)

• Change in Pain Score

  Time of presentation and on the day of discharge (up to 554.8 days)

• Change in Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Score

  Within 12 hours of study drug delivery, and on the day of discharge (up to 554.8 days)

• Change in PROMIS Pain Behavior Score

  Within 12 hours of study drug delivery, and on the day of discharge (up to 554.8 days)

• Change in PROMIS Fatigue Score

  Within 12 hours of study drug delivery and on the day of discharge (up to 554.8 days)

Other Outcomes (7)

• Medication Quantification Score (MQS)

  Pre-dose and on day of discharge (up to 2 months)

• Hospital Length of Stay

  Up to 6 months

• Pediatric PROMIS Score

  Within 12 hours of study drug delivery and on the day of discharge (up to 2 months)

Study Arms (2)

L-Arginine Hydrochloride

EXPERIMENTAL

Participants receiving L-arginine hydrochloride in parenteral form. Participants receive up to 21 doses, with participants who are discharged early receiving fewer doses.

Drug: L-Arginine Hydrochloride

Placebo

PLACEBO COMPARATOR

Participants receiving normal saline as a placebo for L-arginine hydrochloride for up to 21 doses, with participants who are discharged early receiving fewer doses.

Other: Normal saline

Interventions

L-Arginine Hydrochloride DRUG

A one-time L-arginine hydrochloride loading dose of 200 mg/kg will be administered intravenously (IV) followed by a standard dose of 100 mg/kg given by IV three times per day (TID).

L-Arginine Hydrochloride

Normal saline OTHER

A placebo of normal saline will be administered by IV with a loading dose of 2ml/kg followed by 1ml/kg given by IV three times per day (TID).

Placebo

Eligibility Criteria

• Age: 3 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age 3-21 years of age, inclusive
• Established diagnosis of sickle cell disease (any genotype)
• Pain requiring medical care in an acute care setting (emergency department, hospital ward, day hospital, clinic) not attributable to non-sickle cell causes, treated with parenteral opioids

You may not qualify if:

• Responds to 2 doses of IV opioids sufficiently for outpatient management
• Greater than 12 hours from first dose of intravenous opioids to treat current pain in acute care setting
• Hemoglobin less than 5 gm/dL or emergent need for red blood cell transfusion for hemodynamically unstable patient
• Ketamine use in the emergency department for treatment of VOE
• Glutamine within 30 days
• New SCD drug use \< 3 months (e.g. Hydroxyurea, voxelotor, crizanlizumab, etc)
• Acute mental status or neurological changes
• Acute stroke or clinical concern for stroke
• Three or more ED visits for sickle cell related pain receiving parenteral opioids in previous 7 days (not including current emergency department visit)
• Hospital discharge within previous 7 days
• Hypotension requiring clinical intervention; hemodynamic instability; septic shock
• Previous randomization in this arginine phase 3 randomized controlled trial
• Use of inhaled nitric oxide, sildenafil or arginine within the last month
• Non-English speaking or requires a translator for clinical care
• Pregnancy

Sponsors & Collaborators

• Claudia R. Morris: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (10)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

UCSF Benioff Children's Hospital

San Francisco, California, 94158, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Children's Healthcare of Atlanta at Hughes Spalding

Atlanta, Georgia, 03322, United States

Location

Children's Healthcare of Atlanta at Egleston

Atlanta, Georgia, 30322, United States

Location

Washington University/St. Louis Children's Hospital

St Louis, Missouri, 63110, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Texas Children's Hospital/Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Medical College of Wisconsin/Wisconsin Children's Hospital

Wauwatosa, Wisconsin, 53226, United States

Location

Related Publications (12)

• Korman R, Hatabah D, Brown LA, Harris F, Wilkinson H, Rees CA, Bakshi N, Archer DR, Dampier C, Morris CR. Impact of arginine therapy on kyotorphin in children with sickle cell disease and vaso-occlusive pain. Blood Adv. 2024 Jun 25;8(12):3267-3271. doi: 10.1182/bloodadvances.2023012209.

  PMID: 38527291 BACKGROUND

• Onalo R, Cilliers A, Cooper P, Morris CR. Arginine Therapy and Cardiopulmonary Hemodynamics in Hospitalized Children with Sickle Cell Anemia: A Prospective, Double-blinded, Randomized Placebo-controlled Clinical Trial. Am J Respir Crit Care Med. 2022 Jul 1;206(1):70-80. doi: 10.1164/rccm.202108-1930OC.

  PMID: 35426778 BACKGROUND

• Reyes LZ, Figueroa J, Leake D, Khemani K, Kumari P, Bakshi N, Lane PA, Dampier C, Morris CR. Safety of intravenous arginine therapy in children with sickle cell disease hospitalized for vaso-occlusive pain: A randomized placebo-controlled trial in progress. Am J Hematol. 2022 Jan 1;97(1):E21-E24. doi: 10.1002/ajh.26396. Epub 2021 Nov 12. No abstract available.

  PMID: 34724240 BACKGROUND

• Morris CR, Brown LAS, Reynolds M, Dampier CD, Lane PA, Watt A, Kumari P, Harris F, Manoranjithan S, Mendis RD, Figueroa J, Shiva S. Impact of arginine therapy on mitochondrial function in children with sickle cell disease during vaso-occlusive pain. Blood. 2020 Sep 17;136(12):1402-1406. doi: 10.1182/blood.2019003672.

  PMID: 32384147 BACKGROUND

• Onalo R, Cooper P, Cilliers A, Vorster BC, Uche NA, Oluseyi OO, Onalo VD, Zubairu Y, Ayodele-Kehinde AU, Damilare OM, Figueroa J, Morris CR. Randomized control trial of oral arginine therapy for children with sickle cell anemia hospitalized for pain in Nigeria. Am J Hematol. 2021 Jan;96(1):89-97. doi: 10.1002/ajh.26028. Epub 2020 Nov 20.

  PMID: 33075179 BACKGROUND

• Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, Hazen SL, Vichinsky EP, Morris SM Jr, Gladwin MT. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA. 2005 Jul 6;294(1):81-90. doi: 10.1001/jama.294.1.81.

  PMID: 15998894 BACKGROUND

• Morris CR, Kuypers FA, Lavrisha L, Ansari M, Sweeters N, Stewart M, Gildengorin G, Neumayr L, Vichinsky EP. A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. Haematologica. 2013 Sep;98(9):1375-82. doi: 10.3324/haematol.2013.086637. Epub 2013 May 3.

  PMID: 23645695 BACKGROUND

• Sadeghi A, Taherifard E, Dehdari Ebrahimi N, Rafiei E, Hadianfard F, Taherifard E. Effects of l-arginine supplementation in patients with sickle cell disease: A systematic review and meta-analysis of clinical trials. Health Sci Rep. 2023 Apr 11;6(4):e1167. doi: 10.1002/hsr2.1167. eCollection 2023 Apr.

  PMID: 37064309 BACKGROUND

• Onalo R, Cilliers A, Cooper P. Impact of oral L-arginine supplementation on blood pressure dynamics in children with severe sickle cell vaso-occlusive crisis. Am J Cardiovasc Dis. 2021 Feb 15;11(1):136-147. eCollection 2021.

  PMID: 33815929 BACKGROUND

• Morris CR, Morris SM Jr, Hagar W, Van Warmerdam J, Claster S, Kepka-Lenhart D, Machado L, Kuypers FA, Vichinsky EP. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med. 2003 Jul 1;168(1):63-9. doi: 10.1164/rccm.200208-967OC. Epub 2003 Mar 5.

  PMID: 12626350 BACKGROUND

• Rees CA, Brousseau DC, Cohen DM, Villella A, Dampier C, Brown K, Campbell A, Chumpitazi CE, Airewele G, Chang T, Denton C, Ellison A, Thompson A, Ahmad F, Bakshi N, Coleman KD, Leibovich S, Leake D, Hatabah D, Wilkinson H, Robinson M, Casper TC, Vichinsky E, Morris CR; SCD Arginine Study Group and PECARN. Sickle Cell Disease Treatment with Arginine Therapy (STArT): study protocol for a phase 3 randomized controlled trial. Trials. 2023 Aug 17;24(1):538. doi: 10.1186/s13063-023-07538-z.

  PMID: 37587492 RESULT

• Bolarinwa AB, Oduwole O, Okebe J, Ogbenna AA, Otokiti OE, Olatinwo AT. Antioxidant supplementation for sickle cell disease. Cochrane Database Syst Rev. 2024 May 22;5(5):CD013590. doi: 10.1002/14651858.CD013590.pub2.

  PMID: 38775255 DERIVED

MeSH Terms

Conditions

Anemia, Sickle Cell; Agnosia

Interventions

Saline Solution

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Perceptual Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Claudia Morris, MD
• Organization: Emory University

claudia.r.morris@emory.edu

404-785-7141

Study Officials

• Claudia Morris, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: April 8, 2021
• First Posted: April 9, 2021
• Study Start: June 21, 2021
• Primary Completion: July 11, 2024
• Study Completion: July 11, 2024
• Last Updated: July 30, 2025
• Results First Posted: July 30, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Individual participant data will be made available for sharing after publication of findings from this study
• Access Criteria: Interested investigators can request de-identified data by sending an email to the principal investigator.

Locations

US (10)