Arginine Therapy for the Treatment of Pain in Children With Sickle Cell Disease (R34 pK/PD)

Arginine Therapy for the Treatment of Vaso-Occlusive Events in Children With Severe Sickle Cell Disease

The purpose of this study is to determine whether giving extra arginine to patients with sickle cell disease seeking treatment for vaso-occlusive painful events (VOE) will decrease pain scores, decrease need for pain medications or decrease length of hospital stay or emergency department visit.

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Arginine; Drug: Arginine (Continuous); Drug: Arginine (Loading)

Detailed Description

Arginine is a simple amino acid that is found in many foods and is part of the proteins in a human's body. Patients with sickle cell disease have low levels of the amino acid arginine and these low levels may be related to pain episodes. Increasing levels of arginine in the blood may lower pain and/or lower the amount of pain medication (like morphine) that is needed to treated them. It may also decrease the amount of time spent in the hospital.

Available data suggest that, L-arginine is a safe & efficacious intervention with narcotic-sparing effects in pediatric SCD patients with VOE. The addition of a higher loading dose to the standard dose or use of a continuous infusion may provide additional clinical benefits by overcoming multiple mechanisms that limit global arginine bioavailability in SCD.

• Study Type: Interventional
• Enrollment (Estimated): 21
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Reshika Mendis, MBBS; Phone Number: 404-785-4525; Email: Reshika.mendis@choa.org
• Study Contact Backup: Name: Claudia Morris, MD; Phone Number: 404 727-5500; Email: claudia.r.morris@emory.edu

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Recruiting
      • Children's Healthcare fo Atlanta at Hughes Spalding
      • Contact: Arnetria Dancy; Phone Number: 404-778-1873; Email: arnetria.dancy@emory.edu
    • Atlanta, Georgia, United States, 30329
      • Recruiting
      • Children's Healthcare of Atlanta at Arthur M. Blank Hospital
      • Contact: Arnetria Dancy; Phone Number: 404-778-1873; Email: arnetria.dancy@emory.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Established diagnosis of sickle cell disease--Hemoglobin SS (Hb-SS) or Sβᴼ-thalassemia
• 7-21 years of age
• Weight >= 25kg (55lbs)
• Pain requiring medical care in an acute care setting (emergency department (ED), hospital ward, day hospital, clinic) requiring parenteral opioids, not attributable to non-sickle cell causes.

Exclusion Criteria:

• Decision to discharge home from acute care setting.
• Diagnosis of sickle cell disease with any of the following types: hemoglobin SC disease (HbSC), hemoglobin beta thalassemia (Hb-Beta Thal), hemoglobin SD disease (HbSD), hemoglobin SE disease (HbSE), hemoglobin SO disease (HbSO), hemoglobin AS carrier (Hb AS)
• Hemoglobin less than 5 gm/dL
• Immediate Red cell transfusion anticipated
• Renal dysfunction: Creatinine >1.0 or 2 x baseline
• Mental status or neurological changes
• Acute stroke or clinical concern for stroke
• Pregnancy
• Allergy to arginine
• Previous hospitalization < 7 days
• Use of inhaled nitric oxide, sildenafil or arginine within the last 14 days
• Not an appropriate candidate in the investigator's judgement

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard dose; Subjects with sickle cell disease (SCD) and vaso-occlusive painful events (VOE) will be randomized to receive an intravenous (IV) infusion of a standard dose of arginine (100 mg/kg) three times a day for seven days or until discharged from the hospital, whichever occurs first	Drug: Arginine; Arginine will be dispensed intravenously (in the vein) in the standard dose of arginine as 100 mg/kg three times a day for seven days or until discharge.; Loading dose: 200 mg/kg once; Continuous IV: 300 mg/kg/24 hours; Other Names: Arginine Hydrochloride Injection, R-Gene® 10
Experimental: Loading dose + standard dose; Subjects with sickle cell disease and vaso-occlusive painful events (VOE) will be randomized to receive an intravenous (IV) infusion of an initial loading dose of arginine (200 mg/kg) given over 30 minutes and then receive an intravenous (IV) infusion of a standard dose of arginine (100 mg/kg) three times a day for seven days or until discharged from the hospital, whichever occurs first	Drug: Arginine; Arginine will be dispensed intravenously (in the vein) in the standard dose of arginine as 100 mg/kg three times a day for seven days or until discharge.; Loading dose: 200 mg/kg once; Continuous IV: 300 mg/kg/24 hours; Other Names: Arginine Hydrochloride Injection, R-Gene® 10; Drug: Arginine (Loading); Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) at each specified group dose once, followed by a standard dose of 100mg/kg every 8 hours until discharge or for a total of 21 doses of arginine, whichever comes first.; Other Names: Arginine Hydrochloride Injection, R-Gene® 10
Experimental: Loading dose + continuous infusion; Subjects with sickle cell disease and vaso-occlusive painful events (VOE) will be randomized to receive an intravenous (IV) infusion of an initial loading dose of arginine (200 mg/kg) given over 30 minutes and then receive a continuous intravenous (IV) infusion of 300 mg/kg/24hr for 7 days or until discharged from the hospital, whichever occurs first	Drug: Arginine (Continuous); Arginine will be dispensed intravenously (in the vein) as a continuous IV infusion of 300 mg/kg/24hr; Other Names: Arginine Hydrochloride Injection, R-Gene® 10; Drug: Arginine (Loading); Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) at each specified group dose once, followed by a standard dose of 100mg/kg every 8 hours until discharge or for a total of 21 doses of arginine, whichever comes first.; Other Names: Arginine Hydrochloride Injection, R-Gene® 10
Experimental: Non-Randomized Loading dose 500 mg/kg + standard dose; Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) arginine dose at 500 mg/kg once, followed by a standard dose of 100mg/kg every 8 hours until discharge or for a total of 21 doses of arginine, whichever comes first.	Drug: Arginine (Loading); Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) at each specified group dose once, followed by a standard dose of 100mg/kg every 8 hours until discharge or for a total of 21 doses of arginine, whichever comes first.; Other Names: Arginine Hydrochloride Injection, R-Gene® 10
Experimental: Non-Randomized Loading dose 300 mg/kg + standard dose; Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) arginine dose at 300 mg/kg once, followed by a standard dose of 100mg/kg every 8 hours until discharge or for a total of 21 doses of arginine, whichever comes first.	Drug: Arginine (Loading); Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) at each specified group dose once, followed by a standard dose of 100mg/kg every 8 hours until discharge or for a total of 21 doses of arginine, whichever comes first.; Other Names: Arginine Hydrochloride Injection, R-Gene® 10
Experimental: Non-Randomized Loading dose 400mg/kg + standard dose; Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) arginine dose at 400 mg/kg once, followed by a standard dose of 100mg/kg every 8 hours until discharge or for a total of 21 doses of arginine, whichever comes first.	Drug: Arginine (Loading); Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) at each specified group dose once, followed by a standard dose of 100mg/kg every 8 hours until discharge or for a total of 21 doses of arginine, whichever comes first.; Other Names: Arginine Hydrochloride Injection, R-Gene® 10

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of IV arginine, measured by plasma arginine concentration over time	Total time plasma arginine levels are maintained above the half-saturating concentration (Km) of cationic amino acid transporter protein-1 (CAT-1), which is 150 µM (normal range of extracellular plasma arginine concentration). pK samples will be collected at 6 time-points within 8 hours: prior to arginine treatment (time 0), and at 60, 90, 120 minutes, 4 and 8 hours after the initiation of arginine therapy, and then every 24 hours up to 7 days.	Day 1 through study completion, an average of up to 7 days
Change in nitric oxide metabolites	The formation of NO metabolites will be measured by determination of its stable end products in serum; nitrite (NO2-) and nitrate (NO3-). Change in nitric oxide metabolites will be calculated as the difference in metabolites from the time prior to arginine treatment (baseline) to the end of the intervention period.	Baseline, day 1 through study completion, an average of up to 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration -Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration for Arginine	AUC is derived from drug concentration and time so it gives a measure of how much and how long a drug stays in a body. AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC[0-tlqc])	Day 1
Maximum observed plasma concentration of arginine	Maximum measured concentration of the arginine in plasma	Day 1
Apparent clearance of arginine	The clearance of a drug measures the rate at which the drug is removed from the body after the dose. Clearance of arginine after intravenous administration on day 1.	Day 1
Terminal elimination half-life (t1/2) for arginine	Terminal phase elimination half-life (t1/2) is the time required for half of the drug to be eliminated from the plasma.	Day 1
Change in red blood cell (RBC) arginine	Change in rbc arginine will be calculated as rbc arginine at the end of arginine administration minus rbc arginine at baseline.	Baseline, day 1 through study completion, an average of up to 7 days
Daily urine arginine	Total amount of arginine excreted in urine daily	From Day 1 until study completion, an average of up to 7 days
Global arginine bioavailability (GABR)	GABR represents a measure of endothelial function. GABR will be calculated by arginine divided by the sum of ornithine plus citrulline [arginine/(ornithine+citrulline)].	From enrollment through study completion, an average of up to 7 days
Change in asymmetric dimethylarginine (ADMA) levels	ADMA is is a metabolic by-product of continual protein modification processes and interferes with L-arginine in the production of nitric oxide. Change in ADMA levels will be calculated as ADMA levels at the end of arginine administration minus ADMA levels at baseline.	Baseline, day 1 and through study completion, an average of up to 7 days
Biomarkers of hemolysis	Biomarkers of hemolysis (lactate dehydrogenase, hemoglobin, reticulocytes, arginase, indirect bilirubin) represent intravascular hemolysis and nitric oxide bioavailability.	From enrollment through study completion, an average of up to 7 days
Erythrocyte glutathione levels	Erythrocyte glutathione is a biomarker for oxidative stress. It will be measured by using liquid chromatography.	From enrollment through study completion, an average of up to 7 days
Level of cytokines	Cytokines are biomarkers for inflammation. Cell supernatants will be collected and analyzed for different cytokines.	From enrollment through study completion, an average of up to 7 days
Modeling nitric oxide (NOx) level versus plasma arginine level	Modeling nitric oxide (NOx) level versus plasma arginine level will be measured.	From enrollment through study completion, an average of up to 7 days

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: National Center for Complementary and Integrative Health (NCCIH); Children's Healthcare of Atlanta
• Investigators: Principal Investigator: Claudia Morris, MD, Emory University

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: May 15, 2015
• First Submitted That Met QC Criteria: May 15, 2015
• First Posted (Estimated): May 19, 2015

Study Record Updates

• Last Update Posted (Actual): July 11, 2025
• Last Update Submitted That Met QC Criteria: July 8, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Anemia, Sickle Cell
• Other Study ID Numbers: IRB00077736; 1K24AT009893-01 (U.S. NIH Grant/Contract)