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NCT Number: NCT02447874

Arginine Therapy for the Treatment of Pain in Children With 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.

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Key information

Conditions

Sickle Cell Disease Anemia Anemia, Hemolytic Anemia, Hemolytic, Congenital Anemia, Sickle Cell Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Hematologic Diseases Hemic and Lymphatic Diseases Hemoglobinopathies

Age range

7 year–21 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Children's Healthcare fo Atlanta at Hughes Spalding, Atlanta, Georgia, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Arginine

Drug

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

Arginine (Loading)

Drug

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

Arginine (Continuous)

Drug

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

Primary outcomes

  1. Pharmacokinetics of IV arginine, measured by plasma arginine concentration over time

    Time frame: Day 1 through study completion, an average of up to 7 days

    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.

  2. Change in nitric oxide metabolites

    Time frame: Baseline, day 1 through study completion, an average of up to 7 days

    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.

Secondary outcomes

  1. Area Under the Plasma Concentration -Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration for Arginine

    Time frame: Day 1

    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])

  2. Maximum observed plasma concentration of arginine

    Time frame: Day 1

    Maximum measured concentration of the arginine in plasma

  3. Apparent clearance of arginine

    Time frame: Day 1

    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.

  4. Terminal elimination half-life (t1/2) for arginine

    Time frame: Day 1

    Terminal phase elimination half-life (t1/2) is the time required for half of the drug to be eliminated from the plasma.

  5. Change in red blood cell (RBC) arginine

    Time frame: Baseline, day 1 through study completion, an average of up to 7 days

    Change in rbc arginine will be calculated as rbc arginine at the end of arginine administration minus rbc arginine at baseline.

  6. Daily urine arginine

    Time frame: From Day 1 until study completion, an average of up to 7 days

    Total amount of arginine excreted in urine daily

  7. Global arginine bioavailability (GABR)

    Time frame: From enrollment through study completion, an average of up to 7 days

    GABR represents a measure of endothelial function. GABR will be calculated by arginine divided by the sum of ornithine plus citrulline [arginine/(ornithine+citrulline)].

  8. Change in asymmetric dimethylarginine (ADMA) levels

    Time frame: Baseline, day 1 and through study completion, an average of up to 7 days

    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.

  9. Modeling nitric oxide (NOx) level versus plasma arginine level

    Time frame: From enrollment through study completion, an average of up to 7 days

    Modeling nitric oxide (NOx) level versus plasma arginine level will be measured.

  10. Biomarkers of hemolysis

    Time frame: From enrollment through study completion, an average of up to 7 days

    Biomarkers of hemolysis (lactate dehydrogenase, hemoglobin, reticulocytes, arginase, indirect bilirubin) represent intravascular hemolysis and nitric oxide bioavailability.

  11. Erythrocyte glutathione levels

    Time frame: From enrollment through study completion, an average of up to 7 days

    Erythrocyte glutathione is a biomarker for oxidative stress. It will be measured by using liquid chromatography.

  12. Level of cytokines

    Time frame: From enrollment through study completion, an average of up to 7 days

    Cytokines are biomarkers for inflammation. Cell supernatants will be collected and analyzed for different cytokines.

Study contacts

Contact information is provided by the study sponsor or research team.

Claudia Morris, MD

CONTACT

[email protected]

404 727-5500

Reshika Mendis, MBBS

CONTACT

[email protected]

404-785-4525

Sponsors and collaborators

Lead sponsor

Emory University

Other

Collaborators

  • Children's Healthcare of Atlanta
  • National Center for Complementary and Integrative Health (NCCIH)

Registry information

Official study title

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

Acronym: R34 pK/PD

Important dates

Study start
2015
Primary completion
2026
Study completion
2026
First posted
May 19, 2015
Registry last updated
Jul 11, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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