Arginine Therapy for the Treatment of Pain in Children With Sickle Cell Disease

Official title

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

Overview

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.

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.

Interventions

• 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
• 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.
• Drug Arginine (Continuous)
  Arginine will be dispensed intravenously (in the vein) as a continuous IV infusion of 300 mg/kg/24hr

Primary outcome measures

• 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]
• Change in nitric oxide metabolites [Time frame: Baseline, day 1 through study completion, an average of up to 7 days]

Secondary outcome measures (12)

• 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]
• Maximum observed plasma concentration of arginine [Time frame: Day 1]
• Apparent clearance of arginine [Time frame: Day 1]
• Terminal elimination half-life (t1/2) for arginine [Time frame: Day 1]
• Change in red blood cell (RBC) arginine [Time frame: Baseline, day 1 through study completion, an average of up to 7 days]
• Daily urine arginine [Time frame: From Day 1 until study completion, an average of up to 7 days]
• Global arginine bioavailability (GABR) [Time frame: From enrollment through study completion, an average of up to 7 days]
• Change in asymmetric dimethylarginine (ADMA) levels [Time frame: Baseline, day 1 and through study completion, an average of up to 7 days]
• Modeling nitric oxide (NOx) level versus plasma arginine level [Time frame: From enrollment through study completion, an average of up to 7 days]
• Biomarkers of hemolysis [Time frame: From enrollment through study completion, an average of up to 7 days]
• Erythrocyte glutathione levels [Time frame: From enrollment through study completion, an average of up to 7 days]
• Level of cytokines [Time frame: From enrollment through study completion, an average of up to 7 days]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 2 centers

• Children's Healthcare fo Atlanta at Hughes Spalding — Atlanta
• Children's Healthcare of Atlanta at Arthur M. Blank Hospital — Atlanta

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. PMID 32384147
• 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
• Korman R, Yasmine M, Hatabah D, Alzraikat N, Harris F, Brown LA, Chonat S, Bakshi N, Rees CA, Dampier C, Morris CR. Secretory Phospholipase A2 in Patients With Sickle Cell Disease Hospitalized for Vaso-Occlusive Pain Episodes. Pediatr Blood Cancer. 2026 Aug 4:e70615. doi: 10.1002/1545-5017.70615. Online ahead of print. PMID 42549972

Identifiers

NCT: NCT02447874 · IRB00077736 · 1K24AT009893-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗