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

Sickle Cell Disease Clinical Trial

— R34 pK/PD  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02447874
• Other study ID #: IRB00077736
• Secondary ID: 1K24AT009893-01
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 2015
• Est. completion date: July 2026

Study information

• Verified date: June 2024
• Source: Emory University
• Contact: Reshika Mendis, MBBS
• Phone: 404-785-4525
• Email: Reshika.mendis[@]choa.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 21
• Est. completion date: July 2026
• Est. primary completion date: July 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 7 Years to 21 Years

Eligibility

Inclusion Criteria:

• Established diagnosis of sickle cell disease--Hemoglobin SS (Hb-SS) or Sß?-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

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

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

Locations

Country	Name	City	State
United States	Children's Healthcare fo Atlanta at Hughes Spalding	Atlanta	Georgia
United States	Children's Healthcare of Atlanta at Egleston	Atlanta	Georgia

Sponsors (3)

Lead Sponsor	Collaborator
Emory University	Children's Healthcare of Atlanta, National Center for Complementary and Integrative Health (NCCIH)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	Maximum observed plasma concentration of arginine	Maximum measured concentration of the arginine in plasma	Day 1
Secondary	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
Secondary	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
Secondary	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
Secondary	Daily urine arginine	Total amount of arginine excreted in urine daily	From Day 1 until study completion, an average of up to 7 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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