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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Arginine
* Drug: Arginine (Loading)
* Drug: Arginine (Continuous)


Participation Criteria
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Eligibility Criteria
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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 Hepatic dysfunction: serum glutamic pyruvic transaminase (SGPT) > 3X upper value 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 Previous randomization in this arginine pK study (patient consented and screened failed before receiving study drug or placebo remains eligible for future participation) Use of inhaled nitric oxide, sildenafil or arginine within the last month

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard dose<br>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<br>* 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<br>* Other names: Arginine Hydrochloride Injection, R-Gene® 10;|
| Experimental: Loading dose + standard dose<br>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<br>* 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<br>* Other names: Arginine Hydrochloride Injection, R-Gene® 10;Drug: Arginine (Loading)<br>* Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) arginine dose at 200 mg/kg once<br>* Other names: Arginine Hydrochloride Injection, R-Gene® 10;|
| Experimental: Loading dose + continuous infusion<br>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 (Loading)<br>* Arginine will be dispensed intravenously (in the vein) as an initial bolus (loading) arginine dose at 200 mg/kg once<br>* Other names: Arginine Hydrochloride Injection, R-Gene® 10;Drug: Arginine (Continuous)<br>* Arginine will be dispensed intravenously (in the vein) as a continuous IV infusion of 300 mg/kg/24hr<br>* Other names: Arginine Hydrochloride Injection, R-Gene® 10;|

What is the study measuring?
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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 | 
| Modeling nitric oxide (NOx) level versus plasma arginine level |  | From enrollment 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 |