Arginine Therapy for the Treatment of Vaso-Occlusive Events in Children With Severe Sickle Cell Disease
Overview
- Phase
- Phase 1
- Intervention
- Arginine
- Conditions
- Sickle Cell Disease
- Sponsor
- Emory University
- Enrollment
- 21
- Locations
- 2
- Primary Endpoint
- Pharmacokinetics of IV arginine, measured by plasma arginine concentration over time
- Status
- Recruiting
- Last Updated
- 9 months ago
Overview
Brief 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.
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.
Investigators
Claudia R. Morris
Professor
Emory University
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
Arms & Interventions
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
Intervention: Arginine
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
Intervention: Arginine
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
Intervention: Arginine (Loading)
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
Intervention: Arginine (Loading)
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
Intervention: Arginine (Continuous)
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.
Intervention: Arginine (Loading)
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.
Intervention: Arginine (Loading)
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.
Intervention: Arginine (Loading)
Outcomes
Primary Outcomes
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.
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
- Area Under the Plasma Concentration -Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration for Arginine(Day 1)
- Maximum observed plasma concentration of arginine(Day 1)
- Apparent clearance of arginine(Day 1)
- Change in red blood cell (RBC) arginine(Baseline, day 1 through study completion, an average of up to 7 days)
- Change in asymmetric dimethylarginine (ADMA) levels(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(From enrollment through study completion, an average of up to 7 days)
- Level of cytokines(From enrollment through study completion, an average of up to 7 days)
- Erythrocyte glutathione levels(From enrollment through study completion, an average of up to 7 days)
- Terminal elimination half-life (t1/2) for arginine(Day 1)
- Daily urine arginine(From Day 1 until study completion, an average of up to 7 days)
- Global arginine bioavailability (GABR)(From enrollment through study completion, an average of up to 7 days)