Arginine Therapy for the Treatment of Vaso-Occlusive Events in Children With Severe Sickle Cell Disease
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 21
- 试验地点
- 4
- 主要终点
- Pharmacokinetics of IV arginine, measured by plasma arginine concentration over time
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 7 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
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
干预措施: Arginine (Loading) (Drug)
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
干预措施: Arginine (Drug)
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
干预措施: Arginine (Loading) (Drug)
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
干预措施: Arginine (Drug)
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.
干预措施: Arginine (Loading) (Drug)
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
干预措施: Arginine (Continuous) (Drug)
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.
干预措施: Arginine (Loading) (Drug)
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.
干预措施: Arginine (Loading) (Drug)
结局指标
主要结局
Pharmacokinetics of IV arginine, measured by plasma arginine concentration over time
时间窗: 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
时间窗: 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.
次要结局
- 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)
研究者
Claudia R. Morris
Professor
Emory University