A Phase I/IIA Open-label Dose-Finding Study With Subsequent Double-blind, Placebo-controlled, Randomized Study of L-citrulline in Sickle Cell Disease Presenting to Emergency Department (ED) in Vaso Occlusive Crisis (VOC) in Children, Adolescents and Young Adults (6 to 21 Years)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 120
- 试验地点
- 2
- 主要终点
- To determine the how the study medication is processed by the body.
研究概览
简要总结
The purpose of this study is to determine if intravenous L-citrulline can abrogate an active vaso-occlusive crisis in sickle cell disease, resulting in decreased pain, reduction or elimination of opiate usage, and reduction or elimination of hospital admission. The applicant is developing intravenous L-citrulline (Turnobi™) for treatment of sickle cell disease (SCD). The current development program targets treatment of sickle cell-associated vaso-occlusive crisis (VOC) specifically. The aim of Part 1 is to identify the optimum dose regimens for the Part 2 of the trial which is a double-blind, placebo controlled adaptive 'pick-the-winner' design. This study will allow assignment of more subjects to the better treatment arm/s based on emerging data. The study, initially, will evaluate efficacy and tolerability of incremental doses of intravenous (IV) L-citrulline (Turnobi™) in patients with SCD while receiving standard of care therapy for VOC.
详细描述
Overall Design:
This is a study in children, adolescents, and young adults (6 to 21 years) with SCD presenting to an emergency department (ED) with VOC. Children below age 6 are likely to be recruited in a subsequent phase, once proof of concept is established on optimized dose regimen. Eligible subjects will have documented SCD. Intravenous L citrulline (Turnobi™) or placebo will be administered in addition to standard of care VOC therapy to children, adolescents, and young adults presenting with SCD VOC - defined as painful episode without other apparent causes of pain and without significant organ dysfunction or signs of systemic infection.
This is a single center study, conducted in 2 parts:
Part 1: This is an open-label, ascending dose part of the study. After obtaining the informed consent/assent, the enrolled subjects will be in the ED for up to 7 hours where L-citrulline will be administered as depicted in the dosing panel below. Each dose will be administered sequentially until 5 subjects per dose cohort are accrued.
Dosing panels in Part 1:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double blind placebo controlled (Part 2)
入排标准
- 年龄范围
- 6 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Sickle cell disease (all genotypes)
- •Children, adolescents and young adults between ages 6 to 21 years
- •In a steady disease state and not in the midst of any acute complication other than VOC due to sickle cell disease at study entry
- •For female of childbearing potential, a negative urine pregnancy test and using an adequate method of contraception, or denies sexual activity
- •Subjects or parents or legal guardian of the subject who are willing and able to sign and provide consent and assent (where appropriate for the age of the child).
排除标准
- •Current pain lasting >3 days
- •>6 hospital admissions in the prior year
- •History of opioid dependence/substance abuse
- •Has been on a clinical trial of a new therapy for sickle cell disease within the last 3 months
- •Presence of any other complication related to sickle cell disease such as splenic sequestration, hepatic sequestration, stroke, avascular necrosis of the hip/shoulder, acute priapism, renal dysfunction, dactylitis, acute chest syndrome and other major medical conditions or organ dysfunction
- •Severe anemia (hemoglobin <6 g/dL)
- •History of red blood cell transfusion within the last 30 days
- •Systemic steroid therapy within the last 48 hours
- •Pregnancy or lactation (subjects must have a negative urine pregnancy test)
- •Serum creatinine levels:
- •Age 6 to 13 years >0.9 mg/dL
- •Age 14 to 17 years >1.0 mg/dL
- •Age >18 years >1.5 mg/dL
- •Report of fever (>38°C) within last 48 hours
- •Presence of acute chest syndrome, sepsis, bacterial infection, hemodynamic instability
- •Subjects with inability to have parental assent given (ages 6 to 17 years) or consent (ages 18 through 21 years).
- •Note: Parents or legal guardians can provide consent for subjects who are unable to provide assent (eg, sleepy or preoccupied by their pain).
- •History of allergic reaction to L-citrulline product
- •Medications that are known to be contra-indicated with use of L-citrulline
- •History of diabetes.
- •Subjects with a baseline prothrombin time International Normalized ratio (INR) >2.
- •Received any blood products within 3 weeks of the screening visit.
- •Unreliable venous access
- •The PI considers that the subject will be unable to comply with the study requirements.
研究组 & 干预措施
Arm 1 (L-citrulline)
25 mg/kg bolus + 9 mg/kg/hr continuous infusion of L-citrulline for up to 7 hours
干预措施: L-citrulline (Drug)
Arm 2 (L-citrulline)
50 mg/kg bolus + 9 mg/kg/hr continuous infusion of L-citrulline for up to 7 hours
干预措施: L-citrulline (Drug)
Arm 3 (L-citrulline)
100 mg/kg bolus + 9 mg/kg/hr continuous infusion of L-citrulline for up to 7 hours
干预措施: L-citrulline (Drug)
Arm 4 (L-citrulline)
100 mg/kg bolus + 11 mg/kg/hr continuous infusion of L-citrulline for up to 7 hours
干预措施: L-citrulline (Drug)
Part 2 Arm 1 (L-citrulline)
Subjects will be randomized to 2 of the doses selected from Part 1 and placebo in a 1:1:1 ratio. L-citrulline will be administered to the active arm.
干预措施: L-citrulline (Drug)
Part 2 Arm 2 D5 1/2NS
Subjects will be randomized to 2 of the doses selected from Part 1 and placebo in a 1:1:1 ratio.
干预措施: D5 1/2NS (Other)
结局指标
主要结局
To determine the how the study medication is processed by the body.
时间窗: Collected from enrollment to Emergency room Discharge, Approximability 7 Hours
About 5 milliliters of blood will be collected before study medication is administered and then every 15 minutes to measure how much study drug is in your blood stream. The blood sample collected will be analyzed for Pharmacokinetic parameters of AUC of drug in the blood will be measured
Dose Optimization (Part 1)
时间窗: Collected from enrollment to end of study over 18 months
During Part 1 of the study four cohorts will be enrolled. Cohorts will be squentially completed. Each cohort has a different dosing schema.
Change in Visual Analogue Scale (VAS) pain score
时间窗: Collected from enrollment to end of study over 18 months
Please note that scale info should be entered in the outcome measure description field: at least 2-point decrease or 30% change in pain intensity VAS or Faces Pain Scale score RANGE from 0 (No pain) to 100 (Maximum Pain) (for subjects 6 to 7 years old) when compared with baseline value; assessed every 15 minutes
Discharge from ED/hospital within 7 hours
时间窗: Collected from enrollment to end of study over 18 months
Time spent in the ED/hospital will be collected
Change from baseline in amount of overall opioid use
时间窗: Collected from enrollment to end of study over 18 months
Opioid consumption will be recorded from baseline to end of study.
Assessment of safety
时间窗: Collected from enrollment to end of study over 18 months
The rate of reported AE analysis and Lab abnormalities for each cohort
次要结局
- Duration or length of hospital stay(Collected from enrollment to end of study (30-Days))
- Preliminary assessment of pain change measured(Collected from enrollment to end of study (2-Days))
- Time to clinical resolution of VOC(Collected from enrollment to end of study (30 Days))
- Preliminary assessment of change of opioid use overall(Collected from enrollment to end of study (30 Days))