A Phase III Double-Blind, Randomized, Placebo Controlled, Multi Center Clinical Study to Evaluate the Efficacy and Safety of Intravenous L-Citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury Induced by Cardiopulmonary Bypass in Pediatric Patients Undergoing Surgery for Congenital Heart Defects
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 97
- 试验地点
- 10
- 主要终点
- Post-operative need for mechanical ventilation
研究概览
简要总结
This is a randomized, double-blind, placebo controlled, multicenter study to compare the efficacy and safety of L-citrulline versus placebo in patients undergoing surgery for congenital heart defects. Eligible patients undergoing repair of a large unrestrictive ventricular septal defect (VSD), a partial or complete atrioventricular septal defect (AVSD), or an ostium primum atrial septal defect (primum ASD) will be eligible for enrollment.
详细描述
This is a randomized, double-blind, placebo controlled, multicenter study that will compare the efficacy and safety of L- citrulline versus placebo in patients undergoing surgery for congenital heart defects. Eligible patients undergoing repair of a large unrestrictive ventricular septal defect (VSD), a partial or complete atrioventricular septal defect (AVSD), or an ostium primum atrial septal defect (primum ASD) will be eligible for enrollment.
Each enrolled patient will be randomized to receive either L citrulline or placebo throughout all administrations in the study. Patients will receive:
- an L-citrulline bolus of 150 mg/kg or placebo at the initiation of cardiopulmonary bypass
- the addition L-citrulline or placebo to maintain a steady state target concentration of approximately 100 μmol/L of L-Citrulline or placebo during cardiopulmonary bypass
- an L-citrulline bolus of 10 mg/kg or placebo 30 minutes after decannulation from cardiopulmonary bypass, followed immediately by a 9 mg/kg/hour continuous L-citrulline infusion or placebo for up to 48 hours post-first dose. The infusion rate will be adjusted (up or down titration of drug infusion) to achieve a target steady state concentration of 100 µmol/L.
The study drug or placebo infusion will be discontinued once invasive arterial blood pressure monitoring is discontinued or at 48 hours, whichever occurs first. Patients will be followed until Day 28 or discharge from the hospital, whichever occurs first. For patients discharged prior to Day 28, a final assessment via telephone will be conducted at Day 28.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Randomization via an IWRS. Study drug or placebo will be prepared and labeled with the appropriate subject identifiers only; no information that would reveal the contents of the dose to be administered (active versus placebo) will be included on the label. Study drug (citrulline or placebo) will be provided in either identical syringes or bags and mask labeled. The bags will be the same size, shape, and fluid clarity, and hence masked to both investigators and staff administering the drug. Only the pharmacist and the unblinded monitor responsible for performing drug accountability (a different monitor than the person performing routine data monitoring) will be aware of the treatment assignment.
入排标准
- 年龄范围
- — 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients, parents, or legal guardian willing and able to sign informed consent
- •Male and female subjects aged ≤18 years of age (females of child-bearing potential willing to practice an acceptable form of birth control)
- •Patients undergoing cardiopulmonary bypass for repair of a large unrestrictive ventricular septal defect, an ostium primum/secundum atrial septal defect, or a partial or complete atrioventricular septal defect
- •Pre-operative echocardiogram confirming cardiovascular anatomy and defect to be repaired
排除标准
- •Evidence of pulmonary artery or vein abnormalities that will not be addressed surgically. Specific abnormalities excluded include:
- •significant pulmonary artery narrowing not amenable to surgical correction
- •previous pulmonary artery stent placement
- •significant left sided AV valve regurgitation not amenable to surgical correction
- •pulmonary venous return abnormalities not amenable to surgical correction
- •pulmonary vein stenosis not amenable to surgical correction
- •Preoperative requirement for mechanical ventilation or IV inotrope support
- •Presence of fixed or idiopathic pulmonary hypertension (i.e. Eisenmenger's Syndrome) prior to surgical repair
- •Pre-operative use of medications to treat pulmonary hypertension
- •Pregnancy; Sexually active females of child-bearing potential must be willing to practice an acceptable method of birth control for the duration of study participation (e.g. oral contraceptive, hormonal implant, intra-uterine device)
- •Participation in another clinical trial within 30 days of Screening or while participating in the current study, including the 28 days of follow-up post study drug administration.
- •Any condition which, in the opinion of the investigator, might interfere with the study objectives
研究组 & 干预措施
Active
Patients will receive:
- an L-citrulline bolus of 150 mg/kg at the initiation of cardiopulmonary bypass
- the addition L-citrulline to maintain a steady state target concentration of approximately 100 μmol/L of L-citrulline during cardiopulmonary bypass
- an L-citrulline bolus of 10 mg/kg 30 minutes after decannulation from cardiopulmonary bypass, followed immediately by a 9 mg/kg/hour continuous L-citrulline infusion or placebo for up to 48 hours post-first dose. The infusion rate will be adjusted (up or down titration of drug infusion) to achieve a target steady state concentration of 100 μmol/L.
Infusion will be discontinued once invasive arterial blood pressure monitoring is discontinued or at 48 hours, whichever occurs first.
干预措施: L-citrulline (Drug)
Placebo
Plasmalyte A administered to the same schedule as the active treatment arm.
干预措施: Plasmalyte A (Drug)
结局指标
主要结局
Post-operative need for mechanical ventilation
时间窗: Time in hours from separation from CPB until discontinuation of all mechanical ventilation including non-invasive support or Day 28, whichever occurs first
Mechanical ventilation is defined as invasive and non-invasive mechanical ventilation including bilevel positive airway pressure (BPAP), continuous positive airway pressure (CPAP)
次要结局
- Use of inotropes(Measured from first use until discharge or Day 28, whichever occurs first)
- Intubation(From separation from bypass until discontinuation of intubation or Day 28, whichever occurs first)
- Positive pressure ventilation(Time in hours from separation from CPB until discontinuation of all non-invasive mechanical ventilation or Day 28, whichever occurs first)
- Hemodynamic improvement (heart rate)(1, 2, 4, 12, 24, and 48 hours post-dose)
- Early extubation(From end of surgery until 12 hours post-surgery)
- Duration of hospitalization(From surgery until discharge from hospital or Day 28, whichever occurs first)
- Use of vasodilators(Measured from first use until discharge or Day 28, whichever occurs first)
- Volume of chest tube drainage(Duration of chest tube placement or Day 28, whichever occurs first)
- Duration of chest tube placement(From the end of the surgery to the time the chest tube is removed or Day 28, whichever occurs first)
- Hemodynamic improvement (systemic arterial blood pressure)(1, 2, 4, 12, 24, and 48 hours post-dose)
- Hemodynamic improvement (oxygen saturation)(1, 2, 4, 12, 24, and 48 hours post-dose)
- Hemodynamic improvement (central venous pressure)(1, 2, 4, 12, 24, and 48 hours post-dose)
- Hemodynamic improvement (pulmonary arterial pressure)(1, 2, 4, 12, 24, and 48 hours post-dose)
- Arterial blood gasses (PaO2)(Intra-operatively to Day 28)
- Arterial blood gasses (PaCO2)(Intra-operatively to Day 28)
- Arterial blood gasses (HCO3)(Intra-operatively to Day 28)
- Arterial blood gasses (pH)(Intra-operatively to Day 28)
- Plasma levels of L-citrulline to assess PK-PD (exposure-response) relationship(Pre-surgery, 6, 12, 24 and 48 hours after first dose)
- Health Economics: mechanical ventilation(Total over duration of hospitalization or to Day 28 whichever occurs first)
- Health Economics: duration of hospitalisation(Total over duration of hospitalization or to Day 28 whichever occurs first)
- Adverse events(Pre-operatively until Day 28)
- Incidence of refractory hypotension(From the end of surgery until 48 hours after first dose)
- Clinical laboratory values (Blood Hemoglobin and Total Bilirubin)(Intra-operatively, Days 1, 2 and 28)
- Clinical laboratory values (Blood Haematocrit)(Intra-operatively, Days 1, 2 and 28)
- Clinical laboratory values (Red Blood Cell Count)(Intra-operatively, Days 1, 2 and 28)
- Clinical laboratory values (White Blood Cell Count)(Intra-operatively, Days 1, 2 and 28)
- Clinical laboratory values (Blood Platelet Count)(Intra-operatively, Days 1, 2 and 28)
- Clinical laboratory values (Blood Sodium, Potassium, Calcium, Magnesium, Chloride)(Intra-operatively, Days 1, 2 and 28)
- Clinical laboratory values (Blood Urea Nitrogen and Creatinine)(Intra-operatively, Days 1, 2 and 28)
- Clinical laboratory values (Blood Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase)(Intra-operatively, Days 1, 2 and 28)
- Clinical laboratory values (Blood Lactate Dehydrogenase)(Intra-operatively, Days 1, 2 and 28)
- Clinical laboratory values (Blood Activated Clotting Time)(Intra-operatively, Days 1, 2 and 28)