Co-administration of Acetaminophen With Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants - The ACEDUCT Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 310
- 试验地点
- 15
- 主要终点
- Composite of pre-discharge mortality or any grade BPD
研究概览
简要总结
Patent ductus arteriosus (PDA), the most common cardiovascular complication of prematurity, is associated with higher mortality and morbidities in extremely low gestational age neonates (ELGANs, < 27+0 weeks). Ibuprofen and acetaminophen, which act by reducing prostaglandin synthesis, are the most commonly used first and second line agents for PDA treatment across Canada. However, initial treatment failure with monotherapy is a major problem, occurring in >60% ELGANs. Treatment failure is associated with worsening rates of mortality and bronchopulmonary dysplasia (BPD), while early treatment success can achieve rates comparable to neonates without PDA. Treatment failure resulting in prolonged disease exposure is thought to be a major contributor. Recently, combination therapy with acetaminophen and ibuprofen has emerged as a new treatment regime. Acetaminophen exerts anti-prostaglandin effect through a different receptor site than ibuprofen, providing a biological rationale for their synergistic action.
The objective of this study is to evaluate the clinical impact, efficacy and safety of combination regime (Ibuprofen + IV Acetaminophen) for the first treatment course for PDA in ELGANs vs. Ibuprofen alone (current standard treatment).
The study will also evaluate the effects of combination regime vs. ibuprofen alone on neurodevelopmental outcomes at 18-30 months corrected age.
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
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Double-blinded
入排标准
- 年龄范围
- — 至 27 Weeks（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Preterm infants born <27+0 weeks gestational age
- •Permission given by the attending clinician to approach and then consent obtained from parents
- •Diagnosis of PDA ≥ 1.5 mm on echocardiography with unrestrictive predominantly left to right shunt
- •Designated to receive first treatment course with intravenous or enteral ibuprofen, as decided by the attending team.
排除标准
- •Chromosomal anomaly
- •Pre-treatment renal dysfunction defined as urine output < 1ml/kg/hour for the previous 24 hours or serum creatinine > 100 micromol/L
- •Pre-treatment hepatic dysfunction defined as serum aminotransferase (ALT) > 100 units/L94
- •Platelet count <50,000 per microliter
- •Permission denied by the attending clinician to approach parents
- •Parental consent not available
- •Previous exposure to PDA medical treatment with any drug (prophylactic indomethacin use for prevention of intraventricular hemorrhage will not be considered as PDA treatment).
研究组 & 干预措施
Standard Clinical Practice - Monotherapy
Intravenous or enteral ibuprofen, as decided by clinical team, in the standard clinical dose used in participating NICUs (typically, for neonates < 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates > 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) And Placebo [(0.9% saline IV q6h for 3 days).
干预措施: Sodium chloride 0.9% injection (Other)
Combination Therapy
Intravenous or enteral ibuprofen, as decided by clinical team, in the standard clinical dose used in participating NICUs (typically, for neonates < 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates > 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) And study drug (intravenous acetaminophen 15 mg/kg/dose IV q6h for 3 days).
干预措施: Acetaminophen Injection (Drug)
Combination Therapy
Intravenous or enteral ibuprofen, as decided by clinical team, in the standard clinical dose used in participating NICUs (typically, for neonates < 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates > 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) And study drug (intravenous acetaminophen 15 mg/kg/dose IV q6h for 3 days).
干预措施: Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen) (Drug)
Standard Clinical Practice - Monotherapy
Intravenous or enteral ibuprofen, as decided by clinical team, in the standard clinical dose used in participating NICUs (typically, for neonates < 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates > 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) And Placebo [(0.9% saline IV q6h for 3 days).
干预措施: Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen) (Drug)
结局指标
主要结局
Composite of pre-discharge mortality or any grade BPD
时间窗: 36 weeks PMA
Need for oxygen or positive pressure respiratory support at 36 weeks postmenstrual age (PMA)
次要结局
- PDA treatment success(6-10 days post treatment initiation)
- Severity of BPD at 36 weeks PDM using Jensen's criteria(At 36 weeks PDM)
- Procedure for PDA closure(From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization)
- Need for systemic steroids(From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization)
- Further exposure to pharmacological PDA treatments(From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization)
- NEC ≥ stage 2A(From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization)
- Sepsis(From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization)
- Renal or hepatic dysfunction(Occurring within 7 days of treatment initiation)
- Mortality(From date of randomization until date of death (assessed up to a maximum of 250 days after randomization))
- Duration (days) of invasive or non-invasive respiratory support(From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization)
- Need for diuretic use(From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization)