Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 804
- 试验地点
- 36
- 主要终点
- Closure of Ductus Arteriosus (Primary endpoint of phase II)
研究概览
简要总结
TREOCAPA is a Phase II/III European Multicentre study concerning the prophylactic treatment by Acetaminophen of extremely preterm infant during the first five days after birth.
The Phase II is a dose finding phase in order to assess the minimum effective dose regimen of acetaminophen for the closure of PDA for neonates with a gestational age less than 27 weeks This part of the study will be conducted in 11 NICUs, in 4 countries (France, UK, Finland and Denmark).
The Phase III is The phase III is a randomized, multicenter, double-blind, placebo-controlled superiority trial, two arms in a 1:1 ratio, evaluating an increasing of 10% of the percentage of survival without severe morbidity at 36 weeks of post menstrual age. In the intervention arm, 20 mg/kg followed by 7.5 mg/kg quarter in die (QID) will be administered to the 27-28 weeks gestational age group (dosage confirmed through PK/PD data analysis from the previous Finnian study) and the dosage selected after the conclusion of the Phase II will be administered to the 23-26 weeks gestational age group. A group sequential design, with a total of 3 analyses (2 interim analyses and a final) and the O'Brien-Fleming alpha spending function is chosen for the trial. At the same time, a Bayesian sequential analysis is planned for safety endpoints
详细描述
The Phase II will be conducted in 11 NICUs, in 4 countries (France, UK, Finland and Denmark). The estimated recruitment period is 6 months to enroll 30 preterm infants of 23-26 weeks of gestation. Four different loading/maintenance doses will be tested. The first level will be 20 mg/kg followed by 7.5 mg/kg quarter in die (QID) which correspond to the dosage selected for neonates with a PMA ≥27 weeks in the phase III according to data from Finland (Härkin, J Pediatr. 2016). The 2nd, 3rd and 4th level doses will stand for 25%, 50%, and 75% increase of the first level:
- 20 mg/kg loading dose then 7.5 mg/kg/6hours during 5 days (total = 20 doses)
- 25 mg/kg loading dose then 10 mg/kg/6hours during 5 days (total = 20 doses)
- 30 mg/kg loading dose then 12 mg/kg/6hours during 5 days (total = 20 doses)
- 35 mg/kg loading dose then 15 mg/kg/6hours during 5 days (total = 20 doses)
The first cohort of patients will be treated at the lowest starting dose level. Both, the Data Safety Monitoring Board (DSMB) and the statistician will be informed about the therapeutic response observed and the safety of treatment. The statistician will use these data for re-estimation of the posterior probability of success. The DSMB will be then informed about the statistical recommendation for the next dose level to use in the next cohort of 3 patients. The decision to go up, go down or stay on the same dose level will remain to the DSMB who will be free to follow or not the statistical recommendation. Dose escalation will not increase by more than one level, although dose de-escalations could be large.
At inclusion, basic data (pregnancy, blood results, birth and transfer) are recorded. After inclusion, systemic arterial pressure is measured before administration of the first dose of acetaminophen. Then the preterm infant receives a loading dose of acetaminophen. A first blood sample is collected just after end of loading dose infusion (T15min) to analyze Acetaminophen plasma level (0.2mL) ans ALT/AST (0.1ml to 0.3ml, according to local biological laboratory). Each 6 hours during the first 5 days of life, each preterm infant receives a perfusion of acetaminophen, so 20 doses are administered in total. Systemic arterial pressure is measured at 30', 60', 90', 120' after each dose. Each day, a cardiac echography is performed. After Dose 10, a second blood sample (0.3 ml to 0.5 ml according to local biological laboratory) is collected to analyze acetaminophen plasma level and ALAT & ASAT.
During visit 1 at day 3, eCRF is completed for period Day 1 to Day 3. A few "bottom of blood tubes" sampled for routine care will be kept for others acetaminophen plasma level analysis. This will be done in centres where this procedure is possible.After the last dose of acetaminophen, a blood sample of 0,3 to 0.5ml (ideally 6 hours after the start of last infusion) is collected to analyze ALAT & ASAT and Acetaminophen plasma level (0.2 ml).
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
The active product is a 10 ml polyethylene ampoule of acetaminophen containing 100 mg of acetaminophen, solution for infusion, B BRAUN. The placebo product is a polyethylene ampoule of 10ml of NaCL 0.9%, B BRAUN. Polyethylene ampoule of active and placebo products are with the same appearance, in accordance with Good Manufacturing Practices Drugs for Clinical Trials
入排标准
- 年龄范围
- 23 Weeks 至 28 Weeks（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Birth between 23-26 W for Phase II, between 23-28 W for Phase III
- •Post natal age < 12 hours
- •Parental or Legal Authority Consent
- •Parents with a social security or health insurance (if applicable according to the local regulation)
排除标准
- •Birth defect / Congenital anomaly
- •Twin-to-twin transfusion syndrome not cured
- •Suspicion of pulmonary hypoplasia
- •Suspicion of hepatic impairment (hemorrhagic syndrome and/or severe hypoglycemia)
- •Clinical instability that can lead to rapid death
- •Impossibility to start treatment before 12 hours of life
- •Parents placed under judicial protection
- •Participation in other clinical trial using acetaminophen during the first 5 days of life, indomethacin or ibuprofen during the first 3 days of life or using rescue treatment of PDA not recommended in the TREOCAPA trial
研究组 & 干预措施
Acetaminophen
The active product is a 10 ml polyethylene ampoule of acetaminophen containing 100 mg of acetaminophen, solution for infusion, B BRAUN.
干预措施: Acetaminophen (Drug)
NaCL 0.9%
The placebo product is a polyethylene ampoule of 10ml of NaCL 0.9%, B BRAUN. Polyethylene ampoule of active and placebo products are with the same appearance, in accordance with Good Manufacturing Practices Drugs for Clinical Trials.
干预措施: NACL 0.9% (Drug)
结局指标
主要结局
Closure of Ductus Arteriosus (Primary endpoint of phase II)
时间窗: Day 7
Number of participants with closed Ductus Arteriosus (DA) assessed by echocardiography during the first 7 days of life, defined as DA closed at two consecutive echocardiographies or if the DA is closed at echocardiography of Day 7
The survival without severe morbidity (Primary endpoint of phase III)
时间窗: Up to 36 weeks of post menstrual age
the survival without severe morbidity at 36 weeks of post menstrual age or at first discharge home, whichever comes first. The severe morbidities include bronchopulmonary dysplasia (BPD Grade 3 according to NIH consensus), necrotizing enterocolitis (NEC) of Bell's stage II or III, intraventricular hemorrhage (IVH) grade III-IV or cystic leukomalacia observed at any time up to 36 weeks of post menstrual age
次要结局
- Number of back-up treatment of PDA (Secondary endpoint of phase III)(At 36 weeks of Post menstrual age)
- Analgesia/sedation drugs consumption during first week after birth (Secondary endpoint of phase III)(Day 7)
- Number of days during the first week after birth with catecholamines administration (Secondary endpoint of phase III)(Day 7)
- Early pulmonary hemorrhage (Secondary endpoint of phase III)(Day 7)
- Blood acetaminophen levels in extrem preterm infant (Secondary endpoint of Phase II and Phase III)(Day 7)
- Closure of Ductus arteriosus (Secondary endpoint of phase III)(Day 7)
- Toxicity of Acetaminophen in extrem preterm infant (Secondary endpoint of Phase II and Phase III)(Day 7)