Single-dose Prophylactic INdomethacin in Extremely Preterm Infants - A Multicenter Randomized Blinded Placebo-Controlled Trial (the SPIN RCT)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 500
- 试验地点
- 15
- 主要终点
- Survival without severe intraventricular hemorrhage (sIVH)
研究概览
简要总结
In Canada, about 900 babies each year are born very early (<26 weeks of gestation) and have a high chance of dying or having a serious bleed in the brain. Families of these extremely preterm babies consider preventing severe brain bleeding as critical to their child's health and well-being. A medicine called indomethacin, when given intravenously in 3-doses, is known to reduce severe brain bleeding. But use of this drug is variable among clinicians working in the neonatal intensive care unit (NICU) due to (a) its side effects on the gut; (b) possible harm when used with other medications; (c) a notion that despite reducing brain bleeds, the child's long-term brain development is not improved. Emerging evidence suggests that a single low-dose indomethacin regimen may be equally effective in reducing severe brain bleeding as compared to a traditional 3-dose regimen.
The investigators propose a blinded randomized controlled trial, a study design where babies born <26 weeks will be randomly assigned within 12 hours of birth to either a single dose of intravenous indomethacin or similar looking placebo in the form a saline solution. The study will test if a single dose indomethacin regimen is effective in improving survival of these babies without the devastating complication of severe brain bleeding. In this study the care providers and researchers will be unaware as to which baby receives indomethacin and which baby receives placebo to ensure no one's expectations or biases can influence the results.
The investigators will conduct the study in multiple NICUs across Canada, the United States and Australia in 2 phases: First, an internal pilot phase that will enroll 104 babies born <26 weeks or <750 g birth weight over a period of 1 year. If the investigators are successful in achieving their target enrolment in the pilot phase, they will move on to the second phase and continue enrollment up to a total of 500 babies born <26 weeks or <750 g birth weight over a period of 3 years. The total of 500 babies will include the 104 babies enrolled in the first phase of the study. This study will help the investigators determine in the most unbiased way whether a single dose of indomethacin given immediately after birth in the smallest babies born <26 weeks of gestation can safely and effectively reduce severe brain bleeding.
详细描述
BACKGROUND & IMPORTANCE In Canada, about 900 infants are born extremely preterm at <26 weeks of gestation (GA); nearly four out of 10 of them do not survive or develop severe intraventricular hemorrhage (sIVH). Existing evidence shows that a 3-dose regimen of prophylactic intravenous indomethacin (0.1mg/kg/dose every 24h for 3 doses most commonly used clinically) results in a significant reduction in sIVH, an outcome deemed critical by families. However, use of the conventional 3-dose regimen has declined among clinicians due to perceived adverse effects on the gut, presumed lack of long-term neurodevelopmental benefit and preclusion of other early therapeutic interventions such as ibuprofen or hydrocortisone due to potential increased risk of gut perforation with concomitant use with indomethacin.
Recent pharmacokinetic studies show that indomethacin drug clearance is significantly reduced in infants born ≤26 weeks GA in the first week of life due to their developmental immaturity; and consequently a single 0.1 mg/kg dose likely maintains therapeutic levels for at least 72h - the most critical period of sIVH onset in these smallest infants. However, no RCTs have yet been conducted to establish effectiveness and safety of this single dose regimen in this highest risk population.
GOAL(S) / RESEARCH AIMS Primary goal: To determine the effectiveness and safety of single dose prophylactic indomethacin to prevent morbidity and mortality in extremely preterm infants born <26 weeks GA.
The investigators hypothesize that in preterm infants born <26 weeks GA, when compared to placebo, a single 0.1 mg/kg dose of intravenous indomethacin given prophylactically within the first 12 hours of birth will improve survival without sIVH.
METHODS/APPROACHES/EXPERTISE Study design: Multicenter, blinded, placebo-controlled, individually randomized, Bayesian design RCT Population: Preterm infants born <26 weeks GA and/or <750 g birth weight Intervention: Prophylactic indomethacin: Single-dose intravenous indomethacin (0.1 mg/kg) given within 12 hours of birth. Comparison: Equal volume saline placebo.
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
The indomethacin and placebo will be provided to the bedside nurse as per allocation using pre-filled syringes masked with a yellow tape (as reconstituted indomethacin has a slightly yellow tinge). All members of the medical team and outcome assessors will remain blinded to the allocation throughout the trial duration.
入排标准
- 年龄范围
- 0 Hours 至 12 Hours（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Extremely preterm infants born <26 completed weeks of GA and/or extremely low BW infants born <750g
排除标准
- •antenatal diagnosis of duct dependent CHD
- •acute hypoxic respiratory failure [defined as fraction of inspired oxygen (FiO2)>0.60 for ≥2h)
- •inhaled nitric oxide (iNO) therapy due to suspected or confirmed acute pulmonary hypertension (PH)
- •receipt of prophylactic or therapeutic hydrocortisone
- •antenatal diagnosis of renal anomalies
- •initial platelet count <50x109/L
- •decision to withhold/withdraw life-sustaining treatments
研究组 & 干预措施
Single-dose prophylactic indomethacin - SPIN
Infants randomized to the SPIN group will receive a single 0.1 mg/kg dose of intravenous indomethacin within 12h of birth as a slow infusion over 20 mins.
干预措施: Indomethacin (Drug)
Control
Equal volume saline placebo administered intravenously over 20 mins
干预措施: Placebo (Drug)
结局指标
主要结局
Survival without severe intraventricular hemorrhage (sIVH)
时间窗: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Any IVH more than grade 2 (i.e., grade 3, grade 4/intraparenchymal hemorrhage/perventricular hemorrhagic infarction is classified as sIVH
次要结局
- Persistent patent ductus arteriosus(7 days postnatal age)
- Severe IVH(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Mortality(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Gastrointestinal perforation(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Acute kidney injury (AKI)(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Chronic pulmonary hypertension(birth through 36 weeks' postmenstrual age (PMA))
- Postnatal corticosteroid use(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Periventricular leukomalacia (any grade)(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Necrotizing enterocolitis (NEC)(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Procedural PDA closure(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Pulmonary hemorrhage(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Duration of invasive mechanical ventilation in days(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Severe retinopathy of prematurity (ROP)(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Grade 3 Bronchopulmonary dysplasia (BPD)(birth through 36 weeks' postmenstrual age (PMA))
- IVH (any grade)(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- White matter injury (WMI)(Term corrected age (approximately 20 weeks postnatal age))
- Major neurodevelopmental impairment(24 (±6) months postmenstrual age (PMA))
研究者
Souvik Mitra, MD PhD
Principal Investigator
University of British Columbia