Clinical trial NCT06572917: Single-dose Prophylactic INdomethacin in Extremely Preterm Infants
Official title: Single-dose Prophylactic INdomethacin in Extremely Preterm Infants - A Multicenter Randomized Blinded Placebo-Controlled Trial (the SPIN RCT)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Extreme Prematurity
Intraventricular Hemorrhage
Morbidity;Newborn
Keywords: extremely preterm
severe intraventricular hemorrhage
mortality
prophylactic indomethacin
Lead sponsor: University of British Columbia
Sponsor class: OTHER
First posted: 2024-08-27
Enrollment: 500
Sex: ALL
Minimum age (years): 0
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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 and will enroll 500 babies born \<26 weeks or \<750 g birth weight over a period of 3 years. 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.

Detailed description: 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.

Sample size and analysis: The proposed sample size is 500 neonates (250 per arm). The primary analysis will utilize a Bayesian approach using an informative prior that assumes a 5% expected net benefit (in absolute risk difference) with an uncertainty of 5%, with regards to the primary outcome. The trial will be considered successful if it shows that the posterior probability of a positive net benefit is at least 90%.

Setting: Neonatal intensive care units across Canada, the United States and Australia over 3 years Primary outcome: Survival without sIVH (grades 3 and 4) at hospital discharge Secondary outcomes include in-hospital clinical outcomes; white matter injury on MRI at term corrected age; neurodevelopmental impairment at 24 (±6) months; pharmacokinetic (PK) profile of single-dose indomethacin; total hospital costs and costs per sIVH or death averted.

EXPECTED OUTCOMES This will be the first RCT to explore the effectiveness and safety of single dose prophylactic indomethacin exclusively in infants born \<26 weeks GA who are at the highest risk of severe IVH and death. Apart from the primary and secondary clinical outcomes, this trial will describe the PK profile of single dose indomethacin to establish the ideal therapeutic window for sIVH prevention as well as ascertain the value for money of this therapy in preventing death and sIVH in infants born \<26 weeks GA.

Eligibility criteria: Inclusion Criteria:

* Extremely preterm infants born \<26 completed weeks of GA and/or extremely low BW infants born \<750g

Exclusion Criteria:

* 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

Primary outcomes:
measure: Survival without severe intraventricular hemorrhage (sIVH)
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Secondary outcomes:
measure: Mortality
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Severe IVH
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Gastrointestinal perforation
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Necrotizing enterocolitis (NEC)
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Acute kidney injury (AKI)
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Persistent patent ductus arteriosus
timeFrame: 7 days postnatal age
measure: Procedural PDA closure
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Chronic pulmonary hypertension
timeFrame: birth through 36 weeks' postmenstrual age (PMA)
measure: Grade 3 Bronchopulmonary dysplasia (BPD)
timeFrame: birth through 36 weeks' postmenstrual age (PMA)
measure: Pulmonary hemorrhage
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Duration of invasive mechanical ventilation in days
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Postnatal corticosteroid use
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: IVH (any grade)
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Periventricular leukomalacia (any grade)
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: White matter injury (WMI)
timeFrame: Term corrected age (approximately 20 weeks postnatal age)
measure: Severe retinopathy of prematurity (ROP)
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Major neurodevelopmental impairment
timeFrame: 24 (±6) months postmenstrual age (PMA)
Other outcomes:
measure: Pharmacokinetic outcomes
timeFrame: 7 days postnatal age
measure: Health Economic outcomes
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Locations:
city: Roseville
country: United States
facility: Kaiser Roseville
state: California
city: Sacramento
country: United States
facility: UC Davis Health
state: California
city: Pittsburgh
country: United States
facility: University of Pittsburgh School of Medicine
state: Pennsylvania
city: Melbourne
country: Australia
facility: Monash Children's Hospital
state: Victoria
city: Melbourne
country: Australia
facility: The Royal Women's Hospital
state: Victoria
city: Calgary
country: Canada
facility: Foothills Medical Center
state: Alberta
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: New Westminster
country: Canada
facility: Royal Columbian Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: BC Women's Hospital
state: British Columbia
city: Halifax
country: Canada
facility: IWK Health
state: Nova Scotia
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Montréal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Quebec City
country: Canada
facility: CHU de Quebec
state: Quebec
Study officials:
affiliation: University of British Columbia
name: Souvik Mitra, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: