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Single-dose Prophylactic INdomethacin in Extremely Preterm Infants
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.
Study details:
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
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Inclusion criteria
Exclusion criteria
Eligibility
Age eligible for study : 0 and older
Healthy volunteers accepted : No
Gender eligible for study: All
Things to know
Study dates
Study start: 2025-06-01
Primary completion: 2028-05-31
Study completion finish: 2030-12-31
Study type
PREVENTION
Phase
PHASE3
Trial ID
NCT06572917
Intervention or treatment
DRUG: Indomethacin
DRUG: Placebo
Conditions
- • Extreme Prematurity
- • Intraventricular Hemorrhage
- • Morbidity;Newborn
Find a site
Closest Location:
Monash Children's Hospital
Research sites nearby
Select from list below to view details:
Monash Children's Hospital
Melbourne, Victoria, Australia
The Royal Women's Hospital
Melbourne, Victoria, Australia
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: Single-dose prophylactic indomethacin - SPIN
| DRUG: Indomethacin
|
PLACEBO_COMPARATOR: Control
| DRUG: Placebo
|
What is the study measuring?
Primary outcome
| Primary Outcome Measure | Primary Outcome Description | Primary Outcome Time Frame |
|---|---|---|
| Survival without severe intraventricular hemorrhage (sIVH) | Any IVH more than grade 2 (i.e., grade 3, grade 4/intraparenchymal hemorrhage/perventricular hemorrhagic infarction is classified as sIVH | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
Secondary outcome
| Secondary Outcome Measure | Secondary Outcome Description | Secondary Outcome Time Frame |
|---|---|---|
| Mortality | Not Specified | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
| Severe IVH | Any IVH more than grade 2 (i.e., grade 3, grade 4/intraparenchymal hemorrhage/perventricular hemorrhagic infarction is classified as sIVH | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
| Gastrointestinal perforation | Not Specified | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
| Necrotizing enterocolitis (NEC) | Bell Stage ≥stage 2 | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
| Acute kidney injury (AKI) | Defined as ≥stage 1 according to the Neonatal AKI KDIGO classification) | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
| Persistent patent ductus arteriosus | Defined as presence of PDA status on day 7 echocardiogram | 7 days postnatal age |
| Procedural PDA closure | Definitive PDA closure either by surgical ligation or interventional percutaneous catheter based closure | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
| Chronic pulmonary hypertension | Echocardiographic evidence of chronic pulmonary hypertension | birth through 36 weeks' postmenstrual age (PMA) |
| Grade 3 Bronchopulmonary dysplasia (BPD) | Defined as need for invasive mechanical ventilation at 36 weeks' postmenstrual age | birth through 36 weeks' postmenstrual age (PMA) |
| Pulmonary hemorrhage | Defined as blood stained respiratory secretions with an acute significant increase in respiratory requirements (Mean Airway Pressure\>12 cm H2O and/or Fraction of inspired O2\>60% | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
| Duration of invasive mechanical ventilation in days | Not Specified | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
| Postnatal corticosteroid use | Not Specified | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
| IVH (any grade) | Not Specified | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
| Periventricular leukomalacia (any grade) | Not Specified | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
| White matter injury (WMI) | Defined on MRI brain as discrete areas of abnormal white matter T1 hyperintensity in the absence of marked T2 hypo-intensity, or by low-intensity T1 foci | Term corrected age (approximately 20 weeks postnatal age) |
| Severe retinopathy of prematurity (ROP) | Defined as ROP ≥stage 3 | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) |
| Major neurodevelopmental impairment | Defined as any one of: (i) CP with an inability to walk unassisted; (ii) major developmental delay involving cognition or language or (iii) visual (cannot fixate/legally blind, or corrected acuity \<6/60 in both eyes), or hearing impairment (requiring a hearing aid or cochlear implants) | 24 (±6) months postmenstrual age (PMA) |
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