Single-dose Prophylactic INdomethacin in Extremely Preterm Infants
NCT Number: NCT06572917
Acronym: SPIN
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE3
Conditions: Extreme Prematurity|Intraventricular Hemorrhage|Morbidity;Newborn
Interventions: DRUG: Indomethacin|DRUG: Placebo
Sponsor: University of British Columbia
Sex: ALL
Age: CHILD
Enrollment: 500
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: QUADRUPLE (PARTICIPANT, CARE_PROVIDER, INVESTIGATOR, OUTCOMES_ASSESSOR)|Primary Purpose: PREVENTION
Start Date: 2025-06-01
Completion Date: 2030-12-31
Locations: Kaiser Roseville, Roseville, California, 95661, United States|UC Davis Health, Sacramento, California, 95817, United States|University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15224-1334, United States|Monash Children's Hospital, Melbourne, Victoria, Australia|The Royal Women's Hospital, Melbourne, Victoria, Australia|Foothills Medical Center, Calgary, Alberta, Canada|Royal Alexandra Hospital, Edmonton, Alberta, Canada|Royal Columbian Hospital, New Westminster, British Columbia, Canada|BC Women's Hospital, Vancouver, British Columbia, V6H 3N1, Canada|IWK Health, Halifax, Nova Scotia, Canada|Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada|Montreal Children's Hospital, Montréal, Quebec, Canada|CHU de Quebec, Quebec City, Quebec, Canada

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.

Primary Outcome Measures: 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 Measures: Mortality, 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, 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, through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)|Postnatal corticosteroid use, through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)|IVH (any grade), 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)|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)
Other Outcome Measures: Pharmacokinetic outcomes, clearance, volume of distribution and plasma exposure of single-dose indomethacin, 7 days postnatal age|Health Economic outcomes, Total healthcare costs (measured to first discharge home); cost per sIVH or death averted; and cost per death averted, through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)