Single-dose Prophylactic INdomethacin in Extremely Preterm Infants (SPIN)

Single-dose Prophylactic INdomethacin in Extremely Preterm Infants - A Multicenter Randomized Blinded Placebo-Controlled Trial (the SPIN RCT)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Intraventricular Hemorrhage; Morbidity;Newborn; Extreme Prematurity
• Intervention / Treatment: Drug: Indomethacin; Drug: Placebo

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. The study will be conducted in 2 phases: (i) an internal pilot phase that will enroll 104 infants born <26 weeks or <750 g birth weight over a period of 1 year; (ii) 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 infants born <26 weeks or <750 g birth weight over a period of 3 years. The total of 500 infants will include the 104 infants enrolled in the first phase of the study.

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.

• Study Type: Interventional
• Enrollment (Estimated): 500
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Souvik Mitra, MD, PhD; Phone Number: 6048752000; Email: souvik.mitra@cw.bc.ca

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia
      • Monash Children's Hospital
      • Contact: Calum Roberts, MBChB PhD; Email: calum.roberts@monash.edu
    • Melbourne, Victoria, Australia
      • Mercy Hospital for Women
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Foothills Medical Center & Alberta Children's Hospital
      • Contact: Hussein Zein, MD; Email: hussein.zein@albertahealthservices.ca
      • Contact: Khorshid Mohammad, MD, MSc
    • Edmonton, Alberta, Canada
      • Royal Alexandra Hospital
      • Contact: Georg Schmolzer, MD, PhD; Email: georg.schmoelzer@me.com
  • British Columbia
    • New Westminster, British Columbia, Canada
      • Royal Columbian Hospital
      • Contact: Miroslav Stavel, MD; Email: miroslav.stavel@fraserhealth.ca
    • Vancouver, British Columbia, Canada, V6H 3N1
      • BC Women's Hospital
      • Contact: Souvik Mitra, MD, PhD; Phone Number: 6048752000; Email: souvik.mitra@cw.bc.ca
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • IWK Health
  • Ontario
    • Toronto, Ontario, Canada
      • Sunnybrook Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada
      • Montreal Children's Hospital
      • Contact: Marc Beltempo, MD, MSc; Email: marc.beltempo@mcgill.ca
    • Québec, Quebec, Canada
      • Chu De Quebec
      • Contact: Audrey Hebert, MD; Email: audrey.hebert.2@ulaval.ca
• United States
  • California
    • Roseville, California, United States, 95661
      • Kaiser Roseville
      • Contact: Shayna Gaman-Bean, MD; Email: shayna.k.gaman-bean@kp.org
    • Sacramento, California, United States, 95817
      • UC Davis Health
      • Contact: Steven McElroy, MD; Email: sjmcelroy@ucdavis.edu
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224-1334
      • University of Pittsburgh School of Medicine
      • Contact: Toby Yanowitz, MD, MS; Email: yanotd@upmc.edu
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Texas Health Harris Methodist Hospital Fort Worth
      • Contact: Ziad Alhassen, MD; Email: ziad.alhassen@pediatrix.com
      • Contact: Phone Number: 817-250-2000
    • Fort Worth, Texas, United States, 76104
      • Welcome to Baylor Scott & White Health
      • Contact: Ziad Alhassen, MD; Phone Number: 817-926-2544; Email: ziad.alhassen@pediatrix.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Indomethacin; Single dose of 0.1 mg/kg dose intravenous indomethacin as a slow infusion over 20 mins; Other Names: Indocid
Placebo Comparator: Control; Equal volume saline placebo administered intravenously over 20 mins	Drug: Placebo; Single dose of intravenous normal saline placebo as a slow infusion over 20 mins; Other Names: Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	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 Measures

Outcome Measure	Measure Description	Time Frame
Postnatal corticosteroid use		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)
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)
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)
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

Outcome Measure	Measure Description	Time Frame
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)
Primary feasibility outcomes (during the internal pilot)	(1) Proportion of eligible infants randomized during the internal pilot; (2) Proportion of randomized infants with no reported protocol deviation during the internal pilot	Through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Secondary feasibility outcomes (during the internal pilot)	(1) Reasons for non-recruitment and non-adherence to protocol; (2) qualitative views of parents and neonatologists on recruitment strategies	through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)

Collaborators and Investigators

• Sponsor: University of British Columbia
• Investigators: Principal Investigator: Souvik Mitra, MD, PhD, University of British Columbia

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2025
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): March 31, 2031

Study Registration Dates

• First Submitted: August 19, 2024
• First Submitted That Met QC Criteria: August 25, 2024
• First Posted (Actual): August 27, 2024

Study Record Updates

• Last Update Posted (Estimated): September 3, 2025
• Last Update Submitted That Met QC Criteria: August 26, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: mortality; extremely preterm; severe intraventricular hemorrhage; prophylactic indomethacin
• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Substandard Drugs; Pharmaceutical Preparations; Indoles; Crystalloid Solutions; Isotonic Solutions; Solutions; Indomethacin; Counterfeit Drugs; Saline Solution
• Other Study ID Numbers: H24-02525

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data on clinical outcomes collected during the trial will be shared after deidentification.
• IPD Sharing Time Frame: As soon as possible, wherever legally and ethically possible. In addition, data from the trial will be made available upon reasonable request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No