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Single-dose Prophylactic INdomethacin in Extremely Preterm Infants

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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.

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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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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
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    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

    Study type

    PREVENTION

    phase

    Phase

      PHASE3

    trial

    Trial ID

    NCT06572917

    Intervention or treatment

    DRUG: Indomethacin

    DRUG: Placebo

    Conditions

    • Extreme Prematurity
    • Intraventricular Hemorrhage
    • Morbidity;Newborn
    Image related to Extreme Prematurity
    • Condition: Extreme Prematurity, Intraventricular Hemorrhage and more

    • DRUG: Indomethacin and other drugs

    • Melbourne, Victoria, Australia and more

    • Sponsor: University of British Columbia

    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

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    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/ArmIntervention/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
    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

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary 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 sIVHthrough hospital discharge (approximately 20 weeks postnatal age unless death occurs first)

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    MortalityNot Specifiedthrough hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
    Severe IVHAny IVH more than grade 2 (i.e., grade 3, grade 4/intraparenchymal hemorrhage/perventricular hemorrhagic infarction is classified as sIVHthrough hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
    Gastrointestinal perforationNot Specifiedthrough hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
    Necrotizing enterocolitis (NEC)Bell Stage ≥stage 2through 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 arteriosusDefined as presence of PDA status on day 7 echocardiogram7 days postnatal age
    Procedural PDA closureDefinitive PDA closure either by surgical ligation or interventional percutaneous catheter based closurethrough hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
    Chronic pulmonary hypertensionEchocardiographic evidence of chronic pulmonary hypertensionbirth through 36 weeks' postmenstrual age (PMA)
    Grade 3 Bronchopulmonary dysplasia (BPD)Defined as need for invasive mechanical ventilation at 36 weeks' postmenstrual agebirth through 36 weeks' postmenstrual age (PMA)
    Pulmonary hemorrhageDefined 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 daysNot Specifiedthrough hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
    Postnatal corticosteroid useNot Specifiedthrough hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
    IVH (any grade)Not Specifiedthrough hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
    Periventricular leukomalacia (any grade)Not Specifiedthrough 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 fociTerm corrected age (approximately 20 weeks postnatal age)
    Severe retinopathy of prematurity (ROP)Defined as ROP ≥stage 3through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
    Major neurodevelopmental impairmentDefined 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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    References

    Clinical Trials Gov: Single-dose Prophylactic INdomethacin in Extremely Preterm Infants

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