Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP)

Study Overview
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Brief Summary
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This trial was to determine whether giving low-dose indomethacin to infants weight 500 to 999 grams (approximately 1 to 2 pounds) at birth improves their survival without cerebral palsy or developmental problems at 18 to 22 months of age.

Detailed Description
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Prophylactic indomethacin reduces patent ductus arteriosus (PDA) and intraventricular hemorrhage in very low birth weight infants. However, the effects of early indomethacin on long-term neurodevelopment remain uncertain. There is also insufficient evidence to rule out serious adverse effects, such as increases in the risk of necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP). The aim of this trial was to determine if prophylactic administration of indomethacin improves survival without neurosensory impairments in extremely-low-birth-weight infants. Infants (n=1202) with birthweights 500 to 999 grams were randomized between 2 and 6 hours after birth to receive either intravenous indomethacin (0.1 mg/kg) or equal volumes of normal saline placebo, daily for 3 days. The primary outcomes at a corrected age of 18 months was a composite of death, cerebral palsy, cognitive delay, deafness, or blindness. Secondary long-term outcomes were hydrocephalus necessitating the placement of a shunt, seizure disorder, and microcephaly. Secondary short-term outcomes were patent ductus arteriosus, pulmonary hemorrhage, chronic lung disease, cranial ultrasonographic abnormalities, nectrotizing enterocolitis and retinopathy. Infants were evaluated in follow-up at 18-22 months corrected age.

Official Title
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Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP)

Conditions
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Infant, Very Low Birth Weight, Infant, Premature, Ductus Arteriosus, Patent

Intervention / Treatment
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* Drug: indomethacin
* Drug: Indomethacin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Birth weight 500 to 999 grams; Postnatal age greater than 2 hours; Exclusion Criteria: Unable to administer study drug within 6 hours of birth; Structural heart disease and/or renal disease; Dysmorphic features or congenital abnormalities; Tocolytic therapy with indomethacin or other prostaglandin inhibitor within 72 hours prior to delivery; Overt clinical bleeding from more than one site; Platelet count less than 50 x 109/L; Hydrops; Not considered viable

Ages Eligible for Study
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Minimum Age: 2 Hours
Maximum Age: 6 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Indomethacin<br>Indocid P.D.A., Merck Frosst, Kirkland, Que., Canada, and Merck, West Point, Pa. | Drug: indomethacin<br>* Indocid P.D.A., Merck Frosst, Kirkland, Que., Canada, and Merck, West Point, Pa<br>Drug: Indomethacin<br>* 0.1 mg per kilogram of body weight<br>|
| Placebo Comparator: Placebo<br>Saline solution | Drug: Placebo<br>* 0.1 mg per kilogram of body weight<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death or Neurodevelopment Impairment |  | 18-22 Months Corrected Age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patent ductus arteriosus |  | 120 Days of Life | 
| Bronchopulmonary Dysplasia (BPD) | Chronic Lung Disease (CLD) | 120 Days of Life | 
| Necrotizing enterocolitis (NEC) |  | 120 Days of Life | 
| Intracranial abnormalities |  | 120 Days of Life | 
| Retinopathy of Prematurity (ROP) |  | 18-22 Months Corrected Age | 
| Pulmonary hemorrhage |  | 120 Days of Life | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic lung disease, Indocin, Indomethacin, Infants, very low birth weight, Intraventricular hemorrhage, Necrotizing enterocolitis, Patent ductus arteriosus, Pulmonary hemorrhage