Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP)
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...
Brief Summary
Official Title: “Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP)”
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.
- Study Type: Interventional
- Study Design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
- Study Primary Completion Date: March 1999
Detailed Clinical Trial Description
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.
Intervention(s) in this Clinical Trial
- Drug: indomethacin
- Indocid P.D.A., Merck Frosst, Kirkland, Que., Canada, and Merck, West Point, Pa
- Drug: Indomethacin
- 0.1 mg per kilogram of body weight
- Drug: Placebo
- 0.1 mg per kilogram of body weight
Arms, Groups and Cohorts in this Clinical Trial
- Experimental: Indomethacin
- Indocid P.D.A., Merck Frosst, Kirkland, Que., Canada, and Merck, West Point, Pa.
- Placebo Comparator: Placebo
- Saline solution
Outcome Measures for this Clinical Trial
Primary Measures
- Death or Neurodevelopment Impairment
- Time Frame: 18-22 Months Corrected Age
Safety Issue?: Yes
- Time Frame: 18-22 Months Corrected Age
Secondary Measures
- Patent ductus arteriosus
- Time Frame: 120 Days of Life
Safety Issue?: Yes
- Time Frame: 120 Days of Life
- Bronchopulmonary Dysplasia (BPD)
- Time Frame: 120 Days of Life
Safety Issue?: Yes
- Time Frame: 120 Days of Life
- Necrotizing enterocolitis (NEC)
- Time Frame: 120 Days of Life
Safety Issue?: Yes
- Time Frame: 120 Days of Life
- Intracranial abnormalities
- Time Frame: 120 Days of Life
Safety Issue?: Yes
- Time Frame: 120 Days of Life
- Retinopathy of Prematurity (ROP)
- Time Frame: 18-22 Months Corrected Age
Safety Issue?: Yes
- Time Frame: 18-22 Months Corrected Age
- Pulmonary hemorrhage
- Time Frame: 120 Days of Life
Safety Issue?: Yes
- Time Frame: 120 Days of Life
Criteria for Participation in this Clinical Trial
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
Gender Eligibility for this Clinical Trial: Both
Minimum Age for this Clinical Trial: N/A
Maximum Age for this Clinical Trial: 6 Hours
Are Healthy Volunteers Accepted for this Clinical Trial?: No
Clinical Trial Investigator Information
Lead Investigator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) NIH
Overall Clinical Trial Officials and Contacts
Barbara Schmidt, MD Study Director McMaster University
Related Publications
Citations Reporting Results
Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, Solimano A, Vincer M, Wright LL. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med. 2001 Jun 28;344(26):1966-72.
Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA. 2003 Mar 5;289(9):1124-9.
Ambalavanan N, Baibergenova A, Carlo WA, Saigal S, Schmidt B, Thorpe KE; Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators. Early prediction of poor outcome in extremely low birth weight infants by classification tree analysis. J Pediatr. 2006 Apr;148(4):438-444.
Schmidt B, Roberts RS, Fanaroff A, Davis P, Kirpalani HM, Nwaesei C, Vincer M; TIPP Investigators. Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP). J Pediatr. 2006 Jun;148(6):730-734.
Clyman RI, Saha S, Jobe A, Oh W. Indomethacin prophylaxis for preterm infants: the impact of 2 multicentered randomized controlled trials on clinical practice. J Pediatr. 2007 Jan;150(1):46-50.e2.
Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A; Trial of Indomethacin Prophylaxis in Preterms Investigators. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms. J Pediatr. 2007 Mar;150(3):229-34, 234.e1.
Alfaleh K, Smyth JA, Roberts RS, Solimano A, Asztalos EV, Schmidt B; Trial of Indomethacin Prophylaxis in Preterms Investigators. Prevention and 18-month outcomes of serious pulmonary hemorrhage in extremely low birth weight infants: results from the trial of indomethacin prophylaxis in preterms. Pediatrics. 2008 Feb;121(2):e233-8.
Bassler D, Stoll BJ, Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS; Trial of Indomethacin Prophylaxis in Preterms Investigators. Using a count of neonatal morbidities to predict poor outcome in extremely low birth weight infants: added role of neonatal infection. Pediatrics. 2009 Jan;123(1):313-8.
Additional Information
Information obtained from ClinicalTrials.gov on February 09, 2012
Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00009646
Study ID Number: NICHD-NRN-0011
ClinicalTrials.gov Identifier: NCT00009646
Health Authority: United States: Federal Government
NICHD Neonatal Research Network
Cochrane meta-analysis: "Prophylactic intravenous indomethacin in VLBW infants."
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http://clinicaltrialsfeeds.org/clinical-trials/show/NCT00009646
