Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP)

Infant, Premature Clinical Trial

— TIPP  

Official title:

Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00009646
• Other study ID #: NICHD-NRN-0011
• Secondary ID: U10HD034216U10HD
• Status: Completed
• Phase: Phase 3
• First received: February 1, 2001
• Last updated: June 3, 2015
• Start date: November 1993
• Est. completion date: March 2001

Study information

• Verified date: June 2015
• Source: NICHD Neonatal Research Network
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Institutional Review BoardUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1202
• Est. completion date: March 2001
• Est. primary completion date: March 1999
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 6 Hours

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

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

Intervention

Drug:
• indomethacin
Indocid P.D.A., Merck Frosst, Kirkland, Que., Canada, and Merck, West Point, Pa
• Indomethacin
0.1 mg per kilogram of body weight
• Placebo
0.1 mg per kilogram of body weight

Locations

Country	Name	City	State
United States	University of New Mexico	Albuquerque	New Mexico
United States	Emory University	Atlanta	Georgia
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Case Western Reserve University, Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	Wayne State University	Detroit	Michigan
United States	University of Miami	Miami	Florida
United States	Stanford University	Palo Alto	California
United States	Brown University, Women & Infants Hospital of Rhode Island	Providence	Rhode Island

Sponsors (3)

Lead Sponsor	Collaborator
NICHD Neonatal Research Network	Medical Research Council of Canada, National Center for Research Resources (NCRR)

Country where clinical trial is conducted

United States, 

References & Publications (8)

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 tria — View Citation

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. — View Citation

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 o — View Citation

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. — View Citation

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 th — View Citation

Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF; Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth- — View Citation

Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, Solimano A, Vincer M, Wright LL; Trial of Indomethacin Prophylaxis in Preterms Investigators. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J M — View Citation

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Death or Neurodevelopment Impairment		18-22 Months Corrected Age	Yes
Secondary	Patent ductus arteriosus		120 Days of Life	Yes
Secondary	Bronchopulmonary Dysplasia (BPD)	Chronic Lung Disease (CLD)	120 Days of Life	Yes
Secondary	Necrotizing enterocolitis (NEC)		120 Days of Life	Yes
Secondary	Intracranial abnormalities		120 Days of Life	Yes
Secondary	Retinopathy of Prematurity (ROP)		18-22 Months Corrected Age	Yes
Secondary	Pulmonary hemorrhage		120 Days of Life	Yes

External Links

•   NICHD Neonatal Research Network