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

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ClinicalTrials.gov Identifier: NCT00009646

Recruitment Status : Completed

First Posted : February 5, 2001

Last Update Posted : June 8, 2015

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Sponsor:

Collaborators:

Medical Research Council of Canada

National Center for Research Resources (NCRR)

Information provided by:

NICHD Neonatal Research Network

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Infant, Very Low Birth Weight Infant, Premature Ductus Arteriosus, Patent	Drug: indomethacin Drug: Indomethacin Drug: Placebo	Phase 3

Detailed 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	1202 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP)
Study Start Date :	November 1993
Actual Primary Completion Date :	March 1999
Actual Study Completion Date :	March 2001

Resource links provided by the National Library of Medicine

Drug Information available for: Indomethacin

Genetic and Rare Diseases Information Center resources: Necrotizing Enterocolitis Chronic Graft Versus Host Disease Patent Ductus Arteriosus

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Indomethacin Indocid P.D.A., Merck Frosst, Kirkland, Que., Canada, and Merck, West Point, Pa.	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
Placebo Comparator: Placebo Saline solution	Drug: Placebo 0.1 mg per kilogram of body weight

Outcome Measures

Primary Outcome Measures :

Death or Neurodevelopment Impairment [ Time Frame: 18-22 Months Corrected Age ]

Secondary Outcome Measures :

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

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	2 Hours to 6 Hours (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00009646

Locations

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United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
United States, California
Stanford University
Palo Alto, California, United States, 94304
United States, Florida
University of Miami
Miami, Florida, United States, 33136
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30303
United States, Michigan
Wayne State University
Detroit, Michigan, United States, 48201
United States, New Mexico
University of New Mexico
Albuquerque, New Mexico, United States, 87131
United States, Ohio
Case Western Reserve University, Rainbow Babies and Children's Hospital
Cleveland, Ohio, United States, 44106
United States, Rhode Island
Brown University, Women & Infants Hospital of Rhode Island
Providence, Rhode Island, United States, 02905
United States, Texas
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas, United States, 75235

Sponsors and Collaborators

NICHD Neonatal Research Network

Medical Research Council of Canada

National Center for Research Resources (NCRR)

Investigators

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Study Director:	Barbara Schmidt, MD	McMaster University
Principal Investigator:	David K. Stevenson, MD	Stanford University
Principal Investigator:	Lu-Ann Papile, MD	University of New Mexico
Principal Investigator:	Jon E. Tyson, MD MPH	University of Texas
Principal Investigator:	Waldemar A. Carlo, MD	University of Alabama at Birmingham
Principal Investigator:	Seetha Shankaran, MD	Wayne State University
Principal Investigator:	Barbara J. Stoll, MD	Emory University
Principal Investigator:	Avroy A. Fanaroff, MD	Case Western Reserve University
Principal Investigator:	Charles R. Bauer, MD	University of Miami
Principal Investigator:	William Oh, MD	Brown University, Womens and Infants Hospital

More Information

Additional Information:

NICHD Neonatal Research Network This link exits the ClinicalTrials.gov site

Publications of Results:

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 Med. 2001 Jun 28;344(26):1966-72. doi: 10.1056/NEJM200106283442602.

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-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA. 2003 Mar 5;289(9):1124-9. doi: 10.1001/jama.289.9.1124.

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. doi: 10.1016/j.jpeds.2005.11.042.

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. doi: 10.1016/j.jpeds.2006.01.047.

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. doi: 10.1016/j.jpeds.2006.09.001.

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. doi: 10.1016/j.jpeds.2006.11.039.

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. doi: 10.1542/peds.2007-0028.

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. doi: 10.1542/peds.2008-0377.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Schmidt B, Seshia M, Shankaran S, Mildenhall L, Tyson J, Lui K, Fok T, Roberts R; Trial of Indomethacin Prophylaxis in Preterms Investigators. Effects of prophylactic indomethacin in extremely low-birth-weight infants with and without adequate exposure to antenatal corticosteroids. Arch Pediatr Adolesc Med. 2011 Jul;165(7):642-6. doi: 10.1001/archpediatrics.2011.95.

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Responsible Party:	Barbara Schmidt/ Lead Principal Investigator, McMaster University
ClinicalTrials.gov Identifier:	NCT00009646
Other Study ID Numbers:	NICHD-NRN-0011 U10HD034216 ( U.S. NIH Grant/Contract ) U10HD027904 ( U.S. NIH Grant/Contract ) U10HD021364 ( U.S. NIH Grant/Contract ) U10HD027851 ( U.S. NIH Grant/Contract ) U10HD021397 ( U.S. NIH Grant/Contract ) U10HD027881 ( U.S. NIH Grant/Contract ) U10HD027880 ( U.S. NIH Grant/Contract ) U10HD021373 ( U.S. NIH Grant/Contract ) U10HD021385 ( U.S. NIH Grant/Contract ) MT-13288 ( Other Grant/Funding Number: Medical Research Council of Canada ) M01RR000997 ( U.S. NIH Grant/Contract ) M01RR000070 ( U.S. NIH Grant/Contract )
First Posted:	February 5, 2001 Key Record Dates
Last Update Posted:	June 8, 2015
Last Verified:	June 2015

Keywords provided by NICHD Neonatal Research Network:


Chronic lung disease Indocin Indomethacin Infants, very low birth weight	Intraventricular hemorrhage Necrotizing enterocolitis Patent ductus arteriosus Pulmonary hemorrhage

Additional relevant MeSH terms:

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Ductus Arteriosus, Patent Birth Weight Body Weight Heart Defects, Congenital Cardiovascular Abnormalities Cardiovascular Diseases Heart Diseases Congenital Abnormalities Indomethacin Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics	Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Anti-Inflammatory Agents Antirheumatic Agents Gout Suppressants Tocolytic Agents Reproductive Control Agents Cyclooxygenase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action

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