Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP)

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

1202 participants

Study Classification

INTERVENTIONAL

Study Start Date

1993-11-30

Study Completion Date

2001-03-31

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.

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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.

Conditions

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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Indomethacin

Indocid P.D.A., Merck Frosst, Kirkland, Que., Canada, and Merck, West Point, Pa.

Group Type EXPERIMENTAL

indomethacin

Intervention Type DRUG

Indocid P.D.A., Merck Frosst, Kirkland, Que., Canada, and Merck, West Point, Pa

Indomethacin

Intervention Type DRUG

0.1 mg per kilogram of body weight

Placebo

Saline solution

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

0.1 mg per kilogram of body weight

Interventions

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indomethacin

Indocid P.D.A., Merck Frosst, Kirkland, Que., Canada, and Merck, West Point, Pa

Intervention Type DRUG

Indomethacin

0.1 mg per kilogram of body weight

Intervention Type DRUG

Placebo

0.1 mg per kilogram of body weight

Intervention Type DRUG

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

Minimum Eligible Age

2 Hours

Maximum Eligible Age

6 Hours

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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McMaster University

Principal Investigators

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Barbara Schmidt, MD

Role: STUDY_DIRECTOR

McMaster University

David K. Stevenson, MD

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Lu-Ann Papile, MD

Role: PRINCIPAL_INVESTIGATOR

University of New Mexico

Jon E. Tyson, MD MPH

Role: PRINCIPAL_INVESTIGATOR

University of Texas

Waldemar A. Carlo, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Seetha Shankaran, MD

Role: PRINCIPAL_INVESTIGATOR

Wayne State University

Barbara J. Stoll, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Avroy A. Fanaroff, MD

Role: PRINCIPAL_INVESTIGATOR

Case Western Reserve University

Charles R. Bauer, MD

Role: PRINCIPAL_INVESTIGATOR

University of Miami

William Oh, MD

Role: PRINCIPAL_INVESTIGATOR

Brown University, Womens and Infants Hospital

Locations

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University of Alabama at Birmingham

Birmingham, Alabama, United States

Site Status

Stanford University

Palo Alto, California, United States

Site Status

University of Miami

Miami, Florida, United States

Site Status

Emory University

Atlanta, Georgia, United States

Site Status

Wayne State University

Detroit, Michigan, United States

Site Status

University of New Mexico

Albuquerque, New Mexico, United States

Site Status

Case Western Reserve University, Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States

Site Status

Brown University, Women & Infants Hospital of Rhode Island

Providence, Rhode Island, United States

Site Status

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States

Site Status

Countries

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United States

References

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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.

Reference Type RESULT

PMID: 11430325 (View on PubMed)

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.

Reference Type RESULT

PMID: 12622582 (View on PubMed)

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.

Reference Type RESULT

PMID: 16647401 (View on PubMed)

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.

Reference Type RESULT

PMID: 16769377 (View on PubMed)

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.

Reference Type RESULT

PMID: 17188612 (View on PubMed)

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.

Reference Type RESULT

PMID: 17307535 (View on PubMed)

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.

Reference Type RESULT

PMID: 18245398 (View on PubMed)

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.

Reference Type RESULT

PMID: 19117897 (View on PubMed)

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.

Reference Type DERIVED

PMID: 21727276 (View on PubMed)