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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
Medical Research Council of Canada
National Center for Research Resources (NCRR)
Information provided by:
NICHD Neonatal Research Network

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.

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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

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

Primary Outcome Measures :
  1. Death or Neurodevelopment Impairment [ Time Frame: 18-22 Months Corrected Age ]

Secondary Outcome Measures :
  1. Patent ductus arteriosus [ Time Frame: 120 Days of Life ]
  2. Bronchopulmonary Dysplasia (BPD) [ Time Frame: 120 Days of Life ]
    Chronic Lung Disease (CLD)

  3. Necrotizing enterocolitis (NEC) [ Time Frame: 120 Days of Life ]
  4. Intracranial abnormalities [ Time Frame: 120 Days of Life ]
  5. Retinopathy of Prematurity (ROP) [ Time Frame: 18-22 Months Corrected Age ]
  6. Pulmonary hemorrhage [ Time Frame: 120 Days of Life ]

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

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

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

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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)
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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
Additional Information:
Publications of Results:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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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
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
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
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