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

Primary Purpose

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

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
indomethacin
Indomethacin
Placebo
Sponsored by
NICHD Neonatal Research Network
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Infant, Very Low Birth Weight focused on measuring Chronic lung disease, Indocin, Indomethacin, Infants, very low birth weight, Intraventricular hemorrhage, Necrotizing enterocolitis, Patent ductus arteriosus, Pulmonary hemorrhage

Eligibility Criteria

2 Hours - 6 Hours (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Alabama at Birmingham
  • Stanford University
  • University of Miami
  • Emory University
  • Wayne State University
  • University of New Mexico
  • Case Western Reserve University, Rainbow Babies and Children's Hospital
  • Brown University, Women & Infants Hospital of Rhode Island
  • University of Texas Southwestern Medical Center at Dallas

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Indomethacin

Placebo

Arm Description

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

Saline solution

Outcomes

Primary Outcome Measures

Death or Neurodevelopment Impairment

Secondary Outcome Measures

Patent ductus arteriosus
Bronchopulmonary Dysplasia (BPD)
Chronic Lung Disease (CLD)
Necrotizing enterocolitis (NEC)
Intracranial abnormalities
Retinopathy of Prematurity (ROP)
Pulmonary hemorrhage

Full Information

First Posted
February 1, 2001
Last Updated
June 3, 2015
Sponsor
NICHD Neonatal Research Network
Collaborators
Medical Research Council of Canada, National Center for Research Resources (NCRR)
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1. Study Identification

Unique Protocol Identification Number
NCT00009646
Brief Title
Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP)
Acronym
TIPP
Official Title
Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2015
Overall Recruitment Status
Completed
Study Start Date
November 1993 (undefined)
Primary Completion Date
March 1999 (Actual)
Study Completion Date
March 2001 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
NICHD Neonatal Research Network
Collaborators
Medical Research Council of Canada, National Center for Research Resources (NCRR)

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infant, Very Low Birth Weight, Infant, Premature, Ductus Arteriosus, Patent
Keywords
Chronic lung disease, Indocin, Indomethacin, Infants, very low birth weight, Intraventricular hemorrhage, Necrotizing enterocolitis, Patent ductus arteriosus, Pulmonary hemorrhage

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1202 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Indomethacin
Arm Type
Experimental
Arm Description
Indocid P.D.A., Merck Frosst, Kirkland, Que., Canada, and Merck, West Point, Pa.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Saline solution
Intervention Type
Drug
Intervention Name(s)
indomethacin
Intervention Description
Indocid P.D.A., Merck Frosst, Kirkland, Que., Canada, and Merck, West Point, Pa
Intervention Type
Drug
Intervention Name(s)
Indomethacin
Intervention Description
0.1 mg per kilogram of body weight
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
0.1 mg per kilogram of body weight
Primary Outcome Measure Information:
Title
Death or Neurodevelopment Impairment
Time Frame
18-22 Months Corrected Age
Secondary Outcome Measure Information:
Title
Patent ductus arteriosus
Time Frame
120 Days of Life
Title
Bronchopulmonary Dysplasia (BPD)
Description
Chronic Lung Disease (CLD)
Time Frame
120 Days of Life
Title
Necrotizing enterocolitis (NEC)
Time Frame
120 Days of Life
Title
Intracranial abnormalities
Time Frame
120 Days of Life
Title
Retinopathy of Prematurity (ROP)
Time Frame
18-22 Months Corrected Age
Title
Pulmonary hemorrhage
Time Frame
120 Days of Life

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Hours
Maximum Age & Unit of Time
6 Hours
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Barbara Schmidt, MD
Organizational Affiliation
McMaster University
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
David K. Stevenson, MD
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lu-Ann Papile, MD
Organizational Affiliation
University of New Mexico
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jon E. Tyson, MD MPH
Organizational Affiliation
University of Texas
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Waldemar A. Carlo, MD
Organizational Affiliation
University of Alabama at Birmingham
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Seetha Shankaran, MD
Organizational Affiliation
Wayne State University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Barbara J. Stoll, MD
Organizational Affiliation
Emory University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Avroy A. Fanaroff, MD
Organizational Affiliation
Case Western Reserve University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Charles R. Bauer, MD
Organizational Affiliation
University of Miami
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
William Oh, MD
Organizational Affiliation
Brown University, Womens and Infants Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
Stanford University
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
University of Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30303
Country
United States
Facility Name
Wayne State University
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
University of New Mexico
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87131
Country
United States
Facility Name
Case Western Reserve University, Rainbow Babies and Children's Hospital
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Brown University, Women & Infants Hospital of Rhode Island
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02905
Country
United States
Facility Name
University of Texas Southwestern Medical Center at Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
11430325
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 Med. 2001 Jun 28;344(26):1966-72. doi: 10.1056/NEJM200106283442602.
Results Reference
result
PubMed Identifier
12622582
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-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.
Results Reference
result
PubMed Identifier
16647401
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. 2006 Apr;148(4):438-444. doi: 10.1016/j.jpeds.2005.11.042.
Results Reference
result
PubMed Identifier
16769377
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 in Preterms (TIPP). J Pediatr. 2006 Jun;148(6):730-734. doi: 10.1016/j.jpeds.2006.01.047.
Results Reference
result
PubMed Identifier
17188612
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. doi: 10.1016/j.jpeds.2006.09.001.
Results Reference
result
PubMed Identifier
17307535
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 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.
Results Reference
result
PubMed Identifier
18245398
Citation
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.
Results Reference
result
PubMed Identifier
19117897
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 of neonatal infection. Pediatrics. 2009 Jan;123(1):313-8. doi: 10.1542/peds.2008-0377.
Results Reference
result
PubMed Identifier
21727276
Citation
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.
Results Reference
derived
Links:
URL
http://neonatal.rti.org/
Description
NICHD Neonatal Research Network

Learn more about this trial

Trial of Indomethacin Prophylaxis in Preterm Infants (TIPP)

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