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Effects of Delayed Cord Clamp and/or Indomethacin on Preterm Infant Brain Injury

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ClinicalTrials.gov Identifier: NCT02221219
Recruitment Status : Active, not recruiting
First Posted : August 20, 2014
Results First Posted : December 8, 2020
Last Update Posted : December 8, 2020
Sponsor:
Information provided by (Responsible Party):
Hong Huang, University of Kentucky

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Conditions Intraventricular Hemorrhage
Periventricular Leukomalacia
Brain Injury
Renal Injury
Interventions Drug: Indomethacin
Procedure: delay in umbilical cord clamp at birth
Drug: placebo infusion
Procedure: immediate cord clamp at birth
Enrollment 256
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Immediate Cord Clamp & Placebo IV Solution Delay Cord Clamp & Placebo IV Solution Immediate Cord Clamp & Indomethacin IV Indomethacin iv & Delayed Cord Clamp
Hide Arm/Group Description

This Arm will receive immediate clamp of umbilical cord at birth, and an intravenous delivery of placebo drug solution (diluent for active drug, indomethacin) within the first 12hrs of life.

placebo infusion: saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)

immediate cord clamp at birth: no delay in umbilical cord clamp; <10sec (recorded in delivery note)

A delay in cord clamp for 45 seconds will be instituted in the delivery room. Placebo drug solution will be administered within 12hrs post-birth.

delay in umbilical cord clamp at birth: provision of a ~45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note)

placebo infusion: saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)

Umbilical cord will be clamped immediately at birth. Indomethacin will be administered IV, starting within 12hrs of life (0.1mg/kg every 24 hrs for three total doses.This intervention is considered 'standard care' at many Neonatology medical facilities. The dose of indomethacin has been shown to be effective in reducing brain bleeds in preterm infants (although there are also data showing safety concerns).

Indomethacin: indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants

immediate cord clamp at birth: no delay in umbilical cord clamp; <10sec (recorded in delivery note)

A delay in cord clamp of 45 seconds will be instituted in the delivery room. In addition, indomethacin will be administered iv (initiated within 12hrs of life), 0.1mg/kg every 24 hrs for three total doses.

Indomethacin: indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants

delay in umbilical cord clamp at birth: provision of a ~45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note)

Period Title: Overall Study
Started 36 87 41 92
Completed 36 87 41 92
Not Completed 0 0 0 0
Arm/Group Title Immediate Cord Clamp & Placebo IV Solution Delay Cord Clamp & Placebo IV Solution Immediate Cord Clamp & Indomethacin IV Indomethacin iv & Delayed Cord Clamp Total
Hide Arm/Group Description

This Arm will receive immediate clamp of umbilical cord at birth, and an intravenous delivery of placebo drug solution (diluent for active drug, indomethacin) within the first 12hrs of life.

placebo infusion: saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)

immediate cord clamp at birth: no delay in umbilical cord clamp; <10sec (recorded in delivery note)

A delay in cord clamp for 45 seconds will be instituted in the delivery room. Placebo drug solution will be administered within 12hrs post-birth.

delay in umbilical cord clamp at birth: provision of a ~45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note)

placebo infusion: saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)

Umbilical cord will be clamped immediately at birth. Indomethacin will be administered IV, starting within 12hrs of life (0.1mg/kg every 24 hrs for three total doses.This intervention is considered 'standard care' at many Neonatology medical facilities. The dose of indomethacin has been shown to be effective in reducing brain bleeds in preterm infants (although there are also data showing safety concerns).

Indomethacin: indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants

immediate cord clamp at birth: no delay in umbilical cord clamp; <10sec (recorded in delivery note)

A delay in cord clamp of 45 seconds will be instituted in the delivery room. In addition, indomethacin will be administered iv (initiated within 12hrs of life), 0.1mg/kg every 24 hrs for three total doses.

Indomethacin: indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants

delay in umbilical cord clamp at birth: provision of a ~45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note)

Total of all reporting groups
Overall Number of Baseline Participants 36 87 41 92 256
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Weeks
Number Analyzed 36 participants 87 participants 41 participants 92 participants 256 participants
26.2  (1.8) 26.6  (2.0) 26.6  (1.8) 26.4  (1.8) 26.5  (1.9)
Sex/Gender, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 36 participants 87 participants 41 participants 92 participants 256 participants
Male
19
  52.8%
47
  54.0%
19
  46.3%
47
  51.1%
132
  51.6%
Female
17
  47.2%
39
  44.8%
21
  51.2%
45
  48.9%
122
  47.7%
Unknown
0
   0.0%
1
   1.1%
1
   2.4%
0
   0.0%
2
   0.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 36 participants 87 participants 41 participants 92 participants 256 participants
Hispanic or Latino
2
   5.6%
2
   2.3%
1
   2.4%
2
   2.2%
7
   2.7%
Not Hispanic or Latino
32
  88.9%
84
  96.6%
39
  95.1%
90
  97.8%
245
  95.7%
Unknown or Not Reported
2
   5.6%
1
   1.1%
1
   2.4%
0
   0.0%
4
   1.6%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 36 participants 87 participants 41 participants 92 participants 256 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
6
  16.7%
10
  11.5%
3
   7.3%
12
  13.0%
31
  12.1%
White
27
  75.0%
74
  85.1%
36
  87.8%
76
  82.6%
213
  83.2%
More than one race
1
   2.8%
2
   2.3%
1
   2.4%
3
   3.3%
7
   2.7%
Unknown or Not Reported
2
   5.6%
1
   1.1%
1
   2.4%
1
   1.1%
5
   2.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 36 participants 87 participants 41 participants 92 participants 256 participants
36 87 41 92 256
Birth Weight  
Mean (Standard Deviation)
Unit of measure:  Grams
Number Analyzed 36 participants 87 participants 41 participants 92 participants 256 participants
797.2  (267.4) 935.1  (295.0) 902.4  (369.8) 916.8  (254.8) 903.9  (291.2)
1.Primary Outcome
Title Fraction of Survivors With no Severe IVH (Grades 3 or 4) or PVL
Hide Description determined by head ultrasound in Neonatal Intensive Care Unit (NICU) and single head MRI at 38weeks corrected gestational age
Time Frame within first 60 days of life
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Immediate Cord Clamp & Placebo IV Solution Delay Cord Clamp & Placebo IV Solution Immediate Cord Clamp & Indomethacin IV Indomethacin iv & Delayed Cord Clamp
Hide Arm/Group Description:

This Arm will receive immediate clamp of umbilical cord at birth, and an intravenous delivery of placebo drug solution (diluent for active drug, indomethacin) within the first 12hrs of life.

placebo infusion: saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)

immediate cord clamp at birth: no delay in umbilical cord clamp; <10sec (recorded in delivery note)

A delay in cord clamp for 45 seconds will be instituted in the delivery room. Placebo drug solution will be administered within 12hrs post-birth.

delay in umbilical cord clamp at birth: provision of a ~45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note)

placebo infusion: saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)

Umbilical cord will be clamped immediately at birth. Indomethacin will be administered IV, starting within 12hrs of life (0.1mg/kg every 24 hrs for three total doses.This intervention is considered 'standard care' at many Neonatology medical facilities. The dose of indomethacin has been shown to be effective in reducing brain bleeds in preterm infants (although there are also data showing safety concerns).

Indomethacin: indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants

immediate cord clamp at birth: no delay in umbilical cord clamp; <10sec (recorded in delivery note)

A delay in cord clamp of 45 seconds will be instituted in the delivery room. In addition, indomethacin will be administered iv (initiated within 12hrs of life), 0.1mg/kg every 24 hrs for three total doses.

Indomethacin: indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants

delay in umbilical cord clamp at birth: provision of a ~45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note)

Overall Number of Participants Analyzed 36 87 41 92
Measure Type: Number
Unit of Measure: percent of participants
22.2 14.9 17.1 10.9
2.Secondary Outcome
Title Occurrence of Renal Injury and/or Dysfunction
Hide Description measures of BUN, Creatinine, and cystatin C at various times during Neonatal Intensive Care Unit (NICU) stay. General measures of renal injury (which is a common risk of indomethacin treatment in this patient population)
Time Frame first 60 days of life
Outcome Measure Data Not Reported
3.Other Pre-specified Outcome
Title Hematological Status
Hide Description hematocrit, ferritin, hemoglobin at various times during NICU stay
Time Frame first 60 days of life
Outcome Measure Data Not Reported
4.Other Pre-specified Outcome
Title Inflammatory Stress
Hide Description measurement of inflammatory biomarkers (CRP, Interleukin-6, soluble ICAM) at various times during NICU stay
Time Frame first 60 days of life
Outcome Measure Data Not Reported
5.Other Pre-specified Outcome
Title Circulating Progenitor Cell Subpopulations
Hide Description measures of several progenitor cell subtypes in blood during the NICU stay
Time Frame first 60 days of life
Outcome Measure Data Not Reported
6.Other Pre-specified Outcome
Title Neurocognitive Assessments at Post-NICU Followup
Hide Description standardized neurocognitive assessments done at NICU graduate clinic.
Time Frame up to 24 months of corrected gestational age
Outcome Measure Data Not Reported
Time Frame First 60 days of life.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Immediate Cord Clamp & Placebo IV Solution Delay Cord Clamp & Placebo IV Solution Immediate Cord Clamp & Indomethacin IV Indomethacin iv & Delayed Cord Clamp
Hide Arm/Group Description

This Arm will receive immediate clamp of umbilical cord at birth, and an intravenous delivery of placebo drug solution (diluent for active drug, indomethacin) within the first 12hrs of life.

placebo infusion: saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)

immediate cord clamp at birth: no delay in umbilical cord clamp; <10sec (recorded in delivery note)

A delay in cord clamp for 45 seconds will be instituted in the delivery room. Placebo drug solution will be administered within 12hrs post-birth.

delay in umbilical cord clamp at birth: provision of a ~45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note)

placebo infusion: saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)

Umbilical cord will be clamped immediately at birth. Indomethacin will be administered IV, starting within 12hrs of life (0.1mg/kg every 24 hrs for three total doses.This intervention is considered 'standard care' at many Neonatology medical facilities. The dose of indomethacin has been shown to be effective in reducing brain bleeds in preterm infants (although there are also data showing safety concerns).

Indomethacin: indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants

immediate cord clamp at birth: no delay in umbilical cord clamp; <10sec (recorded in delivery note)

A delay in cord clamp of 45 seconds will be instituted in the delivery room. In addition, indomethacin will be administered iv (initiated within 12hrs of life), 0.1mg/kg every 24 hrs for three total doses.

Indomethacin: indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants

delay in umbilical cord clamp at birth: provision of a ~45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note)

All-Cause Mortality
Immediate Cord Clamp & Placebo IV Solution Delay Cord Clamp & Placebo IV Solution Immediate Cord Clamp & Indomethacin IV Indomethacin iv & Delayed Cord Clamp
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   6/36 (16.67%)      10/87 (11.49%)      2/41 (4.88%)      6/92 (6.52%)    
Hide Serious Adverse Events
Immediate Cord Clamp & Placebo IV Solution Delay Cord Clamp & Placebo IV Solution Immediate Cord Clamp & Indomethacin IV Indomethacin iv & Delayed Cord Clamp
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/36 (13.89%)      7/87 (8.05%)      3/41 (7.32%)      10/92 (10.87%)    
Blood and lymphatic system disorders         
Septic Shock   0/36 (0.00%)  0 1/87 (1.15%)  1 0/41 (0.00%)  0 0/92 (0.00%)  0
Gastrointestinal disorders         
Necrotizing Enterocolitis   1/36 (2.78%)  1 0/87 (0.00%)  0 0/41 (0.00%)  0 0/92 (0.00%)  0
Bowel Perforation   0/36 (0.00%)  0 1/87 (1.15%)  1 1/41 (2.44%)  1 3/92 (3.26%)  3
General disorders         
Multiorgan Failure   0/36 (0.00%)  0 1/87 (1.15%)  1 0/41 (0.00%)  0 0/92 (0.00%)  0
Infections and infestations         
CMV   0/36 (0.00%)  0 1/87 (1.15%)  1 0/41 (0.00%)  0 0/92 (0.00%)  0
Pregnancy, puerperium and perinatal conditions         
Extreme Prematurity   4/36 (11.11%)  4 5/87 (5.75%)  5 1/41 (2.44%)  1 5/92 (5.43%)  5
Respiratory, thoracic and mediastinal disorders         
Free Air in Abdomen   1/36 (2.78%)  2 0/87 (0.00%)  0 0/41 (0.00%)  0 1/92 (1.09%)  1
Pneumothorax   0/36 (0.00%)  0 0/87 (0.00%)  0 1/41 (2.44%)  1 1/92 (1.09%)  1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Immediate Cord Clamp & Placebo IV Solution Delay Cord Clamp & Placebo IV Solution Immediate Cord Clamp & Indomethacin IV Indomethacin iv & Delayed Cord Clamp
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/36 (0.00%)      0/87 (0.00%)      0/41 (0.00%)      0/92 (0.00%)    
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Research Protocol Manager/Clinical/UKHC
Organization: University of Kentucky
Phone: (859) 257-1000
EMail: hong.huang@uky.edu
Layout table for additonal information
Responsible Party: Hong Huang, University of Kentucky
ClinicalTrials.gov Identifier: NCT02221219    
Other Study ID Numbers: HD070792
First Submitted: August 18, 2014
First Posted: August 20, 2014
Results First Submitted: November 13, 2020
Results First Posted: December 8, 2020
Last Update Posted: December 8, 2020