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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

Tracking Information
First Submitted Date  ICMJE August 18, 2014
First Posted Date  ICMJE August 20, 2014
Results First Submitted Date  ICMJE November 13, 2020
Results First Posted Date  ICMJE December 8, 2020
Last Update Posted Date December 8, 2020
Actual Study Start Date  ICMJE August 2014
Actual Primary Completion Date October 27, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 18, 2014)
Fraction of Survivors With no Severe IVH (Grades 3 or 4) or PVL [ Time Frame: within first 60 days of life ]
determined by head ultrasound in Neonatal Intensive Care Unit (NICU) and single head MRI at 38weeks corrected gestational age
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 18, 2014)
Occurrence of Renal Injury and/or Dysfunction [ Time Frame: first 60 days of life ]
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)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: August 18, 2014)
  • Hematological Status [ Time Frame: first 60 days of life ]
    hematocrit, ferritin, hemoglobin at various times during NICU stay
  • Inflammatory Stress [ Time Frame: first 60 days of life ]
    measurement of inflammatory biomarkers (CRP, Interleukin-6, soluble ICAM) at various times during NICU stay
  • Circulating Progenitor Cell Subpopulations [ Time Frame: first 60 days of life ]
    measures of several progenitor cell subtypes in blood during the NICU stay
  • Neurocognitive Assessments at Post-NICU Followup [ Time Frame: up to 24 months of corrected gestational age ]
    standardized neurocognitive assessments done at NICU graduate clinic.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Effects of Delayed Cord Clamp and/or Indomethacin on Preterm Infant Brain Injury
Official Title  ICMJE Indomethacin and Delayed Umbilical Cord Clamp for Preterm Infant IVH
Brief Summary Intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) are brain lesions that commonly occur in preterm infants and are well-recognized major contributors to long-term brain injury and related disabilities later in life. Despite its prevalence, long term consequences, and enormous medical and social costs, mechanisms of IVH and optimal strategies to prevent or treat its occurrence are poorly defined, especially for extremely premature infants. Only one medical therapy, prophylactic indomethacin during the first 3 days of life, has been shown to prevent or decrease the severity of IVH in preterm infants, but its use is limited by toxic side effects and debatable effects on long-term outcomes. Several small studies and case reports suggest that delayed umbilical cord-clamping (DCC) may also decrease the incidence of IVH in premature infants, but thus far these trials have indomethacin treatment mixed within their cord clamping protocols. The investigators are conducting a randomized, blinded investigation of 4 treatment groups: 1) Control (no intervention); 2) DCC alone; 3) Prophylactic indomethacin alone; 4) Combination of DCC/indomethacin, with respect to survival, IVH or PVL incidence and severity, neurodevelopmental outcomes, and relevant mechanistic effects. With the steady rise in extreme prematurity births and clear links of IVH to long-term disabilities there is a need to improve care for these patients. This multi- disciplinary project addresses an important medical problem for an understudied patient population, where the current practice has clear limitations.
Detailed Description The investigators will compare efficacy and safety of prophylactic indomethacin, DCC, and their combination, in affecting the incidence and severity of IVH/PVL in infants <30wks gestational age (primary outcome measure of 'fraction of survivors with no severe IVH or PVL' among the 4 groups), and longer term neurocognitive function. Other secondary endpoints and investigations include mechanistic effects of prophylactic indomethacin, DCC, and their combination (blood volume/circulatory status, inflammatory stress, progenitor cells) as well as defining relationships between clinical outcomes and mechanistic measurements among treatment groups.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Intraventricular Hemorrhage
  • Periventricular Leukomalacia
  • Brain Injury
  • Renal Injury
Intervention  ICMJE
  • Drug: Indomethacin
    indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants
    Other Name: indocin
  • Procedure: 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)
  • Drug: placebo infusion
    saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)
  • Procedure: immediate cord clamp at birth
    no delay in umbilical cord clamp; <10sec (recorded in delivery note)
Study Arms  ICMJE
  • Placebo Comparator: immediate cord clamp & placebo IV solution
    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.
    Interventions:
    • Drug: placebo infusion
    • Procedure: immediate cord clamp at birth
  • Experimental: delay cord clamp & placebo IV solution
    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.
    Interventions:
    • Procedure: delay in umbilical cord clamp at birth
    • Drug: placebo infusion
  • Active Comparator: immediate cord clamp & indomethacin IV
    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).
    Interventions:
    • Drug: Indomethacin
    • Procedure: immediate cord clamp at birth
  • Experimental: indomethacin iv & delayed cord clamp
    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.
    Interventions:
    • Drug: Indomethacin
    • Procedure: delay in umbilical cord clamp at birth
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 13, 2020)
256
Original Estimated Enrollment  ICMJE
 (submitted: August 18, 2014)
400
Estimated Study Completion Date  ICMJE August 28, 2021
Actual Primary Completion Date October 27, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • pregnant women admitted >24weeks and <30weeks gestational age,
  • in-hospital birth (allowing for cord clamp randomization)

Exclusion Criteria:

  • preterm infant <24weeks or >30weeks at birth
  • maternal risks identified by obstetrician
  • fetal risks identified by obstetrician
  • any congenital abnormality of newborn infant
  • placental abruption/placental previa
  • delivery less than 2hrs from consenting to study participation
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 24 Weeks to 30 Weeks   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02221219
Other Study ID Numbers  ICMJE HD070792
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Hong Huang, University of Kentucky
Study Sponsor  ICMJE Hong Huang
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Vicki Whitehead, RN UK Section of Neonatology
Principal Investigator: John Bauer, PhD UK Department of Pediatrics
Study Director: Hong Huang, MD-PhD University of Kentucky Section of Neonatology
PRS Account University of Kentucky
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP