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

Indomethacin and Delayed Umbilical Cord Clamp for Preterm Infant IVH

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.

Study Overview

• Status: Completed
• Conditions: Brain Injury; Intraventricular Hemorrhage; Periventricular Leukomalacia; Renal Injury
• Intervention / Treatment: Drug: placebo infusion; Procedure: immediate cord clamp at birth; Procedure: delay in umbilical cord clamp at birth; Drug: Indomethacin

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: Interventional
• Enrollment (Actual): 256
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40506
      • Kentucky Childrens Hospital Neonatal Intensive Care Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 6 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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)
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.	Drug: placebo infusion; saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff); 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)
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).	Procedure: immediate cord clamp at birth; no delay in umbilical cord clamp; <10sec (recorded in delivery note); Drug: Indomethacin; indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants; Other Names: indocin
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.	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: Indomethacin; indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants; Other Names: indocin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Survivors With no Severe IVH (Grades 3 or 4) or PVL	determined by head ultrasound in Neonatal Intensive Care Unit (NICU) and single head MRI at 38weeks corrected gestational age	within first 60 days of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Acute Kidney Injury	measures of serum creatinine and urine output during Neonatal Intensive Care Unit (NICU) stay. General measures of renal injury (which is a common risk of indomethacin treatment in this patient population).	first 60 days of life

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hematological Status	hematocrit, ferritin, hemoglobin at various times during NICU stay	first 60 days of life
Inflammatory Stress	measurement of inflammatory biomarkers (CRP, Interleukin-6, soluble ICAM) at various times during NICU stay	first 60 days of life
Circulating Progenitor Cell Subpopulations	measures of several progenitor cell subtypes in blood during the NICU stay	first 60 days of life
Neurocognitive Assessments at Post-NICU Followup	standardized neurocognitive assessments done at NICU graduate clinic.	up to 24 months of corrected gestational age

Collaborators and Investigators

• Sponsor: Hong Huang
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: 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

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2014
• Primary Completion (ACTUAL): October 27, 2019
• Study Completion (ACTUAL): August 28, 2021

Study Registration Dates

• First Submitted: August 18, 2014
• First Submitted That Met QC Criteria: August 18, 2014
• First Posted (ESTIMATE): August 20, 2014

Study Record Updates

• Last Update Posted (ACTUAL): November 23, 2021
• Last Update Submitted That Met QC Criteria: October 28, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: renal; brain injury; infant; indomethacin
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Infant, Newborn, Diseases; Craniocerebral Trauma; Trauma, Nervous System; Infant, Premature, Diseases; Encephalomalacia; Brain Injuries; Wounds and Injuries; Hemorrhage; Leukomalacia, Periventricular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Reproductive Control Agents; Gout Suppressants; Tocolytic Agents; Indomethacin
• Other Study ID Numbers: HD070792; R01HD070792 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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