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

NCT02221219 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: HD070792R01HD070792
• Study Type: interventional
• Target: 256
• Locations: 1 country
• Sites: 1

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.

Conditions

Intraventricular Hemorrhage; Periventricular Leukomalacia; Brain Injury; Renal Injury

Keywords

infant; brain injury; renal; indomethacin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Number of Participants With Acute Kidney Injury

  first 60 days of life

Other Outcomes (4)

• Hematological Status

  first 60 days of life

• Inflammatory Stress

  first 60 days of life

• Circulating Progenitor Cell Subpopulations

  first 60 days of life

Study Arms (4)

immediate cord clamp & placebo IV solution

PLACEBO COMPARATOR

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; Procedure: immediate cord clamp at birth

delay cord clamp & placebo IV solution

EXPERIMENTAL

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.

Procedure: delay in umbilical cord clamp at birth; Drug: placebo infusion

immediate cord clamp & indomethacin IV

ACTIVE COMPARATOR

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).

Drug: Indomethacin; Procedure: immediate cord clamp at birth

indomethacin iv & delayed cord clamp

EXPERIMENTAL

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.

Drug: Indomethacin; Procedure: delay in umbilical cord clamp at birth

Interventions

Indomethacin DRUG

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

Also known as: indocin

immediate cord clamp & indomethacin IV; indomethacin iv & delayed cord clamp

delay in umbilical cord clamp at birth PROCEDURE

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

delay cord clamp & placebo IV solution; indomethacin iv & delayed cord clamp

placebo infusion DRUG

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

delay cord clamp & placebo IV solution; immediate cord clamp & placebo IV solution

immediate cord clamp at birth PROCEDURE

no delay in umbilical cord clamp; \<10sec (recorded in delivery note)

immediate cord clamp & indomethacin IV; immediate cord clamp & placebo IV solution

Eligibility Criteria

• Age: 24 Weeks - 30 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hong Huang: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Kentucky Childrens Hospital Neonatal Intensive Care Unit

Lexington, Kentucky, 40506, United States

Location

MeSH Terms

Conditions

Leukomalacia, Periventricular; Brain Injuries

Interventions

Indomethacin

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Encephalomalacia; Vascular Diseases; Cardiovascular Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Research Protocol Manager/Clinical/UKHC
• Organization: University of Kentucky

hong.huang@uky.edu

(859) 257-1000

Study Officials

• Vicki Whitehead, RN

  UK Section of Neonatology

  STUDY DIRECTOR

• John Bauer, PhD

  UK Department of Pediatrics

  PRINCIPAL INVESTIGATOR

• Hong Huang, MD-PhD

  University of Kentucky Section of Neonatology

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Research Protocol Manager/Clinical/UKHC

Study Record Dates

• First Submitted: August 18, 2014
• First Posted: August 20, 2014
• Study Start: August 1, 2014
• Primary Completion: October 27, 2019
• Study Completion: August 28, 2021
• Last Updated: November 23, 2021
• Results First Posted: December 8, 2020

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)