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

NCT ID: NCT02221219

Last Updated: 2021-11-23

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

256 participants

Study Classification

INTERVENTIONAL

Study Start Date

2014-08-31

Study Completion Date

2021-08-28

Brief Summary

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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

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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.

Conditions

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Intraventricular Hemorrhage Periventricular Leukomalacia Brain Injury Renal Injury

Keywords

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infant brain injury renal indomethacin

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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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.

Group Type PLACEBO_COMPARATOR

placebo infusion

Intervention Type DRUG

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

immediate cord clamp at birth

Intervention Type PROCEDURE

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

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.

Group Type EXPERIMENTAL

delay in umbilical cord clamp at birth

Intervention Type PROCEDURE

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

placebo infusion

Intervention Type DRUG

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

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).

Group Type ACTIVE_COMPARATOR

Indomethacin

Intervention Type DRUG

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

immediate cord clamp at birth

Intervention Type PROCEDURE

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

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.

Group Type EXPERIMENTAL

Indomethacin

Intervention Type DRUG

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

delay in umbilical cord clamp at birth

Intervention Type PROCEDURE

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

Interventions

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Indomethacin

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

Intervention Type DRUG

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)

Intervention Type PROCEDURE

placebo infusion

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

Intervention Type DRUG

immediate cord clamp at birth

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

Intervention Type PROCEDURE

Other Intervention Names

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indocin

Eligibility Criteria

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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
Minimum Eligible Age

24 Weeks

Maximum Eligible Age

30 Weeks

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role collaborator

Hong Huang

OTHER

Sponsor Role lead

Responsible Party

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Hong Huang

Research Protocol Manager/Clinical/UKHC

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Vicki Whitehead, RN

Role: STUDY_DIRECTOR

UK Section of Neonatology

John Bauer, PhD

Role: PRINCIPAL_INVESTIGATOR

UK Department of Pediatrics

Hong Huang, MD-PhD

Role: STUDY_DIRECTOR

University of Kentucky Section of Neonatology

Locations

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Kentucky Childrens Hospital Neonatal Intensive Care Unit

Lexington, Kentucky, United States

Site Status

Countries

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United States

Provided Documents

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Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

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R01HD070792

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HD070792

Identifier Type: -

Identifier Source: org_study_id