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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 : Recruiting
First Posted : August 20, 2014
Last Update Posted : April 18, 2017
Sponsor:
Information provided by (Responsible Party):
John Bauer, University of Kentucky

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.

Condition or disease Intervention/treatment Phase
Intraventricular Hemorrhage Periventricular Leukomalacia Brain Injury Renal Injury Drug: Indomethacin Procedure: delay in umbilical cord clamp at birth Drug: placebo infusion Procedure: immediate cord clamp at birth Phase 1 Phase 2

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 (n=400 total cases).

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Indomethacin and Delayed Umbilical Cord Clamp for Preterm Infant IVH
Actual Study Start Date : August 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

U.S. FDA Resources

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 6hrs 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 6hrs post-birth.
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)
Active Comparator: immediate cord clamp & indomethacin IV
Umbilical cord will be clamped immediately at birth. Indomethacin will be administered IV, starting within 6hrs 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
indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants
Other Name: indocin
Procedure: immediate cord clamp at birth
no delay in umbilical cord clamp; <10sec (recorded in delivery note)
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 6hrs of life), 0.1mg/kg every 24 hrs for three total doses.
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)



Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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)


Other Outcome Measures:
  1. hematological status [ Time Frame: first 60 days of life ]
    hematocrit, ferritin, hemoglobin at various times during NICU stay

  2. inflammatory stress [ Time Frame: first 60 days of life ]
    measurement of inflammatory biomarkers (CRP, Interleukin-6, soluble ICAM) at various times during NICU stay

  3. circulating progenitor cell subpopulations [ Time Frame: first 60 days of life ]
    measures of several progenitor cell subtypes in blood during the NICU stay

  4. neurocognitive assessments at post-NICU followup [ Time Frame: up to 24 months of corrected gestational age ]
    standardized neurocognitive assessments done at NICU graduate clinic.



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Ages Eligible for Study:   24 Weeks to 30 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02221219


Contacts
Contact: Peter J Giannone, MD peter.giannone@uky.edu

Locations
United States, Kentucky
Kentucky Childrens Hospital Neonatal Intensive Care Unit Recruiting
Lexington, Kentucky, United States, 40506
Sponsors and Collaborators
John Bauer
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

Responsible Party: John Bauer, Professor of Pediatrics, University of Kentucky
ClinicalTrials.gov Identifier: NCT02221219     History of Changes
Other Study ID Numbers: HD070792
First Posted: August 20, 2014    Key Record Dates
Last Update Posted: April 18, 2017
Last Verified: April 2017

Keywords provided by John Bauer, University of Kentucky:
infant
brain injury
renal
indomethacin

Additional relevant MeSH terms:
Wounds and Injuries
Brain Injuries
Hemorrhage
Cerebral Hemorrhage
Leukomalacia, Periventricular
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Pathologic Processes
Intracranial Hemorrhages
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Encephalomalacia
Infant, Premature, Diseases
Infant, Newborn, Diseases
Pharmaceutical Solutions
Indomethacin
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Gout Suppressants
Tocolytic Agents