NVD in Hypothermic HIE Neonates

December 2, 2020 updated by: Dorothea D. Jenkins, Medical University of South Carolina

N-Acetylcysteine and Vitamin D in Infants With Hypoxic Ischemic Encephalopathy Treated With Hypothermia

Neonatal hypoxic ischemic (HI) injury is an unpredictable neurologic injury with devastating, long term consequences for parents who are expecting a normal child. Hypothermia for 72 hr within 6 hrs of birth improves the combined outcome of death or severe disability, and hypothermia is now standard of care in tertiary centers throughout the world. However, approximately 50% of infants with hypoxic ischemic encephalopathy (HIE) treated with hypothermia still have adverse neurologic outcomes, due to ongoing neuroinflammation and oxidative stress in spite of hypothermia. Further, the majority of HIE infants are insufficient or deficient in a critical neurosteroid, 25(OH)vitamin D, which has been shown to adversely affect outcome after adult stroke. By adding vitamin D to N-acetylcysteine (NAC), an antioxidant, the investigators hypothesized that both drugs would increase glutathione (GSH) concentrations in critical brain areas, mitigate continuing oxidative stress after injury during hypothermia and after rewarming, and improve neurodevelopmental outcomes.

This is an open-label, non-randomized, escalating dose, pilot trial to evaluate the disposition and safety of NAC in combination with active vitamin D in neonates who present within 6 hrs of hypoxia ischemia/asphyxial event and received moderate hypothermia to 33 degrees C for 72 hours per routine protocol.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

N-acetylcysteine (NAC) is an FDA-approved drug that has been used in multiple conditions to mitigate oxidative stress. The study investigators' lab and others have shown that NAC provides neuroprotection either alone or in combination with hypothermia when given within 1-6 hrs of insult in animal models of HI injury. However, in neonatal rats subjected to severe hypoxic ischemic insult, NAC + hypothermia did not neuroprotect males as well as females. The study investigators and others determined that the majority of HIE infants are insufficient or deficient in 25(OH)vitamin D, a critical neurosteroid that also augments synthesis of an important antioxidant, glutathione. By adding active, low-dose 1,25-dihydoxy-Vitamin D3 to NAC (NVD), with a 1 hour delay after starting hypothermia, and repeated daily for 14 days in neonatal rat HI model, the study investigators significantly improved severity of brain injury over hypothermia alone in both sexes. Importantly, NVD also significantly improved functional outcomes of strength, sensorimotor and memory functioning 6 weeks after HI, even in male rats with the most severe brain pathology.

NAC and active vitamin D are FDA approved and are safe even in very sick newborns. In the study investigators' trial of NAC in maternal chorioamnionitis, comprehensive physiologic monitoring in preterm and term infants exposed to intrauterine inflammation demonstrated no significant differences in cerebral blood flow, oxygenation, or left ventricular function in infants treated with NAC or saline.

The primary objective of this study in human neonates after HIE birth treated with the standard hypothermia protocol, is to determine the unique pharmacokinetic (PK) parameters of NAC and vitamin D during hypothermia and after rewarming, verify the central nervous system (CNS) effect of NVD on the pharmacodynamic target, reduced glutathione, and determine the duration of CNS effect. The study investigators used low dose NAC (Acetadote, 25-40 mg/kg/dose) every 12 hours and Vitamin D3 (Calcitriol, 0.03 to 0.1microgram/kg) every 12-24 hours, infused IV for 10 days in a dose escalating study. The study investigators determined PK parameters and plasma oxidative stress markers during day 1 of life while hypothermic, and day 5 of life during normothermia (24-36 hours after rewarming). To establish effective dosing of NVD based directly on CNS effect, CNS metabolites were quantified with magnetic resonance spectroscopy (MRS) before and immediately after NVD dosing on DOL 5, infusing NVD during the routine MRI for HIE. In a subset of 10 infants the delayed effects of NVD on CNS metabolomics were determined by MRS between 2-6h after NVD dosing on DOL 5. Development was followed for >24months.

Study Type

Interventional

Enrollment (Actual)

30

Phase

  • Early Phase 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 1 year (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Neonates > 34 weeks, > 2000 grams, within 6h of birth with moderate to severe HIE receiving therapeutic hypothermia

Exclusion Criteria:

  • Evidence of a congenital CNS malformation if known prior to enrollment
  • Evidence of neuromuscular disorder by family history
  • More than 6 hours from birth or known insult
  • Suspected genetic abnormality

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: NAC 25mg/kg, calcitriol 0.05mcg/kg
N-acetylcysteine 25mg/kg iv q 12h, calcitriol 0.05mcg/kg iv q 12h, for 10 days, starting within 6h of birth
Drug: N-acetylcysteine, NAC, and calcitriol
iv administration of antioxidant and active vitamin D
Other Names:
  • hypothermia
Experimental: NAC 25mg/kg, calcitriol 0.03mcg/kg
N-acetylcysteine 25mg/kg iv q 12h, calcitriol 0.03mcg/kg iv q 24h, for 10 days, starting within 6h of birth
Drug: N-acetylcysteine, NAC, and calcitriol
iv administration of antioxidant and active vitamin D
Other Names:
  • hypothermia
Experimental: NAC 40mg/kg, calcitriol 0.03mcg/kg
N-acetylcysteine 40mg/kg iv q 12h, calcitriol 0.03mcg/kg iv q 24h, for 10 days, starting within 6h of birth
Drug: N-acetylcysteine, NAC, and calcitriol
iv administration of antioxidant and active vitamin D
Other Names:
  • hypothermia

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in pharmacokinetic half life of NAC
Time Frame: first week of life
PK parameters of plasma half life around first dose on day of life 1 during hypothermia, and day of life 5 during normothermia
first week of life
pharmacokinetic half life of calcitriol
Time Frame: first week of life
PK parameters of serum half life around first dose on day of life 1 during hypothermia, and day of life 5 during normothermia
first week of life
Change in Glutathione concentration in Basal ganglia
Time Frame: day of life 5
GSH by MRS before, immediately after and up to 6h after NVD infusion on day of life 5
day of life 5

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in plasma oxidative stress markers
Time Frame: day 1 and 5
isofurans measured by Liquid Chromatography-Mass Spectroscopy
day 1 and 5

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Medical University of South Carolina

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)
Carlos III Health Institute
National Institute for Health Research, United Kingdom

Investigators

  • Principal Investigator: Dorothea Jenkins, MD, Medical University of South Carolina

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2015

Primary Completion (Actual)

April 1, 2017

Study Completion (Actual)

March 1, 2020

Study Registration Dates

First Submitted

November 11, 2020

First Submitted That Met QC Criteria

November 19, 2020

First Posted (Actual)

November 25, 2020

Study Record Updates

Last Update Posted (Actual)

December 4, 2020

Last Update Submitted That Met QC Criteria

December 2, 2020

Last Verified

December 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 31254
  • 5F31NS108623-02 (U.S. NIH Grant/Contract)
  • FISPI14/0433 (Other Grant/Funding Number: Instituto Carlos III)
  • 300118 (Other Grant/Funding Number: NIHR)
  • P960743 (Other Grant/Funding Number: NIHR)
  • EC11-246 (Other Grant/Funding Number: Spanish Ministry of Health, Social Services and Equality)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

after publication, upon request

IPD Sharing Time Frame

after publication of main findings

IPD Sharing Access Criteria

written request to PI

IPD Sharing Supporting Information Type

  • Study Protocol

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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