NVD in Hypothermic HIE Neonates

NCT04643821 | Completed Early Phase 1 FDA Drug

• 6 other identifiers: 312545F31NS108623-02FISPI14/0433300118P960743EC11-246
• Study Type: interventional
• Target: 30
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

HIE - Perinatal Hypoxic - Ischemic Encephalopathy

Keywords

oxidative stress; glutathione; pharmacokinetics

Outcome Measures

Primary Outcomes (3)

• Change in pharmacokinetic half life of NAC

  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

  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

  GSH by MRS before, immediately after and up to 6h after NVD infusion on day of life 5

  day of life 5

Secondary Outcomes (1)

• Change in plasma oxidative stress markers

  day 1 and 5

Study Arms (3)

NAC 25mg/kg, calcitriol 0.05mcg/kg

EXPERIMENTAL

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

NAC 25mg/kg, calcitriol 0.03mcg/kg

EXPERIMENTAL

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

NAC 40mg/kg, calcitriol 0.03mcg/kg

EXPERIMENTAL

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

Interventions

N-acetylcysteine, NAC, and calcitriol DRUG

iv administration of antioxidant and active vitamin D

Also known as: hypothermia

NAC 25mg/kg, calcitriol 0.03mcg/kg; NAC 25mg/kg, calcitriol 0.05mcg/kg; NAC 40mg/kg, calcitriol 0.03mcg/kg

Eligibility Criteria

• Age: Up to 6 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Medical University of South Carolina: lead
• National Institute for Health Research, United Kingdom: collaborator
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• Carlos III Health Institute: collaborator

Related Publications (7)

• Jenkins DD, Wiest DB, Mulvihill DM, Hlavacek AM, Majstoravich SJ, Brown TR, Taylor JJ, Buckley JR, Turner RP, Rollins LG, Bentzley JP, Hope KE, Barbour AB, Lowe DW, Martin RH, Chang EY. Fetal and Neonatal Effects of N-Acetylcysteine When Used for Neuroprotection in Maternal Chorioamnionitis. J Pediatr. 2016 Jan;168:67-76.e6. doi: 10.1016/j.jpeds.2015.09.076. Epub 2015 Nov 3.

  PMID: 26545726 BACKGROUND

• Nie X, Lowe DW, Rollins LG, Bentzley J, Fraser JL, Martin R, Singh I, Jenkins D. Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia. Neurosci Res. 2016 Jul;108:24-33. doi: 10.1016/j.neures.2016.01.008. Epub 2016 Feb 3.

  PMID: 26851769 BACKGROUND

• Lowe DW, Fraser JL, Rollins LG, Bentzley J, Nie X, Martin R, Singh I, Jenkins D. Vitamin D improves functional outcomes in neonatal hypoxic ischemic male rats treated with N-acetylcysteine and hypothermia. Neuropharmacology. 2017 Sep 1;123:186-200. doi: 10.1016/j.neuropharm.2017.06.004. Epub 2017 Jun 6.

  PMID: 28599922 BACKGROUND

• Lowe DW, Hollis BW, Wagner CL, Bass T, Kaufman DA, Horgan MJ, Givelichian LM, Sankaran K, Yager JY, Katikaneni LD, Wiest D, Jenkins D. Vitamin D insufficiency in neonatal hypoxic-ischemic encephalopathy. Pediatr Res. 2017 Jul;82(1):55-62. doi: 10.1038/pr.2017.13. Epub 2017 Jan 17.

  PMID: 28099429 BACKGROUND

• Wiest DB, Chang E, Fanning D, Garner S, Cox T, Jenkins DD. Antenatal pharmacokinetics and placental transfer of N-acetylcysteine in chorioamnionitis for fetal neuroprotection. J Pediatr. 2014 Oct;165(4):672-7.e2. doi: 10.1016/j.jpeds.2014.06.044. Epub 2014 Jul 23.

  PMID: 25064164 BACKGROUND

• Moss HG, Brown TR, Wiest DB, Jenkins DD. N-Acetylcysteine rapidly replenishes central nervous system glutathione measured via magnetic resonance spectroscopy in human neonates with hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab. 2018 Jun;38(6):950-958. doi: 10.1177/0271678X18765828. Epub 2018 Mar 21.

  PMID: 29561203 RESULT

• Sanchez-Illana A, Thayyil S, Montaldo P, Jenkins D, Quintas G, Oger C, Galano JM, Vigor C, Durand T, Vento M, Kuligowski J. Novel free-radical mediated lipid peroxidation biomarkers in newborn plasma. Anal Chim Acta. 2017 Dec 15;996:88-97. doi: 10.1016/j.aca.2017.09.026. Epub 2017 Sep 28.

  PMID: 29137711 RESULT

MeSH Terms

Interventions

Acetylcysteine; Calcitriol

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Dihydroxycholecalciferols; Hydroxycholecalciferols; Cholecalciferol; Cholestenes; Cholestanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Lipids

Study Officials

• Dorothea Jenkins, MD

  Medical University of South Carolina

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: unaware of dose or timing of Magnetic resonance spectroscopy
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Pediatrics

Model Details: Open-label, escalating dose design

Study Record Dates

• First Submitted: November 11, 2020
• First Posted: November 25, 2020
• Study Start: January 1, 2015
• Primary Completion: April 1, 2017
• Study Completion: March 1, 2020
• Last Updated: December 4, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: after publication of main findings
• Access Criteria: written request to PI