NVD in Hypothermic HIE Neonates

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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HIE - Perinatal Hypoxic - Ischemic Encephalopathy

Intervention / Treatment
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* Drug: N-acetylcysteine, NAC, and calcitriol


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 6 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Open-label, escalating dose design
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NAC 25mg/kg, calcitriol 0.05mcg/kg<br>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<br>* iv administration of antioxidant and active vitamin D<br>* Other names: hypothermia;|
| Experimental: NAC 25mg/kg, calcitriol 0.03mcg/kg<br>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<br>* iv administration of antioxidant and active vitamin D<br>* Other names: hypothermia;|
| Experimental: NAC 40mg/kg, calcitriol 0.03mcg/kg<br>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<br>* iv administration of antioxidant and active vitamin D<br>* Other names: hypothermia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oxidative stress, glutathione, pharmacokinetics