NVD in Hypothermic HIE Neonates
NVD in Hypothermic HIE Neonates
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.
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.
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