Ignite Creation Date:
2024-05-06 @ 3:28 PM
Last Modification Date:
2024-10-26 @ 1:50 PM
Study NCT ID:
NCT04643821
Status:
COMPLETED
Last Update Posted:
2020-12-04
First Post:
2020-11-11
Brief Title:
NVD in Hypothermic HIE Neonates
Sponsor:
Medical University of South Carolina
Organization:
Medical University of South Carolina
Study Overview
Official Title:
N-Acetylcysteine and Vitamin D in Infants With Hypoxic Ischemic Encephalopathy Treated With Hypothermia
Status:
COMPLETED
Status Verified Date:
2020-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 25OHvitamin 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 ischemiaasphyxial event and received moderate hypothermia to 33 degrees C for 72 hours per routine protocol
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 ischemiaasphyxial event and received moderate hypothermia to 33 degrees C for 72 hours per routine protocol
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 25OHvitamin D a critical neurosteroid that also augments synthesis of an important antioxidant glutathione By adding active low-dose 125-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 mgkgdose every 12 hours and Vitamin D3 Calcitriol 003 to 01microgramkg 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
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 mgkgdose every 12 hours and Vitamin D3 Calcitriol 003 to 01microgramkg 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 5F31NS108623-02 | NIH | None | None |
| FISPI140433 | OTHER_GRANT | None | None |
| 300118 | OTHER_GRANT | None | None |
| P960743 | OTHER_GRANT | None | None |
| EC11-246 | OTHER_GRANT | Spanish Ministry of Health Social Services and Equality | httpsreporternihgovquickSearch5F31NS108623-02 |