NAC +taVNS in IDM Who Are Poor Oral Feeders

Oxidative Stress Clinical Trial

Official title:

N-acetylcysteine Plus Transcutaneous Vagus Nerve Stimulation in Infants of Diabetic Mothers Who Fail Oral Feeding

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04632069
• Other study ID #: 103800
• Secondary ID: P20GM109040
• Status: Active, not recruiting
• Phase: Early Phase 1
• Start date: August 12, 2021
• Est. completion date: July 1, 2024

Study information

• Verified date: January 2024
• Source: Medical University of South Carolina
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Infants of diabetic mothers who are failing to learn oral feeding by term age equivalence have greater CNS oxidative stress, which interact to predict poor neuroplasticity response to transcutaneous vagus nerve stimulation paired with oral feeding. We propose treating the oxidative stress in IDM infants prior to initiating taVNS, with an FDA-approved antioxidant (N-acetylcysteine, NAC) to improve CNS oxidative stress, which in turn regulates expression of many genes including BDNF, that may enhance motor learning.

Description:

Our group has recently conducted a first-in-infants pilot trial of pairing transcutaneous auricular vagus nerve stimulation (taVNS) with feeding to assist learning oromotor skills. We are enrolling preterm and HIE infants who are failing to learn oral feeds and clinically determined to need a G-tube. In preliminary data, taVNS paired with one or two daily feedings for 2 weeks resulted in 50% of infants attaining full feeds and avoiding G-tube.

A notable number of non-responders were infants of diabetic mothers (IDM) exposed to poor glucose control during pregnancy, all of whom required a G-tube. Uncontrolled maternal hyperglycemia is associated with increased systemic and neuro-inflammation, CNS oxidative stress, DNA damage, and worse neonatal outcomes compared to infants of euglycemic mothers. In neonatal animal models, hyperglycemia has been shown to decrease BDNF, alter long-term synaptogenesis and hippocampal neurochemistry, with ongoing CNS oxidative stress and inhibition of the cortical neuronal plasticity required for learning. In our pilot trial of taVNS-paired feeding, CNS glutathione concentrations (GSH), a MR spectroscopy (MRS) marker of oxidative stress, had significant interaction with IDM in predicting outcome, strongly suggesting that ongoing CNS oxidative stress contributes to neuropathology in IDMs failing oral feeding.

NAC is an FDA-approved antioxidant that is safe and crosses the blood brain barrier, increasing CNS GSH. NAC reduces CNS oxidative stress, enhances learning and provides a neuroprotective effect after brain injury in our and others neonatal HI and neuroinflammatory animal models. Both GSH and BDNF enhance neuroplasticity. Therefore, we hypothesize that pre-treatment with NAC in IDMs who are failing oral feeding, followed by taVNS-paired feeding, will decrease oxidative stress induced by maternal hyperglycemia and IDM-associated brain injury, and increase response to taVNS-paired feeding rehabilitation.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 10
• Est. completion date: July 1, 2024
• Est. primary completion date: April 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Weeks to 5 Months

Eligibility

Inclusion Criteria:

• Infants of diabetic mothers who are failing oral feeding, >39weeks gestation at enrollment, who are clinically stable, on minimal respiratory support (nasal cannula or room air), and clinical team has determined are G-tube candidates

Exclusion Criteria:

• Unstable infants or those requiring positive pressure respiratory support

• Infants <39 weeks gestation at enrollment

• Major unrepaired congenital anomalies or anomalies that limit feeding volumes

• Infants with cardiomyopathy

• Repeated episodes of autonomic instability (apnea/ bradycardia) not self resolving

Related Conditions & MeSH terms

• Feeding and Eating Disorders
• Feeding Disorders
• Infant of Diabetic Mother
• Oxidative Stress
• Pregnancy in Diabetics
• Vagus Nerve Stimulation

Intervention

Combination Product:
• N acetyl cysteine + vagus nerve stimulation
NAC x 14 days, taVNS x 10 days

Locations

Country	Name	City	State
United States	Medical University of South Carolina	Charleston	South Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Medical University of South Carolina	National Institute of General Medical Sciences (NIGMS)

Country where clinical trial is conducted

United States, 

References & Publications (2)

Badran BW, Jenkins DD, Cook D, Thompson S, Dancy M, DeVries WH, Mappin G, Summers P, Bikson M, George MS. Transcutaneous Auricular Vagus Nerve Stimulation-Paired Rehabilitation for Oromotor Feeding Problems in Newborns: An Open-Label Pilot Study. Front Hum Neurosci. 2020 Mar 18;14:77. doi: 10.3389/fnhum.2020.00077. eCollection 2020. — View Citation

Badran BW, Jenkins DD, DeVries WH, Dancy M, Summers PM, Mappin GM, Bernstein H, Bikson M, Coker-Bolt P, George MS. Transcutaneous auricular vagus nerve stimulation (taVNS) for improving oromotor function in newborns. Brain Stimul. 2018 Sep-Oct;11(5):1198-1200. doi: 10.1016/j.brs.2018.06.009. Epub 2018 Jun 30. No abstract available. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Diffusion Kurtosis Imaging (DKI)	DKI metrics in white matter tracts before and after NAC+taVNS treatment	14 days
Primary	Daily oral feeding volumes	ml/kg/d of oral feeds, slope of change of oral feeding volumes before and after NAC + taVNS	20 days
Secondary	Metabolite concentrations in basal ganglia	[GSH] and other CNS metabolites by MRS before, and after 3-4 days of NAC and after NAC+taVNS treatment	14 days