NAC +taVNS in IDM Who Are Poor Oral Feeders

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

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.

Study Overview

• Status: Completed
• Conditions: Oxidative Stress; Vagus Nerve Stimulation; Infant of Diabetic Mother; Feeding Disorders
• Intervention / Treatment: Combination product: N acetyl cysteine + vagus nerve stimulation

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 weeks to 5 months (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NAC + taVNS; NAC will be given via nasogastric tube (n,g.) 100mg/kg loading dose, then 75mg/kg/dose n.g. q 6h, administered 1h before a feed, for a total of 14 days. taVNS will be administered to left ear during active sucking with 2 daily feedings starting after 4 days of NAC, continuing for 10 days.	Combination product: N acetyl cysteine + vagus nerve stimulation; NAC x 14 days, taVNS x 10 days; Other Names: NAC, Acetadote, taVNS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily Oral Feeding Volumes : Difference in Mean Increase	Difference in the Mean daily change in oral feeding volume(reported in in ml/kg/d) from Day 1-18 days of NAC+taVNS treatment minus Days -14 to 0 (baseline)	Day -14 to 0, Day 1 to 18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolite Concentrations in Basal Ganglia	Change in [GSH] by MRS from baseline to day 4 of NAC	baseline to 4 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diffusion Kurtosis Imaging (DKI)	DKI metrics in white matter tracts before and after NAC+taVNS treatment	14 days

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Collaborators: National Institute of General Medical Sciences (NIGMS)
• Investigators: Principal Investigator: Dorothea Jenkins, MD, Medical University of South Carolina

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2021
• Primary Completion (Actual): March 1, 2024
• Study Completion (Actual): July 1, 2024

Study Registration Dates

• First Submitted: November 12, 2020
• First Submitted That Met QC Criteria: November 12, 2020
• First Posted (Actual): November 17, 2020

Study Record Updates

• Last Update Posted (Actual): August 29, 2024
• Last Update Submitted That Met QC Criteria: August 6, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Feeding and Eating Disorders; Pregnancy in Diabetics; Fetal Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: 103800; P20GM109040 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: will share de-identified data after publication of results
• IPD Sharing Time Frame: after publication of results
• IPD Sharing Access Criteria: written request of PI
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes