Clinical trial NCT04643808: taVNS Paired With Bottle Feeding in Infants Failing Oral Feeds
Official title: Noninvasive Brain Stimulation to Improve Oromotor Function In Neonates With Advanced Neuroimaging to Determine Safety and Target Engagement of taVNS for Neurorehabilitation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Poor Feeding
Infant Development
Vagus Nerve Stimulation
Lead sponsor: Medical University of South Carolina
Sponsor class: OTHER
Collaborators: name: National Institute of General Medical Sciences (NIGMS)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2020-11-25
Enrollment: 35
Sex: ALL
Minimum age (years): 3
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: The study investigators delivered taVNS once or twice a day during a bottle feed for 2 weeks. Stimulation was paired with nutritive sucking and swallowing, and was paused during rest or burping. If PO feeds had not progressed after 2 weeks of taVNS treatment, the parents and the clinical team made decisions about timing of G-tube placement. If substantial progress in po feeds was made during the treatment period, but the infant was not quite to full oral feeds, the clinical team and parents could elect to continue for 1-2 weeks.
Primary purpose: TREATMENT

Brief summary: Oromotor dysfunction and poor feeding is common after premature birth and hypoxic ischemic encephalopathy (HIE). Pairing vagus nerve stimulation (VNS) with motor activity accelerates functional improvements after stroke. This study is designed to investigate whether transcutaneous auricular VNS (taVNS) paired with oromotor rehabilitation is tolerable, safe, and facilitates motor learning in infants who have failed oral feeding.

Detailed description: Feeding difficulty is the primary reason for delayed hospital discharge from the neonatal intensive care unit (NICU), with increased hospital costs and a negative impact on neurodevelopment. Occupational or speech therapists typically start oral stimulation programs early, then feed infants by mouth (PO) daily to encourage safe feeding while learning this motor skill. Even after weeks or months of rehabilitation with therapists, many infants need a gastrostomy tube (G-tube) surgically placed for adequate nutrition. With improved survival rates of more critically ill neonates, the national rate of G-tube placement has doubled from 2000-2012.

Difficulty learning the motor sequence for oral feeding may be due to brain injury from infection, ischemia, and dysmaturity. In these infants, the normal integrative connectivity that occurs after birth between the cortex, basal ganglia, and brainstem may be disturbed, resulting in poor coordination and failure to learn the complex motor task of feeding, when it should be a normal reflex. Therapies that facilitate motor learning and enhance feeding skills would have a significant impact for infants who fail feeding rehabilitation.

In neonates with brain dysmaturity or overt brain injury, neuromodulation of abnormal circuits may positively boost neuronal connectivity and enhance neuroplasticity. Vagus nerve stimulation (VNS) paired with motor activity facilitates cortical reorganization and neurogenesis, and improves motor function in animal stroke models. A noninvasive form of VNS, transcutaneous auricular VNS (taVNS), targets the auricular branch of the vagus nerve to activate vagal afferent and efferent networks. In adult patients with limb impairment after brain injury, pairing taVNS with motor activation is safe, enhances plasticity and improves functional motor recovery. This work in adult humans extends and supports the animal evidence that pairing VNS with a motor or behavioral intervention restores brain function.

The study investigators applied the model of taVNS paired with a motor behavior to infants in the NICU in a prospective, open-label trial exploring the use of once and twice daily taVNS-paired rehabilitation training to enhance oral feeding in infants who are failing oral feeds and slated to receive a G-tube.

After obtaining informed consent, MRIs are obtained before starting treatment, and at end of 2-3 week treatment period. In a subset of 10 patients the study investigators also obtain modified barium swallows prior to and after the treatment period, with taVNS on and off during swallowing. Daily feeding volumes as well as the slope of change of po feeding volumes are recorded before and after starting taVNS.

Eligibility criteria: Inclusion Criteria:

* Infants must be clinically stable, on minimal respiratory support (nasal cannula, or room air), are not restricted for attempting every feed by mouth, and are currently failing oral feeding such that the clinical team is broaching gastrostomy tube (G-tube) placement with the parents. The infant will be greater than or equal to 39weeks gestation at enrollment and either

  1. Premature at birth and attempting oral feeds for at least 3 weeks or
  2. Infants who are neart-term or term at birth, with significant medical issues that have precluded oral feeding, such as hypoxic ischemic encephalopathy (HIE), and attempting oral feeds for at least 2 weeks.

Exclusion Criteria:

* Unstable infants or those requiring positive pressure respiratory support.
* Infants \<38weeks gestation at enrollment.
* Major unrepaired congenital anomalies or anomalies that limit feeding volumes
* Cardiomyopathy
* Repeated episodes of autonomic instability (apnea or bradycardia) which are not self resolving

Primary outcomes:
measure: Number of Infants Who Took All Feeds by Mouth (Responders)
timeFrame: 3 weeks
measure: ml/kg/d Increase Over 7d During taVNS
timeFrame: 7 days
measure: Neuroplasticity as Measured by the Change in White Matter Tract Integrity Via Fractional Anisotropy
timeFrame: change from baseline to week 3
Secondary outcomes:
measure: Number of Episodes of Bradycardia
timeFrame: 3 weeks, during taVNS sessions
measure: Number of Treatment Sessions With Sustained Increase in 'Neonatal and Infant Pain Scale' (NIPS) Scores During taVNS
timeFrame: 30min treatment session
Other outcomes:
Locations:
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
Study officials:
affiliation: Medical University of South Carolina
name: Dorothea Jenkins, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of South Carolina
name: Bashar Badran, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
citation: Cook DN, Thompson S, Stomberg-Firestein S, Bikson M, George MS, Jenkins DD, Badran BW. Design and validation of a closed-loop, motor-activated auricular vagus nerve stimulation (MAAVNS) system for neurorehabilitation. Brain Stimul. 2020 May-Jun;13(3):800-803. doi: 10.1016/j.brs.2020.02.028. Epub 2020 Feb 27.