Poor FeedingEarly Phase 1NCT04643808
taVNS Paired With Bottle Feeding in Infants Failing Oral Feeds
A Early Phase 1 study testing transcutaneous auricular vagus nerve stimulation in people with Poor Feeding and Infant Development, run by Medical University of South Carolina at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 3 weeks to 5 months
- Conditions the study is for
- Poor Feeding, Infant Development, Vagus Nerve Stimulation
- What is being tested?
- transcutaneous auricular vagus nerve stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 35 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Oct 2017to 1 Jul 2022
- Phase
- Early Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 weeks to 5 months
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
- Premature at birth and attempting oral feeds for at least 3 weeks or
- 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.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Medical University of South Carolina
Charleston, South Carolina, 29425
About this study
Official title: Noninvasive Brain Stimulation to Improve Oromotor Function In Neonates With Advanced Neuroimaging to Determine Safety and Target Engagement of taVNS for Neurorehabilitation
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.
Read the 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.
- Conditions
- Poor Feeding, Infant Development, Vagus Nerve Stimulation
- Being tested
- transcutaneous auricular vagus nerve stimulation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
transcutaneous auricular vagus nerve stimulationDevice
Also called taVNS
Microcurrent stimulation delivered to the left tragus, with stimulation 'on' during sucking from a bottle, and 'off' at rest during bottle feeding
| Study group | Role | What they receive |
|---|---|---|
| taVNS once daily | Experimental | taVNS paired with bottle feeding once daily for 2-3 weeks Receives: Device: transcutaneous auricular vagus nerve stimulation |
| taVNS twice daily | Experimental | taVNS paired with bottle feeding twice daily for 2-3 weeks Receives: Device: transcutaneous auricular vagus nerve stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Infants Who Took All Feeds by Mouth (Responders)
Number of infants who maintained full daily PO intake for 4 days (>120 ml/kg/day) and gained weight adequate for discharge (>20 g/day) were classified as 'Responders'.
Measured: 3 weeks
ml/kg/d Increase Over 7d During taVNS
The change in ml/kg/d of oral feeds over the 7 days during taVNS-paired feeds
Measured: 7 days
Neuroplasticity as Measured by the Change in White Matter Tract Integrity Via Fractional Anisotropy
changes in radial kurtosis diffusion in Corticospinal tracts at the cerebellar peduncles assessed per week of treatment, change from baseline to week 3 reported. Kurtosis is a dimensionless summary statistic that quantifies the amount of non-Gaussianity within the tissue on a scale from 0 to infinity. Higher values indicate greater complexity in the white matter tract. The scale has no title other than diffusion kurtosis.
Measured: change from baseline to week 3
Secondary outcomes (2)
Number of Episodes of Bradycardia
bradycardic episodes = heart rate <80 beats per minute for 5 seconds
Measured: 3 weeks, during taVNS sessions
Number of Treatment Sessions With Sustained Increase in 'Neonatal and Infant Pain Scale' (NIPS) Scores During taVNS
Number of treatment sessions with sustained increase of 3 points in Neonatal and Infant Pain Scale (NIPS) scores from before to during taVNS: NIPS recorded at before, midway, and at the end of each treatment session. NIPS scores range from 0 (no discomfort) to 7 (maximum discomfort). An increase of 3 points on the NIPS scale indicates more discomfort with stimulation.
Measured: 30min treatment session
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Nov 2020
- Study start1 Oct 2017
- Primary completion1 Jun 2022
- Study completion1 Jul 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Poor FeedingStudies of the same condition, open and under way.
- More trials run by Medical University of South CarolinaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- 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.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 35 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medical University of South Carolina
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of General Medical Sciences (NIGMS), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Principal investigator, Dorothea D. Jenkins, Medical University of South Carolina
- Investigators
- Dorothea Jenkins, MD, Principal investigator, Medical University of South CarolinaBashar Badran, PhD, Principal investigator, Medical University of South Carolina
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04643808
- Sponsor's protocol ID
- 67997
- Other IDs
- P20GM109040, P2CHD086844
- Status last verified
- Oct 2023
- First submitted
- 12 Nov 2020
- Last updated
- 30 Oct 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
Publications
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.
PubMed 30146041Badran 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.
PubMed 32256328Cook 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.
PubMed 32289710Jenkins DD, Moss HG, Adams LE, Hunt S, Dancy M, Huffman SM, Cook D, Jensen JH, Summers P, Thompson S, George MS, Badran BW. Higher Dose Noninvasive Transcutaneous Auricular Vagus Nerve Stimulation Increases Feeding Volumes and White Matter Microstructural Complexity in Open-Label Study of Infants Slated for Gastrostomy Tube. J Pediatr. 2023 Nov;262:113563. doi: 10.1016/j.jpeds.2023.113563. Epub 2023 Jun 16.
PubMed 37329979
Study at a glance
From the registry record, last updated by the sponsor on 30 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Noninvasive Brain Stimulation to Improve Oromotor Function In Neonates With Advanced Neuroimaging to Determine Safety and Target Engagement of taVNS for Neurorehabilitation
- ClinicalTrials.gov ID
- NCT04643808
- Acronym / sponsor ID
- 67997
- Conditions
- Poor Feeding, Infant Development, Vagus Nerve Stimulation
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 35 participants (actual)
- Lead sponsor
- Medical University of South CarolinaUniversity, hospital or other
- Collaborators
- National Institute of General Medical Sciences (NIGMS), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- 1 Oct 2017 (actual)
- Primary completion
- 1 Jun 2022 (actual)
- Study completion
- 1 Jul 2022 (actual)
- First posted
- 25 Nov 2020 (actual)
- Results
- Posted 30 Oct 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| taVNS once daily | Experimental | Device: transcutaneous auricular vagus nerve stimulationtaVNS paired with bottle feeding once daily for 2-3 weeks |
| taVNS twice daily | Experimental | Device: transcutaneous auricular vagus nerve stimulationtaVNS paired with bottle feeding twice daily for 2-3 weeks |
Who may qualify
- Ages
- 3 weeks to 5 months
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| transcutaneous auricular vagus nerve stimulationAlso: taVNSMicrocurrent stimulation delivered to the left tragus, with stimulation 'on' during sucking from a bottle, and 'off' at rest during bottle feeding | Device | taVNS once daily, taVNS twice daily |
Primary outcome
Number of Infants Who Took All Feeds by Mouth (Responders)
Time frame: 3 weeks
Number of infants who maintained full daily PO intake for 4 days (>120 ml/kg/day) and gained weight adequate for discharge (>20 g/day) were classified as 'Responders'.
ml/kg/d Increase Over 7d During taVNS
Time frame: 7 days
The change in ml/kg/d of oral feeds over the 7 days during taVNS-paired feeds
Neuroplasticity as Measured by the Change in White Matter Tract Integrity Via Fractional Anisotropy
Time frame: change from baseline to week 3
changes in radial kurtosis diffusion in Corticospinal tracts at the cerebellar peduncles assessed per week of treatment, change from baseline to week 3 reported. Kurtosis is a dimensionless summary statistic that quantifies the amount of non-Gaussianity within the tissue on a scale from 0 to infinity. Higher values indicate greater complexity in the white matter tract. The scale has no title other than diffusion kurtosis.
2 secondary outcomes
Number of Episodes of Bradycardia
Time frame: 3 weeks, during taVNS sessions
Number of Treatment Sessions With Sustained Increase in 'Neonatal and Infant Pain Scale' (NIPS) Scores During taVNS
Time frame: 30min treatment session
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Oct 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 30146041Badran 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.
- Results publication: PubMed 32256328Badran 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.
- Results publication: PubMed 32289710Cook 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.
- Derived from this study: PubMed 37329979Jenkins DD, Moss HG, Adams LE, Hunt S, Dancy M, Huffman SM, Cook D, Jensen JH, Summers P, Thompson S, George MS, Badran BW. Higher Dose Noninvasive Transcutaneous Auricular Vagus Nerve Stimulation Increases Feeding Volumes and White Matter Microstructural Complexity in Open-Label Study of Infants Slated for Gastrostomy Tube. J Pediatr. 2023 Nov;262:113563. doi: 10.1016/j.jpeds.2023.113563. Epub 2023 Jun 16.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dorothea Jenkins, MD principal investigator
Medical University of South Carolina
Bashar Badran, PhD principal investigator
Medical University of South Carolina
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing transcutaneous auricular vagus nerve stimulation in people with Poor Feeding and Infant Development, run by Medical University of South Carolina at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Oct 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Infants Who Took All Feeds by Mouth (Responders) (time frame: 3 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04643808, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Oct 2023.