Non-invasive Vagal Neurostimulation (nVNS) for Traumatic Brain Injury (TBI)-Induced Acute Respiratory Distress

Study Overview
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Brief Summary
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This is a prospective, randomized, two-arm, controlled 30-day investigational pilot trial using the gammaCore Sapphire S non-invasive vagus nerve stimulation (nVNS) device + standard of care (SOC) in newly-hospitalized patients with mild-to-moderate traumatic brain injury (TBI) to prevent the progression towards immunokine storms, systemic inflammatory response syndrome (SIRS), severe respiratory distress, and requirement for invasive mechanical ventilation, and death, when compared to SOC alone (the control arm).

Detailed Description
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A pilot population of 46 individuals between 18-80 years of age inclusive, will be enrolled, with an in-trial monitoring period of up to 30 days following baseline measurements. Study subjects will remain in-trial until one of the following occurs: a) 30 days without any progression to respiratory distress requiring mechanical ventilation; b) requirement for mechanical ventilation prior to 30 days; or c) death prior to 30 days. In addition to the screening, a total of up to 5 additional in-trial events (depending on the time at discharge from hospitalization) plus one additional clinical site visit at the end of the follow-up period will comprise the study events schedule of this trial.

Official Title
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Non-invasive Vagal Neurostimulation (nVNS) to Mitigate Traumatic Brain Injury (TBI)-Induced Acute Respiratory Distress and Acute Lung Injury

Conditions
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Acute Respiratory Distress Syndrome, Acute Lung Injury, Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS), Traumatic Brain Injury

Intervention / Treatment
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* Device: nVNS
* Other: SOC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is between 18-80 years, inclusive Patient has been admitted to the hospital for mild-to-moderate TBI that is restricted to the head and/or neck region. Patient is not on invasive mechanical ventilation Patient has a mild-to-moderate TBI based on a non-resuscitated or post-resuscitated Glasgow Coma Scale (GCS) sum score of =>12 Patient has a Lung Injury Prediction Score (LIPS) of =>2 Administration of the first nVNS treatment must be planned to take place within 24 h of intake A signed, written informed consent form from the patient or legally authorized representative Exclusion Criteria: Patient has a diagnosis of moderate or greater grade of respiratory distress/ARDS according to the Berlin definition of ARDS: Partial pressure of oxygen (PaO2) /Fraction of Inspired Oxygen (FiO2) > 100 mmHg (>13.3 kPa) to ≤ 200 mmHg (≤ 26.6 kPa) with positive end-expiratory pressure (PEEP) ≥ 5 cmH2O) Woman known to be pregnant, lactating or with a positive (urine or serum test) or indeterminate (serum test) pregnancy test Patient simultaneously taking part in another clinical trial Patient is not expected to survive for 24 hours Patient has an underlying clinical condition where, in the opinion of the study physicians and the institutional health provider physician, it would be extremely unlikely that the patient would not progress to invasive mechanical ventilation within 48 hours or any other condition that might require immediate invasive mechanical ventilation (e.g. motor neuron disease, Duchenne muscular dystrophy, or rapidly-progressive interstitial pulmonary fibrosis) Patient has severe chronic obstructive pulmonary disease (COPD) requiring long-term home oxygen therapy or mechanical ventilation (non-invasive ventilation or via tracheotomy) except for continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BIPAP) used solely for sleep-disorder breathing Patient has congestive heart failure Patient has acute left ventricular failure Patient has liver failure (Child-Pugh grade C) Patient is receiving renal dialysis therapy for chronic renal failure Patient is receiving extracorporeal membrane oxygenation, high-frequency oscillatory ventilation (HFOV) or any form of extracorporeal lung support Patient has had any form of mechanical ventilation (invasive or non-invasive, excluding CPAP alone) for longer than 48 h prior to the diagnosis of mild-to-moderate respiratory distress/ARDS Patient has burns to ≥ 15% of their total body surface area

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nVNS<br>nVNS treatment will be applied three times daily. One treatment is defined as 2 consecutive stimulations: one, 2-minute stimulation on the side of the neck followed by a second, 2-minute stimulation on the same side of the neck. The treatment will be done 3 times per day (morning, mid-day and 1 hour before bed at night), every day, until patient is discharged from the hospital or requires mechanical ventilation. Patient will record the time they administered these treatments. If the patient is unable to do this, a research staff member who has been trained on the device can assist. Will also receive SOC for TBI. | Device: nVNS<br>* 3x daily treatment of nVNS + SOC<br>Other: SOC<br>* Standard of care patient management.<br>|
| Other: SOC only<br>Patients will be managed according to the institutional best practices and SOC for TBI. | Other: SOC<br>* Standard of care patient management.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days free of invasive mechanical ventilation | Days free of invasive mechanical ventilation within 30 days from baseline among TBI survivors. | 30 days from baseline | 
| Days free of death | Days free of death within 30 days from baseline | 30 days from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events/Serious Adverse Events (AEs/SAEs) | Incidence, rate and severity of AEs/SAEs | Day 30 from baseline, Day 60, Day 90 | 
| Incidence of abnormal Physical examinations | Physical examination results | Day 30 from baseline or last day in hospital, Day 60, Day 90 | 
| Incidence of abnormal vital signs | vital sign results | Day 30 from baseline or last day in hospital, Day 60, Day 90 | 
| Incidence of abnormal laboratory results | laboratory results | Day 30 from baseline or last day in hospital, Day 60, Day 90 | 
| All-cause mortality | All-cause mortality | Day 30 from baseline, Day 60, Day 90 | 
| Days free of organ failure | assessed using the Sequential Organ Failure Assessment (SOFA) score (numerically quantifies (0-4) the number and severity of failed organs) with higher number being worse | Day 30 from baseline or last day in study, Day 60, Day 90 | 
| Days free of renal support |  | Day 30 from baseline or last day in study | 
| Days free of vasoactive support |  | Day 30 from baseline or last day in study | 
| Number of ICU-free days | assessed at Day 30 or on the last day in the ICU if the patient leaves the ICU before Day 30 | Day 30 from baseline | 
| Days free of invasive mechanical ventilation |  | Day 30 from baseline of last day in study | 
| Length of hospital stay | Number of days in hospital | Study Completion (up to 95 days from baseline) | 
| Forced Expiratory Volume (FEV1) |  | Day 30 from baseline, Day 60 from baseline, Day 90 from baseline | 
| Neurological functioning | 6 minute walk test | Day 30 from baseline, Day 60 from baseline, Day 90 from baseline | 
| PROMIS CAT score (Patient-Reported Outcomes Measurement Information System (PROMIS) computer adaptive testing (CAT)) | 0 to 100, with 0 being the lowest physical function and most disabled and 100 having the highest functioning | Day 30 from baseline, Day 60 from baseline, Day 90 from baseline | 
| Post concussion symptom scale (PCSS) | 27 perceived symptoms, patient reports their current experience of symptoms, on a scale from 0 to 6, with 0 being none/not experiencing particular symptom to 6 being experiencing severe symptom; total point value of scale is from 0 to 162 | Day 30 from baseline, Day 60 from baseline, Day 90 from baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-invasive Vagal Nerve Stimulation