PENFS COVID-19: Neuromodulation With Percutaneous Electrical Nerve Field Stimulation for Adults With COVID-19
Study Details
Study Description
Brief Summary
COVID-19 is a disease caused by the virus, SARS-CoV-2. Patients with this viral infection are at risk for developing pneumonia and acute respiratory distress syndrome (ARDS). Approximately 20% to 30% of hospitalized patients with COVID-19 and pneumonia require intensive care for respiratory support. Clinically, ARDS presents with severe hypoxemia evolving over several days to a week in combination with bilateral pulmonary infiltrates on chest X-ray. Widespread alveolar epithelial cell and pulmonary capillary endothelial injury can lead to severe impairment in gas exchange. In one report of 1,099 patients hospitalized with COVID-19, ARDS occurred in 15.6% of patients with severe pneumonia. In a smaller case series of 138 hospitalized patients, ARDS occurred in 19.6% of patients and in 61.1% of patients admitted to an intensive care unit (ICU).
To date, no effective treatment has been established to treat COVID-19 or to prevent progression of ARDS. It is thought that a heightened immune response with an unbalanced release of inflammatory mediators in the airway is a major cause of morbidity and mortality associated with the disease. It is therefore reasonable to postulate that improved outcomes may be obtained in patients with a balanced immune response with adequate viral control and appropriate counter-regulatory immune responses whereas a poor outcome may be expected in patients with inadequate viral control or a heightened immune response or what is referred to as a "cytokine storm". Thus, modulating the pulmonary immune response without suppressing the immune system would be a viable strategy for patients with COVID-19. The current literature supports the role of neuromodulation, particularly vagal nerve stimulation (VNS), in modulating the immune response. Modulating the pro-inflammatory pathway through VNS has been demonstrated to decrease inflammatory mediators and improve outcomes in several animal models and in humans.
Percutaneous electrical nerve field stimulation (PENFS) provides a novel, non-invasive method of VNS through a non-implantable device applied to the external ear. Already, the FDA has cleared this technology for reducing symptoms of opioid withdrawal in patients with opioid use disorder. Symptoms of opioid withdrawal can be decreased by approximately 90% after 1 hour of stimulation. Similarly, the IB-Stim device has been shown to improve symptom in children with abdominal-pain-related functional GI disorders and recently received market approval by the FDA for that indication. Unpublished studies have demonstrated marked decrease in inflammation with PENFS compared to sham stimulation in a model of TNBS colitis. While the efficacy of PENFS in modulating the progression of pulmonary disease in patients with COVID-19 is unknown, several proposed mechanisms for regulation of the immune response through VNS have already been demonstrated. We propose to perform an open label, randomized study to evaluate the efficacy of PENFS for the treatment of respiratory symptoms in patients with COVID-19.
Condition or Disease | Intervention/Treatment | Phase |
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N/A |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Active Comparator: Active percutaneous neurostimulation Subject randomized to 5 days of active vs sham neurostimulation therapy during hospitalization. |
Device: Auricular percutaneous neurostimulation
The BRIDGE/PENFS device manufactured by Key Electronics, consists of a battery activated generator and wire harness that connects to the generator. Four leads are also attached to the generator, each with a sterile 2 mm, titanium needle. The BRIDGE device settings are standardized and deliver 3.2 volts with alternating frequencies (1 ms pulses of 1 Hz and 10 Hz) every 2 s. This stimulation targets central pain pathways through branches of cranial nerves V, VII, IX, and X, which innervate the external ear. The PENFS device generator has a battery life of 5 days and delivers almost continuous stimulations throughout the 120 hours.
Other Names:
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Sham Comparator: Sham percutaneous neurostimulation Each subject randomized to 5 days of active vs sham neurostimulation therapy during hospitalization. |
Device: Auricular percutaneous neurostimulation
The BRIDGE/PENFS device manufactured by Key Electronics, consists of a battery activated generator and wire harness that connects to the generator. Four leads are also attached to the generator, each with a sterile 2 mm, titanium needle. The BRIDGE device settings are standardized and deliver 3.2 volts with alternating frequencies (1 ms pulses of 1 Hz and 10 Hz) every 2 s. This stimulation targets central pain pathways through branches of cranial nerves V, VII, IX, and X, which innervate the external ear. The PENFS device generator has a battery life of 5 days and delivers almost continuous stimulations throughout the 120 hours.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Hypoxemia via oxygen level, or saturation (SpO2) in percent [up to 14 days or until hospital discharge]
COVID-19 patients with dyspnea from worsening hypoxemia by measuring daily oxygen level, or saturation (SpO2) in percent.
- Progression to mechanical ventilation, ECLS or death [up to 14 days or until hospital discharge]
Progression of COVID-19 patients with dyspnea to mechanical ventilation, ECLS or death.
Secondary Outcome Measures
- Oxygen requirements [up to 14 days or until hospital discharge]
Change in oxygen requirements measured in days of hypoxemia (defined as SpO2 ≤93% on room air or requiring supplemental oxygen)
- Days of hospitalization [up to 14 days or until hospital discharge]
Days of hospitalization among survivors
- Time to hospital discharge [up to 14 days or until hospital discharge]
Time to hospital discharge or "ready for discharge" (as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or ≤2L supplemental oxygen)
- Time to resolution of fever [up to 14 days or until hospital discharge]
Fever will be recorded twice daily. Time to resolution of fever defined as body temperature (≤36.6°C [axilla], or ≤37.2 °C [oral], or ≤37.8°C [rectal or tympanic]) for at least 48 hours without antipyretics or until discharge, whichever is sooner, by clinical severity
- Days of resting respiratory rate [up to 14 days or until hospital discharge]
Days of resting respiratory rate >24 breaths/min recorded twice daily
- Serious adverse events or patient or worsening condition [up to 14 days or until hospital discharge]
Any serious adverse events or patient or worsening condition will be recorded to establish safety and tolerability of PENFS therapy. These include but not limited to skin irritation or reaction at site, pain at site, hypotension, seizure disorders, cardia dysrhythmia, progression to mechanical ventilation.
- Erythrocyte Sedimentation Rate (ESR) [up to 14 days or until hospital discharge]
Evaluation of erythrocyte sedimentation rate (ESR) in mm/hr. This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- C-Reactive Protein (CRP) [up to 14 days or until hospital discharge]
Evaluation of C-reactive protein (CRP) in mg/dL. This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- Ferritin [up to 14 days or until hospital discharge]
Evaluation of ferritin in ng/mL. This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- D-Dimer [up to 14 days or until hospital discharge]
Evaluation of D-dimer in ng/mL. This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- Creatine Phosphokinase, Total (CK) [up to 14 days or until hospital discharge]
Evaluation of creatine phosphokinase, total (CK) in U/L. This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- Troponin [up to 14 days or until hospital discharge]
Evaluation of troponin in ng/mL. This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- Lactate Dehydrogenase (LDH) [up to 14 days or until hospital discharge]
Evaluation of lactate dehydrogenase (LDH) in U/L. This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- Procalcitonin (PCT) [up to 14 days or until hospital discharge]
Evaluation of procalcitonin (PCT) in ng/mL. This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- B-Type Natriuretic Peptide (BNP) [up to 14 days or until hospital discharge]
Evaluation of B-type natriuretic peptide (BNP) in pg/mL. This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- N-Terminal Pro B-Type Natriuretic Peptide (NT-proBNP) [up to 14 days or until hospital discharge]
Evaluation of N-terminal Pro B-type natriuretic peptide (NT-proBNP) in pg/mL. This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- Interleukin-6 (IL-6), High Sensitive ELISA [up to 14 days or until hospital discharge]
Evaluation of Interleukin-6 (IL-6), high sensitive ELISA in pg/mL. This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- Complete Blood Count (CBC) with Differential [up to 14 days or until hospital discharge]
Evaluation of complete blood count (CBC) with differential. This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- Comprehensive Metabolic Panel (CMP) [up to 14 days or until hospital discharge]
Evaluation of comprehensive metabolic panel (CMP). This will be based on standard of care and additional lab draws for the purpose of the study will not be done.
- 7-Point Ordinal Scale of Clinical Status [up to 14 days or until hospital discharge]
Clinical status based on: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high-flow oxygen devices Hospitalized, requiring low-flow supplemental oxygen Hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care (related or not related to Covid-19) Hospitalized, not requiring supplemental oxygen or ongoing medical care (other than that specified in the protocol for remdesivir administration) Not hospitalized
- Modified Borg Dyspnea Scale (MBS) [up to 14 days or until hospital discharge]
Dyspnea based on: 0 - Nothing at all 0.5 - Very, very slight (just noticeable) - Very slight - Slight - Moderate - Somewhat severe - Severe 7 - Very severe 8 9 - Very, very severe (almost maximal) 10 - Maximal
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age ≥18 years at time of signing Informed Consent Form
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Hospitalized with COVID-19 pneumonia confirmed per WHO criteria (including a positive PCR of any specimen, e.g., respiratory, blood, urine, stool, other bodily fluid) and per the investigator, the respiratory compromise is most likely due to COVID-19
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Patient complaint of dyspnea at the time of presentation to ED or hospital
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Patient on room air or oxygen supplementation of no greater than 4 liters at rest to maintaining pulse oximetry of 92% or greater. This can include oxygen supplementation by any modality (BIPAP, CPAP, HFNC, NRB, NC), with the exception of mechanical ventilation or ECLS.
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Signed Informed Consent Form by any patient capable of giving consent, or, when the patient is not capable of giving consent, by his or her legal/authorized representative
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Ability to comply with the study protocol in the investigator's judgment.
Exclusion Criteria:
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Patients who cannot provide informed consent
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History of surgery involving CN V, VII, IX, or X.
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Patient on chronic renal dialysis
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Patients with history of solid organ transplant
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Patients with underlying seizures disorder
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Patients with a cardiac pacemaker
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Patients with any implanted electrical device
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Patients with dermatologic conditions affecting the ear, face, or neck region (i.e. psoriasis), or with cuts or abrasions to the external ear that would interfere with needle placement
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Patients with hemophilia or other bleeding disorders
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Patients who are pregnant or breastfeeding
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Patients with active TB infection
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Patient already on mechanical ventilation or ECLS
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Suspected active bacterial, fungal, viral, or other infection (besides COVID-19)
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In the opinion of the investigator, progression to mechanical ventilation, ECLS or death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments
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Participating in other drug clinical trials
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ALT or AST > 5 x ULN detected within 24 hours at screening or at baseline (according to local laboratory reference ranges)
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ANC < 500/µL at screening and baseline (according to local laboratory reference ranges)
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Platelet count < 50,000/µL at screening and baseline (according to local laboratory reference ranges)
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Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Olive View-UCLA Medical Center | Sylmar | California | United States | 91342 |
Sponsors and Collaborators
- Olive View-UCLA Education & Research Institute
Investigators
- Principal Investigator: Nader Kamangar, M.D., Olive View-UCLA Education & Research Institute
Study Documents (Full-Text)
None provided.More Information
Publications
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