A Prospective, Randomized, Controlled Study Assessing Vagus Nerve Stimulation in CoViD-19 Respiratory Symptoms (SAVIORII)
Phase: NA
Conditions: COVID, Corona Virus Infection, Respiratory Failure, Respiratory Distress Syndrome, Adult, ARDS, Human, SARS (Severe Acute Respiratory Syndrome)
Sponsor: Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)

 
This clinical investigation will be performed in compliance with ICH GCP following US Code of Federal 
Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Parts 50, 56, 312) and 
applicable regulatory requirements. 
 
 
 
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CLINICAL INVESTIGATION PLAN (CIP) 
 
 
 
Title: A Prospective, Randomized, Controlled Study Assessing Vagus Nerve 
Stimulation in CoViD-19 Respiratory Symptoms (SAVIOR II)  
Clinical Investigation Number: 
2020-132-AGH 
Clinical Investigation Medical Device: 
gammaCore® Sapphire 
Indication: 
Acute Respiratory Distress Syndrome 
Device Class: 
IIa 
Version: 
18 
Date: 
10 Dec 2020 
 
NCT#04382391 
Principal Clinical Investigator: 
Dr. Tariq Cheema 
Sponsor: 
Allegheny Health Network 
Allegheny General Hospital  
320 E North Avenue 
Pittsburgh, PA 15212 
USA 

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1 
SYNOPSIS 
CLINICAL INVESTIGATION TITLE: A Prospective, Randomized, Controlled Study Assessing 
Vagus Nerve Stimulation in CoViD-19 Respiratory Symptoms (SAVIOR II) 
CLINICAL INVESTIGATION CODE:   
2020-132-AGH 
 
CLINICAL INVESTIGATIONAL MEDICAL DEVICE(S):  
gammaCore Sapphire® (non-invasive vagus nerve stimulator) 
 
OBJECTIVES: 
The aims of this study are to summarize and compare the incidence of clinical events and pro-
inflammatory cytokine levels in patients randomized to use of gammaCore Sapphire plus 
standard of care vs standard of care alone in patients hospitalized for CoViD-19. In addition, 
this study is intended to demonstrate the safety of gammaCore Sapphire use in patients 
hospitalized for CoViD-19. 
Specific clinical events to be summarized include, but are not limited to: 
 
 
Changes in oxygen support requirements (no oxygen support, low-flow oxygen support, 
nasal high-flow oxygen support, noninvasive mechanical ventilation, and invasive 
mechanical ventilation) 
 
Changes in O2 saturation 
 
PaO2/FiO2 ratio 
 
Proportion of subjects requiring mechanical ventilation 
 
Days to onset of mechanical ventilation 
 
Live discharge from the hospital  
 
Patient length of stay 
 
Mortality 
 
Shortness of Breath 
 
Clinical improvement Scale 
Specific laboratory measurements to be summarized include, but are not limited to: 
 
TNF-α 
 
IL-1β 
 
IL-6 
 
CRP 
 
Ferritin 
 
D Dimer 

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 
Pro-Calcitonin 
OVERALL CLINICAL INVESTIGATION DESIGN:  
 
The study is a prospective, randomized, controlled investigation designed for comparison of 
two groups for the reduction of respiratory distress in a CoViD-19 population, using 
gammaCore Sapphire® (nVNS) plus standard of care (active) vs. standard of care alone (SoC), 
the control group. The gammaCore® (nVNS) treatments will be used acutely and 
prophylactically.  
 
 
 
 
 
 
 
 
 
 
 
 
AND 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Prophylactic  
SoC: No Administration of 
gammaCore® 
Administer one treatment of gammaCore®, 
scheduled three times a day (morning, mid-day 
and 1 hour before bed at night) 
 
One treatment is defined as 2 consecutive 
doses (stimulations). Each dose delivers a 2-
minute stimulation. One dose is applied to the 
left side of the neck, then one is applied to the 
right side  
Acute respiratory 
failure 
(w/hypoxia) 
or 
Shortness of 
breath 
SoC: No Administration of 
gammaCore® 
Administer one treatment of gammaCore® for 
acute treatment of shortness of breath (as 
needed, up to nine times a day) 
 
One treatment is defined as 2 consecutive 
doses (stimulations).  Each dose delivers a 2-
minute stimulation.  One dose is applied to the 
left side of the neck, then one to the right.  If 
shortness of breath (SOB) persists 20 minutes 
after start of first treatment, administer a second 
treatment. If the additional treatments do not 
appear to be providing benefit/relief of 
symptoms (as per patient or physician 
discretion) there is no need to continue with 
additional acute treatments. However, if it there 
appears to be benefit, the patient can administer 
more as needed. The patients can receive up to 
9 acute treatments (or 18 stimulations) per day.  

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INCLUSION AND EXCLUSION CRITERIA:  
Inclusion Criteria 
All patients must meet the following inclusion criteria to be included in this study: 
 
1. Patients (age 18 years and older) who have tested positive or suspected/presumed 
positive for CoViD-19 (PCR real time test)   
2. Patients with cough, shortness of breath or respiratory compromise (RR>24/min, 
increased work of breathing.) 
3. O2 Saturation less than or equal to 96% on room air or sensation 
4. Agrees to use the gammaCore Sapphire device as per protocol and to follow all of 
the requirements of the study including recording required study data 
5. Permission for early am blood draw to freeze for subsequent lab tests and 
sequencing as related to CoViD-19 sequelae 
6. Patient is able to provide signed and witnessed Informed Consent 
Exclusion Criteria   
Patients meeting any of the following criteria cannot be included in this research study:  
 
1. On home/therapy oxygen (i.e. for COPD patients) at baseline prior to development 
of CoViD-19  
2. Already using gammaCore® (nVNS) for other medical conditions 
3. A history of aneurysm, intracranial hemorrhage, brain tumors, or significant head 
trauma  
4. Known or suspected severe atherosclerotic cardiovascular disease, severe carotid 
artery disease (e.g., bruits or history of transient ischemic attack or cerebrovascular 
accident), congestive heart failure, known severe coronary artery disease, 
myocardial infarction documented within past 90 days, or current or recent history 
of life-threatening arrhythmia (sustained ventricular tachycardia, ventricular 
fibrillation, second or third-degree heart block, uncontrolled atrial fibrillation or 

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uncontrolled atrial flutter) 
5. Patients with clinically significant hypertension, hypotension, bradycardia, or 
tachycardia (as per investigator discretion) 
6. Current implantation of an electrical and/or neurostimulator device, including but not 
limited to a cardiac pacemaker or defibrillator, vagal neurostimulator, deep brain 
stimulator, spinal stimulator, bone growth stimulator, or cochlear implant  
7. Current implantation of metal cervical spine hardware or a metallic implant near the 
gammaCore® stimulation site  
8. Belongs to a vulnerable population or has any condition such that his or her ability 
to provide informed consent, comply with the follow-up requirements, or provide 
self-assessments is compromised (e.g. homeless, developmentally disabled and 
prisoner) 
9. Compromised access to peripheral veins for blood sampling. 
10. Pregnant women 
11. Patients with active cancer or those who have had recent cancer treatment 
 
CLINICAL INVESTIGATION PROCEDURE OVERVIEW: 
Enrollment / Admission Day - Day 0 
Study patient must meet all of the following inclusion criteria and none of the exclusion criteria 
 
Patient must sign Informed Consent and witness to signature must occur 
 
Randomization – Upon meeting all eligibility requirements (including verification of 
+CoViD-19 testing), patient’s will be randomized 1:1 into either the control group or 
the treatment group 
 
Intake Collection of: 
o Basic Demographics 
 
Date of Birth (DOB), Race, Sex, Smoking Status, County/Region 
o Medications, Co-morbidities  

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o CoViD-19 Test Results ( Positive / Presumed Positive)  
 
Study Measurements:  
o Height/Wt (BMI) 
o Temperature  
o Blood Pressure 
o O2 Saturation  
o PaO2/FiO2 ratio 
o Shortness of Breath (Yes / No) 
o Cough (Yes / No) 
 
Clinical Labs 
o Immunokine panel (TNF-α, IL-1β, IL-6) 
o Frozen blood sample 
o Leukocyte flow cytometry 
o Pro-Calcitonin 
o CRP 
o Ferritin 
o D Dimer 
o Complete hematology panel (CBC with differential) 
o Comprehensive metabolic panel 
o Serum or urine hCG (for any woman who might be pregnant) 
 
 
Device training: Patient receives device training on gammaCore® Sapphire device 
and receives first treatment with trained study staff* 
 
 
VNS Stimulation Supervised**, record date and times of stimulations 
 
Daily Tx Log Completion 
o Oxygen Required, Oxygen level (%) based on device type (HFNC / NC / 
Bipap / Optiflow), Ventilator Dependence, Date and time of Ventilation, 
Patient discharge home, Date and time of Discharge, Survival  
 
Clinical Improvement Ordinal Scale 
 
Adverse event assessment 
* For those patients allocated to non-invasive vagus nerve stimulation, the patient will be 
instructed by a study physician or study personnel on the gammaCore® technique. They will be 
instructed to use it according to the specified protocol, which will be available at bedside.   
** Protocol:  

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Prophylaxis: Administer gammaCore® Sapphire daily, prophalytically, scheduled three times a 
day (morning, mid-day and 1 hour before bed at night).  One treatment is defined as 2 
consecutive doses (stimulations). Each dose delivers a 2-minute stimulation. One stimulation is 
applied to the left side of the neck, then one is applied to the right.  This would be a total of 6 
treatments (2 stimulations x 3 times per day). 
For acute respiratory distress or shortness of breath (SOB): Administer one treatment of 
gammaCore® for acute treatment of shortness of breath (as needed, up to nine times a day).  
One treatment is defined as 2 consecutive doses (stimulations).  Each dose delivers a 2-
minute stimulation.  One stimulation is applied to the left side of the neck, then one to the right.  
If shortness of breath (SOB) persists 20 minutes after start of first treatment, administer a 
second treatment. If the additional treatments do not appear to be providing benefit/relief of 
symptoms (as per patient or physician discretion) there is no need to continue with additional 
acute treatments. However, if it there appears to be benefit, the patient can administer more as 
needed. The patients can receive up to 9 acute treatments (or 18 stimulations) per day. 
 
Day 1 - 3 
For days 1 through 3, the following assessments will be recorded each day: 
 
Study Measurements:  
o Height/Wt, BMI, Temperature, Blood Pressure, O2 Saturation, PaO2/FiO2 
ratio, Shortness of Breath, Cough 
 
Labs (Research) Early am blood draw (before 10 am) **Day 1 and 3 only** (then 
drawn on all odd days) 
o Immunokine panel (TNF-α, IL-1β, IL-6), Frozen blood sample, Leukocyte 
flow cytometry 
 
Labs (Standard of care) **Day 1 and 3 only** (then drawn on all odd days) 
o Pro-Calcitonin, C-reactive protein, Ferritin, D Dimer, CBC with differential 
 
Comprehensive metabolic panel **Day 3 only** (then drawn on all odd days) 
 
VNS Stimulation supervised 
o Total number of gammaCore® treatments administered, Date and times of 
stimulations 
 
Daily Tx Log  
o Oxygen Required, Oxygen level (%), Ventilator Dependence, Date and 
time of Ventilation, Patient discharge home, Date and time (in 24 hour 

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format) of Discharge, Survival 
 
Clinical Improvement Ordinal Scale 
 
Concomitant medication and adverse event assessments 
 
All Even Days Starting Day 4  
 
Study Measurements 
o Temperature, Blood Pressure, O2 Saturation, Shortness of Breath, Cough 
 
VNS stimulations 
o Total number of gammaCore® treatments administered with Date/time 
 
Daily Tx Log 
o Oxygen Requirements, Oxygen level (%), Ventilator Dependence, Date 
and time of Ventilation, Patient discharge home, (if applicable) Date and 
time of Discharge, Survival 
 
Clinical Improvement Ordinal Scale 
 
Concomitant medication and adverse event assessments 
All Odd Days Starting Day 5   
Same as Days 1 and 3  
 
Study Completion   
The last day of the study will be determined by discharge, transition to mechanical ventilation 
and/or if the patient is unable to continue i.e. death or feasibility impossible.  The following will 
be recorded: 
 
Study Measurements:  
o Height/Wt, BMI, Temperature, Blood Pressure, O2 Saturation, PaO2/FiO2 
ratio, Shortness of Breath, Cough 
 
Labs (Standard of care) 
o 
Pro-Calcitonin, C-reactive protein, Ferritin, D-Dimer, CBC with differential, 

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Comprehensive metabolic panel  
 
Labs (Research) Early am blood draw (before 10 am) 
o TNF-α, IL-1β, IL-6 
 
VNS stimulations 
o Total number of gammaCore® treatments administered, dates/times 
 
Daily Tx Log 
o Oxygen Required, Oxygen level (%) based on device type (HFNC / NC / 
Bipap / Optiflow), Ventilator Dependence (Yes / No), Date and time of 
Ventilation, Patient discharge home (Yes / No), Date and time (in 24 hour 
format) of Discharge, Survival (Yes / No) with Date and Time of Death 
 
Clinical Improvement Ordinal Scale 
 
Concomitant medication and adverse events assessment 
 
 
 

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2 
TABLE OF CONTENTS 
Section 
                                 Page 
1 
SYNOPSIS .................................................................................................................... 2 
Inclusion/Exclusion Criteria .................................................................................. 4 
Overview 4 
2 
TABLE OF CONTENTS .............................................................................................. 10 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................... 122 
3.1 
List of Abbreviations ...................................................................................... 122 
4 
CLINICAL INVESTIGATORS AND CLINICAL INVESTIGATION ADMINISTRATIVE 
STRUCTURE ............................................................................................................ 133 
5 
INTRODUCTION ....................................................................................................... 144 
5.1 
Background .................................................................................................... 144 
6 
CLINICAL INVESTIGATION OBJECTIVES ................................................................ 19 
6.1 
Objectives .............................................................. Error! Bookmark not defined.9 
6.2 
 ................................................................................ Error! Bookmark not defined.9 
7 
DESIGN OF THE CLINICAL INVESTIGATION .......................................................... 20 
7.1 
Overall Clinical Investigation Design .............................................................. 20 
7.2 
Clinical Investigation Procedures and Definitions....................................... 211 
7.2.1 
Schedule of Clinical Investigation Events ....................................... 211 
7.2.1.1 
Intake / Admission (Day 0) ............................................................. 211 
7.2.1.2 
Days 1 – 3 ...................................................................................... 233 
7.2.1.3 
All Even Days Starting Day 4 ......................................................... 244 
7.2.1.4 
All Odd Days Starting Day 5 ............................................................. 25 
7.2.1.5 
Day of Study Completion ............................................................... 266 
7.2.2 
Clinical Investigation Flow Chart ...................................................... 28 
7.3 
Discussion and Justification of Clinical Investigation Design, Including the 
Choice of Control Groups .............................................................................. 309 
7.3.1 
Prior and Concomitant Medication and Procedures ......................... 30 
7.4 
Selection of Population for the Clinical Investigation ................................... 30 
7.4.1 
Number of Patients .......................................................................... 30 
7.4.2 
Inclusion Criteria .............................................................................. 30 
7.4.3 
Exclusion Criteria ............................................................................. 30 
7.4.4 
Removal of Patients from the Clinical Investigation .......................... 31 
7.5 
Identification and Description of the Clinical Investigational Medical Device
 ........................................................................................................................... 32 
7.5.1 
Identification of the Clinical Investigational Medical Device .............. 32 
7.5.2 
Packaging and Labelling of the Clinical Investigational Medical Device
 ........................................................................................................ 33 
7.5.3 
Installation and Use of the Clinical Investigational Medical Device . 343 
7.5.4 
Compliance with Device Usage ...................................................... 344 
7.6 
Risk and Benefits of the Investigational Device and Clinical Investigation354 
7.7 
Performance and Safety Endpoints, Variables and Measurements ........... 376 
7.7.1 
Patient Characteristics ................................................................... 376 
7.7.2 
Objectives ......................................... Error! Bookmark not defined.6 
7.7.3 
Safety Variables and Measurements .............................................. 376 

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7.7.4 
Other Variables and Measurements ............................................... 386 
7.7.5 
Appropriateness of Measurements ................................................. 386 
7.8 
Adverse Events/Adverse Device Effects and Device Deficiencies ............. 387 
7.8.1 
Adverse Event/Adverse Device Effect Definitions .......................... 387 
7.8.2 
Serious Adverse Event/Serious Adverse Device Effect/Unanticipated 
Adverse Device Effect Definitions .................................................. 397 
7.8.3 
Unanticipated serious adverse device effect (USADE) ..................... 38 
7.8.4 
Reporting of Adverse Events/Adverse Device Effects ...................... 38 
7.8.4.1 
Methods for Eliciting Adverse Events/Adverse Device Effects .......... 38 
7.8.4.2 
Follow-up of Patients with Adverse Events ....................................... 40 
7.8.5 
Reporting of Events ......................................................................... 41 
7.8.6 
Device deficiencies .......................................................................... 41 
7.9 
Data Quality Assurance ................................................................................. 432 
7.9.1 
Monitoring, Audits and Inspections ................................................. 432 
7.9.2 
Patient Records and Source Data .................................................. 432 
7.9.3 
Access to Source Data and Documentation ................................... 432 
7.9.4 
Training of Staff .............................................................................. 432 
7.9.5 
Data and Quality Management ....................................................... 443 
7.9.6 
Data Safety Monitoring Board ........................................................ 443 
7.10 Statistical Methods and Determination of Sample Size ............................... 443 
7.10.1 
Statistical Evaluation of Performance and Safety Variables ........... 443 
7.10.1.1 
Data Sets to be Analysed ............................................................... 443 
7.10.1.2 
Summary Statistics .......................................................................... 44 
7.10.1.3 
Performance Analysis ...................................................................... 44 
7.10.1.4 
 ........................................................................................................ 44 
7.10.1.5 
Demographic and Other Baseline Characteristics ............................ 44 
7.10.1.6 
Extent of Device Usage .................................................................... 45 
7.10.1.7 
Concomitant Treatment .................................................................... 45 
7.10.1.8 
Adverse Events/Adverse Device Effects .......................................... 45 
7.10.2 
Handling of Drop-outs and Missing Data .......................................... 45 
7.10.3 
Determination of Sample Size .......................................................... 45 
7.10.4 
Interim Analysis ................................................................................ 46 
7.10.5 
Procedures for Reporting any Deviations from the Original Statistical 
Analysis Plan ................................................................................... 46 
7.11 Amendments to the Clinical Investigation Plan ............................................. 46 
7.12 Deviations from the Clinical Investigation Plan ............................................. 46 
7.13 Report and Publication .................................................................................... 46 
8 
ETHICS ....................................................................................................................... 48 
8.1 
Institutional Ethics Review .............................................................................. 48 
8.2 
Ethical Conduct of the Clinical Investigation ................................................. 48 
8.3 
Patient Information and Consent .................................................................... 48 
9 
PATIENT PROTECTION PROCEDURES ................................................................... 49 
9.1 
Procedures in Case of Medical Emergency.................................................... 49 
9.2 
Patient Data Protection .................................................................................... 49 
10 
REFERENCES ............................................................................................................ 50 
11 
CLINICAL INVESTIGATION PLAN - INVESTIGATOR AGREEMENT FORM .......... 533 
12 
APPENDICES ........................................................................................................... 544 

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3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
3.1 
List of Abbreviations 
 
ADE 
Adverse Device Effect 
AE 
ARDS 
CAP 
Adverse Event 
Acute Respiratory Distress Syndrome 
Cholinergic Anti-inflammatory Pathway 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
DMC 
FAS 
FEV1 
Data Monitoring Committee 
Full analysis set 
Forced Expiratory Volume 
IEC 
IL 
nVNS 
PPS 
Independent Ethics Committee 
Interleukin 
Non-Invasive Vagus Nerve Stimulation 
Per protocol set 
SADE 
Serious Adverse Device Effect 
SAE 
SOB 
SoC 
Serious Adverse Event 
Shortness of Breath 
Standard of Care 
IRB 
Institutional Review Board 
UAE 
UADE 
USADE 
VNS 
WOB 
Unanticipated Adverse Event 
Unanticipated Adverse Device Effect 
Unanticipated Serious Adverse Device Effect  
Vagus Nerve Stimulation 
Work of Breathing 
 
 

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4 
CLINICAL INVESTIGATORS AND CLINICAL INVESTIGATION 
ADMINISTRATIVE STRUCTURE 
COORDINATING CLINICAL INVESTIGATOR 
Name: 
Dr. Tariq Cheema 
Address: 
490 E North Avenue, Suite 300, Pittsburgh, PA 15212, USA 
E-mail: 
Tariq.Cheema@ahn.org 
CLINICAL INVESTIGATION SITE 
 
Name: 
Allegheny General Hospital 
Address: 
320 E North Avenue, Pittsburgh, PA 15212, USA 
Name: 
West Penn Hospital 
Address: 
4800 Friendship Avenue, Pittsburgh, PA 15224, USA 
 
CLINICAL REPRESENTATIVE & PROJECT LEADER 
Name: 
Boyle Cheng, PhD 
Address: 
320 E North Avenue, Suite 311, Pittsburgh, PA 15212, USA 
 
E-mail: 
Boyle.cheng@ahn.org 

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5 
INTRODUCTION 
5.1 
Background 
 
Vagus nerve stimulation (VNS) has an established history of reducing airway distress. VNS has 
at least two mechanisms of action that may profoundly affect respiratory function in patients with 
respiratory distress due to CoVID-19.  
 
First, vagus nerve stimulation modulates bronchoconstriction1-3, acute stimulation has 
demonstrated a marked improvement in Work of Breathing (WOB) as well as Forced Expiratory 
Volume (FEV1) in patients with severe respiratory distress due to airway reactivity.  This effect 
appears to occur via an afferent response to stimulation of the vagus nerve.   
 
Second, and perhaps more importantly, VNS has been shown to be a potent moderator of 
pathologic immune reactions, specifically suppressing pro-inflammatory cytokine levels via 
activation of the Cholinergic Anti-inflammatory Pathway (CAP). VNS is currently being studied to 
modulate pro-inflammatory cytokines patterns and concentrations in a variety of acute and 
progressive inflammatory conditions, ranging from septic shock and asthma to stroke, 
rheumatoid arthritis and Inflammatory Bowel Disease.4-8.   VNS has been studied in animal 
models of acute septic shock, consistently demonstrating life-saving potential.  In one such 
study, cecal ligation and puncture was used to induce a septic state in an animal model.  VNS 
reduced the expression of cytokines which was tightly associated with survival.9 Specifically, in 
animal and human models, this neuromodulatory therapy has the capacity to reduce the 
expression of inflammatory mediators, including TNF-α, IL-6 and IL-1β.  These are precisely the 
same cytokines which are elevated in ARDS and other inflammatory disorders.  In all cases, the 
therapy has shown considerable promise as a potential alternative to steroids (having potent 
anti-inflammatory activity but without the adverse side effects of steroids) and biologic therapies 
targeting pro-inflammatory cytokines (broadly – e.g., tofacitinib, or specifically – e.g., 
adalimumab, etanercept, and infliximab).  
 
Viral-induced acute respiratory distress syndrome (ARDS), including those caused by SARS 
CoV-1 and MERS are characterized by a massive systemic pro-inflammatory state. Although a 
pro-inflammatory environment is required to control the rate of infection as well as the 
eradication of infected and compromised cells, the massive response to these viruses, primarily 
due to leukocytes of the innate arm of the immune system, is part of the problem as a significant 
number of tissues are damaged and lost secondary to the infected tissues in a by-stander and 
collateral manner.10-28 A simple, drug-free approach to attenuate this systemic inflammation 
would be of significant benefit to the progression of the syndrome and potentially improve the 
overall recovery of the patients. 
 
For these reasons, we propose that VNS may ameliorate the over-activity of the pro-
inflammatory immune condition in CoViD-19 patients, thus conferring a superior therapeutic 
option especially for elderly patients and those presenting with respiratory illness in setting of 
comorbid conditions who experience severe symptoms. These groups are at particularly high 
risk of requiring mechanical ventilation, developing ARDS, experiencing severe cytokine storm 
and have a higher mortality rate. 

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Non-Invasive Vagus Nerve Stimulation (nVNS) 
 
Historically, VNS was delivered using implanted signal generators coupled to leads having 
electrodes that wrap around the vagus nerve.  The vagus nerve is located within the carotid 
sheath, and thus the implantation surgery is complicated with inherent risks, particularly in the 
critically ill.  More recently, a non-invasive approach to vagus nerve stimulation (nVNS) was 
cleared by the FDA for the acute treatment of pain associated episodic cluster and migraine 
headaches and the prevention of cluster headaches and migraine headaches. This device, 
gammaCore (electroCore, Inc., Basking Ridge, NJ) is handheld and requires no surgery or 
implants.  The device is applied by healthcare providers or patients to the skin at the neck over 
the vagus nerve to deliver periodic treatments of VNS non-invasively.  
 
An Emergency Use Application for use of VNS in CoViD-19 patients was granted by the FDA on 
July 10, 2020. 
 
With respect to bronchoconstriction, early studies demonstrated modulation of airway reactivity 
in hospitalized asthmatic patients, improving various measures of airway patency.2,29  
 
Non-invasive VNS (nVNS) is a safe method of stimulating the vagus nerve, with minimal side 
effects.  It does not require surgery or an invasive procedure that would otherwise limit its utility 
in the critically ill. The stimulation can be either self-administered or administered by a health 
care practitioner.  There are numerous studies with both implanted and nVNS in multiple animal 
models and humans that have demonstrated a modulation of the inflammatory cascade with an 
improvement in survival.   
 
gammaCore® (nVNS) has been studied in approximately 2,000 patients as part of clinical trials 
with an excellent safety profile. It is available through commercial insurers and the private pay 
market, and is listed on the federal supply schedule available for purchase by the VA and 
Department of Defense and also carries a CE mark for distribution abroad. More than ten 
thousand patients have been successfully treated in the United States and abroad.    
 
CoViD-19 Respiratory Issues Involve Virally-triggered Severe (Lethal) Cytokine 
Expression 
 
COVID-19 (coronavirus disease 2019) is caused by SARS CoV-2 (severe acute 
respiratory syndrome coronavirus 2) and is related to the coronavirus which caused SARS in 
2003 (SARS CoV-1). The virus is transmitted either through airborne droplets (e.g. coughing or 
sneezing) or direct contact (e.g. through a surface containing the virus), with a mean incubation 
period between 4 and 7 days (range 2 days to > 2 weeks). As of April 3, 2020, there are over a 
million confirmed cases and rising with 55,000 individuals deceased to date.   This gives a 
current mortality rate of 5.3 %, although the base case of confirmed cases may be markedly 
underestimated.  Elderly and those with comorbid conditions including heart disease, diabetes, 
and asthma seem to have a higher mortality rate.   
 
Many CoViD-19 patients experience moderate to severe respiratory symptoms, including 
shortness of breath and impaired oxygen saturation.  Eighty-eight percent (88%) of patients 
present with respiratory symptoms. A significant and increasing number of CoViD-19 patients 
require hospitalization, and progress to being intubated and/or ventilator dependent. Given the 

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rapid spread of this contagion, concern exists that the international healthcare systems do not 
have the number of ventilators and/or ICU beds to meet the expected demand in the coming 
months.    
 
The most critically afflicted can experience pneumonia and/or ARDS. Accumulating evidence 
suggests that this subgroup with severe CoViD-19 likely have a cytokine storm syndrome, a 
hallmark of ARDS that includes dramatic increase in the expression of pro-inflammatory 
cytokines, mainly TNF-α, IL-6 and IL-1β among others. Elevations in IL-6 seem to be a 
particularly poor outcome indicator of respiratory compromise. It is believed that the mortality of 
ARDS is at least partially the result of an over activity of the patient’s immune system.30 
Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed CoViD-19 
cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 
ng/ml in survivors; p<0·001) and IL-6 (p<0·0001)31, suggesting that mortality and respiratory 
decompensation may be due to virally driven hyperinflammation.  
 
Therapies that could block the cytokine storm may help improve survival and decrease the need 
for ventilator use and prolonged respiratory support.  Other companies are in fact developing 
pharmaceutical approaches for the treatment of cytokine storm32, or plasma infusions from those 
who have recovered from the virus.   At this point there is no cure or vaccine for the virus and 
neither is there a treatment approach to dampen the systemic inflammation. 
 
Proposal to Use gammaCore nVNS to Reduce Severe Respiratory Disease Associated 
with CoViD-19 
 
Given the CE mark and excellent safety profile, including the twenty year history of the use of 
VNS to block the over production of pro-inflammatory mediators via the CAP (cholinergic anti-
inflammatory pathway), and the lack of other effective or reasonable options during this 
pandemic we propose deploying gammaCore® (nVNS) devices for prophylactic use to those who 
have been diagnosed as infected with the virus, but before the cytokine storm begins to cause 
and/or exacerbate the severe respiratory distress syndrome. The hypothesis is that the 
administration of non-invasive VNS using gammaCore®, during and following severe infection 
with CoViD-19 may prevent the worsening inflammatory response and acute injury associated, 
thus decreasing ventilator dependence and mortality of the virus.  If utilized early enough in the 
course of disease we hope to reduce ventilator dependence and improve survival with a 
scientifically driven safe and cost-effective approach.  Furthermore, through additional acute 
utility of gammaCore® (nVNS) in cases of ARDS and cytokine storm we aspire to effectively 
blunt the pro inflammatory response, reduce mortality and liberate patients from mechanical 
ventilation earlier which will assist in deploying the ventilator to other patients in need during the 
CoViD-19 pandemic. 
 
electroCore has designed a non-invasive vagus nerve stimulation (nVNS) device called 
gammaCore®. The gammaCore® (nVNS) device is a handheld, battery-powered unit that 
produces a proprietary electrical waveform in the vicinity of the vagus nerve in the neck.  Each 
dose (or stimulation) is relatively brief (120 seconds) and the user maintains control over the 
stimulation intensity.   
 
gammaCore® is currently commercially available for the treatment of cluster and migraine 
headaches, and broad safety data with thousands of patients treated in the US Europe and the 
UK in both clinical trials and routine clinical care.    

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Treatment paradigms have been developed and tested in clinical trials to support FDA clearance 
for the acute treatment of pain associated with episodic cluster and migraine headaches, and 
the prevention of cluster and migraine headache. This experience demonstrates that nVNS may 
be administered safely in up to 24 two-minute doses (stimulations) per day. We thus have data 
to draw on as to how to effectively stimulate the vagus nerve.  Given the multiple modes of 
action with blocking the CAP, and acute bronchodilatation, using a similar treatment paradigm 
for a trial to evaluate nVNS treatment of ARDS is reasonable. The device should be used both 
prophylactically and acutely early in the course of the disease prior to mechanical ventilation, 
and once trained, treatment can be fully managed by either a healthcare professional or the 
patient. If one waits until mechanical ventilation has started, it is less likely that a therapy will be 
able to block the cytokine storm and outcomes will be less profound.   
 
With respect to the theoretical cardiac and respiratory side effects of non-invasive treatment, 
historically, stimulation of the vagus nerve is associated with adverse side effects, including 
bradycardia and bronchoconstriction. These effects were shown to be the result of in 
discriminant stimulation of all fibers in the vagal bundle (the vagus nerve is primarily comprised 
of A and C fibers), which could be avoided by specifically tuning the electrical signals to 
selectively stimulate only the A fibers. This is possible because of the difference in electric field 
strengths necessary to activate the different fiber types.34 
 
The intensity, pulse duration and frequency of gammaCore® (nVNS) stimulation parameters 
have been optimized to induce signals in the large, myelinated Aβ fibers of the cervical branch of 
the vagus nerve. Since gammaCore® activates only the low threshold afferent Aβ fibers, versus 
the high threshold efferent C-fibers that innervate the heart, there is no known risk for adverse 
cardiac or other systemic parasympathetic effects. 
 
electroCore has conducted pre-clinical studies to assess the potential risk of vagus nerve 
overstimulation on the heart and airways. Several studies were conducted in beagle dogs with 
hypersensitized airways (worst case for airway reactivity) at maximum stimulation output for 2 
minutes.  Review of heart rate and airway resistance before, during and after stimulation 
indicated that there were no significant adverse changes associated with stimulation.37  These 
results are consistent with the human clinical experience with the gammaCore® device. 
Regarding the theorized mechanism of action, afferent fibers from the vagus nerve enter the 
brain and synapse onto the nucleus tractus solitarius (NTS) in the brain stem1, making 
connections with many structures in the brain including the locus coeruleus (LC), the 
periaqueductal gray (PAG) and the raphe nucleus (RN).35 These structures are known to control 
the release of key inhibitory neurotransmitters.  Numerous animal and clinical studies over the 
last 25 years have implicated the activity of these structures, in particular the LC, in the 
mechanism of action of VNS to inhibit seizures.36   
 
Clinical Use for Clinical Care 
 
                                               
 
 
 
 

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Given the lack of other effective and/or reasonable options for a patient with CoViD-19 
respiratory distress and the anticipated demands on our healthcare system, considering 
gammaCore® (nVNS) therapy, we propose, is a reasonable approach. To achieve goal of 
decreasing health care burden with patient benefit of decreasing ventilator dependency, 
inflammatory response and mortality, plan to use it early in course of disease i.e. prior to severe 
respiratory distress and the need for mechanical ventilation. 
 
The presumptive mechanisms of bronchodilatation and modulation of the cytokine storm would 
suggest that early intervention is ideal in improving pulmonary function and avoiding respiratory 
depression.   
 
1) Prevention. Mitigation of pro-inflammatory immunokine release would be best 
achieved with two doses (stimulations), consisting of a two-minute stimulation, on 
each side of the neck three times a day (am, afternoon and an hour before bed). This 
would be a total of 6 treatments (2 stimulations x 3 times per day) of stimulation as a 
prophylactic/preventive measure. This dosage is well below the known safety dosage 
threshold. 
2) In addition, patients may receive additional treatments when experiencing acute 
respiratory distress. Similarly, one treatment is two doses (stimulations). Each 
treatment (consisting of two-minute stimulation on each side) is performed on the 
neck. If shortness of breath (SOB) persists 20 minutes after start of first treatment, 
administer a second treatment. Maximum number of acute treatments per day is 9. 
This is symptomatic control and can be used to improve FEV1, Work of Breathing or 
dyspnea. 

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6 
CLINICAL INVESTIGATION OBJECTIVES  
The aims of this study are to summarize and compare the incidence of clinical events and pro-
inflammatory cytokine levels in patients randomized to use of gammaCore Sapphire plus 
standard of care vs standard of care alone in patients hospitalized for CoViD-19. In addition, this 
study is intended to demonstrate the safety of gammaCore Sapphire use in patients hospitalized 
for CoViD-19. 
Specific clinical events to be summarized include, but are not limited to: 
 
 
Changes in oxygen support requirements (no oxygen support, low-flow oxygen support, 
nasal high-flow oxygen support, noninvasive mechanical ventilation, and invasive 
mechanical ventilation) 
 
Changes in O2 saturation 
 
PaO2/FiO2 ratio 
 
Proportion of subjects requiring mechanical ventilation 
 
Days to onset of mechanical ventilation 
 
Live discharge from the hospital  
 
Patient length of stay 
 
Mortality 
 
Shortness of Breath 
 
Clinical improvement Scale 
Specific laboratory measurements to be summarized include, but are not limited to: 
 
TNF-α 
 
IL-1β 
 
IL-6 
 
CRP 
 
Ferritin 
 
D Dimer 
 
Pro-Calcitonin 
 

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7 
DESIGN OF THE CLINICAL INVESTIGATION 
7.1 
Overall Clinical Investigation Design 
The study is a prospective, randomized, control investigation designed for comparison of two 
groups for the reduction of respiratory distress in a CoViD-19 population, using gammaCore® 
Sapphire plus standard of care (active) vs. standard of care alone (SoC), the control group. The 
gammaCore® treatments will be used acutely and prophylactically.  
 
Figure 1 
Overall Design 
 
 
 
 
 
 
 
 
 
 
 
 
AND 
 
  
 
 
 
 
 
 
 
 
 
 
Prophylactic  
SoC: No Administration of 
gammaCore® 
Administer one treatment of gammaCore®, scheduled 
three times a day (morning, mid-day and 1 hour before 
bed at night) 
 
One treatment is defined as 2 consecutive doses 
(stimulations). Each dose delivers a 2-minute stimulation. 
One dose is applied to the left side of the neck, then one is 
applied to the right side  
Acute respiratory 
failure 
(w/hypoxia) 
or 
Shortness of 
breath 
SoC: No Administration of 
gammaCore® 
Administer one treatment of gammaCore® for acute 
treatment of shortness of breath (as needed, up to nine 
times a day) 
 
One treatment is defined as 2 consecutive doses 
(stimulations).  Each dose delivers a 2-minute stimulation.  
One dose is applied to the left side of the neck, then one 
to the right.  If shortness of breath (SOB) persists 20 
minutes after start of first treatment, administer a second 
treatment. If the additional treatments do not appear to be 
providing benefit/relief of symptoms (as per patient or 
physician discretion) there is no need to continue with 
additional acute treatments. However, if it there appears 
to be benefit, the patient can administer more as needed. 
The patients can receive up to 9 acute treatments (or 18 
stimulations) per day.  

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7.2 
Clinical Investigation Procedures and Definitions 
Once the patient is admitted to the hospital, the institution shall follow their standard protocol for 
their CoVid-19 patients. The investigator shall administer the consent form, conduct the intake 
and randomize the patient 1:1 into each of the two study arms prior to baseline measurements. 
Once qualified, the patient shall be trained on the use of gammaCore® and provided an initial 
treatment. For every day the patient is in the hospital but not on mechanical ventilation, the 
administration of gammaCore®, prophylactically and acutely, will be recorded on the daily study 
log as per protocol treatment.  
7.2.1 
Schedule of Clinical Investigation Events 
7.2.1.1 
Intake / Admission (Day 0) 
Upon hospital admission, after the patient and the Investigator have signed the Informed 
Consent Form, the patient will be randomized 1:1 into one of the two treatment arms. Patient’s 
severity of condition will be classified based on age, co-morbidities, and oxygen saturation as 
moderate or severe. To prevent allocation bias, the patient will be assigned to the test or control 
arm of the study based on severity of classification in a 1:1 ratio.  Thereafter, the study 
physicians and/or attending physicians participating in the study and if feasible, will conduct a 
complete physical examination and obtain vitals. Medical and demographic information in the 
EMR pertinent to this trial and the patient’s treatment will also be captured into the CRFs.  
 
The following Intake and collection of data will then be conducted: 
 
Intake Collection of: 
o Basic Demographics 
 
Date of Birth (DOB), Race, Sex, Smoking Status, County/Region 
o Medications, Co-morbidities  
o CoViD-19 Test Results ( Positive / Presumed Positive)  
 
Study Measurements:  
o Height/Wt (BMI) 
o Temperature  
o Blood Pressure 
o O2 Saturation  
o PaO2/FiO2 ratio 
o Shortness of Breath (Yes / No) 
o Cough (Yes / No) 
 
Clinical Labs 
o Immunokine panel (TNF-α, IL-1β, IL-6) 
o Frozen blood sample†  
o Leukocyte flow cytometry 
o Pro-Calcitonin 

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o CRP 
o Ferritin 
o D Dimer 
o Complete hematology panel (CBC with differential) 
o Comprehensive metabolic panel 
o Serum or urine hCG (for any woman who might be pregnant) 
 
 
Device training: Patient receives device training on gammaCore® Sapphire device 
and receives first treatment with trained study staff * 
 
 
nVNS Stimulation Supervised** 
 
Study log completion: patient will record date and times of stimulations.  
 
Daily Tx Log Completion 
o Oxygen Required, Oxygen level (%) based on device type (HFNC / NC / 
Bipap / Optiflow), Ventilator Dependence, Date and time of Ventilation, 
Patient discharge home, Date and time of Discharge, Survival  
 
Clinical Improvement Scale 
 
Adverse event assessment 
* For those patients allocated to gammaCore (nVNS), the patient will be instructed by a study 
physician on the gammaCore® technique. They will be instructed to use it according to the 
specified protocol, which will be available at bedside.  Re-training on the device or study log 
completion can occur at any time the patient requests further instruction or clarification and/or if 
research staff feels re-training is necessary during supervised stimulations.  
Instructions for the use of the device will be kept in each patient's room and will not be re-used 
for any other patient, or removed from the patient room for any reason, throughout their study 
participation. 
Study team will provide each patient with a laminated study log for individual patient room, each 
day, to log their treatments.  This log will cleaned for reuse each day for each patient, then 
discarded per institutional policy and will not be used by any other patient. A duplicate paper 
study log will be located on the outside of the room, whereas a trained study investigator will 
transpose the data entered on the log from the patient’s room, onto a CRF, with their signature 
and date, each day while patient is on study. 
** Protocol:  
Prophylaxis: Administer gammaCore® Sapphire daily, prophalytically, scheduled three times a 
day (morning, mid-day and 1 hour before bed at night).  One treatment is defined as 2 
consecutive doses (stimulations). Each dose delivers a 2-minute stimulation. One dose is 
applied to the left side of the neck, then one is applied to the right.  This would be a total of 6 
treatments (2 stimulations x 3 times per day). 

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For acute respiratory distress or shortness of breath (SOB): Administer one treatment of 
gammaCore® for acute treatment of shortness of breath (as needed, up to nine times a day).  
One treatment is defined as 2 consecutive doses (stimulations).  Each dose delivers a 2-minute 
stimulation.  One dose (stimulation) is applied to the left side of the neck, then one to the right.  If 
shortness of breath (SOB) persists 20 minutes after start of first treatment, administer a second 
treatment. If the additional treatments do not appear to be providing benefit/relief of symptoms 
(as per patient or physician discretion) there is no need to continue with additional acute 
treatments. However, if it there appears to be benefit, the patient can administer more as 
needed. The patients can receive up to 9 acute treatments (or 18 stimulations) per day. 
Determination of benefit/relief of symptoms will be determined collaboratively between patient 
and a research investigator who is caring for the patient.  Should the acute treatments not 
provide any relief, the research investigator will determine if/what standard of care therapies are 
necessary, to treat symptoms. If patient remains in stable condition, they can continue with 
prophylactic treatments (3xday), when/if possible.  Once symptoms are treated (standard of 
care) and patient is stable again, they can resume the acute treatments (up to 9x day) and 
continue with this process, until study completion (until they are placed on mechanical 
ventilation, are discharged, or can no longer continue with treatments, per patient or physician 
discretion/withdrawal from study). 
The devices are pre-programmed to not allow more than 30 stimulations in a 24 hour period.  
This is a safeguard with the device that cannot be changed.  Once the maximum daily number of 
treatments has been reached, the device will not deliver any more stimulations until the following 
24-hour period. (The stimulation automatically stops 120 seconds after the device is powered 
on). 
† Frozen blood sample - Cryopreserved leukocytes will be used in future studies, under peer-
reviewed funding support, to determine changes in leukocytes not measured during this trial 
(e.g. Tregs, Bregs, dendritic cells) as well as transcriptomes (RNA-Seq) and epigenotypes. 
7.2.1.2 
Days 1 – 3 
For days 1 through 3, the following assessments will be recorded each day:   
 
 
Study Measurements 
o Height/Wt, BMI 
o Temperature  
o Blood Pressure 
o O2 Saturation  
o PaO2/FiO2 ratio 
o Shortness of Breath (Yes / No) 
o Cough (Yes / No) 
 
Labs to be drawn early am (before 10 am) on odd days only 

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o Immunokine panel, specifically TNF-α, IL-1β, IL-6 
o Frozen blood sample 
o Leukocyte flow cytometry 
o Pro-Calcitonin 
o C-reactive protein 
o Ferritin 
o D-Dimer 
o CBC with differential 
o Comprehensive metabolic panel **Day 3 only**(then drawn on all odd days) 
 
VNS Stimulation supervised 
o Total number of gammaCore® treatments administered 
o Date and times of stimulations 
 
Daily Tx Log (Oxygen dependence & data, ventilator dependence & data, 
discharge data, survival) 
o Oxygen Required (Yes / No) 
o Oxygen level (%) based on device type (HFNC / NC / Bipap / Optiflow) 
o Ventilator Dependence (Yes / No) 
o Date and time of Ventilation 
o Patient discharge home (Yes / No) 
o Date and time (in 24 hour format) of Discharge 
o Survival (Yes / No) 
 
Clinical Improvement Scale 
 
Concomitant medication assessment 
 
Adverse event assessment 
     
7.2.1.3 
All Even Days Starting Day 4 
 For all days starting on day 4, lab work is not required, only the following assessments will be 
recorded each day: 
 
Study Measurements 
o Temperature 
o Blood Pressure 

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o O2 Saturation 
o Shortness of Breath (Yes / No) 
o Cough (Yes/No) 
 
nVNS stimulations 
o Total number of gammaCore® treatments administered 
o Date and times of stimulations 
 
Daily Tx Log 
o Oxygen Required (Yes / No) 
o Oxygen level (%) based on device type (HFNC / NC / Bipap / Optiflow) 
o Ventilator Dependence (Yes / No) 
o Date and time of Ventilation 
o Patient discharge home (Yes / No) 
o Date and time (in 24 hour format) of Discharge 
o Survival (Yes / No) 
 
Clinical Improvement Scale 
 
Concomitant medication assessment 
 
Adverse event assessment 
7.2.1.4 
All Odd Days Starting Day 5 
For all odd days starting on day 5, the following assessments will be recorded each day:  
 
 
Study Measurements 
 
Labs to be drawn early am (before 10 am) 
o Immunokine panel, specifically TNF-α, IL-1β, IL-6 
o Frozen blood sample 
o Leukocyte flow cytometry 
o Pro-Calcitonin 
o C-reactive protein 
o Ferritin 

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o D-Dimer 
o CBC with differential 
o Comprehensive metabolic panel 
 
nVNS stimulations 
o Total number of gammaCore® treatments administered 
o Date and times of stimulations 
 
Daily Tx Log 
o Oxygen Required (Yes / No) 
o Oxygen level (%) based on device type (HFNC / NC / Bipap / Optiflow) 
o Ventilator Dependence (Yes / No) 
o Date and time of Ventilation 
o Patient discharge home (Yes / No) 
o Date and time (in 24 hour format) of Discharge 
o Survival (Yes / No) 
 
Clinical Improvement Scale 
 
Concomitant medications 
 
Adverse event assessment 
7.2.1.5 
Day of Study Completion 
The last day of the study will be determined by discharge, transition to mechanical ventilation 
and/or if the patient is unable to continue.  The following will be recorded: 
 
Study Measurements 
o Height/Wt, BMI 
o Temperature  
o Blood Pressure 
o O2 Saturation  
o PaO2/FiO2 ratio 
o Shortness of Breath (Yes / No) 
o Cough (Yes / No) 
 
Labs  
o Pro-Calcitonin 
o C-reactive protein 

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o Ferritin 
o D Dimer 
o CBC with differential 
o Comprehensive metabolic panel 
 
nVNS stimulations 
o Total number of gammaCore® treatments administered 
o Date and time of stimulations 
 
Daily Tx Log 
o Oxygen Required (Yes / No) 
o Oxygen level (%) based on device type (HFNC / NC / Bipap / Optiflow) 
o Ventilator Dependence (Yes / No) 
o Date and time of Ventilation 
o Patient discharge home (Yes / No) 
o Date and time (in 24 hour format) of Discharge 
o Survival (Yes / No) with Date and Time of Death 
 
Clinical Improvement Scale 
 
Concomitant medication assessment 
 
Adverse event assessment 
 
 

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7.2.2 
Clinical Investigation Flow Chart 
Procedures and outcome measures will be collected as described in the clinical investigation 
flow chart shown in Table 1. 
Table 1 
Clinical Investigation Flow Chart 
 
Study Visit (D=Day) 
Protocol 
requirements 
Admission/ 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Study 
Terminatione 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion criteria 
X 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Complete 
physical exam 
X 
 
 
 
 
 
 
 
 
Enter Device # 
X 
 
 
 
 
 
 
 
 
Intakea 
X 
 
 
 
 
 
 
 
 
Study 
Measurementsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pro-Calcitonin, C-
reactive protein, 
ferritin, D-dimer, 
CBC w/dif 
X 
(+ serum/urine 
hCG for women 
who may be 
pregnant) 
X 
 
X 
 
X 
 
X 
X 
Comprehensive 
metabolic panel 
X 
 
 
X 
 
X 
 
X 
X 
Study labs drawn 
before 10am 
(Frozen blood 
sample, 
Immunokine panel 
(Luminex) 
including (TNF-α, 
IL-1β, IL-6),  
Leukocyte flow 
cytometry 
X 
X 
 
X 
 
X 
 
X 
 
 

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Study Visit (D=Day) 
Protocol 
requirements 
Admission/ 
D0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Study 
Terminatione 
Device trainingc 
X 
 
 
 
 
 
 
 
 
nVNS 
Stimulation 
Supervisedc 
X 
X 
 
 
 
 
 
 
 
VNS Stimulationc 
 
3X 
+prn 
3X 
+prn 
3X 
+prn 
3X 
+prn 
3X 
+prn 
3X 
+prn 
3X 
+prn 
X 
Clinical 
Improvement 
Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily Tx Log 
completedd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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a Includes collection of basic demographics (DOB, Race, Sex, Smoking Status,   
     County/Region), medications, comorbidities CoViD-19 test results) 
b Includes height/weight (BMI), temperature, blood pressure, O2 saturation, PaO2/FiO2 ratio,  
     shortness of breath assessment, cough assessment  
c For the active study arm. Includes record of treatment (time and number of doses 
      administered) 
d The following parameters will be recorded daily: Oxygen dependence & data, ventilator  
    dependence & data, discharge data, survival, device treatment record (active study arm  
    only) 
e Study completion will be determined by discharge, transition to mechanical ventilation  
  and/or if the patient is unable to continue 
 
7.3 
Discussion and Justification of Clinical Investigation Design, Including the 
Choice of Control Groups 
The study design (randomized, including a control group) was chosen to evaluate the usefulness 
of the gammaCore® Sapphire device for symptom improvement in patients suffering CoViD-19 
related respiratory distress compared to standardized institution treatment only.  
 
During hospitalization, the study patients, if able, will administer gammaCore® as prescribed for 
all acute respiratory attacks or shortness of breath, and also prophylactically. If patients are 
unable, study personnel may assist. 
  
7.3.1 
Prior and Concomitant Medication and Procedures 
Medication, which is considered necessary for the patient’s safety and well-being, may be given 
at the discretion of the Investigator.  
 
The study team will document all concomitant medication usage during the investigation in the 
CRF.  
7.4 
Selection of Population for the Clinical Investigation 
7.4.1 
Number of Patients 
After the first 20 patients have been enrolled and completed the study at Allegheny General 
Hospital, the investigator will conduct an interim analysis and submit findings to the IRB for 
approval to increase the enrollment up to 60 patients (30 patients per arm).  Up to 90 patients 
are expected to be screened. 
 

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7.4.2 
Inclusion Criteria 
The patients have to meet all of the following criteria to be eligible to enter the investigation: 
 
1. Patients (age 18 years and older) who have tested positive or suspected/presumed 
positive for CoViD-19 using PCR real-time test 
2. Patients with cough, shortness of breath or respiratory compromise (RR>24/min, 
increased work of breathing) 
3. O2 Saturation less than or equal to 96% on room air or sensation 
4. Agrees to use the gammaCore Sapphire device as per protocol and to follow all of 
the requirements of the study including recording required study data 
5. Permission for early am blood draw to freeze for subsequent lab tests and 
sequencing as related to CoViD-19 sequelae 
6. Patient is able to provide signed and witnessed Informed Consent 
 
7.4.3 
Exclusion Criteria  
 
Patients meeting any of the following criteria cannot be included in this research study:  
 
1. On home/therapy oxygen (i.e. for COPD patients) at baseline prior to development of 
CoViD-19  
2. Already using gammaCore® for other medical conditions 
3. A history of aneurysm, intracranial hemorrhage, brain tumors, or significant head trauma  
4. Known or suspected severe atherosclerotic cardiovascular disease, severe carotid 
artery disease (e.g., bruits or history of transient ischemic attack or cerebrovascular 
accident), congestive heart failure, known severe coronary artery disease, myocardial 
infarction documented within past 90 days, or current or recent history of life-threatening 
arrhythmia (sustained ventricular tachycardia, ventricular fibrillation, second or third-
degree heart block, uncontrolled atrial fibrillation or uncontrolled atrial flutter) 
5. Patients with clinically significant hypertension, hypotension, bradycardia, or tachycardia 
(as per investigator discretion) 

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6. Current implantation of an electrical and/or neurostimulator device, including but not 
limited to a cardiac pacemaker or defibrillator, vagal neurostimulator, deep brain 
stimulator, spinal stimulator, bone growth stimulator, or cochlear implant  
7. Current implantation of metal cervical spine hardware or a metallic implant near the 
gammaCore® stimulation site  
8. Belongs to a vulnerable population or has any condition such that his or her ability to 
provide informed consent, comply with the follow-up requirements, or provide self-
assessments is compromised (e.g. homeless, developmentally disabled and prisoners) 
9. Compromised access to peripheral vein for blood 
10. Pregnant women 
11. Patients with active cancer or those who have had recent cancer treatment 
 
Before enrollment into the study, patients must meet all of the following inclusion criteria and 
none of the following exclusion criteria. 
 
7.4.4 
Removal of Patients from the Clinical Investigation 
Patients are free to discontinue participation in the investigation at any time, without prejudice to 
further treatment. Patients who discontinue the investigation should always be asked about the 
reason(s) for their discontinuation and about the presence of any adverse event (AE)/adverse 
device effect (ADE) and, if possible, be assessed by a Clinical Investigator. 
 
Patients may be withdrawn from investigation treatment and assessments at any time, if deemed 
necessary by the Clinical Investigator.  
 
Specific reasons for withdrawal of patients from this investigation are:  
 
The decision of a patient to withdraw from the investigation (including if the patient 
withdraws informed consent) 
 
Unacceptable adverse event 
 
Patient lost to follow-up; or 
 
Patient is non-compliant with study procedure 
In case of withdrawal, AEs/ADEs should be followed up.  
 
Incorrectly enrolled patients will be withdrawn from further investigation and assessments. A 
protocol deviation will be submitted to the IRB via a prompt report form. 

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7.5 
Identification and Description of the Clinical Investigational Medical Device 
7.5.1 
Identification of the Clinical Investigational Medical Device 
 
gammaCore Sapphire (non-invasive vagus nerve stimulator) is a multi-use, handheld, 
rechargeable, portable device consisting of a rechargeable battery, signal-generating and 
amplifying electronics, and a control button for the patient to control the signal amplitude. The 
device provides visible (display) and audible (beep) feedback on the device and stimulation 
status. A pair of stainless-steel surfaces, which are the skin contact surfaces (“stimulation 
surfaces”), allows the delivery of a proprietary electrical signal. The patient will apply 
electroCore-approved gel to the stimulation surfaces to maintain an uninterrupted conductive 
path from the stimulation surfaces to the skin on the neck. Tubes of electroCore-approved gel 
will be provided with each unit. The stimulation surfaces will be capped when not in use.  
gammaCore® produces a low-voltage electric signal consisting of five 5000-Hz pulses that are 
repeated at a rate of 25 Hz. The waveform of the electric pulses is approximately a sine wave 
with a peak voltage limited to 24 Volts when placed on the skin and a maximum output current of 
60mA. 
The signal is transmitted through the skin of the neck to the vagus nerve. gammaCore® allows 
for the patient to appropriately position and adjust the stimulation intensity level as instructed by 
the research team. Each stimulation is designed to be applied for 2 minutes, after which the 
device automatically stops delivering the stimulation. Each device allows for multiple treatments.  
gammaCore® can deliver up to thirty 120–second stimulations within a 24-hour period. Once the 
maximum daily number of treatments has been reached, the device will not deliver any more 
stimulations until the following 24-hour period. (The stimulation automatically stops 120 seconds 
after the device is powered on).  The gammaCore® Sapphire device includes a charging station 
to hold and charge the device. 
 

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    Figure 1. gammaCore® Sapphire  
 
            Figure 2.  gammaCore® Sapphire with Charging Station 
 
The patient will apply conductive gel (supplied with the device) to the stimulation surfaces and 
then hold the nVNS device on the skin over the vagus nerve on the neck (between the trachea 
and the sternocleidomastoid muscle, over the carotid pulse). Details of device placement and 
operation will be provided in the Instructions for Use (IFU). 
The gammaCore Sapphire device produces a proprietary, low voltage electric signal that 
generates an electric field in the vicinity of the vagus nerve when the device is placed in the 
intended location.  
 
7.5.2 
Packaging and Labelling of the Clinical Investigational Medical Device 
The commercial packages will be used in this Clinical Investigation, all device packaging will be 
marked “For Clinical Investigation Only”. 
 
7.5.3 
Installation and Use of the Clinical Investigational Medical Device 
A qualified research personnel (i.e. device trained) will train the study patients before they can 
start self-administration of stimulations.  The gammaCore® Sapphire device will be used 
following the treatment assigned in this protocol.     
7.5.4 
Compliance with Device Usage 
Patient will record all use of the device in a study log, trained study staff can assist the patient, 
as necessary. Compliance will be assessed in the hospital setting by the research staff. 

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7.6 
Risk and Benefits of the Investigational Device and Clinical Investigation 
The gammaCore Sapphire is being trialled for the acute and prophylactic treatment of CoViD-19 
induced respiratory distress. The anticipated benefits include:  
  
 
No mechanical respirator required 
 
Significant reduction of number of days in hospital 
 
There are no significant risks identified with the participation in this study however study patients 
can rarely experience transient symptoms such as: 
 
 
Muscle twitching, discomfort, or pain during stimulations  
 
Tingling, pricking or a feeling of “pins and needles” on the skin where the device is 
applied (paraesthesia or dysaesthesia) lasting beyond the treatment period  
 
Skin irritation/inflammation 
 
Dizziness 
Study subjects will be exposed to potential risks and complications associated with gammaCore. 
These are anticipated to resolve shortly after discontinuation of the stimulation procedure 
without medical intervention or clinical sequelae.  Occurrence of several of these events can be 
mitigated by the user repositioning the device on the neck and/or decreasing the stimulation 
intensity.  Training on the positioning of the device and controlling the stimulation intensity is 
conducted at the time the device is provided to the subjects.  In addition, the device is provided 
with detailed Instruction for Use.  These potential anticipated adverse events include, but are not 
limited to: 
 
Application site discomfort (4.85%) 
 
Application site irritation/redness (3.74%) 
 
Local pain, face/head/neck area (including toothache) (3.00%) 
 
Muscle twitching and/or contractions, face/head/neck area (including facial droop and/or 
lip pull) (3.47%)  
 
Headache/migraine (2.56%) 
 
Dizziness (2.00%) 
 
Tingling, pricking or a feeling of “pins and needles” on the skin where the device is 
applied (paresthesia/dysesthesia) (1.63%) 

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NOTE: When all available safety data was pooled from all studies, the following AEs occurred in 
>1% of patients, but less than < 5% (there were no reported side effects that occurred in >5% of 
study patients) All adverse events occurred in at least 1 in 100 (1%) patients and are therefore 
“common”. 
 
Risks associated with blood draws 
• Pain or discomfort from needle 
• Bleeding 
• Infection 
 
Pregnancy: 
It is unknown whether gammaCore can harm an unborn child if used during pregnancy.  If you 
are pregnant, you will not be allowed to participate in this study. 
 
The product will be used at the hospital. 
 
Each device is for single patient use. No device sharing will be done. Every patient will have an 
individual device throughout the study. It will be stored in patient room throughout the duration of 
the study and at completion will be discarded by study staff, according to institutional policy and 
following all regulations for disposal of infectious waste and electrical equipment. 
 
All patients must undergo training at the hospital before starting treatment with the device in 
order to learn and optimize where and how to stimulate. Written information will also be 
provided.   
 
All research staff included in study will be trained in the use of device. Patients will administer 
their own treatment unless unable to do so safely. Treatment can be administered by trained 
research staff, if necessary and with patient permission.   
 
Site will be instructed to contact electroCore immediately if the product malfunctions and does 
not work as expected or if the device have been damaged or is suspected to have been 
damaged in some way. If patients are using it without clinical supervision, patients will report any 
product malfunctions to the PI and/or research staff.  Should any type of malfunction occur, the 
patient would discontinue use of the device and the research staff will assess for any adverse 
events.  Any device deficiencies/malfunctions will be reported to the PI, the IRB via a prompt 
report form and the device manufacturer.  The device will be quarantined by the research staff 
and a new device will be provided to the patient. 
 
The benefits of this study are estimated to outweigh the risks as the patient’s improvement is 
expected to be considerably greater than any expected side effects..    

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7.7 
Performance and Safety Endpoints, Variables and Measurements 
7.7.1 
Patient Characteristics 
Date of Birth (DOB), Race, Sex, Smoking Status, County/Region 
7.7.2 
Objectives 
The aims of this study are to summarize and compare the incidence of clinical events and pro-
inflammatory cytokine levels in patients randomized to use of gammaCore Sapphire plus 
standard of care vs standard of care alone in patients hospitalized for CoViD-19. In addition, this 
study is intended to demonstrate the safety of gammaCore Sapphire use in patients hospitalized 
for CoViD-19. 
Specific clinical events to be summarized include, but are not limited to: 
 
 
Changes in oxygen support requirements (no oxygen support, low-flow oxygen support, 
nasal high-flow oxygen support, noninvasive mechanical ventilation, and invasive 
mechanical ventilation) 
 
Changes in O2 saturation 
 
PaO2/FiO2 ratio 
 
Proportion of subjects requiring mechanical ventilation 
 
Days to onset of mechanical ventilation 
 
Live discharge from the hospital  
 
Patient length of stay 
 
Mortality 
 
Shortness of Breath 
 
Clinical improvement Scale 
Specific laboratory measurements to be summarized include, but are not limited to: 
 
TNF-α 
 
IL-1β 
 
IL-6 
 
CRP 
 
Ferritin 
 
D Dimer 
 
Pro-Calcitonin 
 
 
 
7.7.3 
Safety Variables and Measurements 
The primary safety measure for this study is the incidence and occurrence of SAEs related to the 
study treatments.  

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7.7.4 
Other Variables and Measurements 
Comorbidities known to influence course of CoViD-19 including asthma or other underlying 
pulmonary disorders, diabetes and cardiac disease will be recorded. 
 
7.7.5 
Appropriateness of Measurements 
The evaluative measurements include changes in oxygen support, O2 saturation and shortness 
of breath, the need and onset of mechanical ventilation, clinical improvement assesement  and 
mortality.  We will also correlate these with cytokine suppression. It is possible that those who 
have a drop, or do not have an increase in cytokine activation will have a higher survival and 
lower need for oxygen requirments and/or mechanical ventilation. These will permit evaluation of 
the objectives for the study. 
The safety measurements are typical for a clinical trial and permit evaluation of the safety of the 
device. 
7.8 
Adverse Events/Adverse Device Effects and Device Deficiencies  
The definitions and procedures for reporting adverse events (AE), adverse device effects (ADE), 
serious adverse events (SAE), serious adverse device effects (SADE) and are presented in the 
sections below. It is of utmost importance that all staff involved in the investigation are familiar 
with the definitions and procedures and it is the responsibility of the Clinical Investigator to 
ensure this.  
7.8.1 
Adverse Event/Adverse Device Effect Definitions 
Adverse Event 
Any untoward or unfavorable medical occurrence in a human subject, including any abnormal 
sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research 
Adverse Device Effect 
Adverse event related to the use of an investigational medical device.  
Note 1: This definition includes any event resulting from insufficiencies or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
the investigational medical device. 
Note 2: This definition includes any event that is a resulting from a user error or from intentional 
misuse of the investigational medical device. 

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7.8.2 
Serious Adverse Event/Serious Adverse Device Effect/Unanticipated 
Adverse Device Effect Definitions 
Serious Adverse Event 
An adverse event is considered serious and should be reported to IRB when the patient 
outcome is: 
 
Death 
 
Life-threatening -  the patient was at substantial risk of dying at the time of the adverse 
event, or use or continued use of the device or other medical product might have resulted 
in the death of the patient. 
 
Hospitalization (initial or prolonged) - admission to the hospital or prolongation of 
hospitalization was a result of the adverse event.  Emergency room visits that do not 
result in admission to the hospital should be evaluated for one of the other serious 
outcomes (e.g., life-threatening; required intervention to prevent permanent impairment 
or damage; other serious medically important event). 
 
Disability or Permanent Damage - if the adverse event resulted in a substantial 
disruption of a person's ability to conduct normal life functions, i.e., the adverse event 
resulted in a significant, persistent or permanent change, impairment, damage or 
disruption in the patient's body function/structure, physical activities and/or quality of life. 
 
Congenital Anomaly/Birth Defect -  suspected exposure to a medical product prior to 
conception or during pregnancy may have resulted in an adverse outcome in the child. 
 
Required Intervention to Prevent Permanent Impairment or Damage (Devices) -  
medical or surgical intervention was necessary to preclude permanent impairment of a 
body function, or prevent permanent damage to a body structure, either situation 
suspected to be due to the use of a medical product. 
 
Other Serious (Important Medical Events) -  the event does not fit the other outcomes, 
but the event may jeopardize the patient and may require medical or surgical intervention 
(treatment) to prevent one of the other outcomes. Examples include allergic 
brochospasm (a serious problem with breathing) requiring treatment in an emergency 
room, serious blood dyscrasias (blood disorders) or seizures/convulsions that do not 
result in hospitalization. The development of drug dependence or drug abuse would also 
be examples of important medical events. 
Serious Adverse Device Effect 
A SADE is an ADE that results in any of the consequences characteristic of an SAE or that 
might lead to any of these consequences if suitable action is not taken, if intervention is not 
made or if circumstances are less opportune.  

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7.8.3 
Unanticipated serious adverse device effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
Note: Anticipated serious adverse device effect (ASADE) is an effect which by nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
 
7.8.4 
Reporting of Adverse Events/Adverse Device Effects 
7.8.4.1 
Methods for Eliciting Adverse Events/Adverse Device Effects 
All patients will be carefully monitored for the occurrence of AEs during the investigation period 
from the run-in to the completion of follow up.  The Clinical Investigator will collect AE 
information using non-leading questions such as “have you experienced any new health 
problems or worsening of existing conditions”. Events directly observed or spontaneously 
volunteered by patients will also be recorded. 
 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. 
 
All AEs including but not limited to events reported by the patient or reported in response to an 
open question by the Clinical Investigator or member of this team, which fall into any of the 
above definitions must be recorded as an AE in the CRF and should include the following 
information. 
 
Brief description of the event (diagnosis) 
 
Start date (and time, if relevant) 
 
Stop date (and time, if relevant) (or resolution) 
 
Severity 
 
Action taken regarding the medical device 
 
Opinion on causality 
 
Seriousness 
 
Outcome 
Severity 
Severity describes the intensity of an event and will be assessed as: 
 
Mild 
The AE does not interfere in a significant manner with the patient’s normal functioning level. It 
may be an annoyance. 

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Moderate 
The AE produces some impairment of function but not hazardous to health. It is uncomfortable 
and/or an embarrassment. 
 
Severe 
The AE produces significant impairment of functioning or incapacitation and/or it is a hazard to 
the patient. 
 
If an AE changes in severity, it should be reported as an AE of new severity but with the same 
description. 
Causality (Adverse Device Effects/ADE) 
Causality will be assessed as: 
 
 
Related (definitely, possible or probable) - A causal relationship between the clinical 
investigational medical device and the AE is at least a reasonable possibility, i.e. there is 
evidence or argument suggesting a causal relationship.  
 
Not related - There is no indication that the AE was caused by the clinical investigational 
medical device. 
 
7.8.4.2 
Follow-up of Patients with Adverse Events 
Any AE that is ongoing when the patient is withdrawn from the investigation should be followed-
up until the AE is resolved or the Clinical Investigator decides that the AE is stable and needs no 
further follow-up. The date when the Clinical Investigator considers one of these outcomes to 
have occurred for the last ongoing AE for a patient will be considered the last visit for this 
patient, and the outcome should be recorded in the CRF. 

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7.8.5 
Reporting of Events 
 
 
7.8.6 
Device deficiencies 
All device deficiencies related to the identity, quality, durability, reliability, safety or performance 
of an investigational medical device shall be documented on a separate DD form and provided 
to IRB via prompt report and electroCore within 24 hours of the event. 

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7.9 
Data Quality Assurance 
7.9.1 
Monitoring, Audits and Inspections 
During the investigation, the PI will be responsible for the monitoring of the clinical trial to ensure 
the research team is following all aspects of the CIP.  All data must be accurately recorded in the 
CRF. Source data verification (a comparison of data in the CRF with the patient’s medical 
records and other records at the investigation site) with access to records may also be 
performed by the institution’s Quality Coordinator.  
 
Authorized representatives of Regulatory agencies may visit the site to perform audits or 
inspections, including source data verification. 
7.9.2 
Patient Records and Source Data 
Data may be recorded directly in the CRF, which will then be considered as source data.  
It is the responsibility of the Clinical Investigator to record essential information in the medical 
records in accordance with national regulations and requirements, including: 
 
Investigation code 
 
Patient screening number and/or patient number 
 
That informed consent for participating in the study was obtained 
 
Diagnosis 
 
All data entry days during the investigation period 
 
All AEs/ADEs 
 
Treatments  
 
The SN number of the device 
The Clinical Investigator is responsible for ensuring the accuracy, completeness, legibility and 
timeliness of the data recorded in the CRFs. Signed CRFs will be collected and monitored on a 
regular basis. 
7.9.3 
Access to Source Data and Documentation 
The Clinical Investigator should guarantee access to source documents for the Quality 
Coordinator and auditors as well as for inspection by appropriate regulatory agencies, and the 
IRB/IEC, if required. 
7.9.4 
Training of Staff 
The Clinical Investigator will ensure that appropriate training relevant to the investigation is given 
to the medical, nursing and other staff involved and that new information of relevance to the 
performance of this investigation is forwarded to the staff involved. 

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7.9.5 
Data and Quality Management 
 
The data collection tool for this trial will be using CRFs.  Patient data necessary for analysis and 
reporting will be entered into a validated database or data system.  Data management and 
handling will be conducted according to the investigation specific Data Management Plan, 
developed, managed and controlled by Institution. 
 
Any deviations, i.e. discrepancies and additions from the process defined in the Data 
Management Plan, will be described in an investigation specific Data Management report. 
 
7.9.6 
Data Safety Monitoring Board 
 
An independent Data Safety Monitoring Board (DSMB) will meet quarterly with the investigators 
and study coordinator to review study data and any major adverse events. The board will 
conduct interim monitoring of AEs/SAEs, oversight and analysis of study information and data to 
ensure the continuing safety of research participants, efficacy of the study intervention, 
appropriateness of the study, continued relevance of the study question, and integrity of the 
accumulating data throughout the life of the clinical trial. The board will be comprised of three 
physicians specializing in pulmonology. A summary of the DSMB findings will be submitted to 
the IRB with the annual renewal.  
 
7.10 
Statistical Methods and Determination of Sample Size 
7.10.1 
Statistical Evaluation of Performance and Safety Variables 
This section provides a summary of the statistical methodology that will be used by the 
Institution. A more detailed description of analysis methods will be provided in a separate 
statistical analysis plan (SAP). 
7.10.1.1 
Data Sets to be Analysed 
The intention to treat (ITT) population includes all randomized subjects with at least 1 verified 
treatment post-training during study period. The ITT population will be analyzed using the 
subject’s randomized treatment regardless of which treatment the subject actually received.  
Subjects with major protocol deviations will be excluded from the per-protocol (PP) analysis set. 
Subjects not taking the study treatment in the prescribed manner more than 33% of the time will 
be excluded from the PP analysis set. Additional subjects with exclusionary protocol deviations 
will be identified prior to database finalization and unblinding. Analyses for the PP will be 
conducted according to the randomized treatment.  
All subjects entering the study will be included in the safety population. Analyses for safety 
population will be conducted according to the treatment actually received. 

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Definitions 
Generally, a baseline measurement refers to the last non-missing assessment made before the 
first administration of study treatment (at e.g. screening and baseline). 
7.10.1.2 
Summary Statistics 
Data will be presented using summary statistics. For example, categorical data may be 
presented as proportions and counts; continuous data may be presented with the mean, 
median, minimum, maximum, and/or standard deviations. Kaplan-Meier methodology may be 
used to present time to event data. All comparisons between active and control groups are 
nominal in nature; confidence intervals and p-values may be presented, but are not intended for 
inferential purposes. 
  
7.10.1.3 
Analysis of Objectives 
Full details will be described in the Statistical Analysis Plan (SAP).   
 
7.10.1.4 
Demographic and Other Baseline Characteristics 
Full details will be described in the Statistical Analysis Plan (SAP). 
7.10.1.5 
Extent of Device Usage 
Exposure to treatment/device will be presented by using summary statistics for number of days 
with study treatment by each device group. 
7.10.1.6 
Adverse Events/Adverse Device Effects 
Device-related serious adverse events will be tabulated. The overall incidence of device-related 
serious adverse events will be summarized and presented as a proportion and respective 95% 
exact binomial confidence interval. Additionally, an overview of events, to include total numbers 
of events, and total number of subjects with events will be tabulated and presented for all AEs, 
serious AEs, and device-related AEs and device-related serious AEs, as well as deaths. Events 
will be presented overall and by study arm.  
 
7.10.2 
Handling of Drop-outs and Missing Data 
Outliers will be included in summary tables and listings, and will not be handled separately. 
Available data from prematurely withdrawn patients will be included in the analysis as far as 
possible. If data are only partially completed, the available data will be reported as an per 
protocol evaluation 

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7.10.3 
Determination of Sample Size 
This is one of the first studies of GammaCore Vagus Nerve Stimulation treatment in COVID-19. 
There is no published data on anticipated effect size in humans. Hence, a formal power analysis 
could not be done.  
 
Data will be presented using summary statistics. For example, categorical data may be 
presented as proportions and counts; continuous data may be presented with the mean, 
median, minimum, maximum, and/or standard deviations. Kaplan-Meier methodology may be 
used to present time to event data. All comparisons between active and control groups are 
nominal in nature; confidence intervals and p-values may be presented, but are not intended for 
inferential purposes. 
7.10.4 
Interim Analysis  
An analysis of safety and feasibility was conducted on the first 20 patients who completed the 
hospitalization period. Only minor protocol deviations were noted with one SAE unrelated to 
device use. Neither incidence was a reportable event to the IRB. 
7.10.5 
Procedures for Reporting any Deviations from the Original Statistical 
Analysis Plan 
Any deviation(s) from the original statistical analysis plan will be described and justified in a CIP 
Amendment and/or in a revised statistical analysis plan and/or in the final report, as appropriate.  
7.11 
Amendments to the Clinical Investigation Plan 
Any change to the approved CIP must be documented in a written and numbered CIP 
amendment with a justification for the amendment. Changes to the CIP will only be implemented 
after written agreement has been obtained between the Principal/Coordinating Clinical 
Investigator and the IRB.  electroCore will also be notified of any amendments or changes to the 
IRB approved CIP. 
 
An amendment to the CIP may require notification or approval from IRB/IEC and, in many 
countries, the Competent Authority before implementation. Local requirements shall be followed. 
7.12 
Deviations from the Clinical Investigation Plan 
Every effort should be made to comply with the requirements of the protocol.  If the changes or 
deviations may affect the rights, safety, or welfare of participants, IRB/IEC approval is required. 
Deviations will be recorded with an explanation for the change. Corrective action will be 
implemented to avoid repeat deviations.   
The reasons for any patient’s withdrawal and discontinuation from the investigation will be 
recorded. If such discontinuation is because of problems of safety or lack of effectiveness, the 
patient will still be followed up in the investigation, if possible. 

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7.13 
Report and Publication 
The CIP shall specify whether the results of the investigation will be submitted for publication or 
the extent to which and conditions under which the results of the clinical investigation will be 
offered for publication. 
At the completion of the study, the Clinical Investigator may collaborate with the device 
manufacturer, electroCore, to review and use the data collected for publication purposes.  
If/when the Clinical Investigator chooses to publish results of the study, the PI wil provide 
electroCore with the final clinical study report summarizing the study and the results prior to 
publication.  
All publications and presentations must be based upon the clinical investigation report. 
 

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8 
ETHICS 
8.1 
Institutional Ethics Review 
The final CIP, including the final version of the Patient Information and Consent Form, must be 
approved in writing by an IRB/IEC before enrollment of any patient into the investigation. The 
Clinical Investigator is responsible for informing the IRB/IEC of any amendment to the CIP, as 
per local requirements. 
8.2 
Ethical Conduct of the Clinical Investigation 
The investigation will be conducted in compliance with applicable regulatory requirements and 
with the ethical principles of the latest revision of the Declaration of Helsinki as adopted by the 
World Medical Association (Appendix A).   
8.3 
Patient Information and Consent 
All patients will receive written and verbal information regarding the investigation prior to any 
investigation-related procedures. This information will emphasise that participation in the 
investigation is voluntary and that the patient may withdraw from the investigation at any time 
and for any reason. All patients will be given the opportunity to ask questions about the 
investigation and will be given sufficient time to decide whether to participate in the investigation. 
 
Before any investigation-related procedures, the informed consent will be signed and dated by 
the patient , a witness to signature,  and by the Clinical Investigator who gave the patient the 
verbal and written information. 
 
The consent specifies that data will be recorded, collected, processed and used in accordance 
with patient consent and applicable law. 

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9 
PATIENT PROTECTION PROCEDURES 
9.1 
Procedures in Case of Medical Emergency 
The Clinical Investigator is responsible for ensuring that procedures and expertise are available 
to cope with medical emergencies during the investigation. 
9.2 
Patient Data Protection 
Minimal necessary data will be collected and stored on a hospital password protected research 
drive only accessible to the research staff. Risk of breach of confidentiality of this data has been 
minimized as much as possible. We have used the “minimum necessary” standard in choosing 
specific and pertinenet data paramenters for this research.  
 
All key research team members having access to clinical data (containing PHI) being collected 
and analysed currently work within our system. Data containing PHI will be stored on secure, 
password-protected computers by the team and when necessary, will be securely emailed to 
other team memebers using only AHN.org email acconts (as per AHN IT Security Policy). Team 
members will use secure computers and systems to access and work with study spreadsheet 
data/files. When any information is shared with the sponsor, this will be de-identified. PHI will not 
be shared with the sponsor.  
 
At the conclusion of data analysis for the protocol, identifiers will be stripped from the compiled 
datasheet to anonymize the dataset by the PI, or other team member with the goal that the data 
will be presented formally. Patient identifiers will be deleted and the dataset anonymized as 
soon as possible. We will comply with the AHNRI IRB “Records Retention” SOP #72 Section 
4.6.1 which states “…for research involving PHI performed at AHN, the records will be retained 
for 10 years after the study is completed.”  
 
 

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10 
REFERENCES 
In order to determine the scientific background for this clinical investigation as well as to assess 
risks/benefits of the device, a literature review was conducted and a Clinical evaluation has been 
performed according to MDD.  
 
The literature listed below was critically evaluated before serving as background information 
 
1 Staats, P., et al. (2018). In E.Krames, et. al (Eds.) Neuromodulation : Comprehensive Textbook of 
Principles, Technologies, and Therapies Vol 1: Neurostiumulation for Asthma (2nd Edition, pp. 1339-1345). 
London, United Kingdom: Academic Press, Elsevier. 
 
2 Miner, J., et al. “Feasibility of Percutaneous Vagus Nerve Stimulation for the Treatment of Acute Asthma 
Exacerbations.” Acad Emerg Med 19.4 (2012): 421-429.  
 
3 Hoffmann, T., et al. “Inhibition of Histamine-Induced Bronchoconstriction in Guinea Pig and Swine by 
Pulsed Electrical Vagus Nerve Stiumulation.” Neuromodulation 12.4 (2009): 261-269. 
 
4 Pavlov V., et al. "Bioelectronic medicine: from preclinical studies on the inflammatory reflex to new 
approaches in disease diagnosis and treatment." Cold Spring Harbor Perspectives in Medicine 10.3 
(2020): a034140. 
 
5 Koopman F., et al. "Vagus nerve stimulation inhibits cytokine production and attenuates disease severity 
in rheumatoid arthritis." Proceedings of the National Academy of Sciences 113.29 (2016): 8284-8289. 
 
6 Brock C., et al. "Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and 
tumor necrosis factor‐alpha." Neurogastroenterology & Motility 29.5 (2017): e12999. 
 
7 Tarn J., et al. "The effects of noninvasive vagus nerve stimulation on fatigue and immune responses in 
patients with primary sjögren's syndrome." Neuromodulation 22.5 (2019): 580-585. 
 
8 Lerman I., et al. "Noninvasive transcutaneous vagus nerve stimulation decreases whole blood culture‐
derived cytokines and chemokines: a randomized, blinded, healthy control pilot trial." Neuromodulation 
19.3 (2016): 283-290. 
 
9 Huston J., et al. "Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 
levels and improves survival in murine sepsis." Crit Care Med 35.12 (2007): 2762-2768. 
 
10 Haveri A, et al. Serological and molecular findings during SARS-CoV-2 infection: the first case study in 
Finland, January to February 2020.” Euro Surveill 25.11 (2020). doi: 10.2807/1560-
7917.ES.2020.25.11.2000266.  
 
11 Conti P, et al. “Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by  
Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies.” J Biol Regul Homeost Agents 
34.2 (2020). doi: 10.23812/CONTI-E. [Epub ahead of print] 
 
12 Liu L, et al. “Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during 
acute SARS-CoV infection.” JCI Insight 4.4 (2019). doi: 10.1172/jci.insight.123158.    
 
13 Chen IY, et al. “Severe Acute Respiratory Syndrome Coronavirus Viroporin 3a Activates the NLRP3 
Inflammasome.” Front Microbiol 10.50 (2019). doi: 10.3389/fmicb.2019.00050.  

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14 Gralinski LE, et al. “Complement Activation Contributes to Severe Acute Respiratory Syndrome 
Coronavirus Pathogenesis.” mBio 9.5 (2018): e01753-18. doi: 10.1128/mBio.01753-18.     
 
15 McDermott JE, et al. “The effect of inhibition of PP1 and TNFα signaling on pathogenesis of  SARS 
coronavirus.” BMC Syst Biol 10.1 (2016): 93.    
 
16 Newton AH, et al. “The host immune response in respiratory virus infection: balancing virus clearance 
and immunopathology.” Semin Immunopathol 38.4 (2016): 471-482.    
 
17 Gralinski LE, et al. “Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross.” PLoS 
Genet 11.10 (2015).  doi: 10.1371/journal.pgen.1005504  
 
18 Selinger C, et al. “Cytokine systems approach demonstrates differences in innate and pro-inflammatory 
host responses between genetically distinct MERS-CoV isolates.” BMC Genomics 15 (2014): 1161.     
 
19 Burrack KS, et al. “The role of myeloid cell activation and arginine metabolism in the pathogenesis of 
virus-induced diseases.” Front Immunol 5 (2014): 428.    
 
20 van den Brand JM, et al. “The pathology and pathogenesis of experimental severe acute respiratory 
syndrome and  influenza in animal models.” J Comp Pathol 151.1 (2014): 83-112.    
 
21 DeDiego ML, et al. “Inhibition of NF-κB-mediated inflammation in severe acute respiratory syndrome 
coronavirus-infected mice increases survival.” J Virol 88.2 (2014): 913-924.     
 
22 Smits SL, et al. “Exacerbated innate host response to SARS-CoV in aged non-human primates.” PLoS 
Pathog 6.2 (2010): e1000756. doi: 10.1371/journal.ppat.1000756.     
 
23 Kong SL, et al. “Elucidating the molecular physiopathology of acute respiratory distress syndrome in 
severe acute respiratory syndrome patients.” Virus Res 145.2 (2009): 260-269.    
 
24 Wan J, et al. “Inflammation inhibitors were remarkably up-regulated in plasma of severe acute 
respiratory syndrome patients at progressive phase.” Proteomics 6.9 (2006): 2886-2894.    
 
25 Okabayashi T, et al. “Cytokine regulation in SARS coronavirus infection compared to other respiratory 
virus infections.” J Med Virol 78.4 (2006): 417-424.    
 
26 Yu SY, et al. “Gene expression profiles in  peripheral blood mononuclear cells of SARS patients.” World 
J Gastroenterol 11.32 (2005): 5037-5043.    
 
27 Yang YH, et al. “Autoantibodies against human epithelial cells and endothelial cells after severe  acute 
respiratory syndrome (SARS)-associated coronavirus infection.” J Med Virol 77.1 (2005): 1-7.    
 
28 Wang CH, et al. “Persistence of lung inflammation and lung cytokines with high-resolution  CT 
abnormalities during recovery from SARS.” Respir Res 6 (2005) 42.  
 
29 Steyn E, et al. "Non-invasive vagus nerve stimulation for the treatment of acute asthma exacerbations—
results from an initial case series." Int J Emerg Med 6.1 (2013): 7. 
 
30 Tisoncik J, et al. “Into the eye of the cytokine storm.” Microbiol Mol Biol Rev 76.1 (2012): 16-32. 
 
31 Ruan Q, et al. “Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 
patients from Wuhan, China.” Intensive Care Med (2020). doi:10.1007/s00134-020-05991-x. [Epub ahead 
of print] 

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32 Press Release (March 8, 2020). CytoDyn Files IND and Protocol for Phase 2 Clinical Trial for Treatment 
of Patients with Coronavirus with Leronlimab (PRO 140). Retrieved from cytodyn.com/newsroom/press-
releases/detail/391/cytodyn-files-ind-and-protocol-for-phase-2-clinical-trial. 
 
33 Medical Technologies Guidance [MTG 46] (December 2019). gammaCore for Cluster Headache. 
National Institute for Health and Care Excellence. Retrieved from https://www.nice.org.uk/guidance/mtg46. 
 
34 Mourdoukoutas AP, et al. “High-resolution multi-scale computational model for non-invasive cervical 
vagus nerve stimulation.” Neuromodulation 21.3 (2017): 261-268.  
 
35 Henssen D, et al. “Vagus nerve stimulation for primary headache disorders: An anatomical review to 
explain a clinical phenomenon.” Cephalalgia 39.9 (2019): 1180-1194. 
 
36 Fornai F, et al. “The rôle of locus coeruleus in the antiepileptic activity induced by vagus nerve 
stimulation.” Eur J Neurosci 33.12 (2011): 2169-78.  
 
37 Staats P, et al. “Neurostimulation for asthma.” Neuromodulation, Second Ed (2018): 1339-1345.  
 

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11 
CLINICAL INVESTIGATION PLAN - INVESTIGATOR AGREEMENT FORM 
I agree to the terms of this CIP. I will conduct the investigation according to the procedures 
specified herein.  
 
 
Tariq Cheema, MD 
Principal Investigator 
AHN Allegheny General Hospital 
 
 
Signature: _____________________________ Date: _____________________________ 
 

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12 
APPENDICES 
Helsinki Declaration 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research 
on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
not be applied without consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving human 
subjects to adopt these principles.  
 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient's best interest when providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician’s knowledge and 
conscience are dedicated to the fulfilment of this duty.  
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights.  

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8. While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of 
research subjects. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professionals and never with the research subjects, even 
though they have given consent 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment.  
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional.  
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects.   
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
Risk, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by the 
condition under investigation. 
Measures to minimize the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily managed.  
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 

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19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs of priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or 
interventions that result from the research.  
 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and adequate laboratory and, as appropriate, animal experimentation. The 
welfare of animals used for research must be respected.. 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This committee 
must be transparent in its functioning, must be independent of the researcher, the sponsor and 
any other undue influence and must be duly qualified. It must take into consideration the laws 
and regulations of the country of countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and approval by the 
committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions. 
 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
 
Informed Consent 

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25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
 26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits 
and potential risks of the study and the discomfort it may entail, post-study provisions and any 
other relevant aspects of the study. The potential subject must be informed of the right to refuse 
to participate in the study or to withdraw consent to participate at any time without reprisal. 
Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or 
may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorized representative. These individuals must 
not be included in a research study that has no likelihood of benefit for them unless it is intended 
to promote the health of the group represented by the potential subject, the research cannot 
instead be performed with persons capable of providing informed consent, and the research 
entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorized representative. The potential subject’s 
dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorized 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics committee. 
Consent to remain in the research should be obtained as soon as possible from the subject or a 
legally authorized representative. 

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31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw 
from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material 
or data contained in biobanks or similar repositories, physicians must seek informed consent for 
its collection, storage and/or reuse. There may be exceptional situations where consent would 
be impossible or impracticable to obtain for such research. In such situations the research may 
be done only after consideration and approval of a research ethics committee. 
 
Use of placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable 
or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention 
and the patients who receive any intervention less effective than the best proven one, placebo, 
or no intervention will not be subject to additional risks of serious or irreversible harm as a result 
of not receiving the best proven intervention. 
 
Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention identified 
as beneficial in the trial. This information must also be disclosed to participants during the 
informed consent process. 
 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. Researcher, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a duty 
to make publicly available the results of their research on human subjects and are accountable 
for the completeness and accuracy of their reports. All parties should adhere to accepted 
guidelines for ethical reporting. Negative and inconclusive as well as positive results must be 
published or otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest must be declared in the publication. Reports of research not in accordance 
with the principles of this Declaration should not be accepted for publication. 
 
Unproven Interventions in Clinical Practice 

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37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorized representative, may use an unproven 
intervention if in the physician’s judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available.