Pharyngeal Electrical Stimulation Evaluation for Dysphagia After Stroke
Phase: NA
Conditions: Dysphagia Following Cerebral Infarction
Sponsor: Phagenesis Ltd.

 
 
CONFIDENTIAL 
 
 
  
 
Pharyngeal Electrical Stimulation Evaluation 
for Dysphagia after Stroke 
(PhEED) 
 
 
 
 
 
Investigational Device 
Phagenesis Phagenyx System 
Sponsor 
Phagenesis Ltd 
Enterprise House, Pencroft Way 
Manchester Science Park M15 6SE, UK 
Protocol Number 
AHE-05 
Protocol Version 
1.0 
Protocol Date 
January 26, 2018 
Principal Investigator US 
 
 
 
 
 
Co Principal Investigator EU 
Richard L. Harvey, MD 
Shirley Ryan Ability Lab 
355 E. Erie 
Chicago Illinois USA 
 
 
Philip MW Bath, DSc, FMEdSci 
Professor of Stroke Medicine 
Room B51 Clinical Sciences Building 
Nottingham City Hospital 
Hucknall Road 
Nottingham NG5 1PB 
ClinicalTrials.gov Number: NCT03358810 
 
 

Date of Signature 
lnves ator Si 
ture 
Phagenesis Phagenyx System 
PhEED Study 
Version 1.0 
Protocol AHE-05 
26 January 2018 
Investigator Signature Page 
My signature below indicates my agreement to conduct this study in accordance with 
this study protocol, Good Clinical Practices, and applicable requirements of the 
governing IRB/EC and applicable laws and regulations. I agree to supervise the study 
staff and the utilization of investigational study devices including ensuring their usage is 
only in connection with this study and protocol. 
1U0LIidM ktv  
Investigator Name (print) 
CONFIDENTIAL 
Page 2 of 71 

Date of Signature 
lnves ator Si 
ture 
Phagenesis Phagenyx System 
PhEED Study 
Version 1.0 
Protocol AHE-05 
26 January 2018 
Investigator Signature Page 
My signature below indicates my agreement to conduct this study in accordance with 
this study protocol, Good Clinical Practices, and applicable requirements of the 
governing IRB/EC and applicable laws and regulations. I agree to supervise the study 
staff and the utilization of investigational study devices including ensuring their usage is 
only in connection with this study and protocol. 
1U0LIidM ktv  
Investigator Name (print) 
CONFIDENTIAL 
Page 2 of 71 

Phagenesis Phagenyx System 
PhEED Study 
Version 1.0  
Protocol AHE-05 
26 January 2018 
 
CONFIDENTIAL   
 
Page 2 of 71 
 
 
 
Investigator Signature Page 
 
My signature below indicates my agreement to conduct this study in accordance with 
this study protocol, Good Clinical Practices, and applicable requirements of the 
governing IRB/EC and applicable laws and regulations. I agree to supervise the study 
staff and the utilization of investigational study devices including ensuring their usage is 
only in connection with this study and protocol. 
 
 
 
 
 
___________________________________ 
 
Investigator Name (print)  
 
 
 
 
 
 
 
 
___________________________________     _____________________________ 
Investigator Signature 
 
 
 
      
Date of Signature  
 
 

Phagenesis Phagenyx System 
PhEED Study 
Version 1.0  
Protocol AHE-05 
26 January 2018 
 
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Table of Contents 
ABBREVIATIONSAND ACRONYMS ..................................................................................................... 5 
STATEMENT OF COMPLIANCE ............................................................................................................ 8 
1 
PROTOCOL SUMMARY ............................................................................................................... 8 
1.1 
Synopsis ................................................................................................................................ 8 
1.2 
Schema ................................................................................................................................ 12 
1.3 
Schedule of Activities (SoA) .............................................................................................. 13 
2 
INTRODUCTION .......................................................................................................................... 15 
2.1 
Study Background and Rationale ..................................................................................... 15 
2.2 
Current Standard of Care .................................................................................................. 18 
2.3 
Phagenesis Phagenyx® System ...................................................................................... 19 
2.3.1 
Device Development ........................................................................................ 19 
2.3.2 
Device Description ............................................................................................ 21 
2.3.3 
Device Use ........................................................................................................ 23 
2.4 
Risk/Benefit Assessment ................................................................................................... 24 
2.4.1 
Potential and Known Risks .............................................................................. 24 
2.4.2 
Potential Benefits .............................................................................................. 28 
2.4.3 
Assessment of Potential Risks and Benefits ................................................ 29 
3 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................... 30 
4 
STUDY DESIGN ........................................................................................................................... 32 
4.1 
Overall Design ..................................................................................................................... 32 
4.2 
Scientific Rationale for Study Design .............................................................................. 34 
4.3 
Clinical Experience and Justification of PES Level ....................................................... 34 
5 
STUDY POPULATION ................................................................................................................ 34 
5.1 
Inclusion Criteria ................................................................................................................. 34 
5.2 
Exclusion Criteria ................................................................................................................ 35 
5.3 
Screen Failures ................................................................................................................... 36 
5.4 
Strategies for Recruitment and Retention ....................................................................... 36 
6 
STUDY INTERVENTION ............................................................................................................ 36 
6.1 
Study Intervention(s) Administration ................................................................................ 36 
6.1.1 
Phagenyx® Catheter Placement .................................................................... 37 
6.1.2 
Vital Signs Monitoring ...................................................................................... 39 
6.1.3 
Stimulation Level Optimization and Treatment ............................................. 39 
6.1.4 
Disposal ............................................................................................................. 40 
6.2 
Device Accountability, labeling and Storage .................................................................. 40 
6.2.1 
Accountability .................................................................................................... 40 
6.2.2 
LABELING ......................................................................................................... 41 
6.2.3 
Storage 41 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................ 41 
6.4 
Study Intervention Compliance ......................................................................................... 43 
7 
VFSS STOPPING CRITERIA AND PATIENT/SITE/STUDY TERMINATION ..................... 43 
7.1 
VFSS Stopping Criteria ...................................................................................................... 43 
7.2 
Patient TERMINATION ...................................................................................................... 43 

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7.3 
Site Termination and Study Termination ......................................................................... 44 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................... 45 
8.1 
Study Assessments ............................................................................................................ 45 
8.1.1 
Screening and Baseline Assessments .......................................................... 45 
8.1.2 
Nasopharyngeal Examination ......................................................................... 45 
8.1.3 
Videofluoroscopic Study (VFSS) .................................................................... 45 
8.1.4 
Barthel Index ..................................................................................................... 46 
8.1.5 
Modified Rankin ScALE (mRS) ....................................................................... 47 
8.1.6 
NIH Stroke Scale (NIHSS) .............................................................................. 47 
8.1.7 
Functional Oral Intake Scale (FOIS) .............................................................. 48 
8.1.8 
Dysphagia Severity Rating Scale (DSRS) .................................................... 48 
8.1.9 
Quality of Life (QOL) Instruments: EQ-5D, EQ-VAS ................................... 49 
8.1.10 
Pneumonia Assessment .................................................................................. 49 
8.2 
Adverse Events and Serious Adverse Events ................................................................ 50 
8.2.1 
Definition of Adverse Event (AE) .................................................................... 50 
8.2.2 
Definition of Serious Adverse Event (SAE) ................................................... 50 
8.2.3 
Classification of Adverse Events .................................................................... 51 
8.2.4 
Device Deficiencies .......................................................................................... 54 
8.2.5 
Event Assessment and Follow-Up ................................................................. 54 
8.2.6 
Event Reporting ................................................................................................ 55 
9 
STATISTICAL CONSIDERATIONS .......................................................................................... 55 
9.1 
Statistical Hypotheses ........................................................................................................ 55 
9.2 
Sample Size Determination ............................................................................................... 55 
9.3 
Populations for Analyses ................................................................................................... 56 
9.4 
Statistical Analyses ............................................................................................................ 56 
9.4.1 
General Approach ............................................................................................. 56 
9.4.2 
Analysis of the Primary Efficacy Endpoint .................................................... 56 
9.4.3 
Analysis of the Secondary Efficacy Endpoints ............................................. 57 
9.4.4 
Safety Analyses ................................................................................................ 57 
9.4.5 
Baseline Descriptive Statistics ........................................................................ 58 
9.4.6 
Planned Interim Analyses ................................................................................ 58 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............. 58 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................................ 58 
10.1.1 
Informed Consent ............................................................................................. 58 
10.1.2 
Consent Procedures and Documentation ..................................................... 59 
10.1.3 
Study Discontinuation and Closure ................................................................ 59 
10.1.4 
Confidentiality and Privacy .............................................................................. 60 
10.1.5 
Key Roles and Study GOvernance ................................................................ 60 
10.1.6 
Safety Oversight ............................................................................................... 61 
10.2 
Core Laboratory .................................................................................................................. 62 
10.2.1 
Clinical Monitoring ............................................................................................ 62 
10.2.2 
Quality Assurance and Quality Control .......................................................... 63 
10.2.3 
Data Handling and Record Keeping .............................................................. 63 
10.3 
Source Documents ............................................................................................................. 64 
10.4 
Protocol Deviations ............................................................................................................ 65 

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10.5 
Publication and Data Sharing Policy ................................................................................ 66 
10.6 
Conflict of Interest Policy ................................................................................................... 66 
10.7 
Protocol Amendment History ............................................................................................ 67 
11 
REFERENCES ............................................................................................................................. 68 
 
 
 
 
 
ABBREVIATIONSAND ACRONYMS  
 
  
ABS   
Acrylobutdiene Styrene 
ANCOVA Analysis of Covariance 
ASHA 
American Speech Language Hearing Association 
BI 
Barthel Index 
CI 
Confidence Interval 
CMP 
Clinical Monitoring Plan 
COPD 
Chronic Obstructive Pulmonary Disease  
cPAS 
Cumulative Penetration Aspiration Score 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CXR 
Chest X-ray 
CT 
Computed Tomography 
DC 
Discharge from the hospital 
DMC 
Data Monitoring Committee 
DOSS 
Dysphagia Outcome and Severity Score  
DSRS 
Dysphagia Severity Rating Scale 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
EDC 
Electronic Data Capture 
EDSS 
Expanded Disability Status Score 
EMG 
Electromyography 
EQ-5D 
EuroQoL 5 Dimension Questionnaire 
EQ-VAS 
EuroQoL Visual Analogue Scale 
eTMF 
Electronic Trial Master File 
FDA 
Food and Drug Administration 
FEES 
Flexible Endoscopic Evaluation of Swallowing 
FOIS 
Functional Oral Intake Scale 
GCPs 
Good Clinical Practices 
GMP 
Good Manufacturing Practices 
HCP 
Health Care Professional  
HIPAA 
Health Insurance Portability and Accountability Act  
HR 
Hazards Ratio 
Hz 
Hertz 

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ICD 
Implantable Cardiovascular Defibrillator 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ISC 
Independent Statistical Center 
ISO 
International Organization for Standardization 
ITT 
Intent-To-Treat 
LED 
Light Emitting Diode 
LOS 
Length of Stay 
mA 
milli-Amp 
MAUDE 
Manufacturer and User Facility Device Experience 
MBS 
Modified Barium Swallow 
MBSimP 
Modified Barium Swallow Impairment Profile 
MedDRA Medical Dictionary for Regulatory Activities 
mL 
milliliter 
MM 
Medical Monitor 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
MS 
Multiple Sclerosis 
mSv 
milli-Sievert 
NCT 
National Clinical Trial 
NET 
Nasoenteric (or nasoenteral) Tube 
NG 
Nasogastric 
NGT 
Nasogastric Tube 
NIH  
National Institutes of Health 
NIHSS 
National Institutes of Health Stroke Scale 
NSR 
Non-significant Risk 
OD 
Outer Diameter  
OR 
Odds Ratio  
PAS 
Penetration Aspiration Scale 
PEG 
Percutaneous Endoscopic Gastrostomy 
PES 
Pharyngeal Electrical Stimulation 
PI 
Principal Investigator 
PP 
Per Protocol 
PPS 
Pulse Per Second 
QoL 
Quality of Life 
RCT 
Randomized Controlled Trial 
RI 
Roll-in  
RR 
Relative Risk 
SAE 
Serious Adverse Event 
SLP 
Speech Language Pathologist 

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SLT 
Speech Language Therapist 
SAP 
Statistical Analysis Plan 
SOA 
Schedule of Activities 
SSR 
Sample Size Re-assessment  
TMS 
Transcranial Magnetic Stimulation 
tsp 
teaspoon 
UK 
United Kingdom 
US 
United States 
USB 
Universal Serial Bus 
VFSS 
Video Fluoroscopic Swallowing Study 
 
 
 

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STATEMENT OF COMPLIANCE 
 
This study will be conducted in accordance with the relevant parts of the Code of 
Federal Regulations (21 CFR 50, 54, 56, 812), ISO 14155:2011, the International 
Conference on Harmonization (ICH) Guidelines for Good Clinical Practices (GCPs,) and 
the ethical principles that have their origin in the Declaration of Helsinki and its 
subsequent amendments.  Additional state and local regulations will be followed, when 
applicable.  
  
Investigators and sites must have protocols, informed consent forms and any other 
patient materials related to the study plan approved by the Institutional Review Board 
(IRB) or Ethics Committee (EC) in writing.  Prior to enrollment, the sponsor or designee 
will review the written approvals for completeness, including the required elements of 
the consent form, and the sponsor will provide device, protocol and study administration 
training.   The continued eligibility for participation by an investigator and the institution 
requires maintenance of all approvals (e.g. annual reviews, amendment reviews).  
 
Each patient will provide written informed consent, indicated by a signature and date, 
according to the regulatory and legal requirements of the participating site and 
applicable regulations.  The process must allow for ample time, opportunity to ask 
questions and an understanding that informed consent in research is voluntary. A copy 
of the informed consent and any additional patient information must be given to each 
patient. The process and consent execution are also to be documented in the medical 
record.  
  
Patient confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor(s) and their agents.  The study protocol, documentation, data, and all other 
information generated will be held in strict confidence to the extent allowed by law, 
including Protected Health Information (PHI).  No information concerning the study or 
the data will be released to any unauthorized third party without prior written approval of 
the sponsor. 
  
1 
 
PROTOCOL SUMMARY 
1.1 SYNOPSIS   
Title 
Pharyngeal Electrical Stimulation Evaluation  
for Dysphagia after Stroke  (PhEED) 
Study Description 
This is a randomized, sham-controlled, patient masked, 
outcome assessor-blinded study to assess a Pharyngeal 
Electrical Stimulation (PES) Catheter for treatment of 
oropharyngeal dysphagia following a stroke. The main clinical 
outcomes will be measured by videofluoroscopic swallowing 
study (VFSS) and bedside swallowing assessments at 48 
hours. Randomization will use stratification based on site and 
baseline PAS. Minimization may also be included to ensure 

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group balance for study site and additional baseline covariates. 
All patients will have the Phagenyx® Catheter placed prior to 
randomization, and will receive either an active treatment of 
Pharyngeal Electrical Stimulation (PES) or a sham treatment 
performed by a healthcare professional (HCP) that is un-
blinded to treatment assignment.  All other speech pathology 
standard dysphagia care will be provided by a speech 
language pathologist (SLP) that is blinded to treatment 
assignment. Administration of all protocol-specific 
assessments will be conducted by personnel blinded to 
treatment assignment.  
 
The study will follow an adaptive group sequential design with 
unblinded sample size re-assessment. To ensure 180 
evaluable patients with 7-day data and assuming a 20% 
dropout rate, 225 patients will be enrolled initially.  An interim 
analysis for futility will occur after the first 60 patients complete 
their 7-day visits and another interim analysis will be performed 
for efficacy and futility after 120 patients complete their 7-day  
visits.  The total sample size may be increased up to 338 
patients after the second interim analysis to ensure up to 270 
evaluable patients.  Up to 15 investigational centers across the 
US and Europe will participate in this study. The enrollment 
period is expected to be approximately 24 months and patient 
participation will last for approximately 11 weeks.  Patients will 
be assessed at the following intervals: baseline, 48 hours, 7 
days,  14 days or at discharge, whichever is first, and 11 
weeks after completion of the study treatments. 
Study Objectives 
Primary Objective: To evaluate the efficacy of Phagenyx® 
treatment in reducing the severity of unsafe swallows.    
 
Secondary Objective: To evaluate the efficacy of Phagenyx® 
treatment in improving nutritional management. 
 
Exploratory Objectives: 
• To further characterize the efficacy of Phagenyx® treatment 
in reducing the severity of unsafe swallows. 
• To further characterize the efficacy of Phagenyx® treatment 
on nutritional management changes. 
• To evaluate the efficacy of Phagenyx® treatment on 
improving quality of life. 
• To evaluate the efficacy of Phagenyx® treatment on general 
stroke health outcomes. 
Study Endpoints 
Primary Endpoint: Swallowing safety of a bolus based on PAS 
of each swallow, determined by a videofluoroscopic swallowing 
study (VFSS) 48 hours after completion of investigational 

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treatment, converted to a trichotomized ordinal response of 
safe (PAS 1-3), penetration (PAS 4-5), or aspiration (PAS 6-8). 
Each patient contributes up to 12 post-treatment repeated 
measurements using  Penetration Aspiration Scale (PAS) 
including 6 swallows of thin and 6 swallows of nectar 
 
Secondary Endpoints:   
- 
Functional Oral Intake Scale (FOIS) at  7 days  following the 
last investigational treatment 
- 
Dysphagia Severity Rating Scale  (DSRS) at 7 days following 
the last investigational treatment  
 
Exploratory Endpoints: 
 
• The severity of unsafe swallows will be further evaluated 
via: 
o PAS outcome by each consistency (thin and nectar) 
o Physiologic 
measurement 
obtained 
using 
the 
Modified 
Barium 
Swallow 
Impairment 
Profile 
(MBSImP) metrics will be extracted from the thin and 
nectar thick swallows by the core lab by using the 
baseline and follow up VFSS data.  These validated 
and reliable metrics of critical swallowing movements 
will be explored for their relationship to the primary 
study endpoint (PAS). 
o PAS dichotomized as safe (PAS 1-3) or unsafe (PAS 
4-8) 
• Nutritional management changes will be further evaluated 
via: 
o Dysphagia Severity Rating Scale (DSRS) at 14 days 
or discharge, whichever is first, and 11 weeks 
following the last investigational treatment. 
o Time from baseline to removal of enteral feeding (i.e., 
removal of NG tube or PEG or transition to oral 
feeding, or first diet upgrade) 
o Functional Oral Intake Scale (FOIS) at  14 days or 
discharge, 
whichever 
is 
first, 
and 
11 
weeks  
following the last investigational treatment 
• Quality of life (QOL) will be assessed at baseline and 11 
weeks following the last investigational treatment via the 
following instruments:   
o EuroQoL-5 Dimension Questionnaire (EQ-5D) and 
EuroQoL-Visual Analogue Scale (EQ-VAS) 
• General stroke health outcomes will be assessed by: 
o Time to discharge from site in which treatment is 
received   

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o Discharge destination from the site in which treatment 
is received 
o Patient location (home, institution) at 11 weeks  
o Days on antibiotics during hospital stay 
o NIH Stroke Scale (NIHSS) at baseline, 14 days    or 
discharge, and 11 weeks 
o Modified Rankin Scale (mRS) at baseline, 14 days  
or discharge, and 11 weeks 
o Barthel Index (BI) at baseline, 14 days    or 
discharge, and 11 weeks 
o New 
onset 
pneumonia, 
using 
a 
standardized 
definition adapted from the STROKE-INF study26 at 
baseline, 48 hours, 7 days, and 14 days or discharge, 
whichever is first.  
o Hospital readmission rate 
o Number of CXR (related to suspect pneumonia) 
Study Population 
Up to 338 patients who have been diagnosed with dysphagia 
caused by stroke will be enrolled at approximately 15 centers 
across the US and Europe.  
Regulatory 
Classification 
This study is designed to support a de novo submission for a 
non-significant risk (NSR) device in the United States.  The 
study device received CE mark in 2012. 
Number of Sites 
 
There will be approximately 15 centers across the US and 
Europe. The majority of the centers and patients enrolled will 
be from the US.  
Description 
of 
Study Intervention 
The Phagenesis Phagenyx® System is indicated for the 
treatment of neurogenic oropharyngeal dysphagia.  The 
Phagenyx® system is a two-part neurostimulation system. It is 
composed of a durable component called the Base Station and 
the single-use sterile disposable Phagenyx® Catheter.  The 
Base Station acts as the user interface and provides the 
means to generate, optimize and monitor the delivery of 
electrical stimulation.  
The Base Station has the following functions: 
• Stimulation - Generation, optimization and output of 
controlled electrical stimulation 
• User Interface - Receives, stores and outputs data 
regarding the patient, user, product and treatment  
The Phagenyx® Catheter design is based on that of a 
nasogastric tube (NGT), but incorporates electrodes with 
appropriate wiring and insulation for delivery of electrical 
stimulation to the pharyngeal mucosa.  The Phagenyx® 
Catheter has been designed to also deliver enteral nutrition to 
the patient as needed.   
Study Duration 
The study is expected to take approximately 24 months from 

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the time of first patient enrollment to the final study visit.   
Patient Duration 
The duration for each patient will be approximately 11 weeks.  
 
 
1.2 SCHEMA 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Stroke + Dysphagia  
Screening   
     Informed Consent  
          ENROLLED  
VFSS  
Baseline 
Assessments 
PAS >4 
Phagenyx ®Catheter     
Placed 
ACTIVE 
RANDOMIZE  
SHAM  
Assigned Intervention 10 min x 3 consecutive days  
Follow up assessments at 48 hrs (+/- 24 hrs), 7days 
(+/- 1 day)  14 days (+/- 1day) or DC whichever is 
first, and 11 weeks +/- 1 week 
Safety 
Population 

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1.3 SCHEDULE OF ACTIVITIES (SOA) 
 
 
Screening 
Baseline 
Phagenyx 
Treatment 
(10 minutes 
per day, 3 
consecutive 
days) 
48±24 
Hour 
Follow-
up 
7±1 
Days 
Follow
-up   
14-±1 days 
or 
discharge, 
whichever is 
first 
11±1 
Weeks 
Follow
-up 
 
Follow-up timing is based on last Phagenyx treatment. 
Medical History and 
Demographics 
X 
 
 
 
 
 
 
Exam of nasopharynx 
 
  
X1 
 
 
X1 
X 
 
Informed Consent 
X 
 
 
 
 
 
 
ECG monitoring (for the 
first 20 patients randomized to 
active treatment)  
 
 
 X2 
 
 
 
 
Heart Rate and Blood 
Pressure Monitoring(for 
the first 20 patients 
randomized to active 
treatment) 
 
 
X2 
 
 
 
 
NIHSS 
 
X 
 
 
 
X 
X 
Modified Rankin Score 
(mRS) 
 
X 
 
 
 
X 
X 
Barthel Index 
 
X 
 
 
 
X 
X 
FOIS 
 
X 
 
 
X 
X 
X 
DSRS 
 
X 
 
 
X 
X 
X 
EQ-5D, EQ-VAS 
 
X 
 
 
 
 
X 
Pregnancy Test 
 
X3 
 
 
 
 
 

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VFSS 
 
X4 
 
X 
 
 
 
Pneumonia Assessment  
 
X 
 
X 
X 
X 
 
Adverse Event (AE) 
Assessment 
 
X 
X 
X 
X 
X 
X 
Blinding Assessment 
 
 
 
 
 
X 
 
 
1 Assessment of nasopharynx at baseline, 1 week after catheter is in place and at catheter removal using flashlight or pen light.  In the event of patient complaint or 
obvious symotoms, a fiberoptic exam is required and any adverse events are to be reported.  
2 Rhythm strip (30 seconds) printed at immediately prior to commencing PES treatment, 5 minutes into each of the three treatment sessions, and immediately post 
treatment. Continual ECG monitoring during PES to observe for any arrhythmias. Heart rate and Blood Pressure to be documented immediately prior to and after 
PES.   
3 Required only for females of child-bearing potential 
4 Baseline VFSS must meet the threshold criteria of demonstrating a PAS of ≥ 4, in three of the six boli (5 mL/1 tsp/bolus), during swallowing “thin liquid” barium 
media as assessed by the clinical staff administering the VFSS, unless its considered to be too high risk, then 2 swallows will qualify. 

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2 
 
INTRODUCTION 
 
2.1 STUDY BACKGROUND AND RATIONALE  
 
Dysphagia is common in the post-stroke setting.  It is associated with increased 
incidence of in-hospital pneumonia, worse outcome and greater resource utilization.  
The actual incidence of dysphagia is very difficult to estimate since there is no 
standardization across dysphagia screening protocols with respect to administration or 
interpretation.  Martino et. al.,1 attempted to define the incidence of dysphagia in the 
post-stroke setting by performing an extensive review of the stroke literature spanning 
from 1966 through May 2005.  Of 104 articles initially identified, 24 articles included 
relevant information.  Due to the heterogeneous nature of dysphagia assessment, it was 
not possible to pool any results across multiple studies. Only swallow screening tests 
were performed to diagnose dysphagia in nine of the studies.  Incidence based only on 
swallowing screening demonstrated a 37-45% incidence among patients in both acute 
and rehabilitation settings.  More extensive clinical or instrumental testing was 
performed in the remaining 16 studies.  In depth testing was not always performed in 
the acute care setting; however, the highest incidence rates of dysphagia were 
observed among the acute studies that used videofluoroscopy (64-78%). In 4 acute 
studies using very similar clinician testing, incidence rates varied between 51-55%.  
There was a reported incidence range from 40-81% among 3 studies performed in the 
rehabilitation setting, but all three studies limited enrollment to brainstem strokes and 
relied only on clinician testing. 
The timing in the resolution of post-stroke dysphagia is also very difficult to estimate.  
There is a general belief that spontaneous resolution will occur within the first week to 
month, with only a few patients demonstrating persistent dysfunction beyond 6 months.  
Mann et. al.2 set out to systematically define the true persistence at a single referral 
center in Australia.  Sixty-five of 128 patients (51%; 95% CI, 42-60%) had a clinical 
presentation of dysphagia in the acute stroke setting.  This incidence increased to 82 
patients (64%; 95% CI, 55-72%) when videofluoroscopy was used to diagnose 
dysphagia.  Follow up assessments were made at six months.  Ninety-seven (97) of the 
112 patients assessed at six months had returned to their pre-stroke diet (87%; 95% CI, 
79-92%), but clinical evidence of swallowing abnormality remained in 56 patients (50%; 
95% CI, 40-60%) and VFSS confirmed abnormalities in 51 (46%) with full aspiration in 
17 (11%).   
A number of researchers have similarly attempted to quantify the incidence of 
pneumonia, or “chest infection” in the post-stroke setting.  Similar to studies of 
dysphagia incidence, published reports also lack standardization with respect to 
inclusion criteria, diagnostic methods and timeframes for reporting.  Katzan et. al.,3 
performed a large retrospective review of a 29-hospital-wide population cohort in the US 
to determine the incidence of pneumonia and its impact on 30-day mortality from 1991-

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1997.  They report a 6.9% pneumonia incidence among 14,293 patients.  Upon 
excluding patients that were dying or had Do Not Resuscitate orders within the first 3 
days, the incidence became 5.6% out of 11,286 patients.  Bivariate analysis between 
pneumonia and admission factors indicated that stroke severity (NIHSS score) and 
general indictors of frailty were predictors for pneumonia.  No analysis for dysphagia 
was included. 
Mann et al’s study reported chest infections in 26 of 112 patients at 6-months (20%; 
95% CI, 14-28%) with 12% of these occurring within the first month of stroke admission.  
Multivariate analysis demonstrated that the only independent predictor of chest infection 
was dysphagia2.  
Smithard et. al.,4 prospectively studied 121 consecutive stroke patients admitted to their 
center in the UK.   Twenty five percent of patients developed a chest infection.  
Incidence was stratified based on dysphagia diagnosis.  Patients considered to have an 
unsafe swallow via bedside swallow assessment demonstrated a 33% rate of chest 
infection compared to 16% for patients with a safe swallow. 
 
Dziewas et al.,5 Masiero et al.,6 and Arnold et al.,7 all report their single-center 
experiences with pneumonia in patients that are dysphagic in the acute post-stroke 
setting.  Dziewas et. al., prospectively followed 100 patients considered to have severe 
dysphagia among 527 assessed via swallow assessment (19%) at their center in 
Germany5.  Nasogastric tube (NGT) placement was indicated for those with severe 
dysphagia.  Pneumonia developed in 44% of patients in whom an NGT was placed, 
primarily within the first 2-3 days.  There was no difference in the stroke lesions 
characteristics between patients that developed pneumonia and those that did not.  
Multivariate analysis demonstrated that stroke severity (via NIHSS) and severe facial 
palsy were risk factors for developing pneumonia. 
 
Maseiro et al., prospectively studied 67 consecutive patients with oropharyngeal 
dysphagia diagnosed by flexible endoscopic evaluation of swallowing (FEES) within 7 
days of first acute stroke in their hospital in Italy6.  There were an initial 9 incidents of 
pneumonia, but two patients had a recurrence requiring hospital readmission.  Hence, 
the overall incidence was 11 cases for the 67 admissions, or 16.4%, overall.  Among 
dysphagic patients, they found that a history of chronic obstructive pulmonary disease 
(COPD), silent aspiration, and level of consciousness were independent risk factors for 
the development of pneumonia. 
 
Arnold et al., reported on a retrospective review of 507 ischemic stroke patients treated 
at a tertiary care center in Switzerland from Jan 2012 through Nov 20147.  Dysphagia 
was present in 118 patients (20.7%) assessed by extensive clinical testing.  In-hospital 
pneumonia occurred more frequently in dysphagic patients (22.9% vs. 1.1%), and 
multivariate analysis demonstrated the presence of dysphagia was independently 
associated with pneumonia (OR, 27.4; 95% CI, 10.2-73.7; P <0.001).  
 
Martino et al., found that, similar to dysphagia reporting, the reporting of pneumonia is 
also highly variable with respect to timeframe of analysis and means of diagnoses1.  

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Pooling the few studies with sufficient data to allow this, the presence of dysphagia 
conferred a relative risk (RR) of 3.17 (95% CI, 2.07-4.87) for developing pneumonia, 
and the RR increased more than three-fold among patients with confirmed aspiration 
(RR, 11.56; 95% CI; 3.36-39.77). 
 
Katzan et al.’s, retrospective analysis indicated that pneumonia conferred a relative risk 
for 30-day mortality that was six time greater for patients with pneumonia than without 
(26.9% vs. 4.4%, p<0.001)3.  After adjusting for independent factors, the RR for 30-day 
mortality was still almost 3 times greater for patients with pneumonia (2.99; 95% CI, 
2.44 to 3.66).  The authors estimate that 10% of all deaths following stroke are 
attributable to pneumonia. 
The studies that specifically assessed post-stroke dysphagia demonstrate that the 
presence of dysphagia also confers a greater relative risk of poor outcome.  Specifically, 
Dziewas et al., found that dysphagic patients who developed pneumonia needed the 
NGT to remain in place for a longer period of time, with a median of 15 vs. 2 days or an 
average of 16.3±7.2 vs. 4.9±4.8 days (p<0.001) for patients with pneumonia vs. those 
without.  Dziewas et al., found among those having a poor 3-month outcome (modified 
Rankin Score (mRS) ≥ 4), had a higher incidence of pneumonia during their hospital 
stay than did those that had a good (mRS ≤ 1) or moderate (mRS = 2 or 3) outcome, at 
70% vs. 23% and 24%, respectively. Duration of enteral feeding was also longer in 
patients with a poor outcome at 3 months5.     
Smithard et al., and Arnold et al., also report that the presence of dysphagia is 
associated with longer hospital stays and higher mortality.  Mortality was 37% for 
patients with dysphagia vs. 6% for those without dysphagia among patients reported on 
by Smithard et al., and the presence of dysphagia was a significant predictor for 
mortality after adjusting for confounding variables4.  In the 2016 report by Arnold et al., 
mortality was 27% among patients with dysphagia vs. 7.4% for those without.  The risk 
of death was higher for the subgroup of dysphagic patients requiring tube feeding. The 
occurrence of pneumonia was only weakly associated with mortality risk7.    
Mann et al’s study cited only five deaths within the first six months among 117 patients 
for whom six-month data was available; however, all of the deaths occurred in patients 
with dysphagia, and was associated with chest infection in four of the five cases2. 
Several studies have indicated that dysphagia increases hospital length of stay.  
However, additional resources associated with the care for these patients may be found 
in antibiotic requirements and chest radiographs7.  Dysphagic patients are also more 
likely to require in-patient care during post-stroke rehabilitation4,7,8.  Arnold’s study found 
that the presence of dysphagia was a strong independent predictor (OR 3.1, 95% CI, 
1.7-5.5, p<0.001) of institutionalization at 3 months7. 
Bonilha et. al., analyzed the 1-year cost of dysphagia in 3200 patients experiencing a 
first stroke across the state of South Carolina for 20048.  They found that each case of 
dysphagia added a cost of $4510, and additional cost burden was associated with 
hospital and durable medical expenses as well as the need for a skilled nursing facility. 
The 2012 overall cost associated with stroke in the US was 33 billion dollars.  Costs 
associated with stroke are expected to triple by 2030, as the general population ages9.  

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Hence, effective treatments focused on facilitating the recovery of swallowing could 
provide an overall economic benefit to society.   
 
Despite dysphagia imparting both patient-specific and social-economic burden, there is 
very little standardization with respect to dysphagia treatments or even evidence-based 
recommendations for treatment.  Foley et. al.,10 intended to update Martino et al.,’s 
earlier work1 with a follow-on report including data up to Aug 2007, and specifically 
considering targeted treatments and their associated outcomes for post-stroke 
dysphagia.  The published findings demonstrate very heterogeneous results, and 
pooled analyses were not possible.  Descriptive findings anecdotally suggest that 
dysphagia treatment is associated with reduced pneumonia risk in the acute post-stroke 
setting. 
 
2.2 CURRENT STANDARD OF CARE 
The American Speech-Language and Hearing Association (ASHA) provides a “Scope of 
Practice in Speech-Language Pathology” that outlines what a speech-language 
pathologist is trained to evaluate and treat in general terms but does not identify or 
recommend use of specific techniques or modalities.   General approaches in treating 
dysphagia include both direct and indirect therapies.  Direct therapies are those that 
include swallow retraining, training of compensatory mechanisms to improve airway 
protection during swallowing and diet modification to reduce the risk of aspiration.  
Indirect therapies target the underlying pathology associated with the dysphagia through 
medication, surgery, or by muscle strengthening, sensory stimulation (e.g., ice probes, 
air puffs), neuromuscular electrical stimulation or cortical stimulation. 
 
In a recent review of 53 published dysphagia rehabilitation studies spanning an 18-
month period, Druila et. al.,11 found that direct swallowing therapy was used in only one 
of 27 studies, indirect therapies were used in 10 studies, and a combined approach was 
used in the remaining 16.  The size of the effect associated with each therapy was 
calculated and compared across studies.  Their findings indicate that treatment effects 
in dysphagia are small to moderate.  Some studies demonstrated no benefit in objective 
measures but small to moderate effects in patient reported outcome which, they 
conclude, likely reflect placebo effects.  The only studies that demonstrated a large 
effect size were those performed in dysphagic patients in the acute stroke setting, but it 
appeared that spontaneous recovery may have provided a greater effect size than the 
therapy alone based on improvements in sham groups, as well. 
 
AmpcareESP and VitalStim are two neuromuscular electrical stimulation devices 
currently marketed in the US for therapeutic use after dysphagia. Both administer 
external stimulation to the neck. Critical review of the literature for neuromuscular 
stimulation found that results are generally promising, but that no high-quality controlled 
studies have been performed that provide definitive evidence of efficacy12. In a special 
interest website publication, ASHA posted the following opinion regarding the use of 
products such as the VitalStim: “There is scant evidence to support the use of electrical 
stimulation as a treatment strategy for dysphagia in either the adult or pediatric 

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population. ASHA is strongly committed to evidence-based practice and urges members 
to consider the best available evidence before utilizing any product or technique. ASHA 
does not endorse any products, procedures, or programs.”13 
Cortical stimulation to treat dysphagia is being explored by administering pharyngeal 
electrical stimulation, transcranial magnetic stimulation and transcranial direct current 
stimulation. None of these methods are commercially available in the US. 
 
2.3 PHAGENESIS PHAGENYX® SYSTEM 
 
2.3.1 DEVICE DEVELOPMENT 
The design of the Phagenesis Phagenyx® System evolved from basic research into the 
way the motor cortex coordinates and controls swallowing. Studies were initially 
conducted in healthy volunteers to generate a cortical topographical representation of 
the oral, pharyngeal and esophageal swallowing musculature.  Topographical maps 
were 
created 
by 
measuring 
the 
evoked 
motor 
responses 
measured 
via 
electromyography (EMG) in the oropharynx and mylohyoid muscles created by 
stimulating the cortex via transcranial magnetic stimulation at intensities 110% of the 
threshold that evoked a minimal EMG response.  Topographical maps display the areas 
that produce graded magnitudes of the motor responses.  It was discovered that cortical 
control of swallowing is discretely located in the motor and pre-motor cortex of both 
hemispheres of the brain, and the arrangement exhibits an asymmetric bias towards 
one or other of the hemispheres, so that there is a dominant hemisphere14. 
 
Figure 1: Cortical swallowing representation. This healthy individual shows a 
dominance of swallowing control activity in the right hemisphere (yellow 
represents the greatest magnitude of motor response and dark blue a lack of 
response; "X" indicates centerline) 
This discovery led to the hypothesis that a unilateral stroke affecting the dominant 
swallowing hemisphere was likley to give rise to dysphagia, while a stroke affecting the 
non-dominant hemisphere was not.  This hypothesis was confirmed in a study of 20 
patients experiencing a unilateral hemispheric first-time stroke15.  Eight (8) of the 20 
patients presented with swallowing difficulties during the instrumental videofluoroscopic 
swallow study.  All 20 patients underwent transcranial magnetic stimulation with 
recording of evoked potentials in the oropharynx. Dysphagic patients demonstrated 
weak EMG signals associated with stimulation of either hemisphere, whereas patients 

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without dysphagia demonstrated strong EMG signals when the unaffected side was 
stimulated.    
 
Twenty-eight (28) patients with unilateral hemispheric stroke were subsequently studied 
over their initial 3-month post-stroke course. Dysphagia was present in 71% of patients 
upon initial assessment and in 46% and 41% at one and three months, respectively.   
Cortical mapping of the motor pathways to the pharynx was performed at baseline and 
at one and three months using the methodology previously described. Non-dysphagic 
and persistently dysphagic patients showed little change in pharyngeal representation in 
either hemisphere at one and three months compared with baseline, but patients that 
recovered their swallowing function had an increased pharyngeal representation in the 
unaffected hemisphere at one and three months without change in the affected 
hemisphere.  A functional reorganization of the brain by which swallowing control was 
transferred from the damaged hemisphere to the undamaged one was proposed as the 
mechanism of swallowing recovery. 
 
 
 
 
 
 
 
 
Figure 2: Cortical reorganization associated with swallowing recovery. A) Typical 
cortical representation of swallowing motor cortex in a healthy individual; B) Typical 
cortical representation of swallowing function in a dysphagic patient who was thought to 
exhibit dominance in the right hemisphere; C) Typical cortical representation of patient 
who has recovered swallowing function: the dominance of control has moved to the left 
hemisphere.     
 
Following the observation of this natural functional reorganization, Hamdy and 
colleagues began investigating the use of various sensory stimuli to drive this functional 
reorganization.  Sensory inputs were tested (e.g., tactile, temperature, aversive taste) 
as well as experimental modes including transcranial direct current, magnetic field and 
electrical stimulation in the oropharynx (unpublished data).  Transcranial magnetic 
stimulation was used to produce cortical maps based on evoked oropharyngeal motor 
responses to assess the cortical excitability in the motor centers associated with 
swallowing before and after each study intervention to assess the extent to which an 
intervention increased cortical activity.  Pharyngeal electrical stimulation demonstrated 
promise. The rapid increase in cortical excitation after just ten minutes of stimulation is 
illustrated in Figure 3.  Moreover, these changes persisted for 30 minutes after 
stimulation was discontinued thus suggesting that continuous stimulation was not 
necessary to facilitate reorganization16. 
 
A 
B 
C 
L         R 
L         R 
L         R 

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Figure 3: Cortical excitation associated with pharyngeal electrical stimulation 
 
The Phagenesis Phagenyx® System was designed to harness the fact that pharyngeal 
stimulation led to increased and prolonged cortical excitation to expressly facilitate the 
cortical reorganization associated with improved swallow function. Phagenyx 
administers electrical stimulation optimized to drive cortical excitation and facilitate the 
cortical reorganization responsible for swallowing control and coordination.  Electrical 
stimulation is delivered directly to the pharyngeal mucosa which is innervated by nerves 
involved in triggering pharyngeal swallowing and airway protection.  
 
2.3.2 DEVICE DESCRIPTION 
 
The Phagenesis Phagenyx® System is indicated for the treatment of post-stroke 
neurogenic oropharyngeal dysphagia. Phagenyx® is a two-part neurostimulation 
system. It is composed of a durable component, the Base Station, and the single-use 
sterile disposable Phagenyx® Catheter.  The Base Station acts as the user interface 
and provides the means to generate, optimize and monitor the delivery of electrical 
stimulation. The Phagenyx® Catheter design is based on that of an NGT, but 
incorporates electrodes with appropriate wiring and insulation for delivery of electrical 
stimulation to the pharyngeal mucosa.  The Phagenyx® Catheter has been designed to 
also deliver enteral nutrition to the patient as needed.  Phagenyx® received CE Mark in 
2012. 
 
 
The Base Station has the following functions: 
 
• 
Stimulation - Generation, optimization and output of controlled electrical stimulation 
• 
User Interface - Receives, stores and outputs data regarding the patient, user, product and 
treatment  
 
Figure 4 provides the front and back appearances of the Base Station with key features 
labeled. 
 

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The design of the Base Station and associated software complies with medical device 
electrical and software standards.  Moreover, appropriate hardware risk control 
measures have been taken so that a software failure is not associated with risk of 
serious injury.  Hence, the overall safety of the Phagenyx® System is Class A.    
 
 
Figure 4: Phagenyx® Base Station with labeled components:   
a) Touchscreen – Touch sensitive glass screen 
b) Casework – High density Acrylobutdiene Styrene  (ABS.)  Easy clean surface 
c) On/Off switch – Push button switch with integrated LED indicator to show when 
unit is turned on 
d) USB port cover – Easy lift material to provide protection and convenient access to 
USB port 
e) Current and battery indicators – Lights to show when system is actively delivering 
current or being charged  
f) Connector to Phagenyx® Catheter – For connection to the Smart Connector on the 
Phagenyx® Catheter prior to treatment 
g) Cable clip – Securing point for the treatment cable 
h) Cable tidy – Convenient storage position for the treatment cable 
i) Treatment cable – Cable and connector through which data and the treatment 
current is delivered to the patient 
j) Cable groove – Retaining feature on the cable tidy to ensure the correct tension is 
applied to the Treatment cable 
k) Mains Supply socket - Recessed socket to receive standard mains supply cable 
 
The Phagenyx® Catheter is a two-part construction.  The inner core is in the form 
of a nasogastric (NG) feeding tube with a guidewire.  The outer part is in the form 
of a thin walled Sleeve that incorporates two ring electrodes, insulated wires 
located in the walls of the Sleeve to deliver the current, and a connector (the S-
connector) (Figure 5). The Sleeve is designed to be positioned over the NG tube 
and to be capable of freely moving up and down along its length.  The Phagenyx® 
Catheter is available in one size only. The NG tube has an outer diameter (OD) of 

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8F (2.75 mm), and is 123 cm long to provide sufficient length to access the 
stomach for feeding purposes and pH sampling.  The outer Phagenyx® Catheter 
sleeve has an OD of 11.5F (3.85 mm) and is approximately 70 cm long.      
 
The Phagenyx® Catheter is supplied as a single-use sterile product.  The 
Phagenyx® Catheter and accessories are supplied in a formed tray (Figure 6).  
The tray and contents are terminally sterilized using ethylene oxide. 
     
There are two accessories parts supplied with the Phagenyx® Catheter: 
1. A Garment Clip to secure the external parts of the Phagenyx® Catheter to 
alleviate weight 
2. A Transition Adaptor to enable standard connections for feeding delivery 
 
 
Figure 5: Phagenyx Catheter 
 
 
 
 
 
 
 
 
 
Figure 6: Phagenyx® Catheter packaging with accessories 
 
2.3.3 DEVICE USE 
 
The Phagenyx® Catheter is placed so that the electrodes are positioned at the junction 
between the oropharynx and the laryngopharynx at a position that is equivalent to the 
junction between the C3 and C4 cervical vertebrae. Electrical stimulation is applied to 
 
 
 

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the oropharyngeal mucosa via a pair of bipolar ring electrodes as depicted in Figure 7. 
The electrical stimulation is composed of pulse trains at an intensity of 5-50mA with a 
pulse width of 200 µs at a frequency of 5 Hz. Hence, a ten-minute treatment period is 
composed of 3000 swallowing stimuli with 600 ms of “on” time in which electrical current 
is being applied.  Less than 1 kcal of heat is produced over the treatment period with 
minimal local temperature increase.     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 7: Transnasal placement of the Phagenyx® Catheter and area of 
electrical stimulation 
 
 
2.4 RISK/BENEFIT ASSESSMENT   
 
2.4.1 POTENTIAL AND KNOWN RISKS  
 
Design and Manufacturing 
 
Residual risks associated with the design and manufacturing of the Phagenyx® System 
have been reduced to acceptable levels. The electrodes are formed from 304 steel 
polished tubing that is cut, de-burred and rounded to remove any sharp edges.  These 3 
mm wide cylinders are then crimped onto the polyurethane tubing and the tubing is 
subsequently reflowed to seal the edges of the electrodes and bring the surface of the 
tubing to the same level as the surface of the electrodes.  The effect of this processing 
ensures a seamless transition from tubing to electrodes without exposed edges or sharp 
features.  The outer diameter of the electrodes is less than that of a 12 Fr nasogastric 
feeding tube falling within the range of dimensions that represent standard practice for 
enteral feeding devices.  The finish at the tube-electrode interface undergoes a 100% 
inspection at the point of manufacture.  The Phagenyx® Catheter is placed so the 
electrodes are positioned at the junction between the oropharynx and the 
C2 
C3 
C4 
Electrode 
locations 
Electric field 

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laryngopharynx at a position that is equivalent to the junction between the C3 and C4 
cervical vertebrae.  The electrodes are thus in an anatomical area that is much larger 
than the 11.5F Phagenyx® Catheter, and thus mucosa is not expected to be 
compressed against the metal. Relative movement between the electrodes and mucosa 
will certainly occur; however, there is no source of pressure locally to apply force 
between electrodes and tissue. Moreover, the electrode and tubing surfaces are 
contiguous, hence any pressure is evenly spread and analogous to that encountered 
with a standard fine bore feeding tube. 
 
Phagenyx® Catheter Placement 
 
Complications associated with injuring or perforating the nasogastric tract upon 
misplacement of an NGT are a seemingly sparse occurrence with a literature search 
resulting in only rare case reports.  Arguably, the two metal electrodes on the surface of 
the Phagenyx® Catheter may increase the risk of local effect upon the pharyngeal 
mucosa by creating inflammation, erosion, or even ulceration.  As described in the 
paragraph above, the design and anatomical placement of the electrodes minimizes risk 
severity and likelihood.   
 
Patients will be exposed to the inherent risks associated with placement of any NGT, 
and patients who receive nutrition orally or via PEG will be exposed to additional risks of 
requiring the nasogastric Phagenyx® Catheter remain in place for the time required to 
complete the three consecutive daily stimulation sessions.  Patients who participate at 
sites that utilize NGTs for feeding may have the Phagenyx® Catheter indwelling for 
longer than the time required to administer study treatment and therefore may be 
exposed to incremental risks associated with the design of the Phagenyx® Catheter 
incorporating embedded electrodes.  
  
Nasogastric tube feeding is common practice and thousands of tubes are inserted daily 
without incident. However, there is a risk that the tube may become misplaced into the 
lungs 17 during insertion, or move out of the stomach at a later stage.  The actual 
incidence of complications related to NGT placement is very low. Sparks et al., 
performed a meta-analysis which demonstrated the potential severity of pulmonary 
complications as well as the rare incidence in which they occur: pneumothorax and 
subsequent death occurred in 0.35% and 0.05% cases of nasoenteral tube (NET) 
placement, respectively18.   
 
The risk of accidental enteral feeding into the airway following misplacing a nasogastric 
tube is rarely mentioned in published literature.  However, the United Kingdom National 
Patient Safety Agency issued a National Safety Alert in 2011 in attempts to raise 
awareness of this risk and provide guidelines to reduce the risk18 of feeding into the 
airway. The alert emphasizes that while “thousands of tubes are inserted daily without 
incident,” grave harm may result in unrecognized misplacement of a nasogastric tube.  
To mitigate this risk, verification of proper NG tube placement is standard clinical 
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Sinusitis has been linked to the presence of NG tubes used for enteral feeding in 
studies of patients developing nosocomial infections while in intensive care.  The 
presence of the nasal tube causes obstruction in the normal flow of sinus fluids and can 
therefore lead to increased risk of bacterial colonization and development of hospital-
acquired sinusitis19.  Current practice methods in Europe and the US provide for 
replacing nasoenteric feeding tubes with a PEG if an extensive enteral feeding duration 
is required (e.g., 2-3 weeks in Europe20 and typically even sooner in the US), so lengthy 
nasogastric intubation times are not expected in this study.            
 
Nasoenteric feeding tubes may easily become dislodged due to patient mental status, 
transfers, or positional changes.  While this phenomenon is most frequent in acute 
stroke patients, it may also occur in the sub-acute period.  Attachment of the 
Phagenyx® Catheter to the patient's nose will be performed via the standard practice 
used at each investigational site.  The Phagenyx® Catheter is packaged with a garment 
clip so that it may be fastened to the patient’s garment in a manner that will relieve the 
weight of the connectors and attached cables thereby minimizing the risk of any injury to 
the nasal wing tissue. 
       
Placement of an NGT would seemingly place patients at an increased risk of epistaxis; 
however, review of the literature produced only two publications that referenced 
epistaxis in relationship to use of an NGT, and both citations were associated with 
endoscopic NET placement40, 41 rather than NGT placement. 
 
A list of the risks associated with the Phagenyx® System and stroke can be found in 
Section 8.2 
 
Radiation Exposure 
 
The VFSS is considered the “gold standard” in the US for diagnosing the nature and 
severity of dysphagia as well as providing feedback on the effects of dysphagia 
therapy21.  Hence, it would not be unusual for a dysphagic patient to undergo at least 
two VFSS studies over the course of being treated for dysphagia after stroke. The 
investigational protocol specifies two VFSS assessments be performed within a 1-week 
period to standardize baseline measures and to provide feedback on the dysphagia 
treatment under investigation shortly after the intervention. Patients typically undergo a 
non-instrumented dysphagia assessment before referral for an instrumented VFSS.  
Participating sites will be instructed to use the study-specific VFSS protocol for patients 
referred to an instrumented dysphagia assessment if they also appear to meet the rest 
of the study inclusion/exclusion criteria.  Patients meeting the study criteria will require 
one subsequent VFSS performed according to the study-specific VFSS protocol.  
Hence, patients will be exposed to one, and possibly two, more VFSS than they would if 
they were not enrolled in this study.   
 
The VFSS imparts a small dose of ionizing radiation.  Zammit-Maempel et. al., reported 
a median exposure time of 171 seconds and an associated dose of 0.20 milliSieverts or 
mSv43, while Moro and Cazzani reported a median exposure time of 149 seconds and 

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an associated dose of 0.35 mSv44. The standardized VFSS protocol proposed for this 
study is associated with an average duration of 2.9 minutes radiation exposure (95% 
confidence interval 2.8-3.0 minutes).  Extrapolating from the relationship Moro and 
Cazzani published, the VFSS time of 2.9 min (174 sec), relates to an effective dose of 
~0.44mSv45.  
 
Table 1 provides background information on relative average absorbed doses of 
ionizing radiation that a person would experience when exposed to various sources. On 
average, a U.S. resident receives an annual radiation exposure from natural sources of 
about 3.1 mSv. In addition, man-made sources of radiation from medical, commercial 
and industrial activities contribute roughly 3.1 mSv more to our annual exposure46. 
Computed tomography (CT) scans, are among the largest of these sources, with a head 
CT contributing 2mSv47.  
 
The average amount of radiation to which a patient is exposed over the duration of the 
VFSS is expected to be 2.9 minutes with an average absorbed dose of 0.44mSv 
ionizing radiation, with some variation dependent on site-specific imaging equipment. 
Hence patients participating in this study will experience radiation exposures that are 
less than 25% of the radiation associated with a head CT exposure and about 0.9% of 
the annual maximum permitted by the FDA radiation dose for radioactive drug 
research48. Comparing to background radiation, VFSS radiation exposure is equivalent 
to 1.7 months of natural exposure. 
Table 1: Average absorbed radiation doses from various sources 
Radiation Source 
Absorbed Cellular Dose 
(mSv) 
Background naturally occurring radiation, 
yearly 
• 
3.1 
VFSS 
• 
0.44 
Head CT 
• 
2 
 
FDA Regulations on Radioactive  
Drug Research: 
 
Maximum radiation dose to whole body, active 
blood-forming organs, lens of eye, gonads  
• 
Single dose = 35 
• 
Annual and total dose = 50 
Other organs 
• 
Single dose = 50 
• 
Annual and total dose = 150 
 
A strategy that is popularly used to decrease radiation exposure is reducing the pulse 
rate of the radiation beam emitted during VFSS. The emitted radiation beam can be 
either continuous or pulsed. When pulsed, the pulse rate is defined as the number of 
pulses per second (pps) of the x-ray beam. Pulse rates for fluoroscopy commonly 

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include 30, 15, 7.5, and 4pps. Radiation exposure is reduced as pulse rate is reduced. 
Specifically, Aufrichtig et al., demonstrated average dose reductions of 22% at 15 pps 
and 49% at 7.5 pps when compared to doses at 30 pps49. Decreasing pulse rate also 
has a direct and proportional effect on the number of unique images in which a swallow 
is captured. Since the oropharyngeal swallow only lasts approximately one second, 
when pulse rate is decreased from 30 to 15, the number of unique images available to 
judge swallowing impairment also decreases from 30 to 15. Bonilha and colleagues 
reported differences in both judgment of swallowing impairment and treatment 
recommendations when pulse rates are reduced from 30 pps to 15 pps to minimize 
radiation exposure50. Differences between penetration aspiration score for the four 
pulse rates tested indicate that pulse rate may have a high impact on attributes of the 
interpretation of the VFSS.   
 
The standardized VFSS protocol proposed for use in this study specifies a  continuous 
pulse rate of 30 pps. The patient population exposed to ionizing radiation in this study 
will be of advanced age, with similar studies enrolling patients with an average age over 
70 years. Thus the relative incremental risk associated with study-specific exposure to 
ionizing radiation is considered minimal based on the stochastic nature of risk 
associated with ionizing radiation exposure.   
 
Finally, the objective of the VFSS is to assess the degree to which boli of incrementally 
thicker media penetrate or aspirate into the airway.  Hence, the method by which risk of 
aspiration is studied also imparts an incremental risk of patients developing aspiration 
pneumonia after performing the VFSS.  Jo et. al., recently published a retrospective 
review of the occurrence of pneumonia developing after aspiration during VFSS at their 
teaching hospital in Chuncheon, South Korea51. The authors reviewed 696 VFSS for 
cases in which blood cultures were performed within 3 days following the VFSS due to 
newly developed infectious signs.  Pneumonia was suspected when there was some 
evidence of respiratory infectious signs in clinical, radiological, and laboratory findings. 
Fifteen cases of pneumonia were identified in this manner.  Review of the VFSS 
procedure records indicated that only seven of these cases (1%) could be attributed to 
the VFSS. 
 
 
2.4.2 POTENTIAL BENEFITS  
 
Potential benefits resulting from this study: 
 
• Information gained from the conduct of this study may be of benefit to other 
people with oropharyngeal dysphagia following stroke in the future.  
 
The ideal patient population and treatment regimen for optimizing the use of pharyngeal 
electrical stimulation are still not completely understood now.  However, most studies 
have demonstrated that patients with post-stroke dysphagia benefit to some degree 
from pharyngeal electrical stimulation when assessed using standardized measures of 
swallowing function and performance.   

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Alternative treatments include other types of stimulation approaches (e.g., 
neuromuscular, direct neural, transcranial) for which there is little evidence for adoption 
into general practice.  Patients will receive the standard interventions for dysphagia that 
are practiced at the participating institution and generally accepted by ASHA. 
 
2.4.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Post-stroke dysphagia in the hospital setting is associated with poor outcomes.  It is 
known to increase the risk of life threatening and difficult to treat infections as well as 
increase mortality.  If unresolved, dysphagia represents a major long-term disability 
burden, impacting patient survival, cost of care and quality of life. There are no clinically 
proven evidence-based treatments for dysphagia.    
 
The Phagenyx® System is a NSR device.  The safety profile associated with the use of 
the Phagenyx® System is well characterized by evidence accumulated from multiple 
clinical studies and ongoing post-market surveillance involving over 30 institutions in 
five countries over a period of 15 years. There are no characteristic device or treatment 
specific effects that are considered to be serious adverse events.  The additional risks 
associated with the clinical study design are all well understood and can be easily 
mitigated. None of the protocol-specific assessments are expected to add significant 
risk over those risks inherent in the care of patients suffering dysphagia in the subacute 
stroke setting.  
 
Patients participating in this study are expected to be exposed to only marginal 
incremental risk over standard of care, and some patients may experience more 
expedient and more successful outcomes associated with their dysphagia treatment.  
Hence, the benefits associated with study participation are expected to outweigh any 
incidental incremental risk. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3 
STUDY OBJECTIVES AND ENDPOINTS 
 
STUDY OBJECTIVES 
STUDY ENDPOINTS 
Primary 
To 
evaluate 
the 
efficacy 
of 
Phagenyx® treatment in reducing the 
severity of unsafe swallows. 
 
 
 
 
 
 
 
 
 
Swallowing safety of a bolus based on PAS of 
each swallow, determined by a VFSS 48 hours 
after completion of investigational treatment, 
converted to a trichotomized ordinal response 
of safe (PAS 1-3), penetration (PAS 4-5), or 
aspiration (PAS 6-8). Each patient contributes 
up to 12 post-treatment repeated 
measurements (PAS) including 6 swallows of 
thin and 6 swallows of nectar. 
Secondary 
To evaluate the efficacy of Phagenyx 
treatment in improving nutritional 
management.  
Functional Oral Intake Scale (FOIS) at  7 days 
following the last investigational treatment. 
 
Dysphagia Severity Rating Scale (DSRS) at 7 
days following the last investigational treatment  
 
 
Exploratory 

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STUDY OBJECTIVES 
STUDY ENDPOINTS 
To further characterize the efficacy of 
Phagenyx® treatment in reducing the 
severity of unsafe swallows. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To evaluate the efficacy of 
Phagenyx® treatment on nutritional 
management changes. 
 
 
 
 
The severity of unsafe swallows will be further 
evaluated via: 
o PAS outcome by each consistency (thin 
and nectar) 
o Physiologic 
measurement 
obtained 
using the Modified Barium Swallow 
Impairment Profile (MBSImP) metrics will 
be extracted from the thin and nectar 
swallows by the core lab by using the 
baseline and follow up VFSS data. 
These validated and reliable metrics of 
critical swallowing movements will be 
explored for their relationship to the 
primary study endpoint (PAS). 
o PAS dichotomized as safe (PAS 1-3) or 
unsafe (PAS 4-8) 
 
Nutritional management improvement will be 
evaluated via: 
o Dysphagia 
Severity 
Rating 
Scale 
(DSRS) at 14 days or discharge, 
whichever is first, and at 11 weeks  
following 
the 
last 
investigational 
treatment. 
o Time from baseline to removal of enteral 
feeding (i.e., removal of NG tube or 
PEG or transition to oral feeding, or first 
diet upgrade) 
o Functional Oral Intake Scale (FOIS) at  
7 days,  14 days or discharge, 
whichever is first, and 11 weeks    
following the last investigational 
treatment 
To evaluate the efficacy of 
Phagenyx® treatment on improving 
quality of life. 
Quality of life (QOL) will be assessed baseline 
and 11 weeks following the last investigational 
treatment via the following instruments:   
o EuroQoL-5 
Dimension 
Questionnaire 
(EQ-5D) and EuroQoL-Visual Analogue 
Scale (EQ-VAS) 
 
 

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STUDY OBJECTIVES 
STUDY ENDPOINTS 
To evaluate the efficacy of 
Phagenyx® treatment on general 
stroke health outcomes. 
General stroke health outcomes will be 
assessed by: 
o Time to discharge from site in which 
treatment is received   
o Discharge destination from the site in 
which treatment is received  
o Patient location (home, institution) at 11 
weeks  
o Days on antibiotics during hospital stay 
o NIH Stroke Scale (NIHSS) at baseline 
and 14 days or discharge, and 11-week 
follow up  
o Modified Rankin Scale (mRS) at baseline, 
14 days, and 11 week follow up  
o Barthel Index (BI) at baseline, 14 days or 
discharge, and 11-week follow up  
o New 
onset 
pneumonia, 
using 
a 
standardized definition adapted from the 
STROKE-INF study26 at baseline, 48 hrs, 
7 days, and 14 days or discharge  
o Hospital readmission rate 
o Number of CXR (related to suspect 
pneumonia) 
 
 
 
 
4 
STUDY DESIGN  
 
4.1 OVERALL DESIGN 
 
This is randomized, sham-controlled, patient-masked, outcome assessor-blinded, 
prospective, multi-center study designed to support a de novo submission and FDA 
clearance for the Phagenesis Phagenyx® System for treatment of oropharyngeal 
dysphagia following a stroke. The study will follow an adaptive group sequential design 
with unblinded sample size re-assessment.   To ensure 180 evaluable patients with 7-
day data and assuming a 20% dropout rate, 225 patients will be enrolled initially.  An 
interim analysis for futility will occur after the first 60 patients complete their 7-day visit 
and another interim analysis will be performed for efficacy after 120 patients complete 
their 7-day visit.  The total sample size may be increased up to 338 patients after the 
second interim analysis to ensure 270 evaluable patients.  Up to 15 investigational 
centers across the US and Europe will participate in this study. The enrollment period is 
expected to be approximately 24 months and patient participation will last for 
approximately 11 weeks.  Patients will be assessed at the following intervals: baseline, 

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within 48 hours of treatment, 7 days, 14 days or at discharge, whichever is first, and 11 
weeks after completion of study treatments.  
 
Investigational sites will be chosen from centers that have standardized protocols for 
treating patients with dysphagia post-stroke.  Centers will be selected so that US sites 
represent the majority, with the ability to contribute at least 60% of the total patients.  All 
sites must have speech language therapists/pathologists (SLT/SLP) on staff as well as 
affiliated VFSS facilities and personnel. 
 
All enrolled patients will have the Phagenyx® Catheter placed and will receive either an 
active treatment with Pharyngeal Electrical Stimulation or a sham treatment by a HCP 
who is un-blinded to the treatment assignment.  
 
Randomization will use stratification based on site and baseline PAS. Minimization may 
also be included to ensure group balance for study site and additional baseline 
covariates.  
Administration of all protocol-specific assessments, other than PES or sham treatments, 
will be conducted by personnel who are blinded to the treatment assignment, including  
speech pathologists providing  standard dysphagia care (excluding VitalStim and e-
Stim). The standard dysphagia care data will be collected on the eCRF.   
 
A core laboratory will be established for analysis of all procedural VFSS.  The VFSS 
core lab will provide standardized baseline and follow-up analyses of the primary 
endpoint as well as VFSS-related tertiary endpoints. Personnel at the VFSS core lab will 
also be blinded to patient treatment assignment. 
 
Up to three unblinded, active treatment roll-in patients will first be enrolled at each site in 
the US. The need for roll-in patients for European sites will be based on experience with 
the CE-marked device at the site and will be agreed to by Phagenesis and the site 
investigator.  Roll-in patients will enable the site study staff to become fully proficient in 
the most effective way to administer the Phagenyx® treatment as well as perform other 
protocol-specific assessments. The sponsor will provide detailed training and education 
to the site staff in the use of the Phagenyx system and the protocol.   The sponsor will 
provide an on-site representative to oversee and provide aid in the administration of 
PES during treatment of these roll-in patients. The sponsor will complete the Site 
Training and Competency Review form during the visit(s).  The site will be approved to 
begin randomizing patients after the site meets the following competency requirements:  
 
• The treatment administrator successfully and confidently completes up to three 
treatment sessions with little to no prompting or other aid from the sponsor 
representative, 
• The treatment parameters recorded on the Base Station reflect appropriate 
stimulation levels, and 
• Electronic case report forms (eCRFs) for baseline through the acute follow-up 
visit are completed correctly within 5 days of enrollment then within 5 days of 
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A formal review of site competency will be made after one to three roll-in patients have 
been treated, and the site is competent based on the above parameters.  The site 
investigator and other relevant personnel will meet with sponsor personnel or their 
designee(s) via teleconference or on site to review the roll-in patient records and 
answer outstanding questions.  The sponsor or their designee will provide approval to 
begin randomizing patients by controlling access to the randomization module of the 
study’s EDC system. Meeting documentation including recommended actions and 
decisions will be retained in the eTMF for each site.   
 
Roll-in patients will be analyzed independently from the primary analysis population but 
will not contribute to the sample size cap.  
 
Dysphagic patients enrolled into the study will continue to receive enteral or oral 
nutrition via the same manner as prior to study entry and will also have the Phagenyx® 
Catheter placed as part of the study. In the US, patients may receive feeding through 
the Phagenyx® Catheter for up to 2 weeks as needed.  In Europe, patients may receive 
feeding through the Phagenyx Catheter for up to 30 days.  
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Clinical investigation demonstrates that pharyngeal electrical stimulation holds potential 
for treating patients that are dysphagic following stroke. Based on the founding work 
reported by Fraser, cortical excitation is directly related to the amplitude of the 
stimulation signal. The outcome of the STEPS study (Bath et. al.21) had a neutral 
outcome, therefore, this study is designed to overcome some shortcomings that were 
noted in the STEPS study, including: 
 
• Dysphagia entry criterion has been set to PAS ≥ 4 to limit mild dysphagia; 
• Patients will be enrolled at least seven days after their index stroke to omit those 
with early spontaneous recovery; 
• The sham treatment will include Phagenyx Catheter placement but no PES to 
prevent inadvertent treatment. 
 
4.3 CLINICAL EXPERIENCE AND JUSTIFICATION OF PES LEVEL 
The Phagenyx® System, or variants thereof, has been studied over a period of 15 years 
during development and more recent commercial studies in over 30 institutions in five 
countries. Most clinical studies have demonstrated that patients with dysphagia after 
stroke experience a clinical benefit associated with pharyngeal electrical stimulation 
when assessed using standardized measures of swallowing function and performance. 
Please see the Investigator’s Brochure for complete information on these studies. 
 
 
5 
STUDY POPULATION 
 
5.1 INCLUSION CRITERIA 

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To be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Age ≥ 18 and ≤ 90 years.  
2. Acute ischemic or hemorrhagic cerebral stroke within 7-28 days of baseline 
VFSS.  
3. Score of 0 or 1 on NIHSS question 1a, Level of Consciousness. 
4. *Moderate to severe dysphagia (PAS ≥4) on baseline VFSS (Baseline VFSS 
must meet the threshold criteria of demonstrating a PAS of ≥ 4, in three of the six 
boli (5 mL/1 tsp/bolus), during swallowing “thin liquid” barium media as assessed 
by the clinical staff administering the VFSS) unless its deemed too high risk then 
only 2 swallows will qualify.  
5. Willing and able to have the Phagenyx® Catheter placed transnasally.   
6. Willing and able to provide informed consent. 
7. Stated willingness to comply with all study procedures and availability for the 
duration of the study. 
 
*Note that the baseline VFSS will include testing with both thin liquids (up to 6 swallows) and 
nectar liquids (up to 6 swallows). For inclusion criterion 4, only the thin liquid swallows on the 
baseline VFSS will be considered. However, for descriptive statistics and other analyses, both the 
thin liquid and nectar liquid swallows on the VFSS will be considered. 
 
 
5.2 EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation 
in this study: 
1. Brainstem stroke. 
2. Evidence of traumatic brain injury or subarachnoid hemorrhage. 
3. Other, non-cerebrovascular, structural brain diseases, including multiple 
sclerosis or other demyelinating diseases, brain tumors (other than small 
meningioma), neurodegenerative diseases (including Alzheimer and Parkinson 
disease), hydrocephalus, and leukodystrophy 
4. Dysphagia from conditions other than stroke.  
5. Pre-stroke history of swallowing complaints or treatment or history of diseases 
known to be associated with swallowing problems (other neurological, head 
and neck cancer. 
6. Distorted oropharyngeal anatomy (e.g., pharyngeal pouch, major pharyngeal 
surgery or head /neck surgery) 
7. Currently being treatment for pneumonia.  
8. Mute, global aphasia; no usable speech or auditory comprehension (scores 3 
on NIHSS question 9, Best Language) 
9. NIHSS score of >25 
10. Presence of a tracheostomy  
11. Any active implanted device (e.g., cochlear implant, ICD, permanent 
pacemaker) 

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12. Any progressive neurological disorder (e.g., Parkinson’s Disease, Multiple 
Sclerosis) 
13. Cognitive 
impairment 
that 
prevents 
compliance 
with 
protocol-specific 
instructions and assessments  
14. Unstable cardiopulmonary condition, i.e., not on maintenance therapy. 
15. Currently participating in another investigational study 
16. Pregnant or planning to become pregnant while participating in the clinical 
study 
17. Known Allergy to oral radiographic contrast media (specifically barium)    
18. Any other condition in the opinion of the investigator will prohibit the patient 
from participation and follow up. 
 
 
5.3 SCREEN FAILURES 
 
Screen failures are defined as patients who consent to participate in the clinical study 
but are not subsequently randomized to the study intervention or entered in the study.  
A record of screen failures, along with the reason for failure, will be kept in the database 
and/or on a Screening Log. 
 
 
5.4 STRATEGIES FOR RECRUITMENT AND RETENTION 
Patients will be screened and recruited by the investigators and/or coordinators at each 
site.  Eligible patients could be in an inpatient rehabilitation center, having been 
transferred from the acute care facility in which they had been initially treated for the 
stroke, or site standard unit for post-acute stroke patients.  The length of stay for these 
patients should be for up to 2 weeks to complete the study requirements for treatment 
and 14 day (+/- 1 day) follow up.  
 
Stroke patients identified as dysphagic by clinical bedside assessments between the 
ages of 18 and 90 years, will be screened for study enrollment.  The patient or their 
legal guardian will be eligible to sign the ICF after the study team explains the study and 
the patient and family have time to read and understand as well as ask all questions.  
The importance of study compliance will be emphasized throughout the informed 
consent process.  
 
The length of study participation is approximately 11 weeks, including post treatment 
follow-up visits at 48 hours (+/- 24 hrs), 7 days (+/- 1 day), 14 days (+/- 1 day) or 
discharge, whichever is first, and 11 weeks (+/- 1 week).  
 
6 
STUDY INTERVENTION 
 
 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 

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6.1.1 PHAGENYX® CATHETER PLACEMENT 
All patients who have met screening and baseline criteria, signed an informed consent, 
and are enrolled in this study will require transnasal placement of the Phagenyx® 
Catheter which will remain in place for the minimum time required to complete three 
consecutive daily treatment sessions of active or sham stimulation. Patients will 
continue to receive nutrition via the same manner as prior to study entry, and will also 
have the Phagenyx® Catheter placed.  Patients who already have an NGT will need to 
have it replaced with the Phagenyx® Catheter.  Patients may receive feeding through 
the Phagenyx® Catheter as needed for up to 2 weeks in the US and up to 30 days in 
Europe. 
The Phagenyx® Catheter should be configured to fit each patient optimally before it is 
inserted.  This is done to ensure electrodes are in the correct position to deliver 
stimulation and the distal end of the Phagenyx® Catheter is in the proper position for 
the delivery of nutrition to the stomach, if being used for feeding. Numbers printed on 
the exterior of the Phagenyx® Catheter are indexed to align to the correct position in the 
pharynx based on patient measurements.  See Instructions For Use (Phagenyx PNX-
100 Catheter IFU) in the eTMF. 
 
1. The distance from nostrils to earlobe to xiphisternum is 
measured out using the Phagenyx® Catheter with its distal tip 
positioned at the nostrils.  
 
2. The number on the Phagenyx® Catheter printed guide is 
noted for correct Sleeve positioning so electrodes are 
properly placed in the pharynx. 
 
3. The Sleeve is then adjusted so that the positioning guide is 
aligned over the number on the printed guide so that the 
heavy bars appear on either side of the number. 
 

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4. The tube clamp on the Sleeve is closed to fix the relative 
positions of Sleeve and Phagenyx® Catheter components. 
 
5. The Phagenyx® Catheter is inserted nasally using site 
standard technique, until the number below the positioning 
guide is at the patient’s nostril. The position of the NGT is 
verified via standard institutional procedures to ensure the 
distal end is in the stomach via x-ray of catheter placement; 
auscultation of air in the stomach injected through the 
Catheter; and/or aspiration of stomach contents through the 
Catheter to confirm gastric pH, or per standard at each site. 
6. The guidewire is removed and disposed of. 
 
7. The Phagenyx® Catheter is secured in place as per standard 
practice for NGT placement (medical tape or custom 
bandage). 
 
 
 

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8. The Garment clip is attached to the 
patient and proximal end of the 
Phagenyx® Catheter inserted into 
the tube grip for comfort.  
 
 
If the Phagenyx® Catheter will also be used for feeding, the enteral connector is 
connected to a suitable enteral feeding set (use of the supplied adaptor, as 
needed). Prior to NGT feeding, the correct placement of the NGT should be 
verified to avoid feeding into any space other than the stomach. 
6.1.2 VITAL SIGNS MONITORING 
 
Vital signs monitoring is required for approximately the first 20 patients receiving  active 
treatment (including roll-in patients).  To maintain the blind, the vital signs will be 
obtained on all patients including those randomized to sham treatment, until there are 
data for 20 patients who have received active treatment; this applies to all three days of 
treatment. Vital signs monitoring includes blood pressure, heart rate, and ECG 
monitoring.  Immediately (within 5 minutes) prior to beginning PES treatment, the user 
will obtain and record pre-treatment blood pressure and heart rate numbers, as well as 
a 30-second ECG rhythm strip.  Vital signs monitoring will continue throughout the 
duration of study treatment and any significant changes (i.e. noticeable increases) will 
be documented for study records.  A second ECG rhythm strip is required 5 minutes 
into the PES treatment, and a third ECG rhythm strip is required immediately (within 5 
minutes) post treatment. Immediate post-treatment blood pressure and heart rate 
numbers will again be obtained and recorded. 
 
6.1.3 STIMULATION LEVEL OPTIMIZATION AND TREATMENT 
 
The user first verifies that the electrodes are correctly positioned by inspecting the 
positioning guide, and ensuring the same number appears between the heavy bars of 
the positioning guide (refer to Step 3 above).  In the majority of patients, the catheter will 
not need to be repositioned after it is inserted for the first time.  In some patients, it may 
also be possible to visualize the oral guide in the throat. If the Sleeve is no longer 
aligned so that the electrodes are in the correct position, the Sleeve tube clamp can be 
opened and the Sleeve position adjusted until the correct positioning number is visible 

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between the heavy bars of the positioning guide.   Treatment can be carried out after 
confirming the proper placement.   
 
1. The treatment cable from the Base Station is attached to the Phagenyx® Catheter.  
2. The Base Station power is turned on. 
3. The study-specific patient identifier is entered upon first treatment, and is re-called 
for subsequent treatments. 
4. The patient’s Threshold Level (lowest detectable level of stimulation) is established 
via incremental current increase from 5mA to 50mA in 1 mA steps.  This is repeated 
three times, and the average of the three readings is used to determine the 
treatment level of stimulation.  
5. The patient’s Tolerance Level (highest tolerated level of stimulation) is established 
via incremental current increase from the Threshold value in 5mA to a maximum of 
50mA. This is repeated three times, and the average of the three readings is used to 
determine the treatment level of stimulation.   
6. The Stimulation Level is automatically calculated.  This level is tested for eight 
seconds to ensure patient tolerability, and adjusted as needed. 
7. The Stimulation Level is initiated, and lasts for up to 10 minutes. The patient is 
monitored/supervised throughout. 
8. Steps 1-7 are repeated once per day for two subsequent consecutive days 
approximately 24 hours apart, for a total of three treatments over three days. 
9. See the Instructions for Use (Phagenyx Base Station IFU) in the study’s eTMF. 
6.1.4 DISPOSAL  
The Phagenyx® Catheter will become electronically locked once the 3-treatment 
regimen has been completed to prevent over-treatment or use of the device across 
multiple patients.  If the catheter is not being used for feeding,  it is removed after 
completion of the 3 treatments by a qualified health care provider and should be 
disposed of in medical waste as per site-specific procedure.  
 
6.2 DEVICE ACCOUNTABILITY, LABELING AND STORAGE 
 
6.2.1 ACCOUNTABILITY 
Investigators will maintain accurate records of the receipt and disposition of the 
investigational device on the Device Disposition Log supplied by Phagenesis. The Log 
will be used to record device receipt, uses, discards, or returns.  Device disposition will 
be verified by the clinical monitor periodically throughout the study.  The investigator 
shall return the Base Stations, unused devices, and the completed device disposition 
log at completion of the investigation to Phagenesis or their designee, as directed. The 
investigator’s copy of the Device Disposition Log must document the devices used in 
study patients as well as the unused devices that are returned to Phagenesis.  Use of 
the Phagenyx System is prohibited outside of this protocol in US centers.  In Europe, 
although the Phagenyx System is CE marked, the devices supplied for the study will be 
documented on the Device Disposition Log, stored in a secure area away from general 
stock, and only used for study patients. 

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6.2.2 LABELING 
In the US, the Phagenyx® System (Base Station and Catheters) will be labeled as 
investigational.  In Europe, the device is CE-marked and will not be labeled 
investigational. The sites outside of the US will be provided an additional Base Station 
to be used for patients randomized to sham treatment. The Base Stations will be 
identified in such a manner to maintain the blind.  
 
6.2.3 STORAGE 
All Phagenyx® System components are to be stored in an ambient temperature-
controlled, dry secure location where only authorized study personnel can access the 
devices for study use. 
 
The Phagenyx® Base Station requires an overnight connection to an electrical outlet for 
overnight charging once a month.    
 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
All efforts will be taken to maximize treatment assignment blinding of the patient, 
caregivers, and third-party outcome assessors of clinical endpoints. Sites will be 
instructed to assign one healthcare professional to each enrolled patient to administer 
Phagenyx® treatment; this HCP shall not be blinded to the assigned patient’s treatment.  
The designation of this individual will be at the discretion of the site investigator and 
may be a study nurse, SLP, or staff physician. The individual selected to administer the 
Phagenyx® treatment may not be an SLP or qualified health care provider who is 
otherwise involved with care of the study patient. Moreover, rating scales that reflect 
oral diet progression (e.g., Functional Oral Intake Scale and Dysphagia Severity Rating 
Scale) will also be completed by an SLP that is blinded to randomization assignment.  
All persons involved in placement of the catheter, assessments, treatment and follow up 
will be at the discretion of the investigator based on skill set and site standards, and will 
be further trained by the sponsor with a competency review completed.  
 
Randomization will use stratification based on site and baseline PAS. minimization may 
also be included to ensure group balance for study site and additional baseline 
covariates Administrative permission to access the randomization assignment in the 
electronic database will be limited to unblinded HCPs who will administer treatment and 
who will monitor study compliance.   
 
Stimulation parameters for the active treatment sessions will be collected on the eCRF 
to enable monitoring of the performance of the investigational device as well as to 
ensure proper treatment administration.  Stimulation data will be monitored by a 
sponsor representative or designee who is uninvolved with the data analysis.  The 
eCRF in which stimulation parameters are recorded will have strict administrative 
permissions, so that only the individual monitoring the investigational device will be 
allowed access.  This monitor will also be responsible for monitoring compliance with 
the assigned treatment arm.     

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Patients will be masked to treatment and will not be told if they receive the active or 
sham treatment.  Some patients randomized to active treatment will have some 
sensation associated with the pharyngeal stimulation; however, a few with higher 
sensory thresholds may not feel anything as demonstrated in prior studies. The patients 
randomized to the sham treatment will not receive any actual stimulation and thus 
should not have any sensory feeling associated with the sham treatment. The informed 
consent documentation will advise that the patient "may or may not" feel the pharyngeal 
stimulation, so that those patients receiving either the active PES treatment of the sham 
treatment will not necessarily expect to feel anything.  All procedural steps will be 
carried out in a very similar manner for both groups of patients.  The only difference in 
the administration of the two treatments is that no electrical stimulation will be 
administered during the sham treatment.  The way the treatment is administered will not 
give the patient any idea as to their treatment as there are no light or sound indicators 
associated with the administration of PES.  Moreover, the individual administering 
treatment will be facing the patient at all times during the delivery of electrical (or sham) 
stimulations, and the base station will be facing the treatment administrator.  The shape 
of the base station will prevent the patient from seeing what is on the administrator's 
screen during treatment delivery.  The active/sham treatments will also be administered 
in privacy so that no other study personnel or patient caregivers/family members can 
observe the treatment or treatment assignment. 
 
For those patients randomized to the sham group, a different Base Station will be used 
that delivers no electrical current and does not have the ability to treat with PES.  This 
Base Station will have only “demo” software loaded, so the unblinded healthcare 
professional administering the treatment will have a screen and the ability to adjust the 
settings, without any changes or current begin delivered.   
 
An assessment of whether the patient remains blinded will be included at the 14-day 
(+/- 1 day) or discharge whichever is first, follow-up assessment.  This will be done via a 
question to the patient asking them if they believe they received the active or sham 
treatment and their response will be documented on the eCRF.  
 
Evaluation of the VFSS will be performed by an external core lab that is not part of a 
study site.  VFSS records will be anonymized so that records are only identified by site 
number, patient number, and type of study (i.e., baseline or follow-up). Core lab 
personnel will be blinded to the treatment assignment as well as the actual treatment 
received.  
 
Protection of the blind will be maintained for the interim analyses.  Study documents, 
analysis reports, closed meeting minutes and recommendations made by the Data 
Monitoring Committee will be maintained in a separate location not accessible by the 
sponsor or sites.     
 
Patient data monitoring will be performed in a consistent and dynamic manner so that 
there will be no need to disrupt the normal study conduct to provide data needed for an 

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interim analysis.  Sites will not be told the results of any interim analysis unless the 
study is to be terminated early for either futility or success.    
 
6.4 STUDY INTERVENTION COMPLIANCE 
 
Investigational site compliance with all study procedures, including randomization 
assignment and treatment, will be monitored by trained and qualified study sponsor 
representatives and/or designees.      
 
7 
VFSS STOPPING CRITERIA AND PATIENT/SITE/STUDY TERMINATION 
 
 
7.1 VFSS STOPPING CRITERIA 
 
• If the PAS is ≥ 6 (see below) for three consecutive bolus trials of the same 
consistency, that consistency should be stopped and the investigator (or trained and 
authorized designee) can decide if it is safe to move to the next consistency to 
assess dietary modification, or if the study needs to be stopped.  
 
       Penetration Aspiration Score Definitions: 
 
o Score = 6: Material enters the airway, passes below the vocal folds and is 
ejected into the larynx or out of the airway. 
o Score = 7: Material enters the airway, passes below the vocal folds & is not 
ejected from the trachea despite effort  
o Score = 8: Material enters the airway, passes below the vocal folds & no effort is 
made to eject  
 
• A ‘Stop’ may be applied at any time if the Investigator (or trained and authorized 
designee) feels it is unsafe for the patient to continue.  
 
• If VFSS time exceeds 3 minutes, the procedure must be stopped. 
 
Regardless of completion of the PES treatment, patients will be encouraged to remain 
in the study until they have completed the protocol-required follow-up period while 
maintaining respect for all patient rights.  Patients are free to withdraw from participation 
in the study at any time upon request.   
 
7.2 PATIENT TERMINATION  
 
Possible reasons for premature patient termination include but are not limited to the 
following: 
 
• Withdrawal of consent:  The patient decides to withdraw from the study. If a 
patient withdraws from the clinical investigation, the reason(s), if known, will be 

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recorded on the eCRF. If withdrawal is due to problems related to the 
investigational device safety or performance, the investigator shall ask the 
patient’s permission to follow his/her status/condition outside the investigation. 
 
• Lost to follow-up:  If a patient has been discharged to inpatient care at another 
institution, then attempts should be made to retrieve patient records from that 
institution. Telephone follow-up at 11 weeks (+/- 1 week) should be attempted at 
least three times.  If the patient does not respond to the three telephone calls, 
then the investigator should send a letter to the patient.  All attempts should be 
documented in the source documents and on the eCRF. A patient will be 
considered lost to follow up if more than 30 days has elapsed from last contact.  
Patients who discontinue prematurely will be included in the analysis of results 
and will not be replaced. 
 
An investigator may discontinue or withdraw a patient from the study for any reason, 
including the following: 
 
• Pregnancy 
• Significant non-compliance with study protocol 
• If any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study would 
not be in the best interest of the patient 
• Disease progression which requires discontinuation of the study intervention 
• If the patient meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation 
 
The reason for termination from the study will be recorded on the eCRF.  Patients who 
sign the informed consent form and are randomized but do not receive the assigned 
study intervention (whether sham or treatment) may be replaced to achieve the number 
of evaluable patients needed for analysis.  Patients who receive treatment but 
discontinue the study prematurely for any reason will not be replaced. 
 
7.3 SITE TERMINATION AND STUDY TERMINATION 
The sponsor may suspend or prematurely terminate an individual investigative site or 
terminate the entire study for the following reasons: 
• A decision is made to suspend or discontinue testing, evaluation, or development of 
the investigational product for any reason 
• An individual site may be closed for the following reasons: 
o The investigator fails to enroll patients into the study at an acceptable rate, 
o The investigator fails to comply with pertinent regulations of appropriate 
regulatory authorities, 
o Site personnel demonstrate insufficient compliance to protocol requirements, 
and/or 
o Site personnel submit knowingly false information from the research facility to the 
sponsor, study monitor, or appropriate regulatory authority 

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An investigator, IRB/EC, or FDA may suspend or prematurely terminate a site’s 
participation in a clinical investigation. The IRB/EC and FDA may suspend an 
investigation if a suspicion of unacceptable risk to patients arises; the sponsor shall 
terminate the investigation if an unacceptable risk is confirmed.  
 
If the study is terminated early, all specified follow-up data on patients enrolled prior to 
termination will be collected and reported. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 STUDY ASSESSMENTS  
8.1.1 SCREENING AND BASELINE ASSESSMENTS 
In addition to the assessments detailed below, a medical history and demographics data 
will be collected at the screening visit. The medical history can be obtained from the 
patient’s medical record and the physical assessment is part of standard care.   A 
modified physical exam will be conducted at the baseline visit to establish the patient’s 
current condition, to facilitate the appropriate adjudication of adverse events that may 
occur during the study.   Information obtained from these assessments will be recorded 
on the eCRF.   Informed consent will also be obtained, per standards and guidelines at 
each site.   
8.1.2 NASOPHARYNGEAL EXAMINATION 
The patient’s nasopharynx will be examined by means of a visual exam using a 
standard flashlight /penlight at baseline, Day 7 post catheter placement and upon 
removal of catheter.  If there is evidence or symptoms of erosion or trauma, a fiberoptic 
exam should be done to rule out any adverse events.  
  
8.1.3 VIDEOFLUOROSCOPIC STUDY (VFSS) 
The VFSS is a swallow test during which swallowing function is analyzed 
radiographically.  Institutional protocols vary widely with respect to the consistencies of 
the contrast materials and the volumes of each; hence, a standardized approach will be 
used for all protocol-specific assessments.  Baseline VFSS must meet the threshold 
criteria of demonstrating a PAS of ≥ 4, in three of the six boli (5 mL/1 tsp/bolus), during 
swallowing “thin liquid” barium media as assessed by the clinical staff administering the 
VFSS. 
 
Standardized VFSS Approach 
The standardized VFSS examination will be administered using standardized, 
commercial preparations of barium sulfate media and will be comprised of two distinct 
phases: 
1) Thin liquid: 5 mL/1 tsp/bolus x 6 swallows 
2) Nectar  liquid: 5 mL/1 tsp/bolus x 6 swallows 

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Varibar® (Bracco Diagnostics, Inc. Monroe Township, NJ) will be used as the barium 
sulfate (40% w/V) media across all sites whenever possible to ensure standardization of 
the VFSS and its interpretation. Varibar is provided in pre-mixed, ready-to-use 
consistencies, and thus removes the uncertainty that comes with measuring and mixing 
prior to use.  Varibar will be administered by the SLP/SLT personnel at each site per 
site standard practice.   If Varibar is not used at a site, the site may use their standard 
as long as the consistency and viscosity is similar to that of Varibar.   
 
Refer to section 7.1 for VFSS stopping criteria. 
8.1.3.1 Penetration Aspiration Scale (PAS) 
The PAS provides a scoring mechanism for airway closure and clearance during the 
VFSS.  The PAS is a validated 8-point ordinal scale that quantifies penetration and 
aspiration events observed during VFSS28.  Scores are determined primarily by the 
depth to which material passes into the airway and the swallower’s response to the 
material passing into the airway.  For each swallow task, there may be more than one 
swallow.  Each swallow in a task shall be scored via the PAS by the core lab.     
 
Penetration Aspiration Scale 
Score 
Description 
1 
Material does not enter airway 
2 
Material enters the airway, remains above the vocal folds, and is 
ejected from airway  
3 
Material remains above the vocal folds, and is not ejected from airway  
4 
Material contacts the vocal folds, and is ejected from airway  
5 
Material contacts the vocal folds, and is not ejected from airway  
6 
Material passes below the vocal folds [glottis], and is ejected into 
larynx or out of airway  
7 
Material passes below the vocal folds [glottis], and is not ejected from 
trachea despite effort  
8 
Material enters the airway [passes glottis], and no effort is made to 
eject it  
 
 
8.1.4 BARTHEL INDEX 
The Barthel Index is a widely-used measure of functional disability and a measurement 
of quality of life, as it measures the extent to which someone can function independently 
and has mobility in their activities of daily living (ADL) i.e., feeding, bathing, grooming, 
dressing, bowel control, bladder control, toileting, chair transfer, ambulation and 
stair climbing.  It was developed for use in rehabilitation patients with stroke and other 
neuromuscular or musculoskeletal disorders.  The BI is completed by the patient on the 

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provided worksheet and the data are entered on the eCRF. It is completed at the 
baseline, 14-day, and 11-week visits. Details regarding the administration of the BI can 
be found in the eTMF. 
 
8.1.5 MODIFIED RANKIN SCALE (mRS) 
The mRS is a single-item, global outcomes rating scale for patients who are post-stroke. 
It is used to categorize level of functional independence with reference to pre-stroke 
activities rather than on the observed performance of a specific task. 
 
The mRS is used to measure the degree of disability in patients who have had a stroke, as 
follows:  
• 
0: No symptoms at all 
• 
1: No significant disability despite symptoms; able to carry out all usual duties and 
activities 
• 
2: Slight disability; unable to carry out all previous activities, but able to look after 
own affairs without assistance 
• 
3: Moderate disability; requiring some help, but able to walk without assistance 
• 
4: Moderately severe disability; unable to walk without assistance and unable to 
attend to own bodily needs without assistance 
• 
5: Severe disability; bedridden, incontinent and requiring constant nursing care and 
attention 
• 
6: Dead 
 
The mRS is administered by qualified and trained study staff.  It is completed at the 
baseline, 14-day, and 11-week visits and the data will be entered on the eCRF.  Details 
regarding the administration of the mRS can be found in the eTMF. 
 
8.1.6 NIH STROKE SCALE (NIHSS) 
The NIH Stroke Scale is a widely-used tool that was built to assess the cognitive effects 
of a stroke. In more scientific terms, it provides a quantitative measure of stroke-related 
neurologic deficit. Although the NIHSS was first developed as a clinical tool for research 
on stroke patients, it is now used by health professionals to determine the severity of a 
stroke. It also helps create a common language between all people involved in a stroke 
patient’s treatment. In a treatment setting, the scale has three major purposes: 
• It evaluates the severity of the stroke 
• It helps to determine the appropriate treatment 
• It predicts patient outcomes 
It is completed at the baseline, 14-day, and 11-week visits and the data will be entered 
on the eCRF.  Details for the NHISS can be found in the eTMF. 
 

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8.1.7 FUNCTIONAL ORAL INTAKE SCALE (FOIS) 
The FOIS was developed to document the functional level of oral intake of food and 
liquid in stroke patients with dysphagia30.  It is a 7-point ordinal scale that can easily 
completed by clinicians based on information contained in medical charts, dietary 
journals, and/or patient reports.  Verification of patient reports may be obtained by a 
spouse or family members or from a variety of sources for institutionalized patients. The 
FOIS shows strong criterion validity and cross-validation compared with standard 
clinical measures of stroke outcome.  The FOIS has demonstrated sensitivity in 
expected increase in functional oral intake over a 6-month recovery period in stroke 
patients. It is completed at the baseline, 7 day, 14-day, and 11-week visits and the data 
will be entered on the eCRF. Details regarding the administration of the FOIS can be 
found in the eTMF. 
 
Functional Oral Intake Scale 
Level 
Description 
1 
Nothing by mouth (NPO)  
2 
Tube dependent with minimal attempts of food or liquid  
3 
Tube dependent with consistent intake of liquid or food  
4 
Total oral diet of a single consistency  
5 
Total oral diet with multiple consistencies but requiring special preparation 
or compensations.  
6 
Total oral diet with multiple consistencies without special preparation, but 
with specific food limitations.  
7 
Total oral diet with no restriction.  
8.1.8 DYSPHAGIA SEVERITY RATING SCALE (DSRS) 
The DSRS is composed of a 3-component score19 that includes feeding independence, 
but nutrition level and diet modification is split into the components of liquid feeding and 
overall diet consistency.  The DSRS is the sum of the scores of each of the 3 individual 
components rather than a combination of the three components into an ordinal scale.  
Moreover, the DSRS scoring is not based on underlying physiology as the DOSS 
attempts by use of the VFSS, but instead captures only the result of the swallowing 
dysfunction as does the FOIS.  The DSRS has not been formally validated, but it may 
provide more sensitive or specific information than the FOIS with its 13-point scale.  The 
DSRS has been used in prior studies that have assessed PES, and is thus being used 
for this study. It is completed at the baseline, 7 day, 14-day, and 11-week visits and the 
data will be entered on the eCRF. Details regarding the administration of the DSRS can 
be found in the eTMF. 
 
Dysphagia Severity Rating Scale 
Fluids 
Score Diet 
Score Supervision 
Score 
No oral fluids  
4 
Non-oral feeding 
4 
No oral feeding 
4 

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Pudding 
consistency 
3 
Puree 
3 
Therapeutic 
feeding 
(SLP/trained staff) 
3 
Custard 
consistency 
2 
Soft, moist diet 
2 
Feeding by 3rd 
party (untrained) 
2 
Syrup consistency 
1 
Selected textures 
1 
Eating with 
supervision 
1 
Normal fluids 
0 
Normal 
0 
Eating 
independently 
0 
 
Notably, the DSRS was developed in Europe where nomenclature for fluid consistency 
differs from that used in the US.  Hence, in order to standardize the DSRS with the 
modified barium swallow protocol adopted for the MBS/VFSS, the following 
interpretation will be used: 
 
Normal fluids = Thin Liquid 
Syrup consistency = Nectar 
Custard = Honey 
8.1.9 QUALITY OF LIFE (QOL) INSTRUMENTS: EQ-5D, EQ-VAS 
EQ-5D-5L  EuroQuality of Life  
The EQ-5D-5L is a simple measure that comprises five dimensions of health: mobility, 
ability to self-care, ability to undertake usual activities, pain and discomfort, and anxiety 
and depression. There are five options (levels) under each domain.  It is completed at 
the baseline and 11-week visits and the data will be entered on the eCRF.  
 
EQ-VAS EuroQoL Visual Analogue Scale 
The EQ-VAS is a component of the EQ-5D.  It records the respondent’s self-rated 
health on a 20 cm vertical visual analogue scale with the endpoints labelled as “the best 
health you can imagine” and “the worst health you can imagine.”  Patients mark an “x” 
on the scale to indicate how their health is on the day of the assessment and also to 
write the number the marked on the scale in the box on the page.  It is completed at the 
baseline and 11-week visits and the data will be entered on the eCRF. See the eTMF 
for details on administration of the EQ-VAS. 
 
8.1.10 PNEUMONIA ASSESSMENT 
A standardized assessment for clinical signs and symptoms associated with pneumonia 
will be performed over the initial two weeks that patients are enrolled in the study (e.g., 
baseline through the 14 days or discharge, whichever is first, follow-up.  Diagnostic 
methods are not specified; instead, signs, symptoms, and/or diagnostics test results will 
be collected on a regular basis (i.e., baseline and post treatment at 48 hours and on 
days 7, 14 days or discharge, whichever is first, to determine if a standardized diagnosis 
of pneumonia can be made. Information will be obtained via the patient’s medical record 

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and recorded on the eCRF.  A diagnosis of pneumonia must meet the following set of 
criteria: 
 
Temperature:  
a) ≥ 37.5°C or higher on two consecutive measurements or 
b) ≥38.0°C or higher (only need one measurement) 
 
AND 
 
Respiration: 
a) rate ≥ 20 breaths/min or 
b) cough AND breathlessness   or 
c) purulent sputum or 
d) need for oxygen or increase in oxygen flow rate  
 
AND 
 
a) WBC count ≥ 11.0 × 10⁹/L or 
b) Chest infiltrates on radiograph or 
c) Positive sputum culture on microbiology or 
d) Positive blood culture 
 
AND 
 
No other obvious source of infection 
 
If a diagnosis of pneumonia is made, it will be recorded on the AE eCRF and reported 
as an AE/SAE in accordance with Section 8.2, below. 
 
   
8.2 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.2.1 DEFINITION OF ADVERSE EVENT (AE) 
 
An adverse event (AE) is any undesirable experience (sign, symptom, significant 
laboratory abnormality, illness, or other medical event) occurring to a patient that 
appears or worsens during this clinical study, regardless of etiology or relatedness to 
the study device. 
 
 
8.2.2 DEFINITION OF SERIOUS ADVERSE EVENT (SAE)  
A serious adverse event (SAE) is any adverse event that leads to: 
• Death 
• Life-threatening illness or injury 
• Inpatient hospitalization or prolonged hospitalization 

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• Disability or permanent body damage 
• Required intervention to prevent permanent impairment or damage 
• Other serious, medically significant event 
Important medical events that do not meet the above criteria may still be considered an 
SAE if they seriously jeopardize the patient and require immediate medical or surgical 
intervention to prevent one of the aforementioned outcomes. 
 
8.2.3 CLASSIFICATION OF ADVERSE EVENTS 
 
8.2.3.1 SEVERITY  
 
The following criteria will be used by the investigator to classify severity: 
 
• Mild – Events require minimal or no treatment and do not interfere with the 
patient’s daily activities.  
• Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
• Severe – Events interrupt a patient’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially 
life-threatening or incapacitating.  Of note, the term “severe” does not equate to 
“serious.” 
 
 
8.2.3.2 RELATEDNESS 
 
The following criteria will be used by the investigator to classify relatedness to the 
device and/or procedure: 
 
• 
Unrelated -  An AE for which sufficient information exists to indicate that there is 
no causal connection between the event and the device or procedure. The AE is 
due to and readily explained by the patient’s underlying disease state or is due to 
concomitant medication or therapy not related to the use of the device or 
procedure. In addition, the AE may not follow a reasonable temporal sequence 
following the procedure. 
• 
Possibly related - There is a reasonable possibility that the AE may have been 
primarily caused by the device or procedure. The AE has a reasonable temporal 
relationship to the use of the device or procedure and follows a known or 
expected response pattern to device or procedure, but alternative etiology is 
equally or more likely compared to the potential relationship to the use of the 
device or procedure.  
• 
Definitely related - The AE has a strong causal relationship to the device or 
procedure. The AE follows a strong temporal relationship to the use of the device 
or procedure, follows a known response pattern to the device or procedure, and 

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cannot be reasonably explained by known characteristics of the patient’s clinical 
state or other therapies. 
 
8.2.3.3 ANTICIPATED AND UNANTICIPATED ADVERSE EVENTS 
 
The investigator at each site will be responsible for determining whether an adverse 
event (AE) is anticipated or unanticipated.   
 
Anticipated AEs associated with the Phagenyx System, along with risks associated with 
the Phagenyx-related study procedures (i.e., VFSS) include but are not limited to the 
following: 
• 
Bruising, skin 
• 
Bleed, skin 
• 
Death 
• 
Dyspnea/shortness of breath 
• 
Epistaxis 
• 
Erosion, skin or mucosa 
• 
Esophagitis, reflux  
• 
Facial reflex, gagging 
• 
Gastroesophageal reflux 
• 
Gastrointestinal bleed 
• 
Ileus 
• 
Infection or irritation, tube insertion site or nasopharynx   
• 
Ionizing radiation risks 
• 
Ischemia, intestinal 
• 
Nausea 
• 
Necrosis, skin or mucosa 
• 
Peritonitis 
• 
Pneumonia, aspiration  
• 
Pneumothorax 
• 
Sepsis 
• 
Sinusitis 
• 
Sore throat 
• 
Ulceration, skin or mucosa 
• 
Vomiting 
 
Other Anticipated Adverse Events 
Other anticipated AEs, associated with the index stroke or underlying co-morbid 
conditions associated with stroke, are also be expected to occur.  These may include, 
but are not limited to, the following:   
• 
Agitation 
• 
Anemia 
• 
Angina/myocardial infarction/cardiac ischemia 
• 
Anxiety 
• 
Atrial fibrillation/flutter 
• 
Bradycardia 

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• 
Cardiac arrest 
• 
Cardiac dysrhythmia 
• 
Cellulitis 
• 
Cerebral edema 
• 
Cerebral herniation 
• 
Cerebral infarct extension/recurrence 
• 
Coma/diminished level of consciousness 
• 
Confusion 
• 
Congestive heart failure/heart failure 
• 
Constipation 
• 
Death 
• 
Deep venous thrombosis 
• 
Dehydration 
• 
Diarrhea 
• 
Dizziness/vertigo 
• 
Dyspepsia 
• 
Dysphagia 
• 
Dyspnea 
• 
Extracranial bleeding 
• 
Fever 
• 
Gastritis or gastric/duodenal ulcer 
• 
Gastrointestinal bleed 
• 
Headache/migraine 
• 
Hemorrhagic transformation of cerebral infarct 
• 
Hydrocephalus 
• 
Hypokalemia 
• 
Hyperglycemia/hypoglycemia 
• 
Hypoxia 
• 
Insomnia 
• 
Intracerebral hemorrhage expansion 
• 
Intraventricular hemorrhage 
• 
Joint pain (arthralgia) 
• 
Musculoskeletal pain 
• 
Nausea 
• 
Neurologic worsening 
• 
Peripheral vascular disorder 
• 
Peripheral edema 
• 
Pneumonia 
• 
Pressure sore 
• 
Pulmonary edema 
• 
Pulmonary embolism 
• 
Seizure 
• 
Sepsis 
• 
Sleep apnea 
• 
Skin rash 
• 
Limb spasticity 

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• 
Transient ischemic attack 
• 
Urinary incontinence 
• 
Urinary tract infection 
• 
Vomiting 
 
Unanticipated Adverse Device Effect (UADE) is defined as any serious adverse effect 
on health or safety or any life-threatening problem or death caused by – or associated 
with – the device, if that effect, problem or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan (including documents such as 
the protocol, Investigator’s Brochure, informed consent form or other study-related 
documents), or any other unanticipated serious problem associated with the device that 
relates to the rights, safety or welfare of patients.  
 
8.2.4 DEVICE DEFICIENCIES 
 
Device Deficiency 
A device deficiency is an inadequacy of a medical device with respect to its integrity, 
quality, durability, reliability, safety or performance. For the purposes of this study, a 
device deficiency will be defined as a failure of the device to perform its intended 
function when used in accordance with the Instructions for Use.   
 
Device deficiencies will be recorded and evaluated for possible untoward effects on the 
patient. If a significant device deficiency results in an adverse experience in the patient, 
this adverse experience should be considered an adverse event and recorded on the 
AE eCRF. Device failures that do not result in a clinically significant adverse effect on 
the patient will be noted on eCRF regarding device performance, but will not be 
considered an adverse event. 
 
8.2.5 EVENT ASSESSMENT AND FOLLOW-UP 
All AEs and SAEs will be captured on the AE eCRF. Information to be collected includes 
event description, date of onset, seriousness, classification of severity and relatedness, 
treatment, and resolution/stabilization of the event. All AEs/SAEs occurring while on 
study must be documented appropriately regardless of relationship.  Adverse 
events/SAEs will be collected from the time of signing the ICF through the patient’s 
study termination and will be assessed for at each encounter with the patient. Adverse 
events may be reported by patients, elicited through questioning by an Investigator or 
designee, or collected via observation by the Investigator. In addition, patients will be 
instructed to contact the investigator and/or study coordinator if any significant adverse 
events occur between study evaluation visits. 
 
Any medical condition that is present at the time that the patient is screened will be 
considered as baseline and not reported as an AE. However, if the patient’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  

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8.2.6 EVENT REPORTING  
All adverse events are to be reported by the site as soon as possible by recording the 
information on the AE eCRF in the EDC system.  De-identified source documents are to 
be uploaded to the EDC system as soon as possible when they become available. The 
EDC system will notify the sponsor of all SAEs including Unanticipated Adverse Device 
Effects (UADEs). The site investigator is responsible for reporting AEs/SAEs to the 
appropriate IRB/EC as required by the IRB’s/EC’s requirements. 
 
Unanticipated Adverse Device Effects must be reported to the sponsor and the IRB 
within ten working days of discovery. The sponsor is responsible for conducting an 
evaluation of UADE and shall report the results of such evaluation to FDA and all study 
sites/investigators within ten working days after the sponsor first receives notice of the 
UADE.  
 
 
9 
STATISTICAL CONSIDERATIONS  
 
See the separate Statistical Analysis Plan (SAP) for details regarding the statistical 
analyses. 
 
9.1 STATISTICAL HYPOTHESES 
 
The primary efficacy analysis is based on an ordinal logistic model of PAS (1-8 scale) of 
each bolus, determined by VFSS 48 hours following the last investigational treatment, 
and converted to a trichotomized response as follows: Safe (PAS 1-3), Penetration 
(PAS 4-5), or Aspiration (PAS 6-8). Hypothesis testing will be a superiority test on the 
difference in cumulative log odds between treatment.  
 
 
 
9.2 SAMPLE SIZE DETERMINATION 
 
Sample size and power was determined through simulations. The study will follow an 
adaptive group sequential design with unblinded sample size re-assessment.   To 
ensure 180 evaluable patients with 7-day data and assuming a 20% dropout rate, 225 
patients will be enrolled initially.  An interim analysis for futility (non-binding stop) will 
occur after the first 60 patients complete their 7-day visit, and another interim analysis 
will be performed for efficacy after 120 patients for futility stopping, early efficacy 
stopping, and SSR (Sample Size Re-assessment). The SSR strategy will be based on 
both the primary endpoint and DSRS 7 days after last study treatment (key for 
evaluating nutritional management changes). The total sample size may be increased 
up to 338 patients after the second interim analysis to assure up to 270 evaluable 
patients.   

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Based on prior feasibility studies (Bath et. al.21) the primary endpoint is hypothesized to 
have an odds ratio of approximately 2.2 favoring the PES group. With this effect size, 
the power is at least 90% for significance on the primary endpoint. Additional simulation 
results are provided in the Simulation Report. 
 
9.3 POPULATIONS FOR ANALYSES 
 
• The Intent to Treat (ITT) Population will consist of all patients that were 
randomized, irrespective of their protocol adherence and continued participation 
in the study. 
• The Per Protocol (PP) Population will consist of all randomized patients who 
completed the full Phagenyx treatment regimen according to their randomization 
assignment and for whom completed primary endpoint data are also complete. 
• The Safety Population will consist of all patients that were enrolled in the study 
and underwent the pre-procedural VFSS with or without subsequent placement 
of the Phagenyx Catheter.     
• The Roll-In (RI) population will consist of all patients enrolled in a non-blinded 
roll-in manner and remained eligible to receive the Phagenyx treatment after 
initial pre-procedural VFSS testing is completed and the PAS is determined to 
meet entry criterion and no exclusions are found.  All patients in whom treatment 
was attempted, regardless of procedural outcome, will be included in this 
analysis set.  
 
9.4 STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Tabulations will be produced for appropriate demographic, baseline, efficacy, 
pharmacokinetic and safety parameters.  For categorical variables, summary 
tabulations of the number and percentage within each category (with a category for 
missing data) of the parameter will be presented.  For continuous variables, the mean, 
median, standard deviation, minimum and maximum values will be presented.  Time to 
event data will be summarized using Kaplan-Meier methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% confidence intervals, as 
well as percent of censored observations.   
 
Formal statistical hypothesis testing will be conducted at the 1-sided, 0.025 level of 
significance.  
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
 
The primary analysis will be performed on the ITT population. The primary endpoint is 
trichotomized PAS on each bolus, determined by VFSS 48 hours after completion of 
PES treatment. The three ordinal PAS categories are defined as Safe (PAS 1-3), 

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Penetration (PAS 4-5), and Aspiration (PAS 6-8). Each patient contributes 12 
measurements to the primary endpoint, of which 6 are from boli of a thin consistency 
and 6 are from boli of a nectar consistency.  
 
Missing PAS data will be imputed in the primary analysis. PAS values that are missing 
due to application of VFSS stopping criteria will be assigned the worst (highest) post-
treatment PAS value. For patients who have no post-treatment PAS data due to lost-to-
follow-up or death, the post-treatment PAS values will be imputed from baseline PAS 
values and other patient baseline characteristics using multiple imputation. In addition, 
tipping point analysis will be performed as a sensitivity analysis. 
 
A cumulative logistic model will be used to analyze the primary endpoint, and a 
sandwich variance estimator via a generalized estimating equations approach will be 
used to account for correlated PAS outcomes within each patient. Modeling details are 
specified in the SAP. 
 
9.4.3 ANALYSIS OF THE SECONDARY EFFICACY ENDPOINTS 
 
The secondary efficacy endpoints will be tested for statistical significance sequentially 
provided the primary endpoint is found to be statistically significant. The ITT population 
will be used. The first endpoint tested will be FOIS at 7 days following the last 
investigational treatment. The second endpoint tested will be DSRS at 7 days following 
the last investigational treatment. 
 
Analysis details are specified in the SAP. 
 
9.4.4 SAFETY ANALYSES 
 
Safety analyses will be conducted using the Safety Population.  
 
Adverse events will be coded by type using a list of anticipated events.  Events which 
do not meet a pre-defined type will be coded as ‘other’ and will require supporting detail. 
 
Adverse events will be summarized by patient incidence rates, therefore, in any 
tabulation, a patient contributes only once to the count for a given adverse event. 
 
The number and percentage of patients with any adverse events assessed by the 
Investigator as related to treatment (definite, probable, or possible relationship), and 
with any serious adverse event, will be summarized by treatment group and overall.  In 
these tabulations, each patient will contribute only once (i.e., the most related 
occurrence or the most intense occurrence) to each of the incidence rates in the 
descriptive analysis, regardless of the number of episodes. 
 
No formal hypothesis-testing analysis of adverse events incidence rates will be 
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By-patient listings also will be provided for the following: patient deaths, serious adverse 
events, and adverse events leading to withdrawal. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Baseline demographics and medical history information will be summarized for the ITT, 
PP, Safety and RI populations using descriptive statistics.  Summaries will be provided 
by treatment group, stratification factors, and other key baseline parameters if 
applicable. No formal statistical testing will be performed. 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
To ensure 180 evaluable patients with 7-day data and assuming a 20% dropout rate, 
225 patients will be enrolled initially.  An interim analysis for futility (non-binding) will 
occur after the first 60 patients complete their 7-day visit, and another interim analysis 
will be performed for efficacy after 120 patients complete their 7-day visit.  The total 
sample size may be increased up to 338 patients after the second interim analysis to 
ensure 270 evaluable patients.   
 
The interim analysis will be performed by an unblinded Independent Statistical Center 
(ISC) and the recommendation for adaptation or early stopping will be made by the 
DMC. An electronic file exchange platform capable of secure storage of documents with 
audited access will be used to control flow of information during the study. 
 
Details on the interim statistical analysis and decision rules are described in the SAP.  
 
10 SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
10.1.1 
INFORMED CONSENT  
 
The investigator (or designee) is responsible for performing consent procedures in 
accordance with 21 CFR 50 and ISO 14155 for each patient enrolled in the study.  The 
template ICF will be provided to the site by Phagenesis for review and approval by the 
governing IRB/EC. Modifications requested by local IRB/EC must be approved by 
Phagenesis prior to first use.  Each investigator is responsible for ensuring that 
enrollment at his/her site does not commence until Phagenesis and IRB/EC approval of 
the ICF has been obtained and the site training activities have been successfully 
completed. 
 
 

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Consent forms describing in detail the study intervention, study procedures, and risks 
are given to the patient and written documentation of informed consent is required prior 
to starting intervention/administering study assessment or intervention.   
 
10.1.2 
 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
The investigator (or designee if allowed) will explain the research study to the patient 
and answer any questions that may arise. A verbal explanation will be provided in terms 
suited to the patient’s comprehension of the purposes, procedures, and potential risks 
of the study and of their rights as research patients.  Patients will have the opportunity 
to carefully review the written consent form and ask questions prior to signing. The 
patients should have the opportunity to discuss the study with their family or surrogates 
or think about it prior to agreeing to participate. The patient or legally authorized 
representative (if allowed) will sign the ICF prior to any procedures being done 
specifically for the study. Patients must be informed that participation is voluntary and 
that they may withdraw from the study at any time, without prejudice. A copy of the 
informed consent document will be given to the patients for their records. The informed 
consent process will be conducted and documented in the source document. The rights 
and welfare of the patients will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this 
study. 
 
 
10.1.3 
 STUDY DISCONTINUATION AND CLOSURE 
The study may be suspended or discontinued early by the sponsor for reasons that 
include but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
 
The sponsor may terminate investigator and site participation in the study if there is 
evidence of an investigator’s failure to maintain adequate clinical standards or evidence 
of an investigator or staff’s failure to comply with the protocol. 
 
If the study is prematurely terminated or suspended, the investigator will promptly inform 
study patients, the IRB/EC and sponsor and will provide the reason(s) for the 
termination or suspension.  Study patients will be contacted, as applicable, and be 
informed of changes to study visit schedule. 
  

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The study may resume once concerns about safety, protocol compliance, and data 
quality are addressed, and satisfy the sponsor, IRB/EC and/or FDA. 
 
10.1.4 
CONFIDENTIALITY AND PRIVACY  
 
Patient confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor(s) and their agents.  The study protocol, documentation, data, and all other 
information generated will be held in strict confidence to the extent allowed by law, 
including Protected Health Information (PHI).  No information concerning the study or 
the data will be released to any unauthorized third party without prior written approval of 
the sponsor. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the 
study or the data will be released to any unauthorized third party without prior written 
approval of the sponsor.  
 
The investigator will ensure protection of patient personal data and that all reports, 
publications, and any other disclosures, except where required by law are identified only 
by the patient identification number and site identification number to maintain patient 
confidentiality. All patient study records will be kept safely in an access-controlled area. 
Identification code lists linking patient names to patient identification numbers are to be 
stored separate from patient records. In case of data transfer, the sponsor, designees 
and sites will maintain high standards of confidentiality and protection of patient 
personal data.  Clinical information will not be released without the written permission of 
the patient, except for monitoring by regulatory authorities, and the sponsor and their 
designees. 
The patient’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long at least two years (or per regulations) after the study is 
closed, the Phagenyx System receives market clearance, whichever is longer.  Records 
cannot be archived or destroyed by the site without prior written permission from 
Phagenesis, regardless of when the study closed.   
 
Study patient research data will be transmitted to and stored at RCRI via the EDC 
system and eTMF. The study data entry and study management systems used by 
clinical sites and by RCRI will be secured and password protected.  
 
The study monitor, other authorized representatives of the sponsor, representatives of 
the IRB/EC, and/or regulatory agencies may inspect all documents and records required 
to be maintained by the investigator, including but not limited to, medical records (office, 
clinic, or hospital) and pharmacy records for the patients in this study. The clinical study 
site will permit access to such records. 
 
 
10.1.5 
 KEY ROLES AND STUDY GOVERNANCE  
 

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Phagenesis Limited is the Study Sponsor, and has the overall responsibility for the 
conduct and safety of the study, including assurance that the study meets the regulatory 
requirements of the FDA and governing IRBs/ECs.  The Sponsor will have certain direct 
responsibilities and will coordinate other responsibilities to the specified committees, 
core labs and other support services as necessary. 
 
Phagenesis or its designee will maintain copies of correspondence, data, shipment of 
devices, adverse device effects and other records related to the clinical trial as 
appropriate.  
 
Phagenesis or its designee will submit all reports required by FDA and governing IRBs.   
 
The Steering Committee will be responsible for general oversight of the study.  This 
committee will meet periodically to monitor clinical site progress and protocol 
compliance.  The committee will be responsible for reviewing the final results and may 
help determine authorship per standard rules/guidelines. The committee will be 
comprised of qualified professionals (e.g. stroke neurologists, physiatrists, speech 
language pathologist), and at least one sponsor representative.  Members of the 
Steering Committee may also be study investigators.   
 
The independent Data Monitoring Committee (DMC) will act as the appropriate entity to 
recommend all pre-specified study adaptation decisions.  Recommendations are 
expected to be primarily based on efficacy; however, the DMC will also monitor safety 
events (see Section 10.1.6 of this protocol) The DMC members will be independent of 
Phagenesis and any study site.   
 
10.1.6 
SAFETY OVERSIGHT 
  
The Medical Monitor (MM), will be responsible for reviewing pre-specified safety events, 
including all SAEs as well as being available to help with any protocol questions and 
inclusion or exclusion criteria if needed.  The MM will be independent of Phagenesis 
and any study site. Details regarding the MM’s roles and responsibilities are detailed in 
the Safety Management Plan. 
 
A DMC will be established by Phagenesis for the purposes of this study. The DMC is 
responsible for monitoring aggregate safety information and the impact of adverse 
events on the safety and well-being of the patients, particularly as events relate to the 
investigational device and study procedures. The DMC may recommend that the 
sponsor modify or stop the study based on safety information.  The final decision 
regarding modification or stopping the study is the responsibility of the sponsor. 
 
At the recommendation of the DMC the following actions may be taken at the second 
interim analysis: 
 
• Stop the study for futility  
• Stop the study for efficacy  

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• Increase the final sample size up to a maximum of 338 patients 
• Continue the study as planned until reaching 225 patients  
 
Details regarding the DMC’s roles and responsibilities are detailed in the DMC Charter. 
 
10.2 CORE LABORATORY 
A core laboratory will be established for VFSS analysis. Standardized protocols for 
acquiring, transmitting, and analyzing electronic records will be developed and 
documented prior to study initiation. Protocols for the transmission of electronic media 
files will strip personal identifiers from the media. The core laboratory will maintain 
copies of correspondence, data, and other records related to the clinical study as 
appropriate. Refer to the Core Lab Manual of Operations for specific information. 
 
10.2.1 
CLINICAL MONITORING 
 
Clinical site monitoring will be  conducted to help ensure that the rights and well-being 
of patients are protected, that the reported study data are accurate, complete, and 
verifiable, and that the conduct of the study is in compliance with the currently approved 
protocol/amendment(s), with ICH GCPs, and with applicable regulatory requirement(s) 
including federal (US) regulations and ISO 14155. 
 
The sponsor or designee will monitor the study throughout its duration.  Study monitors 
will visit each site at appropriate intervals to review clinical data for accuracy and 
completeness and to help ensure compliance with the protocol. The study monitor may 
inspect all documents and required records maintained by the investigator, including 
medical records (office, clinic, or hospital) for patients enrolled in this study.  The 
investigator will allocate adequate time for such monitoring activities.  The investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is 
given access to all the above noted study-related documents and study related facilities 
(e.g. diagnostic laboratory, etc.), and has adequate space to conduct the monitoring 
visit. 
 
A study termination (close-out) monitoring visit will be conducted at the completion of 
the study.   Clinical study documentation is to be properly documented and stored for a 
minimum of two years following study completion or FDA market clearance, whichever 
is later.  The sponsor or designee will notify each site during the closeout visit of the 
current data storage requirements. 
 
If a monitor becomes aware that an investigator is not complying with the signed 
Investigator Agreement, the protocol, or any conditions of approval imposed by the 
regulatory authorities, the sponsor or designee will immediately attempt to secure 
compliance, suspend enrollment at the site, remove devices from the site, or 
discontinue shipments of the device to the Investigator until compliance is achieved and 
guaranteed.  The sponsor may terminate an investigator’s participation in the study at 

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the sponsor’s discretion. The investigator will be required to return all unused devices to 
the sponsor unless this action would jeopardize the rights, safety or welfare of a patient. 
 
Details of clinical site monitoring are documented in the study-specific Clinical 
Monitoring Plan (CMP). The CMP describes who will conduct the monitoring, at what 
frequency monitoring will be done, at what level of detail monitoring will be performed, 
and the distribution of monitoring reports. 
 
 
10.2.2 
QUALITY ASSURANCE AND QUALITY CONTROL 
 
Quality control procedures will be implemented beginning with the data entry system 
and data quality control checks that will be run on the database will be generated. Any 
missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. 
 
Following Regulatory and Clinical Research Institute’s (RCRI) standard operating 
procedures (SOPs), the monitors will verify that the clinical study is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, 
ICH GCPs, and applicable regulatory requirements.  
 
The investigational site will provide direct access to all study-related source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor 
or designee, and inspection by local and regulatory authorities. 
 
 
10.2.3 
DATA HANDLING AND RECORD KEEPING  
 
10.2.3.1 
STUDY RECORDS RETENTION  
 
Study documents must be maintained by the investigator and sponsor for the duration 
of the study and for a period of at least two years (or per regulations) after market 
clearance or after the study has been formally closed, whichever is later.  Documents 
cannot be archived or destroyed unless prior written approval is granted to the site by 
the sponsor. 
 
10.2.3.2 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
This study will be performed using an EDC system with password protection. The 
investigator and study site staff will receive training and support on the use of the EDC 
system and will be granted specific user privileges. All eCRF data are to be completed 
by the investigator, study coordinator, or other designated site personnel.  The 
investigator will perform a final review and sign-off of all eCRFs in a timely manner. 
 

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Designated site personnel will be trained to enter data into the web-based EDC system.  
Completed eCRFs will be monitored against the medical record by a monitor during the 
onsite and remote data review.  The EDC system will be a closed system, allowing for 
tracking all the data elements and any changes made (audit trail). 
  
The sponsor and RCRI will work with the investigational sites mange the electronic Trial 
Master File (eTMF) to house essential documents including: 
• Signed protocol and amendments, 
• Signed Investigator Agreement, 
• Financial Disclosures 
• IRB/EC approval letters, consent forms and correspondence, 
• Investigator and sponsor reports, 
• Relevant correspondence between the Investigator and Sponsor, 
• Notification to sponsor and IRB/EC of UADEs (and SAEs, if applicable) 
• Device Accountability Records, 
• Administrative Tracking Logs (Monitoring Visits, Training Logs, etc.). 
 
Study documents must be maintained by the investigator and sponsor for the duration 
of the study and for a period of at least two years after FDA market clearance or after 
the study has been formally closed, whichever is later.  Documents cannot be archived 
or destroyed unless prior written approval is granted to the site by the sponsor. 
 
10.3 SOURCE DOCUMENTS 
Source data are all information, original records of clinical findings, observations, or 
other activities from a clinical study necessary for the reconstruction and evaluation of 
the study.  Examples of these original documents, and data records include but are not 
limited to: medical records, clinic and office charts, x-rays, laboratory notes, and study 
specific worksheets. 
 
Regulations require that the investigator maintain information in the patients’ 
medical/hospital records that corroborates data collected for the study.  In order to 
comply with these regulatory requirements, at a minimum, the following is a list of 
information that should be maintained.  
 
• Medical history/general physical condition of the patient before involvement in the 
study of a sufficient nature to verify the protocol eligibility criteria, 
• Dated and signed study/progress notes on the date of entry into the study 
documenting the following: 
o The general health of the patient, 
o A statement that the patient has reviewed, signed and received a copy of the 
patient informed consent form. 
o Adverse events reported and their continuation or resolution, including, 
supporting documents such as discharge summaries, x-ray reports and other 
test reports, 

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o Patient’s general health and medical condition upon completion of or 
withdrawal from the study. 
 
Patient confidentiality will be maintained throughout the clinical study in a manner that 
helps ensure data can be traced back to the source documents.  Additionally, patient 
information will be managed according to HIPAA and European confidential 
requirements specific to the country the patient is enrolled in.   
 
In the event that the patient revokes authorization, the investigator retains the ability to 
use all information collected prior to the revocation.  The investigator should attempt to 
obtain permission to collect at least vital status, i.e., that the patient is alive, at the time 
of patient authorization revocation. 
 
Data collection is the responsibility of the clinical study staff at the site under the 
supervision of the site investigator. The investigator is responsible for ensuring the 
accuracy, completeness, legibility, and timeliness of the data reported. 
 
All source documents are to be completed in a neat, legible manner to ensure accurate 
interpretation of data.   
 
Hardcopies of the study visit worksheets may be provided for use as source document 
worksheets for recording data for each patient enrolled in the study.  Data recorded in 
the eCRF derived from source documents must be consistent with the data recorded on 
the source documents.  
 
 
10.4 PROTOCOL DEVIATIONS  
 
A protocol deviation is defined as an event when the investigator or site personnel 
deviate from the study protocol or study procedures.  It is the investigator’s 
responsibility to ensure that there are no deviations from the protocol without prior 
notification and approval of the sponsor or sponsor’s designee, and in full compliance 
with all established procedures and conditions of the reviewing IRB/EC.   
 
The investigator may deviate from the protocol without prior written approval from the 
sponsor or sponsor’s designee in cases of medical emergencies, when the deviation is 
necessary to eliminate an apparent immediate hazard to the patient.  In that event, the 
investigator will notify the sponsor or sponsor’s designee immediately by phone or 
electronic communication, notify the reviewing IRB/EC and confirm notification to the 
sponsor or designee in writing.  Prior deviation approval is generally not expected in 
situations where unforeseen circumstances are beyond the investigator’s control, for 
example, the patient was not available for a scheduled follow-up office visit.  These 
events, although outside the investigator’s control, are still required to be reported on 
the appropriate protocol deviation form in order to ensure that all deviations from the 
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will inform the sponsor or sponsor’s designee of all deviations, and the reviewing 
IRB/EC of all protocol deviations as per the IRB/EC requirements for this study.   
 
The occurrence of protocol deviations will be monitored by the sponsor or sponsor’s 
designee for evaluation of investigator compliance to the protocol, ICH GCPs, and 
regulatory requirements.   
 
 
10.5 PUBLICATION AND DATA SHARING POLICY 
 
The publication policy will follow International Committee of Medical Journal Editors 
(ICJME) guidelines. The Steering Committee will help adjudicate authorship per 
standard rules/guidelines. 
 
10.6 CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence is critical.  
Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this study will be disclosed and 
managed.  
 
 
 
 

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10.7 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
26 
January 
2018 
N/A 
Initial release 
 
 

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16. Hamdy S. Aziz Q, Rothwell JC, Power M, Singh KD, Nicholson DA, Tallis RC, Thompson 
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