Percutaneous Electrical Phrenic Nerve Stimulation (PEPNS) System Feasibility Study
Phase: NA
Conditions: Ventilator Induced Diaphragmatic Dysfunction (VIDD)
Sponsor: Stimdia Medical Inc.

                                                     PEPNS System Feasibility Study 
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CLINICAL INVESTIGATION PLAN (CIP) 
 
Percutaneous Electrical Phrenic Nerve Stimulation (PEPNS) 
System Feasibility Study 
 
 
Protocol Number: CIP0001 
Version: 4 
 
Date: November 30, 2018  
 
 
 
Study Sponsor 
Stimdia Medical, Inc. 
P.O. Box 251, 5021 Vernon Road 
Edina, MN 55436 
 
 
 
 
 
 
 
 
 
 
 
This document contains confidential information for use by the investigators and their designated representatives 
participating in the clinical trial presented herein.  It must be held confidential and maintained in a secure location.  
It must not be copied or made available for review by any unauthorized person or company. 
 
 

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Revision History 
 
 
Version 
Number 
Description of Change 
Approval Date 
1 
Initial Release 
April 7, 2017 
2 
Update to incorporate HPRA feedback as follows: specified at least 
48 hours of mechanical ventilation, clarified that all patients will be 
followed up for 30 days, better defined difficulty weaning, revised 
exclusion criteria 6 to include patients with neuromuscular or 
inflammatory muscle diseases and specify that letter to general 
practitioner must be sent if patient is lost to follow up. Update to 
incorporate Czech Republic State Institute for Drug Control 
(SUKL) feedback as follows: add investigator and investigative site 
information, add information on the medical device manufacturer, 
total expected study duration, add information on premature 
termination of the study, refer to section 13.1 rather than 14.1 in 
section 13.4.9 since it was incorrect and add information on 
investigation of serious adverse incidents.  Update to clarify 
indications for use by slightly rewording, add diaphragm thickness 
measurements and other minor clean up. 
January 30, 2018 
3 
Update to add the potential risks of asystole and bradycardia due to 
vagus nerve stimulation based on feedback from HPRA. 
July 26, 2018 
4 
Update primary endpoint #2 to WOB (Work of Breathing) kept 
between 0.2 joules/L and 2 joules/L for 80% of stimulated breaths. 
Remove references to patient initials. Change Declaration of 
Helsinki 2008 to 2013 and add General Data Protection Regulation 
(GDPR) and Data Protection Act 2018.  Updated data retention to 
10 years. 
November 30, 2018 

Stimdiak 
PEPNS  
System  Feasibility  Study 
CIP  Approval  
Page  - 
Principal  Investigators 
I,  
the  undersigned,  
have  read  and  understood  
the  Clinical  Investigation  
Plan  and  agree  on  the  contents.  
The 
Clinical  Investigation  
Plan  and  the  Clinical  Investigation  
Agreement  
will  serve  as  a  basis  for  cooperation  
in  the 
clinical  investigation. 
rincipal  Investigator  Name' 
itle 
Site  Name 
6 
Site  Address 
Site  No 
ignature 
Date  
(DD/MMM/YYYY) 
Principal  Investigator  Name 
Title 
Site  Name 
Site  Address 
Site  No 
gnature 
D/MMM/YYYY) 
CIP0001  
Rev  4,  PEPNS  
System  Feasibility  Study  CIP 
Confidential 
Page  
4  of  48 

Stimdia 
PEPNS  
System  Feasibility  Study 
Principal  Investigators 
CIP  Approval  Page 
I,  
the  undersigned,  
have  read  and  understood  
the  Clinical  Investigation  
Plan  and  agree  on  the  contents.  
The 
Clinical  Investigation  
Plan  and  the  Clinical  Investigation  
Agreement  
will  serve  as  a  basis  for  cooperation  
in  the 
clinical  investigation 
Principal  Investigator  Name 
T 
Iu 
Site  Name 
Site  Address 
Site  No 
No  2 
gnature 
te  
(DD/MMM/YYYY) 
Principal  Investigator  Name 
Title 
Site  Name 
Site  Address 
O 
ture 
Date  
(DD/MMM/YYYY) 
CIP0001  
Rev  4,  PEPNS  
System  
Feasibility  Study  CIP 
Confidential 
Page  
4  of  48 

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Table of Contents 
 
STUDY SUMMARY .................................................................................................................................................8 
1. 
 INTRODUCTION ............................................................................................................................................11 
1.1 
General Information .................................................................................................................................11 
1.1.1 
Study Title ............................................................................................................................................11 
1.1.2 
Study Sponsor .......................................................................................................................................11 
1.1.3 
Study Monitor .......................................................................................................................................12 
1.1.4 
Participating Investigation Site(s) & Principal Investigator(s) .............................................................12 
2. 
BACKGROUND & RATIONALE ...................................................................................................................12 
3. 
SUMMARY OF PRE-CLINICAL TESTING ..................................................................................................14 
4. 
INVESTIGATIONAL DEVICE .......................................................................................................................17 
4.1 
Device Description ...................................................................................................................................17 
4.2 
Equipment and Accessories Used .............................................................................................................17 
4.3 
Indications For Use ...................................................................................................................................18 
4.3.1 
Frequency of Use ..................................................................................................................................18 
4.3.2 
Body/Tissue Interacted With ................................................................................................................18 
5. 
STUDY OBJECTIVES .....................................................................................................................................19 
5.1 
Primary Endpoints ....................................................................................................................................19 
5.2 
Secondary Endpoints ................................................................................................................................19 
5.3 
Additional Study Data ..............................................................................................................................19 
6. 
STUDY DESIGN & METHODOLOGY ..........................................................................................................20 
6.1 
Study Data Analysis and Statistical Methods ...........................................................................................20 
6.2 
Inclusion and Exclusion Criteria ..............................................................................................................21 
6.3 
Enrollment ................................................................................................................................................22 
6.4 
Subject Compliance ..................................................................................................................................22 
6.5 
Withdrawal and Discontinuation ..............................................................................................................22 
6.6 
Early Termination or Suspension of Clinical Investigation .....................................................................22 
6.7 
Informed Consent Process ........................................................................................................................22 
6.8 
Study Design and Number of Observations .............................................................................................23 
6.9 
Safety Endpoints .......................................................................................................................................23 
6.10 
Primary Performance Endpoint: Stimulation Pulse to Capture the Diaphragm .......................................23 
6.10.1 
Model:...............................................................................................................................................23 
6.10.2 
Hypothesis: .......................................................................................................................................24 
6.10.3 
Sample Size: .....................................................................................................................................24 
6.10.4 
Methods: ...........................................................................................................................................24 

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6.11 
CMAP and Nerve Conduction Studies .....................................................................................................24 
6.12 
Measurement of Diaphragm Thickness using Ultrasound ........................................................................24 
6.13 
Electrocardiogram (ECG) and X-ray ........................................................................................................25 
6.14 
Secondary Performance Endpoint: Analyzing Phrenic Nerve Stimulation in Synchrony with MV 
Breaths 25 
6.15 
Additional Study Data ..............................................................................................................................26 
7. 
PROCEDURAL GUIDELINES (Treatment Procedure) ..................................................................................27 
7.1 
Operator’s Manual ....................................................................................................................................27 
8. 
SITE SELECTION CRITERIA ........................................................................................................................27 
9. 
SITES AND ENROLLMENT ..........................................................................................................................27 
10. PROCEDURE DURATION AND FOLLOW-UP ............................................................................................27 
11. STUDY SCREENING AND STUDY PROCEDURES ...................................................................................28 
11.1 
Screening ..................................................................................................................................................28 
11.2 
Index Procedure ........................................................................................................................................28 
11.3 
Follow-Up Visits ......................................................................................................................................28 
11.4 
Unscheduled Visit ....................................................................................................................................29 
11.5 
Lost to Follow-up .....................................................................................................................................30 
11.6 
Patient Withdrawal from the Study ..........................................................................................................30 
11.6.1 
Voluntary Withdrawal ......................................................................................................................30 
11.6.2 
Withdrawal for Other Reasons OR Non-Treatment .........................................................................30 
11.6.3 
End of Study .....................................................................................................................................30 
12. DATA RECORDING AND SUBMISSION REQUIREMENTS .....................................................................31 
13. RISK/BENEFIT ANALYSIS ...........................................................................................................................32 
13.1 
Potential Risks ..........................................................................................................................................32 
13.2 
Minimization of Risk ................................................................................................................................32 
13.3 
Potential Benefits ......................................................................................................................................32 
13.4 
Definitions In Line with EN ISO 14155 Unless Otherwise Denoted .......................................................33 
13.4.1 
Adverse events (AE) .........................................................................................................................33 
13.4.2 
Serious adverse events (SAE)...........................................................................................................33 
13.4.3 
Adverse device effect (ADE) ...........................................................................................................33 
13.4.4 
Serious adverse device effect (SADE) .............................................................................................33 
13.4.5 
Unanticipated serious adverse device effect (USADE) ....................................................................33 
13.4.6 
Device Deficiency ............................................................................................................................34 
13.4.7 
Malfunction ......................................................................................................................................34 
13.4.8 
Use error ...........................................................................................................................................34 
13.4.9 
List of Anticipated Adverse Events ..................................................................................................34 

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13.5 
Adverse Event Classification....................................................................................................................34 
13.5.1 
Assessment of Adverse Event Relationship to Investigational Device ............................................34 
13.6 
Adverse Event Severity ............................................................................................................................36 
13.6.1 
Handling and Reporting of Adverse Events .....................................................................................36 
13.6.2 
Regulatory Authority Notification (If applicable) ............................................................................37 
13.6.3 
Follow-up of Unresolved Events ......................................................................................................37 
14. DATA MANAGEMENT ..................................................................................................................................38 
14.1 
Confidentiality ..........................................................................................................................................38 
14.2 
Subject Identification (ID) ........................................................................................................................38 
14.3 
Data Collection .........................................................................................................................................38 
14.4 
Review and Return of Completed Study Data ..........................................................................................38 
14.5 
Study Final Report ....................................................................................................................................38 
14.6 
Study Material and Data Retention/Archiving .........................................................................................38 
15. TRAINING AND EXPERIENCE REQUIREMENTS .....................................................................................39 
15.1 
Clinical Investigation Plan (CIP) Training ...............................................................................................39 
15.2 
Device and Procedure Training ................................................................................................................39 
16. ETHICAL, REGULATORY AND ADMINISTRATIVE REQUIREMENTS ................................................40 
16.1 
Ethics Committee and Regulatory Approvals ..........................................................................................40 
16.2 
Informed Consent and Patient Information ..............................................................................................40 
16.3 
Protocol Deviations ..................................................................................................................................40 
16.4 
Amendments .............................................................................................................................................41 
16.5 
Investigational Device Accountability and Storage .................................................................................41 
16.6 
Monitoring Plan ........................................................................................................................................41 
16.7 
Indemnity ..................................................................................................................................................42 
16.8 
Insurance...................................................................................................................................................42 
16.9 
Investigators Responsibilities ...................................................................................................................42 
16.10 Sponsor Responsibilities ..........................................................................................................................44 
16.11 Statement of Compliance .........................................................................................................................46 
16.12 Publication Policy .....................................................................................................................................46 
17. REFERENCES ..................................................................................................................................................47 
 
 
 

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STUDY SUMMARY 
PEPNS System Feasibility Study Summary 
Title 
Percutaneous Electrical Phrenic Nerve Stimulation (PEPNS) System Feasibility 
Study 
Short Title 
PEPNS System Feasibility Study 
Study Sponsor 
Stimdia Medical, Inc. 
Contacts: 
Patrick Wethington 
President and CEO 
+1 952-807-1371 
pwethington@stimdia.com 
 
John O'Mahony 
Vice President of Research and Development 
+1 763-516-7605 
jomahony@stimdia.com 
 
Laurie E. Lynch, PhD 
Clinical Study Director 
+1 952-221-2468 
llynchassociates@gmail.com 
Protocol Number & 
Version 
CIP0001 Rev 4, November 30, 2018 
Study Device 
Percutaneous Electrical Phrenic Nerve Stimulation (PEPNS) System 
Purpose 
The purpose of this study is to evaluate the safety and performance of the PEPNS 
System in patients that need to be mechanically ventilated for at least 48 hours and 
up to 7 days in the Intensive Care Unit (ICU). 
Study Design 
Prospective; Non-randomized; Open-label 
Enrollment 
Up to 2 sites and up to 10 subjects per site.  The very first 2 subjects will be 
stimulated on the left phrenic nerve and followed for 30 days prior to enrolling 
additional patients. In addition, compound muscle action potential testing (CMAP) 
and nerve conduction studies, will be conducted on the first 2 subjects during the 
index procedure and at or before the 30 day follow up.  
Follow Up 
All subjects will be followed up for 30 days after their index procedure for a total 
participation period of up to 41 days. 
Estimated Study 
Duration 
It is expected that up to 10 subjects will be enrolled per site (up to two sites) during 
the course of 4 to 6 months for a total estimated study duration of up to 18 months 
once both sites start to enroll subjects. 
Study Population 
Patients that need to be mechanically ventilated for at least 48 hours and up to 7 
days in the Intensive Care Unit (ICU).  

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PEPNS System Feasibility Study Summary 
Inclusion Criteria 
Candidates for this study must meet all of the following inclusion criteria: 
1.  18 years or older (Adult). 
2.   Male or Female. 
3.  Able and willing to give informed consent or whose legally authorized 
representative is able and willing to give informed consent. 
 4.  Subject who in the opinion of the admitting consultant/intensivist is likely to be 
ventilated for > 48 hours from time of recruitment since study treatment will be 
for up to 48 hours. 

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PEPNS System Feasibility Study Summary 
Exclusion Criteria 
Candidates for this study will be excluded if ANY of the following conditions are 
present: 
1.     Subject has a left ventricular ejection fraction (LVEF) < 20%.  
2.     Subject unlikely to survive 72 hours due to coexisting medical conditions. 
3.     Subject has an implanted pulse generator or implanted electronic device: 
Examples: Cardiac pacemaker, Defibrillator, ICD, Watchman, Vagal nerve 
stimulator, Spinal cord stimulator, Gastric stimulator or Diaphragmatic 
stimulator. 
4.     Subject has experienced an Acute Myocardial Infarction (AMI) within 72 
hours prior to this screening or patient is on high dose inotropic support or 
subject is deemed to be in cardiogenic shock. 
5.     Subject has significant bleeding diathesis, or is at risk of significant 
haemorrhage, patient is receiving full dose systemic anticoagulation 
6.     Subject has a known or suspected phrenic nerve paralysis or neuromuscular or 
inflammatory muscle diseases where the diaphragm itself may not be 
functional.  
7.     Subject has an active systemic infection or local infection at or around the 
insertion site. Subject is neutropenic or has signs of significant 
immunocompromise. 
8.     Subject is known or suspected to be pregnant or is lactating. 
9.     Subject will be unavailable for, or is unwilling to comply with, follow up 
requirements of the protocol. 
10.   Subject is currently enrolled or is expected to be enrolled in any other study of 
an investigational drug or device who has received treatment under that 
protocol with the investigational product during the 30 days prior to screening. 
11.   Subject has undergone a surgery or interventional procedure within the neck 
region aside from placement of an internal jugular (IJ) vein catheter. 
12.   Subject has been diagnosed and has been treated for neck cancer within the 
past 5 years. 
13.   Subject is known to have a demonstrated intra cardiac thrombus on 
echocardiography. 
14.   Subject has uncontrolled hyperthyroidism, hypertension. 
15.   Subject has had any cerebral ischemic event (Stroke or Transient Ischemic 
Attack TIA) in the 6-month interval preceding the screening date. 
16.   Subject has degenerative nerve disorders such as amyotrophic laterals   
sclerosis (ALS). 
17.  Subject has an elevated hemidiaphragm on chest x-ray.  
18.   Subject written informed consent not obtained. 

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PEPNS System Feasibility Study Summary 
Primary Endpoints 
1. Capture of the Left and/or Right Phrenic Nerve > 80% with an output 
parameter of < 10.5 volts.  
2. WOB (Work of Breathing) kept between 0.2 joules/L and 2 joules/L for 80% 
of stimulated breaths. 
Secondary Endpoints 
1. The percentage of patients who receive safe and successful placement of the 
multipolar lead in the left and right phrenic nerve utilizing ultrasound guidance 
will be determined.   
2. Phrenic nerve stimulation in synchrony with Mechanical Ventilation (MV) 
breaths will be measured to verify that is occurs with inspiration. 
3. The percentage of patients who experience one or more serious 
device/procedure-related adverse events during the study will be reported.  
Additional Study 
Data 
1. Time to weaning from mechanical ventilation data will be collected. 
2. Diaphragm thickness at 0, 24 and 48 hours. 
1.  INTRODUCTION 
This document is the Clinical Investigational Plan for a human feasibility clinical study of the PEPNS System.  
This study is to be conducted according to ICH-GCP (International Conference on Harmonization - Good Clinical 
Practice, E6), EN ISO 14155:2011 (Clinical Investigation of medical devices for human subjects), General Data 
Protection Regulation (GDPR) and Data Protection Act 2018, Declaration of Helsinki - 2013 version, the 
European Union (EU) Medical Device Directive (MDD) (Council Directive 93/42/EEC 14 June 14 1993 and 
2007/47/EC of 5 Sep 2007) and MEDDEV 2.7/3 revision 3, May 2015 - Guidelines on Medical Devices - Clinical 
Investigations: Serious Adverse Event Reporting Under Directives 90/383/EE and 93/42/EEC, Ireland’s Health 
Products Regulatory Authority (HPRA), Medical Device Regulatory Requirements for the Czech Republic, the 
State Institute for Drug Control (SUKL), the Czech Ministry of Health and requirements of other applicable 
government regulations in Ireland and the Czech Republic and institutional research committee policies and 
procedures, whichever accords greater protection to the human subjects. 
1.1 General Information 
1.1.1 Study Title 
Percutaneous Electrical Phrenic Nerve Stimulation (PEPNS) System Feasibility Study 
Study Number & Version: CIP0001 Rev 4, November 30, 2018. 
1.1.2 Study Sponsor 
Stimdia Medical, Inc. 
Study Director   
Name: 
Laurie Lynch, PhD 
 
Address: 
Stimdia Medical, Inc., P.O. Box 251, 5021 Vernon Avenue, 
Edina, MN 55436 
 
Cell Phone: 
+1 952-221-2468 
 
Email: 
llynchassociates@gmail.com 
Name: 
Mr. John O’Mahony 

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Test Article & Data 
Analysis  
Address: 
Stimdia Medical, Inc., P.O. Box 251, 5021 Vernon Avenue, 
Edina, MN 55436 
Cell Phone: 
+1 763-516-7605 
Email: 
jomahony@stimdia.com 
Statistician  
Name: 
Ms. Jennifer Mischke 
Address: 
400 Highway 169, Suite 500, Minneapolis, Minnesota 55426 
Cell Phone: 
+1 612-251-9726  
Email: 
jmischke@namsa.com 
 
1.1.3 Study Monitor 
Stimdia Medical Inc. study personnel and contract study monitors as applicable.  
1.1.4 Participating Investigation Site(s) & Principal Investigator(s) 
Investigative Site Information 
Investigative Site Name/ 
Address 
Beaumont Hospital  
P.O. Box 1297 
Beaumont Road 
Dublin 9, Ireland 
Military University Hospital (ÚVN) 
U Vojenské nemocnice 1200, 
169 02 Praha 6, Czech Republic 
Principle Investigator  
Dr. James O’Rourke, MB, BCH 
BAO, DIBICM, DCH, BSc 
Consultant in Intensive Care 
Medicine 
Anaesthesia and Intensive Care 
Medicine 
MUDr. Michal Soták 
Department of Anaesthesiology, 
Resuscitation and Critical Care 
Co-Principle Investigator 
Professor Gerard Curley, MCR, 
PhD, MB, BCh, BAO 
Professor of Anaesthesia and 
Critical Care 
Anaesthesia and Intensive Care 
Medicine 
None 
 
2. BACKGROUND & RATIONALE 
Ventilator-induced Diaphragm Dysfunction is a significant contributor to weaning difficulty in ventilated 
critically ill patients. It has been hypothesized that electrically pacing the diaphragm during mechanical 
ventilation may reduce diaphragm dysfunction resulting in faster weaning times. 
 
Ventilator induced diaphragm dysfunction (VIDD) is considered a major determinant of the ability to successfully 
wean patients from mechanical ventilation1. After as little as 18-69 hours of mechanical ventilation, autopsy 
specimens from brain-dead organ donors showed greater than 50% reduction in the cross-sectional areas of 
diaphragm myofibers2 and animal models have shown a reduction of diaphragmatic force generating capacity 
proportional to the duration of mechanical ventilation3,4. The hypothesis that electrically pacing the diaphragm 
could prevent VIDD has been previously proposed5. Surgically implanted systems for pacing the phrenic nerves 
and diaphragm have been used for the past 40 years in more than 2,500 adult and pediatric high-level spinal cord 
injury patients6,7 and in late-stage Amyotrophic Lateral Sclerosis patients. Implanted systems are not suitable for 
critically ill patients due to the invasive and complex surgical procedure8,9. Brief transcutaneous stimulation of 

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phrenic nerves is often used for diagnostic purposes, but is not suitable for therapeutic purposes. Transvenous 
phrenic nerve stimulation (TPNS) has been periodically attempted over the past 50 years10. Stimdia has developed 
a novel percutaneous electrical phrenic nerve stimulation (PEPNS) system. 
To evaluate the mitigating effect of phrenic nerve pacing on VIDD we have performed animal studies in canine, 
caprine and porcine models demonstrating that the operational parameters and insertion techniques chosen do not 
damage the surrounding tissue or nerves. Testing in animals has also demonstrated that the diaphragm strength is 
maintained in paced animals versus non-paced animals11,12.  
 
We hypothesize that beginning phrenic nerve pacing soon after initiation of deep sedation and mechanical 
ventilation will minimize the reduction in diaphragm strength over time in ventilated subjects and lead to faster 
weaning times. It has been shown that maintaining some level of work during sedation greatly reduces the 
deleterious decrease in diaphragm strength.  
 
The PEPNS System Feasibility Study is being conducted to confirm the feasibility of phrenic nerve stimulation in 
the neck with PEPNS System to pace the diaphragm. The study will be used to confirm: 
• 
The benefits of ultrasound imaging in guiding the deployment of the pacing leads across the phrenic nerve 
in the patient’s neck;  
• 
The ease of lead deployment in the neck;  
• 
The current stimulation levels required to stimulate and contraction of the diaphragm in synchrony with 
the ventilators inspiratory breaths; and 
• 
Stability of stimulation thresholds as patients are repositioned (supine, recumbent, lateral). 
 
The PEPNS technology consists of two disposable multipolar stimulation leads and an external function generator 
designed to stimulate the phrenic nerve in synchrony with the inspiratory cycle of the ventilator. The purpose 
being to exercise the diaphragm during positive pressure ventilation to minimize the reduction in diaphragmatic 
strength. 
 
Beyond testing the feasibility of the technology in humans the purpose of the study is to also: 
 
Demonstrate that the human experience is consistent with the preclinical trial results. 
 
Collect preliminary data that may refine the most suitable patient population for a pivotal study.  
 
Characterize diaphragm thickness observed on patients using mechanical ventilation and phrenic nerve 
electrical stimulation if feasible. 
 
Diaphragm stimulation parameters in terms of currents, current profile waveforms, voltages and charge density 
are similar to those used in chronic diaphragm pacing patients where ventilatory support is replaced with pacing. 
Subjects will be treated per the standard of care for patients on ventilatory support, with weaning trials conducted 
up to 48 hours where weaning criteria are met.  Time to weaning from mechanical ventilation will be collected.  
Adverse events will also be collected and analyzed. 
 
The PEPNS System provides a minimally invasive alternative therapy to the standard of care for VIDD patients 
that may provide a reduction in mechanical ventilation weaning time.  The target patient population for this study 
is the difficult to wean patients.   The European Respiratory Society, American Thoracic Society, European 
Society of Intensive Care Medicine, Society of Critical Care Medicine, and Societe ´de Re´animation de Langue 
Francaise convened an International Conference on weaning from mechanical ventilation as reported in 2011.  
The definition of difficult to wean patients is based off this panel’s definition.  Difficult to wean patients are 

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patients who required up to 7 days to be extubated from the first attempt of withdrawal from mechanical 
ventilation.13   The study will confirm the protocol procedures to be used in the pivotal trial.  In addition, the data 
from these subjects will provide evidence of the ability of stimulation to improve the time to weaning for subjects. 
This trial will not be powered to be statistically significant to demonstrate a reduction in weaning times.  
 
Condition  
Intervention  
Patients who are having difficulty in 
weaning from mechanical ventilation 
Device:  
Percutaneous Electrical Phrenic Nerve Stimulation  
(PEPNS) System 
Study Type: 
Percutaneous placement of stimulation leads 
Study Design: 
Endpoint Classification: Safety Study 
Intervention Model: Single Group Assignment 
Official Title: 
Percutaneous Electrical Phrenic Nerve Stimulation (PEPNS) System 
Feasibility Study.  Also, referred to as PEPNS System Feasibility 
Study. 
Study Sponsor: 
Stimdia Medical Inc.  
3. SUMMARY OF PRE-CLINICAL TESTING 
The PEPNS System has been evaluated extensively in a total of 26 animal studies.  The main objective of these 
studies was to confirm the stimulation treatment could be delivered safely and effectively for the expected 
duration of use.  These studies were also used to evaluate device reliability and usability as secondary objectives.  
See pre-clinical study table listed below.  

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The initial series of studies were completed to evaluate various:  
a) animal models for durability and suitability,  
b) modes of stimulation and  
c) method of stimulation in synchrony with the inspiratory cycle.   
 
The next series of studies were completed to evaluate the impact of stimulation of the diaphragm via the phrenic 
nerve at lessening the reduction of diaphragm strength in a prolonged mechanically ventilated porcine model 
when comparing the unstimulated control animal.  Diaphragm strength was maintained from baseline in the 
animals receiving electrical stimulation while the control animals had a 20% decline in diaphragm strength from 
the start of the procedure (baseline).   
 
The next series of studies were used to evaluate several stimulation electrode lead configurations and determine 
the best method to deploy the lead in the least invasive way possible. The lead configurations were evaluated for 
positionality, stability (acute and chronic), output/current requirements, durability of stimulation capture and 
size/accessibility criteria. The ideal stimulation electrode lead configuration was found to be the multipolar (4 
electrode). The choice of a four-pole electrode for this application is further supported by the literature14; 
specifically, it has been demonstrated that use of multipole electrode facilitates optimization of the electrical 
stimulus after the lead is deployed percutaneously lying across the phrenic nerve. Crucially, four pole electrode 
leads have previously been used chronically to stimulate the diaphragm via the phrenic nerve in the neck to 
replace ventilator support in humans.  
 
In addition to these assessments of multiple electrode lead configurations, another phase of studies also evaluated a 
percutaneous approach of placement of the lead. Previous phrenic nerve leads detailed in the published literature 
were surgically placed. Whereas the proposed insertion procedure uses a Through-the-Needle (TTN) deployment 
approach, minimizing trauma and scarring for the patient. Currently released medical devices or those in 
Description
Name
Reference Model Duration
Start Date
End Date
Pilot 1
16P10
Porcine 8 hrs
11/5/2015
11/5/2015
Pilot 2
16G1
Caprine 8 hrs
12/29/2015
12/29/2015
Pilot 3
16P97
Porcine 8 hrs
1/5/2016
1/6/2016
Evaluate Best Method of Sensing & Stimulation with Inhalation
Pilot 4
16G3
Caprine 10 hrs
3/1/2016
3/1/2016
Pilot 5
16G4
Caprine 6 hrs
3/14/2016
3/14/2016
Pilot 6
16G5
Caprine 24 hrs
3/15/2016
3/16/2016
Pilot 7
16G6
Caprine 24 hrs
3/17/2016
3/18/2016
Tech 1
16G8
Caprine 24 hrs
3/21/2016
3/22/2016
Tech 2 
16G9
Caprine 24 hrs
3/23/2016
3/24/2016
Select Best Animal Model - Durability to Complete 24 hrs. Studies
Tech 3 
16D40
Canine
24 hrs
3/28/2016
3/29/2016
Tech 4 
16D41
Canine
24 hrs
3/30/2016
3/31/2016
Tech 5
16P163
Porcine 24 hrs
4/13/2016
4/14/2016
Tech 1 
16P0241
Porcine 24 hrs
5/3/2017
5/4/2017
Evaluate Decline in Diaphragm Strength Overtime with and without Stim
Tech 2
16P0261
Porcine 24 hrs
5/5/2017
5/6/2017
Tech 3 
16P0252
Porcine 24 hrs
5/9/2017
5/10/2017
Evaluate Lead Types & Insertion Methods
Lead Pilot1 
16P0344
Porcine 12 hrs
6/16/2017
6/16/2017
Lead Pilot2 
16P0433
Porcine 12 hrs
7/11/2017
7/11/2017
pre-GLP Pilot1 
16P0596
Porcine 24 hrs
8/30/2016
8/31/2016
pre-GLP Pilot2 
16P0684
Porcine 24 hrs
9/27/2016
9/28/2016
pre-GLP Pilot Studies
Needle Position Pilot 
16P0671
Porcine Acute
10/3/2016
10/3/2016
pre-GLP Pilot3 
16P0685
Porcine 24 hrs
10/6/2016
10/7/2016
pre-GLP Pilot4 
16P0687
Porcine 24 hrs.
10/6/2016
10/7/2016
Revised pre-GLP Pilot1 
16P0810
Porcine 30 hrs.
11/21/2016
11/22/2016
Nerve & Diaphragm Stim Integrity Test - 30 Day Chronic
Revised pre-GLP Pilot2 
16P0847
Porcine 12 hrs.
12/1/2016
12/1/2016
Revised pre-GLP Pilot3 
16P0852
Porcine 12 hrs.
12/19/2016
12/19/2016
Revised pre-GLP Pilot4 
16P1000
Porcine 12 hrs.
12/22/2016
12/22/2016

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development require some form of surgery to place the electrodes beside the phrenic nerve.  These methodologies 
are thought to be too invasive and costly for short term use of phrenic nerve stimulation. The use of a percutaneous 
approach for placing a lead across the phrenic nerve was assessed in animal models.  These lead insertion studies 
concluded that the ideal stimulation electrode lead configuration was found to be the multipolar (4 electrode) lead 
design inserted via percutaneous TTN approach in a cannula with a blunt needle design. 
 
The final series of animal studies evaluated the impact of stimulation at maximum stimulation output parameters 
for extended periods of stimulation on the peripheral nerve and diaphragm (equating to nearly 7 days of 
stimulation).  The results indicate the animals tolerated the stimulation during the procedure, had no abnormal 
clinical responses in a 30 day post stimulation procedure period. Gross necropsy and histopathology revealed no 
unusual findings post a 30 day period. 
 
The PEPNS System pre-clinical testing demonstrated that the device was safe and effective for its intended use.  
 
 

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4. INVESTIGATIONAL DEVICE 
4.1 Device Description 
The Percutaneous Electrical Phrenic Nerve Stimulation (PEPNS) System will be used in conjunction with a 
respiratory ventilator.  The PEPNS System will stimulate the patient’s diaphragm to contract in synchrony with 
the inspiratory cycle of the ventilator.  As illustrated in Figure 1 the PEPNS System consists of a signal waveform 
generator, stimulator, flow sensor, two multipolar disposable leads and miscellaneous parts. 
The PEPNS System is manufactured by Stimdia Medical, Inc., the study sponsor, which is located in Edina, MN.  
The PEPNS System device tradename is pdSTIM and this is reflected on some of the device labels. 
Figure 1: The PEPNS System 
 
                                           The PEPNS Lead Electrode and Connector Configuration 
4 x 4mm
300 to 330mm
4 x 1 mm
0.87mm
4 x Electrode
4 x Connector
0
0
1
1
2
2
3
3
90 to 110mm
2 x Marker Bands
 
4.2 Equipment and Accessories Used 
The equipment used during the study may be divided in three categories: 
1. Stimulation System: PEPNS Control system, used to stimulate the left and right phrenic nerve in concert 
with the inspired flow. This equipment, including the pacing leads, insertion kits and lead deployment 
device are provided by Stimdia. 
2. Data Acquisition: PowerLab Data Acquisition System: used to log pressure, flow, WOB and Electrical 
Stimulation in experiments at 1000 Hz. This equipment, which is commercially available, is provided by 
Stimdia. 

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3. Other Equipment: Used to measure patient hemodynamics and vital signs during therapy as well as 
visualize and stimulate phrenic nerve during setup. This equipment is provided by clinical investigation 
site. 
4.3 Indications For Use 
The Stimdia Percutaneous Electrical Phrenic Nerve Stimulation (PEPNS) System is intended to facilitate weaning 
from mechanical ventilation via temporary stimulation in patients who are on mechanical ventilation for 24 hours 
or more and who are at risk of having difficulty in weaning. 
 
4.3.1 Frequency of Use 
During this Feasibility Study, the PEPNS System is intended to be used for up to 2 days while the patient is on a 
mechanical ventilator in the ICU/CCU.  During the study the PEPNS System will be used for up to 48 hours of 
continuous stimulation. The device is not intended for use outside of the hospital environment, such as a long-
term care facility. 
 
4.3.2 Body/Tissue Interacted With 
The pacing leads are placed in close proximity to the phrenic nerves and surrounding muscle tissue in the patients’ 
neck. Electrical stimulation is delivered to stimulate the phrenic nerve and activate the diaphragm.  
 
 

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5. STUDY OBJECTIVES 
The primary aim of this feasibility study is to evaluate the preliminary safety and performance of the PEPNS 
System in patients that need to be mechanically ventilated in the Intensive Care Unit (ICU).  Specific objectives 
are as follows: 
(a)  Determine whether pacing the diaphragm would be of benefit to the difficult to wean patient cohort in the 
ICU. 
(b)  Examine whether the placement of the phrenic nerve pacing leads between the anterior scalene and 
sternocleidomastoid muscles in the patients’ neck would cause significant other muscular contraction (arm 
movements – brachial plexus transmission,) or local contractions (the muscles of the neck themselves - 
Sternocleidomastoid, Anterior scalene muscles). 
(c)  Determine stimulation levels necessary to elicit a change in the Work Of Breathing measurement as 
determined by the wye pneumotachograph and pressure sensor. 
(d)  Determine whether pacing the diaphragm will result in a progressive increase in tidal volume (or volume per 
breath) within the 48-hour period of the study.  
(e)  Determine if diaphragm thickness can be characterized over the 48 hours of electrical stimulation, if feasible. 
5.1 Primary Endpoints 
Primary Endpoints  
1. Capture of the Left and/or Right Phrenic Nerve > 80% with an output parameter of < 10.5 volts.  
2. WOB (Work of Breathing) kept between 0.2 joules/L and 2 joules/L for 80% of stimulated breaths. 
5.2 Secondary Endpoints 
Secondary Endpoints  
1. The percentage of patients who receive safe and successful placement of the multipolar lead in the left 
and right phrenic nerve utilizing ultrasound guidance will be determined.   
2. Phrenic nerve stimulation in synchrony with Mechanical Ventilation (MV) breaths will be measured to 
verify that is occurs with inspiration. 
3. The percentage of patients who experience one or more serious device/procedure-related adverse events 
during the study will be reported. 
5.3 Additional Study Data 
• 
Time to weaning from mechanical ventilation data will be collected. 
• 
Diaphragm thickness of electrically stimulated patients will be characterized using ultrasound at the 
discretion of the physician and based the ability of the site to make the measurement at 0 hours (before 
stimulation), at 24 ± 4 hours after stimulation, and at 48 ± 4 hours or at the end of the stimulation period 
during study. The repeatability of the measurement will be examined. This data collected may be 
characterized relative to the diaphragm thickness of unstimulated patients in the published literature. 
 
 

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6. STUDY DESIGN & METHODOLOGY 
The study will examine performance and safety as defined in primary and secondary endpoints listed in Section 
10.  A maximum of up to 20 subjects will be enrolled in the study at up to 2 sites with up to 10 subjects per site.  
The final number of patients enrolled in the study will be based upon the time duration of the study and the rate of 
enrollment. In the first two patients, the investigator will stimulate the left phrenic nerve only and conduct CMAP 
tests and nerve conduction test on both phrenic nerves prior to and at least 3 weeks after the stimulation. These 
subjects will be examined 30 days’ post study, to confirm safety of this method of stimulation of the phrenic 
nerve before enrolling the remaining patients up to a total of 20 subjects. After successfully demonstrating 30 day 
follow up on the initial two patients, stimulation will occur in both the left and right phrenic nerves 
simultaneously for the remainder of the trial. Typically, stimulation will occur once every 3 to 5 breaths and this 
decision will be left to the discretion of the attending physician. Figure 2 outlines the protocol for placement of 
the leads.  
Optional: Assess Left & right 
Phrenic Nerve (PN) integrity  
using hand held TENS 
stimulator. 
Mandatory: Map 
Left & Right PN with 
ultrasound
Meet criteria
Insert Pajunk Touhy 
needle towards 
under ultrasound 
guidance and 
electrical 
stimulation
Yes
Patient not suitable. 
Look for new 
patient
No
Diaphragm 
movement
No
Yes
Yes
Cease stimulation 
and insert Touhy 
past phrenic nerve 
Insert Multipolar Lead into Pajunk 
Touhy.  Stimulate Left PN with 
Multipolar Lead.  Verify 
corresponding diaphragm movement. 
Secure Multipolar Lead with 
Surgical Glue & Strain Relief 
Loop.  Place Tagadem over access 
site. Stimulate for duration of 
treatment
Turn stimulation off.  Gently 
and safely remove the 
multipolar lead from the 
patient. Clean access site – 
place bandage over access 
site.
Left PN
Repeat 
Right PN
No
ASEPTIC TECHNIQUE REQUIRED
Stimulate for 
duration of 
treatment
Left and Right PN 
insertion complete. 
yes
Total number of study 
patients enrolled
No
End Study
Yes
START: No Safety concerns 
with Left Phrenic Nerve 
Stimulation of two patients
 
Figure 2. Study Left and Right Phrenic Nerve Pacing 
Stimulation will occur for a maximum duration of 48 hours. A number of evaluations will also be conducted to 
measure the ease of placing and removing the stimulation leads as well as the ability of the lead to accommodate 
positional changes made by or to the patient. 
 
6.1 Study Data Analysis and Statistical Methods 
In general, summary statistics will include the mean, median, standard deviation, minimum and maximum for 
continuous measures and the number and frequency for categorical measures. All analyses will be conducted 
using SAS v9.3 or greater (SAS Institute Inc., Cary, NC, USA). Sample size calculations were conducted using 

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PASS v14 (PASS 14 Power Analysis and Sample Size Software (2015). NCSS, LLC. Kaysville, Utah, USA, 
ncss.com/software/pass). 
6.2 Inclusion and Exclusion Criteria  
Inclusion Criteria:  Candidates for this study must meet all of the following inclusion criteria: 
1.  18 years or older (Adult). 
2.   Male or Female. 
3.  Able and willing to give informed consent or whose legally authorized representative is able and   
willing to give informed consent. 
4.  Subject who in the opinion of the admitting consultant/intensivist is likely to be ventilated for > 48 
hours from time of recruitment since study treatment will be for up to 48 hours. 
 
Exclusion Criteria:   Candidates for this study will be excluded if ANY of the following conditions are 
present: 
1. Subject has a left ventricular ejection fraction (LVEF) < 20%.  
2. Subject unlikely to survive 72 hours due to coexisting medical conditions. 
3. Subject has an implanted pulse generator or implanted electronic device: Examples: Cardiac 
pacemaker, Defibrillator, ICD, Watchman, Vagal nerve stimulator, Spinal cord stimulator, Gastric 
stimulator or Diaphragmatic stimulator. 
4. Subject has experienced an Acute Myocardial Infarction (AMI) within 72 hours prior to this screening 
or subject is on high dose inotropic support or patient is deemed to be in cardiogenic shock. 
5. Subject has significant bleeding diathesis, or is at risk of significant haemorrhage, patient is receiving 
full dose systemic anticoagulation 
6. 
Subject has a known or suspected phrenic nerve paralysis or neuromuscular or inflammatory muscle 
diseases where the diaphragm itself may not be functional. 
7. Subject has an active systemic infection or local infection at or around the insertion site. Subject is 
neutropenic or has signs of significant immunocompromise. 
8. Subject is known or suspected to be pregnant or is lactating. 
9. Subject will be unavailable for, or is unwilling to comply with, follow up requirements of the protocol. 
10. Subject is currently enrolled or is expected to be enrolled in any other study of an investigational drug 
or device who has received treatment under that protocol with the investigational product during the 30 
days prior to screening. 
11. Subject has undergone a surgery or interventional procedure within the neck region aside from 
placement of an internal jugular (IJ) vein catheter. 
12. Subject has been diagnosed and has been treated for neck cancer within the past 5 years. 
13. Subject is known to have a demonstrated intra cardiac thrombus on echocardiography. 
14. Subject has uncontrolled hyperthyroidism, hypertension. 
15. Subject has had any cerebral ischemic event (Stroke or Transient Ischemic Attack TIA) in the 6-month 
interval preceding the screening date. 
16. Subject has degenerative nerve disorders such as amyotrophic laterals sclerosis (ALS). 
17. Subject has an elevated hemidiaphragm on chest x-ray. 
18. Subject written informed consent not obtained. 

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6.3 Enrollment 
Subjects will be screened to determine eligibility i.e., who meet all inclusion and exclusion criteria. Those 
subjects that meet the eligibility criteria and who agree to participate in the study will sign an Informed Consent 
form. Subject is deemed to be enrolled into study when the subject provides written informed consent and agrees 
to participate in the clinical investigation.  
All patients that were attempted to be treated with the PEPNS System (i.e., intent-to-treat patients) but the 
procedure was aborted will also be followed for 30 days (+7 days) post index procedure for safety (i.e., adverse 
event collection).   
A screening log will be used to determine why patients were screened out of the study. 
 
6.4 Subject Compliance 
Subjects will be asked to return to the site for follow up visit at 30 days from the date of treatment to have a chest 
x-ray and to assess them for adverse events. 
 
6.5 Withdrawal and Discontinuation 
Subjects have the right to withdraw from the clinical investigation at any time and for any reason without 
prejudice to their future medical care by the investigation team or investigation site. Investigator will ask reason 
for their withdrawal. Investigator will record all information regarding the patient withdrawal and discontinuation.  
A subject may be withdrawn from the clinical investigation for the following reasons:  
• 
Subjects may choose to withdraw from the clinical investigation under the terms of the Declaration of 
Helsinki and General Data Protection Regulation (GDPR) and Data Protection Act 2018 and their 
consent documentation without having to give a reason;  
• 
Any unanticipated adverse reaction which is, in the opinion of the Investigator, related to the treatment 
and will endanger the well-being of the patient if treatment is continued;  
• 
Development of any illness(es), infection or condition(s) that might interfere with the protocol;  
• 
Non-compliance with the clinical investigation procedures deemed by the Investigator to be sufficient to 
cause discontinuation; and 
• 
Any problem deemed by the Investigator to be sufficient to cause discontinuation. 
Subject withdrawal and discontinuation will not affect the standard of care the patient receives. 
 
6.6 Early Termination or Suspension of Clinical Investigation 
Both the Sponsor and Investigator reserve the right to terminate the clinical investigation at any time. After 
review of the clinical safety data and consultation with Principal Investigator, Sponsor will make a final 
determination on whether to terminate or suspend the study.  In the event of premature termination or suspension 
of the study, the sponsor will promptly notify the investigational center and governing regulatory agencies and 
communicate a plan for orderly termination or suspension.  Any subjects already enrolled in the study will still be 
followed up for 30 days. 
 
6.7 Informed Consent Process 
After a normal clinical assessment, the Principal Investigator may approach patients whom he or she feels may be 
suitable for entry into this clinical investigation.  The Principal Investigator should introduce the patient or the 
patient’s legally authorized representative to the clinical investigation by explaining the Clinical Investigation 

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Plan, procedures and objectives to the patient or his/her legally authorized representative.  The Principal 
Investigator will then provide an information sheet describing the clinical investigation, potential discomforts, 
risks and benefits of participation.  The patient or his/her legally authorized representative will have 24 hours to 
decide whether they wish to participate in this clinical investigation due to the criticality of the timing that the 
treatment is applied once the patient is on a mechanical ventilator.   
Any queries that patients may have regarding this clinical investigation will be addressed appropriately by the 
Principal Investigator, or another member of the investigative team at the hospital.  Patients or their legally 
authorized representatives will be instructed that they are free to obtain further information from the Principal 
Investigator at any time and that they are free to withdraw their consent and to discontinue their participation in 
the clinical investigation at any time without prejudice.  
If the patient is willing to participate in the clinical investigation, he/she or his/her legally authorized 
representative must read, understand and sign the informed consent form.  The Principal Investigator will also 
sign this at the same occasion.  Two copies of the consent form will be made. The original signed consent form 
will be kept in the Investigation Site File.  A copy will be kept in the subject’s medical notes and a further copy 
provided to the subject or his/her legally authorized representative. 
Since the subjects will be unconscious and mechanically ventilated at the time of the informed consent process 
should they regain consciousness they will be allowed to withdraw from the study if desired without any impact 
on their medical treatment.  If subjects do regain consciousness during the treatment they will be asked to sign the 
informed consent form if they are able.  
 
6.8 Study Design and Number of Observations 
The study design includes a planned total of one to sites with up to 10 subjects per site.  Defined data analysis will 
be conducted on enrolled and associated data. 
 
6.9 Safety Endpoints 
The secondary safety endpoints are the percentage of patients who receive safe and successful placement of the 
multipolar lead in the left and right phrenic nerve utilizing ultrasound guidance and the percentage of patients who 
experience one or more serious device/procedure-related adverse events during the study.  
No formal hypothesis tests will be conducted; therefore, power and significance level are not relevant in this 
context. However, the sample size was chosen to provide sufficient data on the occurrence of adverse safety 
findings. According to Virzi (1992), 80% of all usability issues are detected with four or five subjects. With up to 
10 to 16 humans, the percentage of problems detected is approximately 95% to 98% (with 30% probability of at 
least one event). (Ref: Virzi, RA. Refining the Test Phase of Usability Evaluation: How Many Subjects is 
Enough? Human Factors, 1992. 34(4), 457-468.).  
 
6.10 Primary Performance Endpoint: Stimulation Pulse to Capture the Diaphragm 
The ability of the stimulation pulse to capture the diaphragm will be assessed using WOB (Work of Breathing 
Measurements). A logistic regression model with successful capture as the outcome will be used.  The model will 
include repeated measurements within a subject. 
 
6.10.1 Model: 
capture = (timepoint) (subject) 
where subject is a random effect, and the outcome of capture is yes/no based on whether the stimulation captures 
the diaphragm. 

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6.10.2 Hypothesis: 
Ho:  The proportion of capture is less than or equal to the performance goal (PG) of 90%. 
Ho:   𝑝𝑝̂1  ≤  PG 
HA:   The proportion of capture is greater than the performance goal of 90%.   
HA:   𝑝𝑝̂1 > PG, 
where  𝑝𝑝̂1 is the estimated proportion of capture from the logistic model accounting for repeated measurements 
within a subject. 
6.10.3 Sample Size:  
The following assumptions were the basis for the sample size calculation for the performance endpoint evaluating 
stimulation capture of the diaphragm: 
• 
Power: 80% 
• 
1-sided α: 0.025 
• 
Performance goal: 90% 
• 
Expected success rate: 97.5% 
With an anticipated success rate of 97.5% and a performance goal of 90%, 80 observations would yield ≥80% 
power. Note that, for the purposes of sample size calculations, the observations are assumed to be independent. 
However, the primary analyses will account for within patient correlation, as described below.  Increasing the 
number of observations will increase the statistical power.  
6.10.4 Methods: 
The proportion of successful capture will be analyzed using a logistic regression model accounting for patient as a 
random effect.  The null hypothesis will be tested comparing the lower bound of the 95% two-sided confidence 
interval for the estimated percent agreement to the performance goal of 90%.  If the lower bound is greater than 
90%, the null hypothesis will be rejected and the endpoint will be considered met.  
 
6.11 CMAP and Nerve Conduction Studies 
Compound muscle action potential (CMAP) testing and nerve conduction studies will be conducted on the first 
two subjects during the index procedure and at or before the 30 day follow up. CMAP is a non-invasive test that 
causes minimal or no discomfort.  A hand held electrical stimulator will be used to generate a bipolar electrical 
phrenic stimulation in the neck, while recording diaphragm electromyographic responses on the surface of the 
chest. These studies will be performed by an Electrophysiologist skilled in the performance of these tests who will 
make a clinical assessment regarding the effects of stimulation. The studies will measure the CMAP on both the 
left and right diaphragm as well as the conduction latency of the phrenic nerves before the initiation of treatment 
on the first two patients. This data will be compared to the measurement data generated at a follow up test 
performed post cessation of treatment. Electrical stimulation will only be performed on the left phrenic nerve (the 
smaller of the two lungs) on the first two patients, affording the opportunity to use the patient as their own control 
and assess any difference induced by the PEPNS therapy between the stimulation and unstimulating phrenic 
nerves and diaphragm of each patient using a comparison of the CMAP voltage amplitude and nerve conduction 
latency.  Fluoroscopy may be done on first two patients if differences are seen in the CMAP and nerve conduction 
studies by the electrophysiologist for the treated phrenic nerve.  The data will also be compared to the published 
literature for phrenic nerve conduction latency15,16 and CMAP17,18 voltage amplitudes. 
 
6.12 Measurement of Diaphragm Thickness using Ultrasound 
Diaphragm muscle thickness will be measured using a standardized technique described similar to that previously 
by Cohn et al19 and Ueki et al20 and later modified by Francis et al.21 Imaging will be performed using the M-

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Turbo ultrasound system (SonoSite, Inc) with a 7.5-10.0-mHz transducer probe or its equivalent in two-
dimensional B-mode.  
 
6.13 Electrocardiogram (ECG) and X-ray 
The electrocardiogram testing will be conducted using 12 leads prior to the stimulation and during the stimulation 
approximately every 24 hours following standard hospital procedures for running this test so that a cardiologist 
can determine if there have been any ECG changes during or post stimulation.  
A routine chest x-ray will be taken prior to the stimulation and at or before the 30 day follow up, to determine if 
there has been any obvious change in lung volume or degree of atelectasis (in comparison to the contralateral lung 
as a consequence of stimulation). 
 
6.14 Secondary Performance Endpoint: Analyzing Phrenic Nerve Stimulation in Synchrony 
with MV Breaths 
A breath by breath stim count analysis will be performed to determine the effectiveness of electrical stimulation 
on the inspiratory breaths stimulated. Effectiveness will be determined by measuring an effect on the work 
performed by the diaphragm and its ability to remain within normal physiological levels of work of breathing.  
 
Figure 3. Sample Data Acquisition Data using Labchart for Qwye, Pwye, WOB and Stim Signals 
 
The analysis will be performed for WOB as follows. A count will be performed to determine the number of 
stimulated breaths the measured WOB falls within a predetermined upper and lower control level for the 
stimulated breaths. This will be compared to the number of breaths electrically stimulated. These counts will be 
used to determine the effectiveness of electrical stimulation based upon percentage of electrical stimulation 
signals capturing breaths as intended.  
 

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6.15 Additional Study Data  
Time to weaning from mechanical ventilation data will be collected and reported. 
The effect of electrical stimulation on diaphragm thickness, blood gas parameters, vital signs, end tidal CO2 and 
tidal volume may be characterized. To this end, stimulation will be stopped for a single period of 1 hour within 
the middle period of the 6 hour blood gas analysis collection period, when the patient has been deemed to be 
hemodynamically stable by the attending physician. Data will be collected on blood gasses, pulse rate, blood 
pressure, SpO2, end tidal CO2 and tidal volume at the end of the 1 hour period. This data will be used to 
characterize the effect of electrical stimulation on hemodynamics. The mode of ventilation will also be recorded 
because stimulation is predicted to have little effect on tidal volume in flow controlled modes whereas it is 
predicted to increase in pressure control modes of ventilation. Tidal volume may also be adjusted to be the same 
as when electrical stimulation was turned on to eliminate any confounding effects of decreased minute and tidal 
volumes when stimulation is turned off. All other parameters such as breath rate, PEEP, FIO2 etc. will be kept the 
same. 
The diaphragm thickness may be measured prior to the stimulation, at 24 hours and at 48 hours or after the 
completion of all of the stimulation using ultrasound when clinically feasible, i.e., 0 hours, 24 hours and 48 hours 
or end of stimulation.    
 
 

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7. PROCEDURAL GUIDELINES (Treatment Procedure) 
7.1 Operator’s Manual 
Detailed instructions are provided for the console and lead insertion and all participating investigators will be 
trained on how to use the PEPNS System. Refer to LM0001 PEPNS System Operator’s Manual for detailed 
information. 
8. SITE SELECTION CRITERIA  
Site Selection Criteria  
Number of ICU beds & state of the art status of ICUs and staffing (minimum of 10 ICU beds)  
Number of Ventilation Patients – enrollment capacity (minimum of 300 mechanically ventilated 
patients on an annual basis) 
• 
Critical Care Research (previous & existing and no competing studies, etc.) 
• 
Outcomes (existing trials) 
• 
Dedicated ICU/Critical Care Research Nurse 
• 
Proficiency in mapping nerves with ultrasound and placing leads in the neck region within the 
ICU setting 
• 
None of the investigators can be in the FDA disqualification proceedings database. 
 
9. SITES AND ENROLLMENT 
Sites and Enrollment   
Up to 2 trained and enrolling sites 
Up to 10 patients at each site 
 
10. PROCEDURE DURATION AND FOLLOW-UP 
Procedure Duration and Follow-up   
Up to 48 hours of continuous stimulation time 
Upon expiration of the 48 hour stimulation period the stimulation will be turned off and the PEPNS 
multipolar leads will be removed from the patient.  
 
Patient Follow-up   
Each patient will be followed for a total of 30 days after stimulation end to determine if he/she 
experienced any adverse events with a clinic follow-up visit and for a chest x-ray. This follow up may 
occur within +7 days of the 30-day follow-up period giving an allowable follow-up range of 30 to 37 
days for AE’s and 30 ± 7 days for the chest x-ray. 
 
The total expected duration of the clinical trial is up to 18 months once both sites start to enroll subjects. 
 

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11.  STUDY SCREENING AND STUDY PROCEDURES 
11.1 Screening 
Potential study candidates undergo a screening evaluation that includes: 
• 
An evaluation of their suitability for enrollment in the study by the site Investigator including their current 
state of health, demographics and medical history; 
• 
Height, weight and body mass index (BMI) 
• 
Neck diameter at the cricoid cartilage  
• 
Ventilation information 
• 
Blood pressure 
• 
Chest x-ray 
11.2 Index Procedure 
Once the study subject or authorized representative signs an ICF and his/her eligibility to participate in the study 
is confirmed, the PEPNS System procedure can be initiated. A primary operator will be performing the PEPNS 
System procedure, but an additional qualified operator may be present or assisting. A Stimdia representative may 
also be present during index procedure to provide technical guidance to the primary operator. 
The Investigator will follow the procedure technique outlined in LM0001, PEPNS System Operator’s Manual. 
Prior to the start of electrical stimulation, the subject’s diaphragm thickness may be measured using ultrasound 
and the subject will have a 12 lead ECG. In addition, baseline standard blood gasses such as pH and paO2, paCO2, 
SaO2, HCO3 etc. and exhaled gas analysis such as end-tidal CO2 data will be garnered for up to 24 hours prior to 
stimulation.  
A four pole pacing lead electrodes will be percutaneously placed beside the phrenic nerves using ultrasound 
guidance and the ultrasound screen shots will be captured if possible. The ease of gain pacing lead access and 
setup will be assessed and logged. 
The subjects phrenic nerve(s) will then be electrically stimulated for up to 48 hours and device and procedure 
information, ventilation and PEPNS System stimulation will be recorded. In addition, patient vital signs including 
heart and respiratory rate, blood pressure, temperature, pH, paCO2, paO2, hematocrit, end-tidal CO2, will be 
collected when available unless otherwise specified in table 1 below. If the patient is weaned from the mechanical 
ventilator during this time the time to weaning will also be recorded. Also, a chest x-ray will be obtained if the 
patients has not had one in the last 30 days.  In addition, Critical Care Pain Observation Tool22,23 (CPOT) and 
Richmond Agitation & Sedation Scale24,25 (RASS) assessments will be administered prior to the electrical 
stimulation and every 6 hours during it. Patients will also be physically observed for any muscle twitching during 
the simulation period to try and determine if any other nerves were stimulated. Diaphragm thickness may be 
measured again at 24 and 48 hours or at the end of the stimulation period. 
The ability of the pacing lead to accommodate neck movement and patient positional changes will also be 
assessed and logged during electrical stimulation.  
The ease of removing the pacing leads from the patient’s neck will also be assessed during lead extraction and 
logged.   
Compound muscle action potential (CMAP) testing and nerve conduction studies will be conducted on the first 2 
subjects during the index procedure and at or before the 30 day follow up. 
 
11.3 Follow-Up Visits 
All subjects will be followed up at 30 days to 37 days for adverse events and 30 ± 7 days for the chest x-ray.  At 
this time hospital discharge and ventilation weaning time data will also be collected. Table 1 summarizes all 
required and optional test and procedures throughout the study including each visit’s compliance windows. 

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Table 1:  Study Procedures and Follow Up 
Test / Evaluation 
Screening 
(within 2 days pre-procedure) 
Index 
procedure 
30 day 
follow up 
Signed Informed Consent 
X 
 
 
Subject Demographics 
X 
 
 
Medical History 
X 
 
 
Height/Weight/BMI 
X 
 
 
Blood Pressure 
X 
 
 
Chest x-ray 
X1 
 
X 
12 lead ECG 
 
X 
 
Lead Insertion assessment 
 
X 
 
1 hr. cessation of electrical 
stimulation 
 
X 
 
Patient movement / repositioning 
assessment 
 
X 
 
CMAP2 
 
X 
X 
CPOT/RASS assessments 
 
X 
 
Muscle twitching observation 
 
X 
 
Ultrasound screen shots (optional) 
Ventilation settings and end-tidal 
CO2 required 
Stimulation Data 
Vital Signs / pulse oximetry 
Standard Blood gases: pH, paO2, 
PaCO2 etc. 
Diaphragm thickness (optional) 
 
X 
 
Lead Removal assessment 
 
X 
 
Adverse Events 
 
X 
X 
Device Malfunctions 
 
X 
 
1 It is acceptable if this has been taken up to 30 days prior to the screening visit.  
2 Only for the first 2 patients enrolled.  
11.4 Unscheduled Visit 
In addition to scheduled follow-up visits, the participants will be instructed and encouraged to contact the 
Investigator at any time during the follow-up period if he/she has questions or concerns relating to the PEPNS 
System therapy. If the patient is seen by the Investigator between scheduled follow-up visits (i.e., not a study 
required visit): 
•  No adverse events noted during unscheduled visit – no forms need to be completed. 
•  Adverse event noted – The Adverse Event (AE) Case Report Form (CRF) needs to be completed for each event. 
The patient will still be required to return for the next scheduled follow-up visit if the unscheduled visit is out of 
the compliance with the follow-up window. 

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If the patient is treated by a health-care professional other than the Investigator for treatment-related 
complications, the Investigator must request copies of the medical records and, if necessary, complete an AE 
CRF. 
 
11.5 Lost to Follow-up 
If a patient is lost to follow-up, a Patient Deposition CRF must be completed. If a patient fails to comply with 
follow-up evaluations, the study center must make repeated attempts (at least three) to contact the patient. Each 
attempt to contact the patient and the method used (e.g., telephone contact, registered letter) must be documented 
in the patient’s records. Also, a letter to the patient’s general practitioner will be sent informing him/her that 
his/her patient was lost to follow-up.  
 
11.6 Patient Withdrawal from the Study 
11.6.1 Voluntary Withdrawal 
A patient may voluntarily withdraw from the study at any time. The Patient Deposition CRF must be completed. 
If the patient has experienced an AE, where possible the patient should be followed until its resolution. 
11.6.2 Withdrawal for Other Reasons OR Non-Treatment 
If the patient has signed the ICF but was later found to not meet inclusion/exclusion criteria prior to enrollment or 
deemed not suitable for treatment by the physician the patient will not be considered enrolled in the study.  
11.6.3 End of Study 
Patients will exit the study at the time the study is closed or after the 30 day of follow up, whichever comes first. 
Patients may also exit the study by withdrawing his/her participation voluntarily. A Patient Disposition CRF is 
required at the time of study completion or discontinuation for all enrolled patients. 
 
 

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12. DATA RECORDING AND SUBMISSION REQUIREMENTS 
Data 
All aspects of the study will maintain patient privacy and be Declaration of Helsinki and General Data 
Protection Regulation (GDPR) and Data Protection Act 2018 compliant. 
All raw data will be entered into an Excel or validated spreadsheet format (with patient names excluded) 
and include all data collected on the patients up to the time the data is frozen including baseline, 
procedure, and all follow up data available.  All data sets provided shall be clean with all queries 
resolved.   
The following are the types of data in the study: 
RAW DATA: 
1. PEPNS System electronic archive – data recording by the PEPNS system will be electronically 
archived by Stimdia Medical. 
2. Patient history file – this document will confirm patient meets inclusion and exclusion criteria 
while also documenting all demographic and physiology aspects of the enrolled patient. 
3. PEPNS System procedure report – documentation of procedure related information, e.g., 
sedation, ventilation, stimulation, ultrasound, test article documentation, procedure step checklist 
and procedure related specifics noted. 
CASE REPORT FORMS (CRF): 
1. Screening form 
2. Index procedure form  
3. Adverse event form 
4. Patient disposition form 
5. Protocol deviation form 
6. Device malfunction form 
7. Follow up form  
SPREADSHEET AND ANALYSES: 
1. All data relevant to analysis will be maintained in a validated Excel spreadsheet until the 
completion of the study.  The master spreadsheet will be validated and maintained by Stimdia 
Medical. All Excel files used for the data analysis must be password protected and only 
authorized study personnel can have access to the passwords. 
Interim analysis and results will be reviewed with the steering committee in a periodic manner. 
 
 

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13. RISK/BENEFIT ANALYSIS 
An analysis of the risks associated with the intended use of the device was undertaken according to the guidelines 
laid down in the standard EN ISO 14971:2012, Medical Devices – application of Risk Management to Medical 
Device. A complete Risk Assessment has been documented and resides within the design history file. 
13.1 Potential Risks 
The potential risks related to the PEPNS System and procedure may include but are not limited to the following:  
1. Blood loss > 10 mL 
2. Burn  
3. Cardiac pacing 
4. Diaphragm fatigue 
5. Infection 
6. Inflammation 
7. Nerve damage 
8. Pain 
9. Pneumothorax (punctured lung) 
10. Procedure failure  
11. Scar 
12. Vagus nerve stimulation, potentially resulting in asystole or bradycardia  
 
The risks were mitigated to an acceptable level by design, fault detection, use of standards, training and labeling. 
The use of this device is considered to be relatively benign and testing performed so far in animals has confirmed 
this.   
There are also some potential risks due to the mechanical ventilation and underlying patient comorbidities such as 
the following: 
1. Barotrauma / volutrauma 
2. Hypercarbia 
3. Hypoxia  
There may also be other risks related to use of the PEPNS System and procedure that are not listed or that are not 
known at this time. This study will help characterize the risks associated with the PEPNS System. 
13.2 Minimization of Risk 
To minimize the risks, the PEPNS System has undergone extensive pre-clinical and bench testing. In addition, all 
Investigators will undergo training on the PEPNS System and procedure and subjects will be screened and 
evaluated for medical histories/conditions that may compromise successful performance of the PEPNS System. 
13.3 Potential Benefits 
Up to 40% of patients admitted to intensive care units (ICUs) may require mechanical ventilation (MV) due to 
acute respiratory failure (ARF) or acute on chronic respiratory failure (ACRF), and this need is increasing. Most 
ACRF patients and, to a lesser extent, some patients with de novo ARF, may be treated with noninvasive MV, 
whereas a minority of these patients in the ICU need invasive MV. There is evidence that 65–85% of these 
patients undergoing invasive MV, under appropriate clinical conditions, can be successfully extubated, whereas 
up to 20% of patients will need a prolonged ICU length of stay (LOS) due to difficult weaning. This therapy has 
the potential to reduce the LOS for these difficult to wean patient by accelerating the time to wean by maintain 
diaphragm strength during sedation.  
The proposed study is a first in human study (FIH) which will help define a pivotal study which will be needed 
for the regulatory approval of this device. During use of this device patients will have their diaphragms exercised 

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and it is believed that diaphragm strength may be maintained or increased. The study will provide real world data 
for design and validation for the safety and operational use of the PEPNS system.   
 
SAFETY REPORTING 
13.4 Definitions In Line with EN ISO 14155 Unless Otherwise Denoted 
13.4.1 Adverse events (AE) 
An adverse event is any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the 
investigational medical device.  
Notes:  
• 
This definition includes events related to the investigational medical device. 
• 
This definition includes events related to the procedures involved. 
• 
For users or other persons, this definition is restricted to events related to investigational devices. 
 
13.4.2 Serious adverse events (SAE) 
A serious adverse event is an adverse event that: 
• 
Led to death, 
• 
Led to serious deterioration in the health of the subject, that either resulted in 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient or prolonged hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
• 
Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by the protocol, without serious 
deterioration in health, is not considered a serious adverse event. 
13.4.3 Adverse device effect (ADE) 
Adverse event related to the use of an investigational medical device. 
Notes:   
• 
This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical 
device.   
• 
This definition includes any event resulting from use error or from intentional misuse of the 
investigational medical device. 
13.4.4 Serious adverse device effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse event 
13.4.5 Unanticipated serious adverse device effect (USADE) 
Serious adverse device effect, which by its nature, incidence, severity or outcome has not been identified in the 
current version of the risk analysis report 
Note: Anticipated serious adverse device effect is a serious adverse device effect which by its nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
 

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13.4.6 Device Deficiency 
A device deficiency is an inadequacy of an investigational medical device with respect to its identity, quality, 
durability, reliability, safety or performance.  
Note: Device deficiencies include malfunctions, use errors, and inadequate labeling. 
13.4.7 Malfunction  
Failure of an investigational medical device to perform in accordance with its intended purpose when used in 
accordance with the instructions for use or protocol. 
13.4.8 Use error 
Act or omission of an act that results in a different medical device response than intended by the manufacturer or 
expected by the user 
Notes:   
• 
Use error includes slips, lapses, and mistakes. 
• 
An unexpected physiological response of the subject does not in itself constitute a use error. 
13.4.9 List of Anticipated Adverse Events 
See section 13.1 for a list of anticipated adverse events. 
 
13.5 Adverse Event Classification 
The severity of all adverse events and their relationship to the investigational device/study procedures will be 
classified by the investigator and reviewed by the steering committee or a clinical events committee. This review 
will include indication of any actions recommended be taken to protect patient safety and/or maintain data 
integrity. 
13.5.1 Assessment of Adverse Event Relationship to Investigational Device 
Investigators are required to assess whether there is a reasonable possibility that the Investigational Device caused 
or contributed to an SAE.  Sponsor defines four degrees of relatedness: not related, unlikely, possible, probable, 
possible and causally related to the Investigational Device.  The following definitions will be used to assess the 
relationship of the SAE to use of the Investigational Device per MEDEV 2.7/3 revisions 3 May 2015: 
Not Related 
The relationship to the device or procedures can be excluded when: 
• 
the event is not a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
• 
the event has no temporal relationship with the use of the investigational device or the 
procedures;  
• 
the serious event does not follow a known response pattern to the medical device (if 
the response pattern is previously known) and is biologically implausible;  
• 
the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact on the serious event;  
• 
the event involves a body-site or an organ not expected to be affected by the device or 
procedure;  
• 
the serious event can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other risk 
factors); 
• 
the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; 

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• 
harms to the subject are not clearly due to use error; 
• 
In order to establish the non-relatedness, not all the criteria listed above might be met 
at the same time, depending on the type of device/ procedures and the serious event. 
Unlikely  
The relationship with the use of the investigational device is weak but cannot be ruled out 
completely. Alternative causes are also possible (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or treatment). Cases were relatedness 
cannot be assessed or no information has been obtained should also be classified as possible. 
Possible  
The temporal sequence between use of the Investigational Device and the effect is such that the 
relationship is not unlikely or Subject’s condition or concomitant therapy could have caused 
the AE. 
Probable  
The relationship with the use of the investigational device seems relevant and/or the event 
cannot be reasonably explained by another cause, but additional information may be obtained. 
Causal 
Relationship 
The serious event is associated with the investigational device or with procedures beyond 
reasonable doubt when: 
• 
the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
• 
the event has a temporal relationship with investigational device use/application or 
procedures; 
• 
the event involves a body-site or organ that 
- 
the investigational device or procedures are applied to; 
- 
the investigational device or procedures have an effect on; 
• 
the serious event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
• 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
• 
other possible causes (e.g. an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled out; 
• 
harm to the subject is due to error in use; 
• 
the event depends on a false result given by the investigational device used for 
diagnosis, when applicable 
• 
In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
 
The sponsor and the investigators will distinguish between the serious adverse events related to the investigational 
device and those related to the procedures (any procedure specific to the clinical investigation). An adverse event 
can be related both to procedures and the investigational device. Complications of procedures are considered not 
related if the said procedures would have been applied to the patients also in the absence of investigational device 
use/application. 
In some particular cases the event may be not adequately assessed because information is insufficient or 
contradictory and/or the data cannot be verified or supplemented. The sponsor and the Investigators will make the 
maximum effort to define and categorize the event and avoid these situations. Where the sponsor remains 
uncertain about classifying the serious event, it should not exclude the relatedness and classify the event as 
“possible”. 

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If any Serious Adverse Event is considered to be either “possibly”, “probably”, or ‘causally’ related to the use of 
the Investigational Device, that event will be classed as an SADE. 
13.6 Adverse Event Severity 
The Investigator will also evaluate the severity in compliance with International Conference of Harmonization 
(ICH) – Good Clinical Practice (CGP) guidelines according to definitions from the Common Terminology 
Criteria for Adverse Events (CTCAE) from the department of U.S. Department of Health and Human Services.26 
See below for the applicable definitions 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). Instrumental ADL 
refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL. Self-care ADL refer to bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
 
These definitions are for descriptive purposes only and are independent of the judgment of whether an event is 
classified as an AE or an SAE. 
13.6.1 Handling and Reporting of Adverse Events 
Investigator will report “to the sponsor, without unjustified delay, all serious adverse events and device 
deficiencies that could have led to a serious adverse device effect; this information shall be promptly followed by 
detailed written reports”. Device malfunctions and use errors should also be reported without unjustified delay.  
All Serious Adverse Events (SA(D)Es) and/or device deficiencies must be reported to the Sponsor by telephone 
within 3 calendar days of the principal investigator becoming aware of it using the contact information below: 
Reporting all Serious Adverse Events (SA(D)Es), including all device deficiencies can also be done by 
completing the CRF (AE/SAE and Device Deficiency forms) within 3 calendar days of event knowledge. 
Where possible, Investigator will return the device involved in the deficiency to Sponsor for analysis. 
Investigator will document all AEs on the Adverse Event Form, including (at a minimum) a description of the 
event, date of onset, severity, relationship to the investigational device and/or procedure, required interventions, 
duration, and outcome. The investigator will monitor all AEs until they are resolved, determined to be a chronic 
condition or the subject is lost to follow-up.  Investigator will report all AEs regardless of whether it is anticipated 
or unanticipated and regardless of classification, seriousness, intensity, outcome or causality. 
In the event of subject death, the investigator will make reasonable effort to obtain a copy of the autopsy report 
and/or death summary. The investigator will determine the cause of death and its relationship to the 
investigational device; Investigator will record results on the Adverse Event Form. The investigator will include 
copies of an autopsy report, if available, and/or a death summary with this form. 
It is the responsibility of each Investigator to report all Serious Adverse Events and/or Serious Adverse Device 
Effects to the Local Ethics Committee in a timely manner, according to national regulations and Ethics 
Committee requirements. A copy of the Ethics Committee report should be forwarded to Sponsor. 

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13.6.2 Regulatory Authority Notification (If applicable) 
Sponsor is responsible for the classification and reporting of serious adverse events and ongoing safety evaluation 
of the study in line with ICH-GCP/EN ISO 14155:2011/MEDDEV 2.7/3, Ireland’s HPRA, the Czech Ministry of 
Health and other applicable regulatory requirements. 
The sponsor will assess, together with the investigator, any serious adverse incidents arising from the 
investigation of the medical device and inform other investigators, HPRA and SUKL and the ethics committees 
thereabout immediately after their occurrence. 
It is the obligation and responsibility of the Sponsor to report to HPRA and SUKL all serious adverse events, 
serious adverse device effects and/or unexpected serious adverse device effects received from a Principal 
Investigator within 2 calendar days after learning of the event.  
The Sponsor will also inform the other participating Principal Investigators and ethics committees of all serious 
adverse events, serious adverse device effects and/or unanticipated adverse device effects that are reported within 
3 calendar days after learning of the event.  
13.6.3 Follow-up of Unresolved Events  
All serious adverse events, serious adverse device effects and/or unexpected adverse device effects will be 
followed until they are resolved or until the subject’s participation in the clinical investigation ends. 
 
 

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14. DATA MANAGEMENT 
14.1 Confidentiality 
Confidentiality of subject data will be maintained at all times. Subject confidentiality will be maintained 
throughout the clinical study in a way that ensures the information can always be tracked back to the source data. 
Subject anonymity will be guaranteed and all documentation relating to a subject will be kept in a secure location. 
14.2 Subject Identification (ID) 
A unique Subject Identifier (ID) will identify enrolled patients, which is a combination of a non-repeating, 
sequential number starting with P01, followed by the site ID. The site ID for UVN is S01 and the site ID for 
Beaumont Hospital is S02. In the advent of new sites being added, additional site numbers will be assigned 
sequentially.   
14.3 Data Collection 
The Paper based Case Report Form (CRF) is the primary data collection instrument for this study.  Prior to the 
start of the clinical investigation, Sponsor will provide the Case Report Forms (CRF) for each individual subject. 
The recording of data on the visit specific Case Report Forms will be completed in full by Investigator/Study 
Coordinator for each individual subject. The sponsor or its designee will promptly address any data issues with 
the Investigator. All missing data must be explained.  If a space on the CRF is left blank because the procedure 
was not done or the question was not asked, write “N/D”.  If the item is not applicable to the individual case, write 
“N/A”.  All entries should be printed legibly in black or blue ink.  If any entry error has been made, to correct 
such an error, draw a single straight line through the incorrect entry and enter the correct data, above it.  All such 
changes must be initialed and dated by the individual making the correction.  DO NOT ERASE OR WHITE OUT 
ERRORS.   
The personal data recorded on all documents will be regarded as confidential.   
Note: The site must record the subject’s participation in this clinical investigation in the subject’s medical records. 
14.4 Review and Return of Completed Study Data 
The investigator will maintain all source documents as required by the CIP, including laboratory results, 
supporting medical records, and signed Informed Consent forms. Sponsor and/or monitor will use source 
documents during the regular monitoring visits to verify data entered in the CRF. All CRFs will be reviewed for 
accuracy and the Principal Investigator will sign and date each completed CRF to document approval.  
A copy of fully completed original CRFs will be made available to Sponsor. 
Once all the subject data has been collected and verified, the analysis and reporting will be conducted. Any data 
existing for subjects who have not received treatment with PEPNS System will not be used in the analysis. Details 
of these subjects will, however, are referenced in the final report. 
14.5 Study Final Report 
The final report will be compiled by Stimdia Medical, Inc. and reviewed, approved and signed off by the Principal 
Investigator of participating site(s). 
14.6 Study Material and Data Retention/Archiving 
Data files used for statistical analyses will be retained by each investigational center and study sponsor for at least 
10 years after the study has been completed.  
 
 

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15. TRAINING AND EXPERIENCE REQUIREMENTS 
Sponsor will maintain records documenting all training. 
15.1 Clinical Investigation Plan (CIP) Training 
Prior to subject enrollment, Sponsor/CRO will conduct training that will include reviewing the CIP, study 
procedures and study administrative procedures. Sponsor or designee will provide periodic updates to review 
procedures changes, amendments to the CIP, or for any changes in investigative team members at the site. 
15.2 Device and Procedure Training 
To ensure familiarity with the instrumentation and treatment techniques, Sponsor will train each Investigator prior 
to enrolling their first subject in the clinical investigation and may attend some or all of the cases at each 
Investigation site to ensure proper device use.  
 
 

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16. ETHICAL, REGULATORY AND ADMINISTRATIVE REQUIREMENTS 
16.1 Ethics Committee and Regulatory Approvals 
Before study commencement, the Principal Investigator must submit the Clinical Investigation Plan, 
Investigator’s Brochure, Essential Requirements Checklist, Patient information sheet and Informed consent form 
and any other documents as may be required to the appropriate Ethics Committee (EC) for review and approval. 
The Principal Investigator, and any other member of the investigative team, is a member of the Ethics Committee, 
must not participate in the decision-making. A signed and dated EC approval letter must be provided to Sponsor. 
The study will not start until written documentation of all required local and national regulatory approvals are 
obtained. 
Any report of withdrawal of Ethics Committee approval will be submitted to the Sponsor within five (5) working 
days. 
16.2 Informed Consent and Patient Information 
A signed and dated informed consent must be obtained for all subjects enrolled. The Principal Investigator must 
explain to each subject or his/her legally authorized representative the nature of the clinical investigation, 
including any risks and benefits, its purpose and procedures, and expected duration of involvement in the clinical 
investigation.  The subject or his/her legally authorized representative must have the opportunity to ask questions 
and must be informed that participation in the clinical investigation is voluntary and non-participation will not 
affect his / her right to the most appropriate standard treatment or affect the doctor/clinician-patient relationship.  
Subjects or their legally authorized representatives have full rights to withdraw from the clinical investigation at 
any time, irrespective of their initial consent.  
Each subject must also give their permission for representatives of the Sponsor, auditor and regulatory authorities 
to review their hospital records for the purposes of source data verification. The informed consent form must also 
be signed and dated by the research team member obtaining consent.  The signed informed consent form must 
remain in the subject’s study file and be available for review by the study monitor. 
16.3 Protocol Deviations 
A protocol deviation is defined as an event where the clinical Investigator or site personnel did not conduct the 
study according to the Investigational Plan or the Investigator Agreement. The Investigator is not allowed to 
deviate from the Investigational Plan.  
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well-being of 
human subjects may proceed without prior approval of the sponsor and the Ethics Committee.  Reports of any 
deviation from the protocol under emergency circumstances will be reported to the Sponsor and to the Ethics 
Committee as soon as possible after detection, but no later 5 working days from the time of the deviation. 
Deviations shall be reported to the study sponsor regardless of whether medically justifiable, preapproved, or 
taken to protect the subject in an emergency. Subject specific deviations will be reported on the Case Report Form 
or Protocol Deviation Form. Non-subject specific deviations will be reported to the Sponsor in writing. 
Investigators will also adhere to procedures for reporting study deviations to their EC in accordance with their 
specific EC reporting policies and procedures. 
Any deviations from the protocol must be documented in detail by the Investigator and reported to the study 
monitor as soon as possible. 
Regulations (ICH-GCP/EN ISO 14155) require that Investigators maintain accurate, complete and current 
records, including documents showing the dates and reasons for each deviation from the protocol. 
The following deviations are considered as major:  
• 
ICF collection process not respected. 
• 
Inclusion/Exclusion criteria not respected. 

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• 
Misuse of medical device. 
• 
Lack in SAE reporting.  
• 
Any protocol assessment in relation with the primary endpoints that is not respected. 
If a Study Monitor becomes aware that an Investigator is not complying with the signed Investigator’s 
Agreement, the Investigational Plan, the requirements of ICH-GCP/EN ISO 14155 or other applicable 
regulations, or any conditions of approval imposed by the reviewing Ethics Committee, Sponsor will immediately 
either secure compliance or discontinue shipments of the device to the Investigator and terminate the 
Investigator’s participation in the investigation.  The Investigator will be required to return all investigational 
devices, unless this action would jeopardize the rights, safety or welfare of a patient. 
Protocol deviations will be analyzed by Sponsor for the impact to the overall integrity of the study.  
Disqualification is warranted when an investigator has repeatedly or deliberately violated governing regulations or 
has repeatedly or deliberately submitted false information in any report.  Where protocol deviations occur which 
do not warrant disqualification from a study, Sponsor will implement appropriate corrective and preventive 
actions, including repeat training as deemed necessary. 
16.4 Amendments 
The Clinical Investigational Plan, CRFs, Informed consent form and other subject information, or other clinical 
investigation documents will be amended as needed throughout the clinical investigation, and a justification 
statement will be included with each amended section of a document. Proposed amendments to the Protocol will 
be agreed upon between the sponsor and principal investigator(s).  
The amendments to the Protocol and the subject's informed consent form will be submitted to obtain approval the 
EC and regulatory authorities, if required. The version number and date of amendments will be documented. 
16.5 Investigational Device Accountability and Storage 
The investigator must ensure that the device is used only in accordance with the protocol. Each individual PEPNS 
System that is used will be fully traced in the subjects’ medical records and the Clinical Investigator File to ensure 
full accountability. 
The investigator or designee is responsible for device accountability at the trial site i.e., to keep records 
documenting the receipt, use, return and disposal of the investigational devices.  For that, a Device Accountability 
Log (DAL) will be provided to each investigational site. Such log shall record dates, quantities, batch/serial 
numbers, expiration dates, and the unique code numbers assigned to the trial subjects, and date of procedure. A 
space will be provided for recording returned product and the reason for the return. The investigator should 
maintain records that adequately document that subjects were treated with the investigational device as specified 
by the protocol.  
Upon receipt of an investigational device shipment, the Investigator or designee is required to reconcile inventory 
of the product received and verify the shipment by signing the packing list.  All investigational devices must be 
stored in a locked storage facility to which only the investigator or designee will have access.  The secure location 
should be a dry and ambient room temperature location. 
16.6 Monitoring Plan 
The study monitor will be responsible for securing the compliance of Principal Investigator(s) to the signed 
clinical trial agreement.  
The study monitor appointed by the sponsor to oversee the conduct and progress of the study is the primary 
communication link between the sponsor and Investigator.  Monitor responsibilities may include investigator 
selection and training, assurance of current Ethics Committee approvals, periodic on-site inspection and audit of 
site records to ensure continued compliance with the protocol, adequacy of the investigator and the facility to 
carry out the study, and verification that the device is being using in accordance with instructions for use.  
Functions that the monitor/sponsor will perform include: 

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• 
Pre-Investigation Screening to ensure sufficient staffing, cooperation, investigator training and adequate 
numbers of potential subjects. 
• 
Review of study required documentation including signed agreements, protocol, required institutional 
approvals, Ethics Committee Approval. 
• 
Study site initiation to review with site staff the protocol requirements, case report forms, data collection 
methods and any electronic data capturing system.  Requirements for timely and accurate reporting of 
clinical data and unanticipated adverse events will be reviewed.  During this visit the monitor will ensure 
training in proper use of the investigational device as well as ensuring safe and secure storage of study 
devices and device accountability.  
• 
Investigational device accountability records will be reviewed including devices received, receipt dates, 
quantity, lot numbers, storage and signature of study personnel responsible for accountability. 
• 
Personal contact with the investigator and staff throughout the study by telephone, mail and on-site visits, 
to continue until study is completed.  This monitoring will ensure continued protocol compliance, 
adequate enrollment, accurate data reporting and query resolution and continued Ethics Committee 
approval of the study.  A full record of monitoring activities will be maintained. 
• 
Final on-site study close out visit at the completion of the investigation to collect outstanding documents 
and resolve outstanding queries, confirm site files are complete and accurate, review record retention 
requirements with the investigator and provide for return of unused study devices to sponsor.   
16.7 Indemnity 
Sponsor recognizes its liability in law to compensate for any injury sustained by a subject participating in this 
clinical investigation but only to the extent the study has been conducted in compliance with the protocol. 
16.8 Insurance 
All subjects enrolled in this study are covered by Clinical Trial Liability Insurance. The name and address of the 
relevant insurance company, the certificate of insurance, the policy number and the sum insured is provided in the 
Investigator’s Site File. 
16.9 Investigators Responsibilities 
• 
Sign and adhere to the Clinical Trail Agreement (CTA). 
• 
Sign and adhere to all of the required elements of the Study Protocol. 
• 
Resolve queries in a timely manner. 
• 
Participate in Investigator meetings as required. 
• 
Comply with the 2013 Declaration of Helsinki and the General Data Protection Regulation (GDPR) and 
Data Protection Act 2018. 
• 
Obtain written Informed Consent from each study participant before any study specific procedures are 
performed.  
• 
Complete all required case report forms (CRFs) for each subject. 
• 
Comply with all applicable regulations and codes of approvals from Ethics Committees and other 
regulatory authorities. 
• 
Notify Sponsor/CRO of any personnel changes at site that may affect the study protocol. 
• 
Retain all records and study files until Sponsor/CRO notifies that files may be destroyed. 
• 
Allow direct access to source data/documents, including subject records, in case of monitoring, auditing 
and/or inspection by the Ethics Committee and other regulatory authorities. 
The investigator is responsible for the preparation and submission of the reports listed in table below: 

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Report 
Submitted to 
Description 
All serious adverse events 
(SAE’s), device deficiencies 
that may have led to an SAE if  
a) suitable action had not been 
taken or 
b) intervention had not been 
made or 
c) if circumstances had been 
less fortunate 
and new findings/updates in 
relation to already reported 
events.  
Sponsor & EC 
The investigator’s report on 
any SAEs must be submitted 
within 3 calendar days after 
the investigator first learns of 
the event. 
Withdrawal of/EC approval  
Sponsor 
The investigator must report a 
withdrawal of reviewing EC 
approval within 5 working 
days.  
Failure to obtain Informed 
Consent 
Sponsor & EC 
Notification must be made 
within 5 working days of use 
of the device. 
Emergency deviations from 
the protocol  
Sponsor and EC 
Notification must be made 
within 5 working days of the 
occurrence of an emergency 
deviation (made to protect the 
life or physical well-being of a 
patient).  
If the deviation affects the 
rights, safety, or welfare of the 
patients (and is not an 
emergency), or the scientific 
soundness of the investigation, 
prior approval must be 
obtained from Stimdia 
Medical, the reviewing EC. 
All deviations must be 
documented on a Protocol 
Deviation Form 
Progress Report 
Sponsor & EC 
The investigator must submit a 
progress report on an annual 
basis or as required by the 
governing regulatory agencies. 
Final Report 
Sponsor & EC 
This report must be submitted 
within 3 months after 
termination or completion of 
the clinical study. 

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16.10 Sponsor Responsibilities 
Stimdia Medical will maintain all records pertaining to the investigation including: 
• EC approvals 
• Signed Investigator Agreements and related materials 
• Site monitoring reports 
• Records concerning adverse device events 
• All CRFs and received source documentation 
• Financial Disclosure Forms 
• Site Monitoring Visit Log 
• All correspondence  
Stimdia Medical or its approved representative is responsible for the preparation and submission of the 
reports listed below: 
Report 
Submitted to 
Description 
All serious adverse events 
(SAE’s), device deficiencies 
that may have led to an SAE 
if  
a) suitable action had not 
been taken or 
b) intervention had not been 
made or 
c) if circumstances had been 
less fortunate 
and new findings/updates in 
relation to already reported 
events.  
Reportable events occurring 
in Third Countries in which 
a clinical investigation is 
performed under the same 
clinical investigation plan. 
This includes events 
occurring in third Countries 
after European sites have 
closed. 
National Competent 
Authority (NCA) 
The sponsor or approved representative 
report on any SAEs must be submitted 
within 2 days after the sponsor or 
approved representative first learns of 
the event. 
Any other reportable events 
such as:  
- any SAE, 
- any Device Deficiency that 
might have led to a SAE if: 
a) suitable action had not 
been taken or 
NCA 
Any other reportable events or a new 
finding/update to it: immediately, but 
not later than 7 calendar days following 
the date of awareness by the sponsor of 
the new reportable event or of new 
information in relation with an already 
reported event. 

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Report 
Submitted to 
Description 
b) intervention had not 
been made or 
c) if circumstances had 
been less fortunate 
- new findings/updates in 
relation to already reported 
events. 
Withdrawal of EC approval 
EC, Investigators & 
approving regulatory 
agency(s) 
Notification, when appropriate, will be 
made within 5 working days after 
Stimdia Medical receives notice of 
withdrawal of EC approval. 
Withdrawal of regulatory 
agency approval 
(e.g. HPRA, SUKL) 
EC & Investigators 
Notification will be made within 5 
working days after Stimdia Medical 
receives notice of withdrawal of 
regulatory agency approval. 
Safety Reports 
NCA 
The EU requires that safety line listings 
and a cover letter that contains an 
assessment of the safety data and 
whether or not safety measures need to 
be taken and justification must be 
submitted quarterly. 
The EU requires and annual safety 
report that must include any new 
findings from the literature and the 
investigator’s brochure must also be 
updated annually. 
Progress Report 
EC, Investigators & 
regulatory agencies 
A progress report will be submitted at 
least yearly or as required by the EC or 
governing regulatory agencies.   
Recall and Device 
Disposition 
EC, Investigators & 
regulatory agencies 
Notification will be made within 30 
working days of Stimdia Medical’s 
request that an investigator return, 
repair or otherwise dispose of any 
devices.  Such notification will state 
why the request was made. 
Notification of Termination 
or Completion 
EC, Investigators & 
regulatory agencies 
Notification will be made within 90 
days.   
Final Report 
EC, Investigators & 
regulatory agencies 
A final report will be submitted within 
3 months after study completion or 
termination and be signed by the 
investigator. 
Failure to Obtain Informed 
Consent 
Regulatory agencies 
Notification will be made within 5 
working days of receipt of notice. 

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Report 
Submitted to 
Description 
Emergency Deviations from 
Investigational Plan 
EC 
Notification will be made within 5 
working days after Stimdia Medical 
learns of an emergency deviation from 
the Investigational Plan where the 
deviation was made to protect the life or 
physical well-being of a subject. 
16.11 Statement of Compliance 
• 
Sponsor and Investigator will conduct the clinical investigation in accordance with the ethical principles 
that have their origin in the Declaration of Helsinki and General Data Protection Regulation (GDPR) and 
Data Protection Act 2018. 
• 
Sponsor and Investigator will comply with EN ISO 14155:2011 and any regional or national regulations, 
as appropriate. 
• 
Investigator will not begin the clinical investigation until Investigator obtains the required written 
approval or favorable opinion from the EC or regulatory authority, if appropriate. 
• 
Investigator will follow any additional requirements imposed by the EC or regulatory authority, if 
appropriate. 
• 
Sponsor will provide insurance for subjects. 
 
16.12 Publication Policy 
At the conclusion of the trial, a multi-center manuscript will be prepared for publication in a reputable scientific 
journal by the Sponsor, Stimdia Medical, Inc. The study will be registered in clinicaltrials.gov.  
 
 

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