Randomized Study of TransAeris® System for Enhanced Recovery After Surgery (ERAS) in Cardiac Surgery Patients in France at Risk of Prolonged Mechanical Ventilation
Phase: NA
Conditions: Ventilator-Induced Diaphragm Dysfunction
Sponsor: Synapse Biomedical

 
 
 
 
 
Clinical Study Protocol with Statistical Considerations 
 
Randomized Study of TransAeris® system for Enhanced Recovery After Surgery (ERAS) 
in cardiac surgery patients in France at risk of prolonged mechanical ventilation 
 
Protocol number 20-1000-108 Version D 
 
NCT05404477 
 
November 5, 2024 

 
  
 
 
 
Synapse Biomedical– CONFIDENTIAL 
 
Page 1 of 38 
Clinical Study Protocol #: 20-1000-108 Rev D 
 
Clinical Study Protocol: 
Randomized Study of TransAeris® system for Enhanced Recovery 
After Surgery (ERAS) in cardiac surgery patients in France at risk 
of prolonged mechanical ventilation  
Short Title: ERAS TransAeris® Study  
Protocol number: 20-1000-108 
Revision: 
 
VERSION D 
Date:  
 
April 19, 2022 
Sponsor: 
 
Synapse Biomedical - Europe 
7 Rue de la Liberation 
95880 Enghien Les Bains, France 
 
Investigator: 
Dr Charles-Henri DAVID 
Chirurgien Cardio-thoracique  
Service de CTCV - CHU Nantes  
02401(68569) 
Email: CharlesHenri.david@chu-nantes.fr 
 
 
 
 
 
 
 
 
CONFIDENTIAL:  This document contains confidential information and is limited in its distribution outside 
Synapse Biomedical to investigators, IRBs/ethics committees, and regulatory agencies. Copying of the 
confidential information is not permitted without the written approval of Synapse Biomedical. 

 
  
 
 
 
Synapse Biomedical– CONFIDENTIAL 
 
Page 2 of 38 
Clinical Study Protocol #: 20-1000-108 Rev D 
 
PROTOCOL SIGNATURE PAGE 
Protocol Number:  20-1000-108 
Revision: 
 
VERSION D  
Date:  
 
April 19, 2022 
Sponsor: 
 
Synapse Biomedical - Europe 
7 Rue de la Liberation 
95880 Enghien Les Bains, France 
 
Title: Randomized Study of TransAeris® system for Enhanced Recovery After Surgery (ERAS) in 
cardiac surgery patients in France at risk of prolonged mechanical ventilation  
I have read the protocol and I agree to conduct the study in accordance with the design and specific 
provisions of this protocol, in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with Good Clinical Practice (GCP) and the applicable regulatory 
requirements.  The study will be performed in accordance with the standard EN ISO 14155:2020 on Clinical 
Investigations with Medical Devices on Human Subjects, European Medical Regulation MDR 2017/745, any 
regional or national regulations, as appropriate, and recommendations guiding physicians in biomedical 
research involving human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964 
and later revisions. 
I guarantee that the information and data contained in this document will be considered and treated as 
strictly confidential: any information contained in it may not be divulged without the prior written approval of 
the Synapse Biomedical and will be used exclusively for the evaluation and conduct of the clinical trial. 
 
Site Name:  _______________________________________ 
Printed Name of Principal Investigator:  _____________________________________ 
 
 
Signature of the Principal Investigator 
Date 
 
Printed Name of Sponsor Representative:  _____________________________________ 
 
 
 
Signature of the Sponsor Representative 
Date 
 
 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
Revision History 
 
Revision 
Release Date 
Description 
A 
29Nov2021 
Initial release 
B 
10Jan2022 
Short Title added  
Section 15 updated as per MDR 2017/745 requirements  
C 
3March2022 
Edits to respond to EC Review (26-Jan-2022) for resubmission to 
EC 
D 
19April2022 
Edits to respond to EC Review (7April2022) _ CPP Nord Ouest 2 
 
 
 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS ................................................................................................................... 6 
2. 
ABBREVIATIONS AND ACRONYMS .............................................................................................. 9 
3. 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE .............................. 11 
3.1 
Summary Description of Investigational Device and Intended Purpose ............................. 11 
3.2 
Manufacturer of Investigational Device ................................................................................ 11 
3.3 
Device Name .......................................................................................................................... 11 
3.4 
Device Traceability ................................................................................................................. 11 
3.5 
Intended Purpose of Device; Patient Population and Indication ......................................... 11 
3.6 
Description of Investigational Device ................................................................................... 11 
3.7 
Summary of Necessary Training and Experience to Use Investigational Device ............... 14 
4. 
JUSTIFICATION FOR DESIGN OF CLINICAL INVESTIGATION ................................................... 14 
4.1 
Summary of Relevant Preclinical and Clinical Data ............................................................. 14 
4.2 
Application of PICO Model to current study ......................................................................... 16 
5. 
RISKS AND BENEFITS OF THE DEVICE AND CLINICAL INVESTIGATION ................................ 18 
5.1 
Anticipated Clinical Benefits ................................................................................................. 18 
5.2 
Anticipated Adverse Device Effects ...................................................................................... 18 
5.3 
Possible Interactions with Concomitant Medical Treatments .............................................. 18 
5.4 
Risk Mitigation Strategies ...................................................................................................... 19 
5.5 
Risk to Benefit Rationale ....................................................................................................... 19 
6. 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION ..................................... 19 
6.1 
Purpose .................................................................................................................................. 19 
6.2 
Objectives .............................................................................................................................. 19 
7. 
DESIGN OF THE CLINICAL INVESTIGATION ............................................................................... 20 
7.1 
Type of Clinical Investigation ................................................................................................ 20 
7.2 
Outcome Measures ................................................................................................................ 20 
7.3 
Investigational Devices and Comparators ............................................................................ 20 
7.4 
Subjects .................................................................................................................................. 21 
7.5 
Procedures ............................................................................................................................. 22 
7.6 
Monitoring Plan ...................................................................................................................... 28 
7.7 
Data Protection ...................................................................................................................... 29 
8. 
STATISTICAL CONSIDERATIONS ................................................................................................ 29 
8.1 
Study Design and Statistical Objective ................................................................................. 29 
8.2 
General Considerations ......................................................................................................... 29 
8.3 
Analysis Population and Significance Testing ..................................................................... 29 
8.4 
Endpoints ............................................................................................................................... 30 
8.5 
Determination of Sample Size ............................................................................................... 31 
8.6 
Interim Analysis ..................................................................................................................... 31 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
8.7 
Handling of Missing Data ....................................................................................................... 31 
8.8 
Poolability of Outcomes ........................................................................................................ 31 
9. 
DATA MANAGEMENT ................................................................................................................... 31 
10. 
PROTOCOL AMENDMENTS ...................................................................................................... 31 
11. 
PROTOCOL DEVIATIONS .......................................................................................................... 32 
12. 
DEVICE ACCOUNTABLILTY ...................................................................................................... 32 
13. 
REGULATORY COMPLIANCE ................................................................................................... 32 
14. 
INFORMED CONSENT PROCESS ............................................................................................. 32 
15. 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES ................... 33 
15.1 Definitions as per ISO 14155:2020 & MDR 2017/745 ............................................................. 33 
15.2 Causality/Relationship ........................................................................................................... 34 
15.3 Adverse Event Reporting ....................................................................................................... 36 
16. 
SAFETY MONITORING .............................................................................................................. 37 
17. 
STUDY EARLY TERMINATION .................................................................................................. 37 
18. 
REFERENCES ............................................................................................................................ 38 
  
 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
1. 
PROTOCOL SYNOPSIS 
Title 
Randomized Study of TransAeris® system for Enhanced Recovery After 
Surgery (ERAS) in cardiac surgery patients in France at risk of prolonged 
mechanical ventilation  
Protocol Number 
20-1000-108 
Device Tested 
TransAeris® System 
Purpose 
This study will be conducted as a randomized trial of the TransAeris system for 
the prevention and treatment of ventilator-induced diaphragm dysfunction 
(VIDD) in patients identified prior to surgery to be at greater risk of prolonged 
mechanical ventilation (PMV). 
Study Objectives 
The specific objectives of this study are:  
Primary objective: 
 
Evaluate the credibility of expected treatment benefits 
Secondary objectives: 
 
Identify safety concerns  
 
Identify barriers to enrollment 
 
Evaluate the randomized protocol in single site setting, prior to multi-
center expansion 
 
Assess the capability of collecting the specified evaluation criteria 
 
Assess the capability to quantify diaphragm electrical activity through 
diaphragm EMG monitoring 
Study Design 
This study is an open label, randomized, cross-over study in adult open cardiac 
surgery patients. All subjects will receive TransLoc electrodes at the time of open 
sternotomy cardiac procedure.  Half of subjects will have TransAeris turned on 
upon entry to ICU, the other half will receive standard of care with TransAeris 
turned on if still intubated on mechanical ventilation after 120 hours. 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
Outcome 
Measures 
Primary Safety: Incidence of Serious Device Related Adverse Events 
Primary Efficacy: Mechanical ventilation time and proportion of patients 
weaned at 48- and 120-hours post-op 
Ancillary Outcomes: 
Safety:   
 
Interference with ICU care 
 
Device related adverse events 
 
30-day mortality 
Efficacy:   
 Time on mechanical ventilation 
 
measured in hours from entry to ICU and reversal of 
paralytics 
 
EMG analysis of cross-over patients  
Ventilator Free Days 
 
Length of stay, ICU & Hospital 
Enrollment 
30 subjects will be randomized prior to surgical placement of TransLoc 
electrodes 
Participating Site 
1 French site will participate in this study 
Inclusion Criteria 
1. Subject is undergoing an open cardiac procedure by median sternotomy 
2. Subject is at risk of prolonged mechanical ventilation according to one or 
more of the following criteria: 
a. Prior open cardiac surgery 
b. Left Ventricular Ejection Fraction (LVEF) ≤ 30% 
c. History of TIA or CVA 
d. Pre-operative or anticipated intraoperative intra-aortic balloon pump 
e. History of COPD 
3. Subject is at least 22 years of age 
4. Informed consent has been obtained from the subject 
5. Subject is covered by a healthcare insurance  
Non-Inclusion 
Criteria 
1. Subject is on invasive mechanical ventilation prior to procedure 
2. Subject has known or pre-existing phrenic nerve paralysis 
3. Subject is having a left ventricular assist device (LVAD) implanted 
4. Subject has progressive, non-reversible neuromuscular disease affecting 
the diaphragm 
5. Subject is pregnant or lactating 
6. Subject is actively participating in another clinical study which could affect 
outcomes in this study 
7. Subject deprived of liberty 
8. Subject under court protection 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
Estimated Duration 
of the Study 
 
Enrollment period estimated:  4 months 
 
Per subject study duration estimated:  1-30 days on device, up to 60 days 
with 30-day post-explant follow-up 
 
Study completion estimated: 6 months 
Sponsor 
Synapse Biomedical - Europe 
7 Rue de la Liberation 
95880 Enghien Les Bains, France  
 
 
 
 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
2. 
ABBREVIATIONS AND ACRONYMS 
CIF- Cumulative Incidence Function
COPD – Chronic Obstructive Pulmonary Disease 
CVA – Cerebro-Vascular Accident 
EMG – Diaphragm Electromyograph 
EUA – Emergency Use Authorization 
FTW – Failure to Wean 
HDE – Humanitarian Device Exemption 
HFNC – High-Flow Nasal Cannula 
HLOS – Hospital Length of Stay 
IABP – Intra-Aortic Balloon Pump 
IC – Cathodic Current 
ICU – Intensive Care Unit 
IDE – Investigational Device Exemption 
LOS – Length of Stay 
LVEF – Left Ventricular Ejection Fraction 
MV – Mechanical Ventilation 
NC – Nasal Cannula 
NeuRx DPS – NeuRx Diaphragm Pacing System 
NIV – Non-Invasive Ventilation 
PMV – Prolonged Mechanical Ventilation 
POD – Post-Operative Day 
PPV – Positive Predictive Value 
PW – Cathodic Pulse Duration 
RR – Risk Reduction 
SCI – Spinal Cord Injury 
SOC – Standard of Care 
STS – Society of Thoracic Surgeons 
TIA – Transient Ischemic Attack 
VFD – Ventilator Free Day 
VIDD – Ventilator-Induced Diaphragm 
Dysfunction
 
  

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
 
Figure 1:   Study Flowchart 
Abbreviations: 
MV – Mechanical Ventilation 
PMV – Prolonged Mechanical Ventilation 
IABP – intra-aortic balloon pump 
LVEF – left ventricular ejection fraction 
TIA – transient ischemic attack 
CVA – cerebrovascular accident 
COPD – chronic obstructive pulmonary disease 
ICU – intensive care unit 
LOS – length of stay 
HLOS – hospital length of stay 
HFNC – high-flow nasal cannula 
NC – nasal cannula 
NIV – non-invasive ventilation 
POD – post-operative day 
EMG – diaphragm electromyograph 
VFD – ventilator free day 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
3. 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE 
3.1 Summary Description of Investigational Device and Intended Purpose 
The TransAeris® System is a temporary percutaneous intramuscular diaphragm stimulator intended for 
patients at risk of or on prolonged positive pressure mechanical ventilation. TransAeris is a CE marked 
medical device and is indicated for use in the prevention and treatment of ventilator-induced diaphragm 
dysfunction (VIDD).The TransAeris System includes four TransLoc® intramuscular diaphragm electrodes, 
the TransAeris external stimulator, and the FrictionLoc™ connectors which provide the interface between 
the TransLoc electrodes and the TransAeris stimulator.  Placement of the diaphragm electrodes can be 
performed in conjunction with another surgical procedure or as the primary procedure.  TransAeris is used 
to provide neuromuscular electrical stimulation to the diaphragm while the patient is on mechanical 
ventilation to prevent, slow, or reverse diaphragm disuse atrophy and, more generally, to prevent and treat 
VIDD.  Before discharge, the electrodes are removed from the patient. 
3.2 Manufacturer of Investigational Device 
Synapse Biomedical, Inc. 
300 Artino St. 
Oberlin, Ohio 44074  
U.S.A. 
Tel: (440) 774-2488 
3.3 Device Name 
TransAeris® System Kit REF 20-1002 
TransLoc® Electrode Kit REF 20-1004 
3.4 Device Traceability 
Each device will be labeled as investigational and will include a lot and/or serial number. 
3.5 Intended Purpose of Device; Patient Population and Indication 
TransAeris is a temporary percutaneous intramuscular diaphragm stimulator intended for patients at risk of 
or on prolonged positive pressure mechanical ventilation. TransAeris is indicated for use in the prevention 
and treatment of ventilator-induced diaphragm dysfunction (VIDD). 
3.6 Description of Investigational Device 
3.6.1 
Introduction 
See User Manuals REF 77-1000-FR_B & REF 77-1002-FR_C for complete device instructions. 
The TransAeris System is a temporary percutaneous intramuscular diaphragm stimulator intended for 
patients at risk of or on prolonged positive pressure mechanical ventilation (MV). TransAeris is indicated for 
use in the prevention and treatment of ventilator-induced diaphragm dysfunction (VIDD). 

 
  
 
 
 
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The TransAeris System includes four TransLoc® intramuscular diaphragm electrodes, the TransAeris 
external stimulator, and the FrictionLoc® connectors which provide the interface between the TransLoc 
electrodes and the TransAeris stimulator.  Placement of the diaphragm electrodes can be performed in 
conjunction with another surgical procedure or as the primary procedure.  TransAeris is used to provide 
neuromuscular electrical stimulation to the diaphragm while the patient is on mechanical ventilation to 
prevent, slow, or reverse diaphragm disuse atrophy and, more generally, to treat VIDD.  Once the patient is 
successfully liberated from mechanical ventilation for 48 hours, the electrodes can be removed from the 
patient. 
A cornerstone of the rationale and evidence supporting the use of intramuscular diaphragm stimulation in 
the treatment of VIDD comes from the clinical experience with Synapse’s NeuRx DPS® (IDE (investigational 
device exemption) G920162, HDE (humanitarian device exemption) H070003). Patients who have been 
ventilator dependent for months to years due to chronic high-level spinal cord injury (SCI) have undergone 
a regimen of diaphragm stimulation with the permanently implanted NeuRx DPS to reverse disuse atrophy 
and re-educate the muscle. Although diaphragm dysfunction was advanced having accrued over months to 
years, diaphragm function was substantially restored after just a few days of reconditioning with 
intramuscular diaphragm stimulation.   
Because NeuRx DPS is intended for chronic use, the associated PermaLoc® electrode includes a 
polypropylene barb affixed to the stimulus end of the electrode which promotes fixation of the electrode to 
the diaphragm. However, TransAeris is intended for temporary inpatient use and thus, to promote its 
removability, the associated TransLoc® electrode does not include the polypropylene barb. A study (IDE 
G150040) demonstrated the safety and performance of TransLoc electrodes for (a) intraoperative 
placement during routine open and laparoscopic procedures, (b) diaphragm stimulation, (c) stability of 
placement, and (d) removal after temporary in-hospital use. 
Based on available data, it is believed that temporary diaphragm stimulation leads, similar to temporary 
percutaneous epicardial leads placed during cardiac surgery, can be placed in higher risk patients during 
thoracic and upper abdominal procedures, as the procedure is already occurring near the diaphragm. 
Alternatively, the electrodes can be placed with a simple standard minimally invasive laparoscopic 
procedure. These leads, connected to an external pulse generator, provide the ability to stimulate the 
diaphragm while the patient is on mechanical ventilation to prevent or minimize the diaphragm atrophy, 
which may reduce the total time on MV thereby reducing the morbidity and mortality associated with 
prolonged MV use. 
3.6.2 
Principle of Operation 
Diaphragm pacing with the TransAeris platform technology works at neuromuscular junctions and with 
propagation of action potentials to surrounding motor endplates. The TransLoc intramuscular electrodes are 
placed at locations on the surface of the diaphragm called the “motor point”. The motor points are the 
locations in the diaphragm in proximity to where the phrenic nerve axons enter and branches into many 
subsequent axon terminals. Each axon terminal synapses with muscle sarcolemma for individual fiber 
contraction. By placing two TransLoc electrodes in each hemi-diaphragm at motor points, the greatest 
number of motor endplates may be stimulated to create a diffuse contraction of the diaphragm. The proximity 
of the TransLoc electrodes to the motor point allows the spread of the electrochemical reaction and 
propagating action potentials induced by the stimulus charge to recruit the desired contraction strength 
without the risk of axonal degeneration or demyelination from contact with the phrenic nerve. The level and 
coordination of stimulus to each electrode is controlled by the external stimulator to provide a smooth and 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
sufficient inspiration.  Electrical activation of the diaphragm through motor point stimulation conditions the 
muscle to mitigate disuse atrophy. 
3.6.3 
TransLoc Electrode 
The TransLoc electrode is a unipolar temporary diaphragm stimulation and sensing lead.  It consists of a 
de-insulated multi-filament 316LVM stainless steel electrode (A) (Figure 2), that continues as an insulated 
multi-filament lead (B) and terminates in a crimped pin (C) at the proximal end. A blue monofilament (D) 
extends through the length of the electrode and lead and terminates distally in a curved needle (E) and 
proximally in a percutaneous access needle (F).  The curved needle provides insertion of the electrode into 
the diaphragm muscle. The percutaneous access needle permits exiting the lead through the abdominal or 
chest wall.   
The TransLoc electrodes are for temporary use and are to be removed prior to hospital discharge. The 
electrodes are stabilized on the skin surface by sutures which should be removed prior to attempting 
electrode removal.  The electrodes are then removed by applying gentle traction to the electrode until it 
releases from the skin and can be extracted from the body. Each wire should be examined for completeness. 
Any retained electrode fragments should be documented.  
 
Figure 2:  TransLoc Electrode 
(Figure labels A-F are described in the section above) 
3.6.4 
Method of Use 
3.6.4.1 
Device Implantation 
Placement of the diaphragm electrodes will be in conjunction with the primary cardiac procedure and will be 
placed during the procedure. The implant approach to the diaphragm is from the superior (chest) aspect of 
the diaphragm surface. From the superior aspect, two electrodes are implanted on the right hemi diaphragm 
and two electrodes on the left hemi diaphragm. They are implanted next to where the phrenic nerve comes 
into the central tendon.  
Once the desired locations for each of the electrodes are identified, the TransLoc electrodes will be 
implanted into the diaphragm such that the exposed stimulating surface will be completely within the 
muscular layers and the blue polypropylene suture extends out of the diaphragm. The blue polypropylene 
suture will be cut to remove the curved needle from the distal end of the electrode.  Adequate electrode 
length will be left near the diaphragm so that there will not be any tension on the lead during muscle 
contraction.  The process will be repeated for up to four electrodes placed in the diaphragm (two in each 
hemi-diaphragm). 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
Each electrode is externalized so that it exits the thoracic cavity in as direct a path as possible to the 
percutaneous exit site to facilitate easier removal, which is accomplished by using the percutaneous access 
needle to bring the lead out through the skin in the desired location.  The needle is then removed from the 
lead by cutting through the blue polypropylene suture at the tip of the connector pin. 
3.6.4.2 
Device Programming  
The TransAeris stimulator is programmed for the patient with intensity and frequency set up to elicit 
diaphragm recruitment without pain or discomfort from the stimulation. The clinician may program the 
intensity of each channel to optimize diaphragm recruitment. Frequency creates a tetanic or fused 
diaphragm contraction. Frequency affects all four channels and is set by the clinician to create a fused 
contraction. The pulse bursting is used to increase patient comfort with the stimulation. The trade-off of burst 
modulation settings is a reduction in diaphragm recruitment. 
The stimulator has four independent channels of stimulation. The stimulation is a charge balanced, 
capacitively coupled current-regulated waveform.  The maximum charge per cathodic phase is 5μC.  The 
charge is calculated as the Cathodic Current (IC) times the Cathodic Pulse Duration (PW).  Stimulus 
waveforms can be selected as single cathodic pulse followed by the anodic recharge phase or as a burst of 
four cathodic pulses followed by the anodic recharge.  The latter, burst mode stimulation, delivers the 
cathodic charge at a lower amplitude (1/4 of the single pulse value) and distributes four cathodic pulse at 
1ms intervals.  The burst mode stimulation may be selected to overcome a patient’s reported stimulation 
discomfort. 
3.7 Summary of Necessary Training and Experience to Use Investigational Device 
Device programming and use training for all study staff will be provided by Synapse Biomedical.  Placement 
of TransLoc electrodes will be performed by surgeons with prior experience, from the TransLoc feasibility 
trial (G150040), TransAeris pilot trial (G170294), TransLoc EUA, or will be trained by those surgeons. 
4. 
JUSTIFICATION FOR DESIGN OF CLINICAL INVESTIGATION 
4.1 Summary of Relevant Preclinical and Clinical Data 
Mechanical ventilation (MV) is a life sustaining treatment in patients who are unable to maintain 
spontaneous ventilation. In the hospital setting, MV is utilized for treatment of acute respiratory failure, 
trauma, as well as intra-operatively and during post-operative recovery. Unless required due to 
comorbidities or operative/postoperative complications, the majority of patients undergoing cardiac surgery 
are liberated from mechanical ventilation during the first 24 hours after surgery(1).  However, a review of 
the STS (Society of Thoracic Surgeons) Adult Cardiac Database over a 3 year period (2014 - 2017) revealed 
that of the 883,661 patients with known ventilation time, 109,380 (12.3%) remained intubated and on 
mechanical ventilation after 24 hours, 72,240 (8.2%) after 48 hours, and 38,120 (4.4%) required MV after 5 
days (120 hours) (Figure 3).  Failure to wean (FTW) from MV occurs in upwards of 40-45% of patients(2-5) 
and results in significant morbidity, mortality and health care costs. 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
Figure 3. Evaluation group definition graph 
 
The etiology of FTW is multi-factorial, but inspiratory muscle atrophy has been shown to be a significant 
contributor to this condition(3,5). Research has shown that short exposure to MV leads to decreases in 
protein synthesis(6) and increased proteoloysis(5,7,8), which is histopathologically manifested as 
diaphragm muscle atrophy(3). The severity of this muscle atrophy increases with increased time of MV 
exposure. There is an identified clinical need for treatments to prevent the muscle atrophy that leads to 
VIDD. Direct electrical stimulation of muscle has been shown to reduce muscle atrophy. The diaphragm 
pacing system (DPS) has been approved for patients with high spinal cord injuries (SCI) and has been 
shown to facilitate weaning from MV and be the primary ventilatory support following successful removal 
from MV(9,10). The current study is designed to evaluate the implementation of TransAeris for the 
prevention and treatment of VIDD in a surgical population.  
The STS performance measures include a quality performance measure (NFQ #0129) for prolonged 
mechanical ventilation (PMV), defined as the need for intubation greater than 24 hours. The STS and other 
published data on this study population will provide the basis for comparison of the observed feasibility of 
safety and efficacy and thus determine the progression to a randomized controlled pivotal study.  Current 
literature(11,12) on PMV illustrates the need for a therapy and identifies that an “enriched study population” 
based on the risk for PMV may be the most suitable target for an intervention(12). 
The initial investigation of TransAeris (IDE G150040) also enrolled in a surgical population.  That 
investigation was primarily focused on placement, stability and removal of the TransLoc electrode during 
and after the surgical procedure.  That study was able to enroll rapidly (twelve patients in under eight weeks) 
and demonstrated the successful placement, stability and removal of the electrodes in the surgical 
population. 
The next investigation of TransAeris (IDE G170294) focused on enrollment in an “enriched study population” 
undergoing an open sternotomy cardiac surgery.  In this enriched population, meeting identified risk factors 
for PMV, it was anticipated that the study would provide an apparent visibility to potential benefit.  There 
were 32 patients implanted in this study, 10 received experienced PMV and received TransAeris stimulation.  
There were no device or procedure related serious adverse events reported in any of the patients.  The risk 
factors for PMV identified five specific criteria that are able to further enrich the study population.  Although 
there is a high incidence of complications and mortality in the targeted high-risk cardiac surgery patient 
group the patients in this study appeared to benefit from the TransAeris stimulation. Overall, there were 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
eight of ten patients that received TransAeris stimulation who were successfully extubated within the 30 
days or prior to death.  At 48 hours post-op, there were 60% of the stimulated patients weaned and at 120 
hours there were 70% weaned.  
4.2 Application of PICO Model to current study 
The PICO model is applied to assess the study construct.   
P (Problem / Patient / Population): Ventilator induced diaphragm dysfunction in cardiac surgery patients 
I (Intervention): TransAeris stimulation 
C (comparison): no stimulation over initial five days 
O (outcome of interest): reduction in proportion of cardiac surgery patient requiring MV at 48 hours of 
stimulation 
 
The Patient population, in general for the intended use, are patients that are at risk of/or experiencing 
ventilator induced diaphragm dysfunction (VIDD).  To study in a more homogeneous population, the patient 
population is further restricted to cardiac surgery patients.  As discussed above, the overall population of 
cardiac surgery patients has approximately 8% who are on still on mechanical ventilation at 48 hours and 
5% who are still mechanically ventilated at 5 days.   
 
To optimize the effect size, we attempted to enrich the study population by introducing the stimulation in 
patients at higher risk of ≥ 24 hours of mechanical ventilation (MV); the enriched PMV population.  These 
patients represent ≈12% of cardiac patients.  The patients requiring 48 hours and ≥5 days of MV from the 
enriched PMV population is ≈ 66% and 35%, respectively.  From the STS 2014 – 2017 Adult Cardiac 
Database this includes, roughly, 36,460 U.S. patients per year; for this homogeneous enriched population 
of patients requiring MV for ≥ 24 hours. 
 
The prior pilot study of TransAeris (G170294) identified nine risk factors for PMV as an initial prognostic 
enrichment inclusion criterion.  Based on the resulting MV use of 44 consented patients there were five risk 
factors identified to be the most significant criteria for determining PMV.  They correctly identified 13 out of 
14 patients (92.9%) that required PMV as the true positive patients that could potentially benefit from the 
TransAeris therapy. Conversely, the five risk factors identified 10 out of 29 patients (34.5%) not requiring 
PMV incorrectly as false positive patients.  Defining the positive predictive value (PPV) as the true positive 
patients (n=13) out of the total positive (n=23) identifications results in a PPV of 56.5%.  One additional 
modification, based on review by cardiac surgeons that participated in the study, the accepted categorization 
by the American College of Cardiology (ACC), and literature review, is to set the left ventricular ejection 
fraction (LVEF) accepted for inclusion risk to less than or equal to 30% (LVEF ≤ 30%).  This is consistent 
with the ACC category of “Severe Dysfunction” and is the consistent with the LVEF levels discussed in 
Hessels, et.al.(12) 
 
The Intervention is the application of the diaphragm stimulation in the enriched PMV population.  Of course, 
to apply the TransAeris intervention, the TransLoc electrodes will have to be placed prophylactically at the 
time of cardiac surgery.  This also reduces the risk of the intervention, as the 2015 feasibility (G150040) 
safety study showed that the TransLoc electrodes could be safely placed at the time of cardiac surgery, 
taking less than 5 minutes at the end of the procedure.  The pilot study in cardiac surgery patients (G170294) 
also demonstrated 100% successful electrode removal.  The electrodes were able to be removed fully intact 
in these studies and all other applications of the device, to date.   
 
The Comparator in the model for efficacy in this study is twofold.  The primary outcome of this study is to 
assess the prevention of VIDD through the difference in MV time and proportion of patients weaned at 48- 

 
  
 
 
 
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and 120-hours post-op between the treatment and control groups. The secondary outcome is to assess the 
treatment of VIDD by crossing over the control patients that remain on mechanical ventilation at 120 hours 
and observe if there is an effect on the ability to wean those remaining patients with stimulation.   
 
To assess the initial expected outcome, the observational pilot study of TransAeris, resulted in six patients 
weaned by 48 hours on MV, for a 60% proportion weaned.  This compares 34.1% (=1 - 65.9%) weaned 
from three recent datasets from Suarez-Pierre (2019), Hessels (2019) and the STS Adult Cardiac Database 
from July 2014 – June 2017.(12,13)   
 
Table 1: Datasets of PMV patients 
 
Total Patients on MV 
Dataset 
at 24 hours 
at 48 hours 
at 120 hours 
Hessels (2019) 
229 
127 (55.5%) 
Not reported 
Suarez-Pierre (2019) 
1698 
1024 (60.3%) 
494 (29.1%) 
STS (2014 – 2017) 
109,380 
72,240 (66.0%) 
38,120 (34.9%) 
TOTAL 
111,307 
73,391 (65.9%) 
38,614 (34.8%) 
 
To power a pivotal study for a 20% risk reduction (RR) in the pivotal study, we would need a total of ≈192 
patients randomized.  Where the RR is calculated as: 
 
RR = 20% = [Control On MV at 48hrs – Treatment on MV at 48hrs] 
 
 
       = 65.9% - 45.9% 
 
Thus, both groups would have the same rate of patients that would wean prior to 24 hours, based on the 
prognostic enrichment inclusion criterion, of 43.5% (= 1 – PPV).  The TransAeris stimulated group would be 
anticipated to have 46% of the PMV group still on MV at 48 hours and the control group to have 66% on MV 
at 48 hours.  In the observational pilot we saw 40% on MV at 48 hours.  This would translate, in a 40-patient 
study, to 4 to 5 treatment patients on MV and 6 to 7 control patients on MV at 48 hours.  While still anticipated 
to be statistically inconclusive, with the small sample size requested, as a next step this single-site 
randomized study is expected to lead into the total 340 implanted patients to yield 192 PMV sample multi-
center pivotal study. That is derived from the target 192 patients with PMV and 56.5% positive prediction 
rate requiring a pool of 340 enrolled patients implanted. 
 
A secondary comparator is to the STS adult cardiac dataset reported number of the enriched PMV group 
reaching 5 days of MV.  As discussed above, we would expect 35% of those patients to still need MV at 5 
days.  Thus, in a set of 15 control patients, we would expect 2 to 3 patients to still be on MV at 5 days.     
 
Another secondary comparator is the diaphragm EMG activity of the cross-over control patients. It is 
anticipated that we will see a difference in the bilateral EMG activity from baseline (POD 0) to the point of 
cross-over at POD 5.  It is anticipated that the median frequency, during resting breathing should increase 
between baseline and the progression of VIDD at POD 5, then reverse back to baseline with TransAeris 
stimulation.  This would be indicative of the use of more glycolytic fibers that have faster conduction 
velocities with VIDD and then the return of the use of oxidative slow twitch fibers as VIDD is treated with 
TransAeris. 
 
The intended Outcome of TransAeris for the PICO model is a reduction in time on MV. For this study it is, 
as stated above for the comparators, a possible reduction in proportion on MV at 48 hours, a potential 
treatment of VIDD in cross-over patients on MV at 120 hours.  Additionally, a difference in EMG analysis 
between the cross-over patients with more than 120 hours of MV will be assessed as an outcome. 
 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
5. 
RISKS AND BENEFITS OF THE DEVICE AND CLINICAL INVESTIGATION 
5.1 Anticipated Clinical Benefits 
The benefits of TransAeris stimulation in this subject population are unproven at this time although 
preliminary evidence suggests that a higher proportion of subjects will be weaned from MV by 48 hours with 
TransAeris therapy.  Subjects may receive no direct benefits from study participation. It is possible that the 
use of TransAeris may result in the avoidance of prolonged mechanical ventilation due to VIDD, and 
reduction of MV-associated morbidity. The findings of this study are expected to benefit medical research 
and advance the development of TransAeris System, which would provide neuromuscular electrical 
stimulation to the diaphragm while the patient is on mechanical ventilation in the ICU to prevent, slow, or 
reverse diaphragm disuse atrophy and, more generally, to treat VIDD. 
5.2 Anticipated Adverse Device Effects 
The theoretical risks related to the study device are listed below, with the observed occurrence in the pilot 
study: 
 
Stimulus interferes with heart rhythm; 0 occurrences out of 10 patients 
 
Stimulus interaction with implanted cardiac defibrillator or cardiac pacemaker; 0 occurrences out of 
10 patients 
 
Pain due to stimulation; 0 occurrences out of 10 patients 
 
Percutaneous electrode exit site infection requiring antibiotics; 0 occurrences out of 10 patients 
 
The theoretical risks related to the procedure to insert or remove the TransLoc electrodes are listed below, 
with the observed occurrence in the pilot study: 
 
Bleeding during surgery due to insertion of the electrode; 0 occurrences out of 32 patients 
 
Tissue or organ damage during surgery due to insertion of the electrodes; 0 occurrences out of 32 
patients 
 
Breakage of electrode lead; 0 occurrences out of 128 electrodes 
 
Accidental dislodgement of electrode from diaphragm; 1 occurrence out of 128 electrodes 
 
Unintentional device fragment retained after removal of electrode; 0 occurrences out of 108 
removals 
 
Bleeding after removal of the electrodes; 0 occurrences out of 32 patients 
 
Exit site pain after removal of the electrodes; 0 occurrences out of 32 patients 
5.3 Possible Interactions with Concomitant Medical Treatments 
Warnings regarding possible interactions with other medical devices are included in the warnings section of 
the User Manuals (REF 77-1000-FR_B & REF 77-1002-FR_C) which is part of this investigational plan.  In 
case of any identified or suspected interaction with other devices used in the care of the patient, the 
TransAeris stimulation will be ceased. If the interaction is verified, it will be noted as an adverse event, the 
TransLoc electrodes will be withdrawn and the patients’ participation in the study will conclude. 

 
  
 
 
 
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5.4 Risk Mitigation Strategies 
Stimulus interference with heart rhythm are mitigated in this protocol per study procedures sections 7.5.1.3.1 
and 7.5.1.3.2 which describes cardiac rhythm monitoring.  Pain due to stimulation is mitigated through 
device programming including programmable intensity and frequency settings and the optional burst mode 
as described in study procedures section 3.6.4.2.  Percutaneous electrode exit site infection is mitigated by 
limiting TransAeris use to the hospital setting where proper exit site maintenance can be ensured. Infection 
is also mitigated by limiting the TransAeris stimulator to single patient use to prevent transmission of any 
bacterium from patient to patient on the device.   
Additionally, procedure-related risks were mitigated through a prior feasibility study (IDE’s G150040 & 
G170294) which investigated the safety and performance of the TransLoc electrodes including their 
insertion and removal and investigated the safety and performance of the TransAeris stimulation on open 
cardiac surgery patients.  In total, 176 electrodes were successfully placed in 44 patients during these two 
pilot studies. Electrodes were placed concomitant to a primary surgical procedure done using one of three 
approaches: laparoscopic, open abdominal, and open chest.  Electrode stability was demonstrated by the 
collection of daily diaphragm EMG readings. No unretrieved device fragments were left with the removal of 
electrodes.  No device or procedure related adverse events from implantation through electrode removal 
were reported. 
5.5 Risk to Benefit Rationale 
Synapse applies the EN ISO 14971 standard for Risk Management in Medical Devices to evaluate identified 
risks, determine a risk rating and apply our risk acceptance policy. The procedures of analysis, as identified 
in our standard operating procedures for risk management, are kept up to date with findings from device 
performance in commercial use, as well as investigational use. Risk mitigation is performed through design 
practices, protective measures, or informational (instructions for use) with evaluation of these activities on 
at least an annual basis. An assessment of the detailed evaluation is performed by the Synapse 
management team and a determination is made if overall residual risk, after mitigation activities, is at an 
acceptable level. For this clinical investigation, the residual risks have been reviewed by the Synapse 
management team and the site investigators and determined that they are at an acceptable level. The 
potential benefits, while they may not apply directly to the individual patients in this study, outweigh the 
potential risks and the device is safe for human use in the context of the clinical investigation for the 
proposed intended use. 
6. 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION 
6.1 Purpose  
This study will be conducted as a randomized trial of the TransAeris system for the prevention and treatment 
of ventilator-induced diaphragm dysfunction (VIDD) in patients identified prior to surgery to be at greater 
risk of prolonged mechanical ventilation (MV).  
6.2 Objectives 
The specific objectives of this study are: 
Primary objective: 
 
Evaluate the credibility of expected treatment benefits 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
Secondary objectives: 
 
Identify safety concerns  
 
Identify barriers to enrollment 
 
Evaluate the randomized protocol in single site setting, prior to multi-center expansion 
 
Assess the capability of collecting the specified evaluation criteria 
 
Assess the capability to quantify diaphragm electrical activity through diaphragm EMG monitoring 
 
7. 
DESIGN OF THE CLINICAL INVESTIGATION 
7.1 Type of Clinical Investigation 
This study is a monocentric and open label randomized study in adult open cardiac surgery patients.  Eligible 
patients from whom informed consent is obtained are enrolled in the study. All subjects will be implanted 
with the TransLoc electrodes during their primary surgery.  Patients are randomized to treatment or control 
groups prior to surgical placement of the TransLoc electrodes.   
 
7.2 Outcome Measures 
7.2.1 
Primary Safety Outcome 
Incidence of serious device-related adverse effects 
7.2.2 
Primary Efficacy Outcome 
Time on Mechanical Ventilation and Proportion of patients weaned at 48- and 120-hours 
post-op 
7.2.3 
Ancillary Outcomes 
Safety:   
 
Interference with ICU care 
 
Device related adverse events 
 
30-day mortality 
Efficacy:   
 
Time on mechanical ventilation,  
 
 
(measured in hours from entry to ICU and reversal of paralytics) 
 
EMG analysis of cross-over patients  
Ventilator Free Days 
 
Length of stay, ICU & Hospital 
7.3 Investigational Devices and Comparators 
Eligible patients from whom informed consent is obtained are enrolled in the study. All subjects will be 
implanted with the TransLoc electrodes during their primary surgery.  Comparison will be made between 
treatment and control patients during the initial 120 hours of study, then comparison of cross-over control 
patients’ EMG from baseline to treatment. Further comparison of MV Time, ventilator free days and other 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
outcome measures will be made for all patients, over the course of the 30-day treatment period, to literature 
on an observational basis. 
7.4 Subjects 
7.4.1 
Inclusion and Non-Inclusion Criteria 
The study investigators will screen patients and evaluate their eligibility for this study. Patients will not be 
enrolled in the study unless they meet all of the inclusion criteria and none of the non-inclusion criteria.   
7.4.1.1 
Inclusion Criteria 
1. Subject is undergoing an open cardiac procedure by median sternotomy 
2. Subject is at risk of prolonged mechanical ventilation according to one or more of the following 
criteria: 
 
Prior open cardiac surgery 
 
Left Ventricular Ejection Fraction (LVEF) ≤ 30% 
 
History of TIA or CVA 
 
Pre-operative or anticipated intraoperative intra-aortic balloon pump 
 
History of COPD 
3. Subject is at least 22 years of age 
4. Informed consent has been obtained from the patient  
7.4.1.2 
Non-Inclusion Criteria 
1. Subject is on invasive mechanical ventilation prior to procedure 
2. Subject has known or pre-existing phrenic nerve paralysis 
3. Subject is having a left ventricular assist device implanted 
4. Subject has progressive, non-reversible neuromuscular disease affecting the diaphragm 
5. Subject is pregnant or lactating 
6. Subject is actively participating in another clinical study which could affect outcomes in this study 
 
7.4.2 
Point of Enrollment 
30 subjects will receive TransLoc electrodes.  Subjects from whom informed consent is obtained are 
enrolled in the study.  Subjects will be randomized to: 
Group 1: Tx (Treatment with TransAeris stimulation upon completion of procedure), or;  
Group 2: SOC (Control with cross-over to Treatment if still on MV at 120 hours post-op).   
7.4.2.1 
Randomization 
Subject randomization list will be created prior to the start of the study using a block randomization 
technique.  Subject randomization letters will be provided in sealed envelopes in each subject binder.  All 
subject binders will be maintained in the site's clinical research department.  Each envelop will be unsealed 
prior to surgery, and after the subject has signed the consent form.  

 
  
 
 
 
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7.4.3 
Subject Withdrawal or Discontinuation 
All subjects enrolled in the clinical study shall be accounted for and documented.  If a subject withdraws 
consent before implantation of the TransLoc electrodes, all study-related activities will end.  If the subject is 
implanted with the TransLoc electrodes and withdraws consent, all study-related activities will end and the 
electrodes will be removed.  If the investigator withdraws the subject from the clinical investigation, all study-
related activities will end and the reason(s) for withdrawal shall be reported.   
7.4.4 
Procedures for Replacement Subjects 
Subjects that do not have the TransLoc electrodes inserted during their primary surgery will be withdrawn 
from the study and a replacement will be assigned.  The reason for not placing the electrodes will be 
documented on the Study Exit form for non-implanted patients.  Additionally, a chart review will be performed 
for the non-implanted patients to record their time on mechanical ventilation time, length of ICU and hospital 
stay and any complications that they experienced during their post-operative stay.  Since these patients are 
consented, this information will be evaluated to determine any relation to their reason for not being implanted 
to their outcomes and the inclusion criteria.   
7.4.5 
Enrollment Period and Duration of the Clinical Investigation 
 It is estimated that enrollment will last approximately four months.  The estimated duration of the study from 
first enrollment to last follow-up is six months.  Total study duration per subject is estimated less than 60 
days from screening to last follow-up day.   
7.5 Procedures 
7.5.1 
Description of Investigational Procedures 
Table 2 lists the data to be collected at each study interval.  Study activities are recorded on the case report 
forms by the clinical coordinator or other clinician designated by the principal investigator.  The clinician 
completing the form signs in the entry designated for completion and the principal investigator reviews all 
forms and signs in the designated location to indicate review and confirmation of the data entered. 
Table 2a: Schedule of Study Activities and Data Collection – Initial All Patients 
Activity/Procedure/ 
Assessment 
Screening 
and 
Enrollment 
At Time of 
Cardiac 
Surgery 
ICU 
Informed  Consent 
X 
 
 
Inclusion/non-inclusion criteria  
X 
 
 
Demographics, medical history 
X 
 
 
TransLoc electrode insertion 
  
X 
 
Concomitant Interventions  
 
X 
 
Serious adverse events 
  
X 
 
Adverse device effects 
  
X 
 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
Activity/Procedure/ 
Assessment 
Screening 
and 
Enrollment 
At Time of 
Cardiac 
Surgery 
ICU 
Device deficiencies  
 
X 
 
Randomization 
 
X 
 
Concomitant Interventions 
 
 
X 
Start / Stop date and time of MV use 
 
 
X 
EMG Baseline recording 
 
 
X 
 
 
Table 2b: Schedule of Study Activities and Data Collection – Treatment Patients 
 
 
 
 
 
 
 
 
 
 
 
Table 2c: Schedule of Study Activities and Data Collection – Control Patients 
Activity/Procedure/ 
Assessment 
ICU 
First 120hrs 
ICU 
At 120hrs 
ICU 
After 
120hrs 
EMG VIDD Progression recording 
 
X 
 
TransAeris Start & Settings 
 
X 
 
TransAeris Start/Stop & Settings 
 
 
X 
Competing events 
X 
X 
X 
Serious adverse events 
X 
X 
X 
Adverse device effects 
X 
X 
X 
Device deficiencies  
X 
X 
X 
 
 
Activity/Procedure/ 
Assessment 
ICU  
Start / Stop date of TransAeris 
stimulation  
X 
Competing events 
X 
Serious adverse events 
X 
Adverse device effects 
X 
Device deficiencies  
X 

 
  
 
 
 
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Table 2d: Schedule of Study Activities and Data Collection – Conclusion All Patients 
Activity/Procedure/ 
Assessment 
Discharge 
30 Days 
Post 
Electrode 
Removal 
Serious adverse events 
X 
X 
Adverse device effects 
X 
 
Device deficiencies  
X 
 
EMG Wean/Discharge recording 
X 
 
TransLoc electrode removal 
X 
 
Follow-up questionnaire  
 
X 
7.5.1.1 
Screening and Enrollment 
Subjects who have been identified prior to surgery to be at risk of prolonged mechanical ventilation after 
surgery are eligible for this study. Potential subjects will be screened by the investigator for eligibility in the 
study with respect to the inclusion and non-inclusion criteria (sections 7.4.1.1 – 7.4.1.3).  Potential subjects 
who meet the inclusion and non-inclusion criteria and give informed consent will have demographic, 
screening, and medical history information including:  
 
Height 
 
Weight 
 
Gender 
 
Month and Year of birth 
 
Pregnancy test for women of child-bearing potential 
 
Admitting diagnosis 
 
Surgical procedure 
 
Medical history 
Enrollment, demographic information and medical history on documented on case report forms page 1, 2 
and 3, respectively. 
7.5.1.2 
Prolonged Mechanical Ventilation Risk Identification 
Prolonged Mechanical Ventilation (PMV) for the purpose of this study is defined as ≥ 24 hours on mechanical 
ventilation post-surgery.  If the patient meets the other inclusion / non-inclusion criteria and has any of the 
following risk factors for PMV then they will be included if they give informed consent.  At least one of the 
risk factors below must be answered YES on the case report form. 
1. Pre-operative or anticipated intraoperative IABP 
2. Any prior open cardiac surgery 
3. LVEF ≤ 30% 
4. History of TIA or CVA 
5. History of COPD 
The specific risk factors met are to be documented on the enrollment case report form, page 1. 

 
  
 
 
 
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For those undergoing procedures where the STS risk calculator (riskcalc.sts.org) can provide a score, those 
scores will be calculated and the risk score of PMV for the specific patient will be entered on the case report 
form, page 2. The risk score and variables will be documented in the case history. 
7.5.1.3 
Electrode Placement and Device Use 
All subjects will be randomized to treatment or control groups prior to implantation of the TransLoc 
electrodes.  Subjects not implanted will be withdrawn from the study.  The procedure information is recorded 
on the case report form, page 4.  Specific information concerning the cardiac procedure that the patient is 
undergoing is recorded on the form as well as procedure time, pump time and any concomitant interventions 
that the patient undergoes at the time of the cardiac surgery.  The device tracking information for the 
electrodes are recorded in the procedure information as well as an indication of successful electrode 
placement, or occurrence of an adverse event, competing event or device deficiency.  
Patients are randomized to the Treatment or Standard of Care groups as per section 7.4.2.1.  The group 
assignment is recorded on the Post-Op case report form, page 5.  This case report form is completed for 
each patient for each day in protocol, beginning with the day of surgery as day 0.  The reversal or time when 
paralytics are worn off is recorded as well as the current ventilatory support in terms of intubation, extubation, 
and any type of post-extubation ventilatory support that may be required. 
Once the paralytics have been reversed from the surgery, an initial diaphragm EMG is recorded on case 
report form, page 6.  If bilateral EMG is not observed, then a competing event is recorded as described 
below in section 7.5.1.4. 
7.5.1.3.1 
Treatment (Tx) Group 
TransAeris use begins, in the Tx group as soon as practical.  TransAeris stimulation will not begin 
unless the patient is connected to cardiac monitoring.    The cardiac rhythm will be observed for any 
potential cardiac capture when stimulation is initiated, or any changes are made.  The observation 
of cardiac rhythm interaction is recorded with the stimulator settings on the daily post-op case report 
form, page 5.  TransAeris stimulator settings (stimulus intensity, stimulus frequency, and burst 
on/off) will be programmed to optimize diaphragm recruitment without compromising patient 
comfort.  Refer to section 3.6.4.2 Device Programming.  If stimulation settings cannot be adjusted 
or the stimulation cannot be applied without eliciting patient discomfort or pain due to the stimulation, 
then an adverse event indicated on the daily post-op case report form and an adverse event case 
report form, page 11, should be completed.   Stimulation pain should be assessed daily using verbal 
and/or non-verbal cues from the patient using the visual analog scale shown below. In the event of 
pain that cannot be eliminated by reducing stimulation intensity then it should recorded as such on 
the adverse event case report form. 
 
 
 

 
  
 
 
 
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TransAeris stimulation will continue as needed until the patient is successfully weaned.  Stimulation 
may continue beyond successful weaning at the clinician’s discretion to provide any additional 
support to avoid reintubation, but no longer than 30-days post-op. 
7.5.1.3.2 
Standard of Care (SOC) Group 
The SOC group does not receive TransAeris stimulation for the first 120 hours of mechanical 
ventilation.  SOC group patients will not be stimulated unless they are still on mechanical ventilation 
at 120 hours, at which point they will have an EMG recording made on the case report form, page 
6.  If intact bilateral EMG is not observed a competing event will be recorded on the competing event 
case report form, page 10.  Otherwise the patient will be identified as a Cross-over patient on the 
daily post-op case report form, page 5, and follow the process for the Tx group as identified in 
section 7.5.1.3.1, with the start of TransAeris stimulation.   
 
Any device deficiencies or competing events, that would inhibit or preclude weaning, should be indicated 
on the daily post-op case report form and the associated detail case report form for device deficiencies, 
page 12, or competing events, page 10, should be completed for all patients, Tx, SOC or cross-over. 
 
A final EMG recording will be performed prior to electrode removal in all patients.  Recordings will be made 
for a period of at least one minute during quiet, resting breathing or quiet, mechanical ventilation support. 
7.5.1.4 
Competing Events 
At any point during the study both groups will be monitored for competing events that preclude or impede 
the progression of weaning, i.e. causes other than VIDD that are the source of an inability to wean.  These 
are typically adverse events, unrelated to the device or procedure that will also be recorded in detail, as per 
Section 15.  Identification as a competing event, with time and date of the event, will establish the point of 
censoring for purposes of analysis of efficacy outcomes.  An indication of the occurrence is recorded on the 
daily post-op case report form (page 5) with more detail of the event, including specific cause of the event 
and status of the event (as described below) recorded on the competing event detail case report form (page 
10).  The patient may continue with the TransAeris therapy, if initiated, at the discretion of the clinician.   
The event of interest is successful wean from mechanical ventilation and is classified as a Status=0 event.  
Death prior to successful weaning from mechanical ventilation is a competing event that precludes further 
weaning and would be classified as a Status=2, right censored event.  Other events that hinder the event 
of interest and alter the probability of occurrence are classified as a Status=1, right censored event.  This is 
depicted below in Figure 3: Competing Event Model. 
 

 
  
 
 
 
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Clinical Study Protocol #: 20-1000-108 Rev D 
 
Figure 3: Competing Event Model 
 
The pre-specified competing events and censoring status are provided in Table 3, below.  The events that 
would hinder weaning from mechanical ventilation are right censored with Status 1.  Since an intact phrenic 
lower motor neuron is required for the stimulation to propagate through the diaphragm muscle, bilateral 
phrenic function, as identified by an observed EMG on both left and right hemidiaphragms, is necessary for 
the TransAeris stimulation to be effective.  Lack of observed bilateral function, indicating a damaged phrenic 
nerve prior to or during surgery, is considered a competing event that would impede weaning with 
TransAeris.  Additional right censor events may be considered that would meet the definition of precluding 
or impeding the event of interest (i.e. successful wean) from occurring. 
 
Table 3: Competing Events 
Event type 
Censor 
Status 
Description 
Observed 
(Suarez-Pierre) 
Desired Event
0
Successful wean
39.7%*
Right Censor 
2 
Death prior to wean, precludes event of interest 
20%** 
Right Censor 
1 
Renal failure w/ dialysis initiated post-operatively 
9.7% 
Right Censor
1
Hemorrhage requiring reoperation
10.4%
Right Censor 
1 
Delayed Sternal Closure, reoperation 
8.3% 
Right Censor
1
Sepsis
6.1%
Right Censor 
1 
TIA or CVA 
5.8% 
Right Censor 
1 
Cardiogenic shock, cardiac arrest 
13.8% 
Right Censor
1
Lack of bilateral diaphragm EMG function
n/a
*Percentage no longer on MV at 48 hours, from Suarez-Pierre (2019) Figure 1 
**Approximate 96 hour predicted mortality from Suarez-Pierre (2019) Figure 2 
7.5.1.5 
Prior to Discharge 
The investigator will remove the electrodes prior to ICU discharge or 30 days post-implant procedure, 
whichever comes first.  The electrodes may be withdrawn earlier if the patient has been successfully 
extubated (and will no longer be at risk of re-intubation).  After removal, subjects will be monitored for 
adverse events prior to ICU discharge or 30 days post-implant procedure, whichever comes first. 

 
  
 
 
 
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7.5.1.6 
30 Days Post Electrode Removal 
For implanted patients a follow-up questionnaire will be administered by phone, email, or visit to assess at 
30 days post-electrode removal the subject’s survival, any readmission or reintubation, any post-procedure 
complications, and subject’s location (home, nursing home, long term acute care hospital). 
7.5.1.7 
Adverse Events and Device Deficiencies 
Each subject will be monitored for: 
 
Serious adverse events 
 
Adverse device effects 
 
Device deficiencies (malfunctions, failures, or technical issues) 
 
The investigator and sponsor will assess the incidence of adverse events comparatively between the 
treatment and control patients. If a significant difference is identified, further study implants will be paused 
until resolution is identified. 
7.5.2 
Equipment Used for Study Evaluations 
The diaphragm EMG will be recorded with an EMG recorder suitable for recording continuous EMG, such 
as the Crystal PSG device from Cleveland Medical Devices or other similar device.     
7.5.3 
Description of Activities Performed by Sponsor Representatives 
Synapse Biomedical, Inc. will provide onsite training, technical support, and troubleshooting assistance as 
needed, including support for TransLoc electrode implantation and device programming and use in the 
patient room. 
7.6 Monitoring Plan 
The sponsor, Synapse Biomedical, will monitor the study in accordance with its standard operating 
procedures to ensure that the study is conducted, recorded, and reported in accordance with the 
investigational plan, investigator agreement, and applicable EC and regulatory requirements. 
Prior to the initiation of the study, the monitor will assess the study site via virtual meeting or physical meeting 
to assure that the investigator has adequate resources to conduct the clinical study and that the investigator 
understands his or her obligation regarding:  conducting the study in accordance with the agreement with 
the sponsor, the investigational plan, the EC requirements, and French regulations; obtaining EC review 
and approval of the clinical study and ensure continuing review; obtaining informed consent; maintaining 
study records; permitting inspection by French regulators; submitting reports; protocol deviations; 
investigational device accountability; and financial disclosure, if applicable. 
During a monitoring visit, the monitor will review:  the continued adequacy of resources to conduct the 
clinical study; EC approval and other study-related EC records; informed consent records; investigational 
device storage facilities and accountability practices; investigational device accountability records; 
correspondence (with the EC, sponsor, or CA, if applicable) including required reports; protocol deviation 
records; and subject case report forms, adverse device effect reports, and their consistency with source 
documents.   

 
  
 
 
 
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7.7 Data Protection 
All participant data collected during the course of this investigation will be kept strictly confidential. Any 
information that could identify a subject will remain with the investigator where it will be archived with study 
documents. Data from all participants will remain pseudo-anonymized for the purposes of data analysis. 
Data collected for the purposes of this study should be made available for the sponsor/designee at all 
monitoring visits.  
 
Should the investigation require future review, it may be necessary to allow limited access to the 
sponsor/designee and regulatory authorities for audit purposes only. They will be granted direct access to 
the study subjects’ original medical records for verification of clinical study procedures and/or data, without 
violating the confidentiality of the subjects to the extent permitted by the law and regulations.  
 
The sites and the sponsor must follow the General Data Protection Regulation (GDPR) 2016/679, as it 
applies to the protection and privacy of subject data.  
 
In any presentations of the results of this study or in publications, the subjects’ identity will remain 
confidential.  
 
Study participants and related data will be identified by a unique study identification number. This will not 
include the participant’s contact or identifying information. 
 
The clinical investigation will be registered in a publicly accessible database, on www.clinicaltrials.gov, in 
accordance with the FDA Modernization Act prior to enrollment of the first subject. Results of the clinical 
investigation will be made public on this website in accordance with the applicable requirements. 
8. 
STATISTICAL CONSIDERATIONS 
8.1 Study Design and Statistical Objective 
This study is designed to gather data on the use of TransAeris in subjects identified prior to surgery to be 
at greater risk of prolonged mechanical ventilation after surgery. Data collected will be compared 
qualitatively to the relevant clinical literature and used to inform the design and statistical parameters for a 
subsequent multi-center pivotal trial. 
8.2 General Considerations 
Continuous data will be summarized using descriptive statistics:  mean, standard deviation, median and 
interquartile range.  Categorical variables will be summarized using frequency counts and percentages.  For 
events which can occur more than once in a single subject (e.g., adverse events), the primary analysis will 
be based on the count of subjects experiencing the event; both patient and event counts will be reported. 
All statistical analyses will be performed in STATA version 13.1 or later, or other widely accepted statistical 
analysis software packages. 
8.3 Analysis Population and Significance Testing 
The primary analysis will consist of all available data from all enrolled subjects, referred to in ICH E9 
(“Statistical Principles for Clinical Trials”) as the full analysis set. As the intended analyses of study outcomes 

 
  
 
 
 
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are descriptive in nature, a priori hypothesis tests are not proposed; however, any p-values computed and 
reported will be two-sided, with values less than 0.05 indicating statistical significance. 
8.4 Endpoints 
8.4.1 
Primary Safety Endpoint 
The primary safety endpoint is the incidence of serious adverse device effects (SADE), as that term is 
defined in Section 15. 
8.4.2 
Primary Efficacy Endpoint 
The primary efficacy endpoints are the mechanical ventilation time and proportion of patients successfully 
weaned at 48- and 120-hours post-op.  These will each be evaluated separately for efficacy. A wean will be 
considered successful if the patient is not reintubated within 48 hours of extubation.  The mechanical 
ventilation time will be the cumulative proportion of time on mechanical ventilation over the 48- or 120-hour 
period from the entry to the ICU (recorded as ICU Admit Time on the procedure information case report 
form).  If an extubation is attempted but is not successful (i.e., less than 48 hours) then that time will not be 
considered off of mechanical ventilation. The proportion weaned will be derived from the cumulative 
incidence function (CIF) of a competing risk analysis.   
Data will be analyzed for all patients and using a predictive enrichment threshold of patients on mechanical 
ventilation.  The enrichment strategy is applied to identify patients that may more likely respond to 
TransAeris stimulation and decrease variability, as per FDA guidance.(14)  As the TransAeris treatment is 
not intended to produce immediate results, but rather is intended to prevent or treat VIDD, patients that are 
on MV for short periods are expected to have improved spontaneously and thus increase the variability in 
the outcome measures if included in analysis.  Similarly, patients, during the initial hours of mechanical 
ventilation with paralytic anesthesia still impacting contraction, are not expected to respond to the treatment 
and thus excluding patients that are weaned from mechanical ventilation during the initial 10 hours post-op 
will be considered as not part of the predictive enrichment analysis.  The data will be considered non-
proportional and will be assessed using non-parametric techniques. 
8.4.3 
Secondary Endpoints 
Secondary endpoints are defined as follows: 
 
All-cause mortality through 30 days 
 
Mechanical Ventilation time, as the cumulative time on mechanical ventilation from ICU entry and 
paralytic reversal to successful wean, 
 
Ventilator-free days, defined(15) as time free from mechanical ventilation during first 28 days, 
where: 
VFD28 = (28 – Time on MV) if Time on MV is less than 28 days; 
 
= 0 if Time on MV ≥ 28 days 
 
= 0 if death within 28 days 
 
Hospital length of stay (admission to discharge) 
 
ICU length of stay 
 
Change in median frequency and total power of the power density spectrum (PSD) analysis of 
inspirations at baseline, pre-stimulation, and post-stimulation in cross-over control patients 

 
  
 
 
 
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All endpoints will be summarized and reported descriptively to characterize outcomes.  No a priori 
hypothesis testing is planned for this study. 
8.5 Determination of Sample Size 
The purpose of this study is to gather information on safety and effectiveness as a lead-in to a subsequent 
multi-center pivotal trial, and no therefore formal hypothesis testing is defined a priori.  For this purpose, 
implant of up to 30 subjects is deemed sufficient for reasonable precision of estimation of study parameters.  
Based on prior pilot study (G170294) it is anticipated that there will be consented patients that do not get 
implanted. These non-implanted patients will be accounted for and documented.  
8.6 Interim Analysis 
No formal interim analysis for early stopping is specified.  Accordingly, any analyses of study results which 
may be performed during study conduct will not be interpreted to permit early stopping of the study for 
success, although early stopping for safety is permitted as always. 
8.7 Handling of Missing Data 
Every effort will be made to reduce the incidence of missing data. The study will be conducted with proper 
screening of study subjects, complete training of participating investigators, study coordinators and 
monitors.  All subject data that are available on subjects who drop out during the study will be included. 
Missing data will not otherwise be replaced or otherwise imputed, as the primary analysis is to be conducted 
on the ICH E9 definition of the full analysis set. 
The number and proportion of subjects eligible for and compliant with each follow-up examination will be 
presented. Subjects who withdraw from the study will be tabulated with reasons for withdrawal. 
8.8 Poolability of Outcomes 
As no formal statistical hypotheses are to be tested, no formal assessment of poolability will be performed. 
9. 
DATA MANAGEMENT 
The sponsor will collect study data using paper or electronic case report forms (CRFs).  Paper case report 
forms are filled out by designated site personnel, reviewed and approved by the investigator, submitted to 
the sponsor, and entered by the sponsor into a clinical data management system (CDMS).  The investigator 
may be prompted by queries from the sponsor data management personnel or monitors to clarify, correct, 
or confirm data which are missing, out of range, or illogical.   
10. 
PROTOCOL AMENDMENTS 
The sponsor, as per MDR 2017/745 and national regulation, must submit and, where necessary, obtain 
approval from the EC and CA for all subsequent study amendments, such as protocol changes, IB changes, 
or changes to the Informed Consent Form. 

 
  
 
 
 
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11. 
PROTOCOL DEVIATIONS 
Deviations to the clinical study protocol are not permitted except as necessary to protect the rights, safety 
and well-being of human subjects.  These deviations shall be reported to the sponsor and as part of the final 
study report submitted to the EC.    
When possible, investigators shall notify the sponsor prior to any deviation from the protocol.  All non-
emergent deviations will be noted on the appropriate case report form (CRF) and will be reviewed by 
monitors during monitoring visits.   
 
The sponsor shall review all deviations to determine investigator protocol compliance.  Action will be taken 
to secure compliance if repeated protocol non-compliance is noted.  This may take the form of training, other 
corrective actions or, if necessary, disqualification of the investigator from the study.   
12. 
DEVICE ACCOUNTABLILTY 
Investigational devices will only be shipped to qualified investigators.  Each study device will be labeled for 
investigational use only and will contain an identifying lot and/or serial number. The date of receipt, use, 
disposition, subject identifier, and date of return (as applicable) will be recorded on a device accountability 
log for each device shipped to the site.  
13. 
REGULATORY COMPLIANCE 
This study will be conducted in compliance with current standard ISO 14155:2020 (Clinical Investigation of 
Medical Devices for Human Subjects – Good Clinical Practice), the ethical principles of the Declaration of 
Helsinki and European Medical Device Regulation MDR 2017/745, and other applicable regulatory 
requirements. The study protocol and consent must be approved by the responsible EC and per national 
regulations. Study activities must not commence prior to receipt of documentation of EC approval and 
Competent Authority approval by the site and sponsor. The Investigator and study staff must comply with 
the requirements of the EC. 
14. 
INFORMED CONSENT PROCESS 
An informed consent document suitable for use in this study, including the elements of informed consent in 
conformance with ISO 14155:2020. Iterations of this document must also include the elements of informed 
consent in conformance with ISO 14155:2020 must be approved by the reviewing Ethics Committee. 
Subjects must be presented with the most current EC approved version of the consent form for signature 
and study enrollment. 
Country specific consent regulations and language requirements should be followed and incorporated into 
the consent document. 
 
Prior to enrolling in this trial, the subject will review the informed consent materials with the investigator or 
appointed designee.  The consent form and consent discussion should be in a language the subject 
understands. 
 
In order to provide consent for study participation, each subject must be fully informed about the 
investigational device, requirements, risks and benefits, and must sign and date the informed consent form 
acknowledging that participation is voluntary.  The subject will sign and date the approved study-specific 

 
  
 
 
 
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informed consent form prior to any study related procedure or testing being performed. However, historical 
and standard of care medical tests and records may be used to determine eligibility (e.g. imaging, lab tests). 
Subjects may withdraw participation at any time during the investigation without sacrificing their rights as a 
patient or compromising their quality of medical care. 
15. 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES 
15.1 Definitions as per ISO 14155:2020 & MDR 2017/745  
Adverse Event (AE):  Any untoward medical occurrence, unintended disease or injury or any untoward 
clinical signs, including an abnormal laboratory findings, in subjects, users or other persons, in the context 
of a clinical investigation, whether or not related to the investigational medical device. 
Note 1: This definition includes events related to the investigational medical device or the comparator.  
Note 2: This definition includes events related to the procedures involved.  
Note 3: For users or other persons, this definition is restricted to events related to the use of investigational 
medical devices or comparators. 
Adverse Device Effect (ADE):  Adverse event related to the use of an investigational medical device.  
Note 1: 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. 
Note 2: This definition includes any event resulting from use error or from intentional misuse of the 
investigational medical device. 
Note 3: This includes ‘comparator’ if the comparator is a medical device. 
 
Serious Adverse Event (SAE):  Any adverse event that led to any of the following: 
a) Death, 
b) serious deterioration in the health of the subject, that resulted in any of the following: 
1) a life-threatening illness or injury,  
2) a permanent impairment of a body structure or a body function,  
3) hospitalization or prolongation of patient hospitalisation 
4) medical or surgical intervention to prevent life-threatening illness or injury, or permanent impairment 
to a body structure or a body function, 
5) chronic disease, 
c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect 
 
Note 1: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without 
serious deterioration in health, is not considered a serious adverse event.  
Events that do not meet these criteria are considered non-serious. 
 
Serious Adverse Device Effect (SADE):  Adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
 
Unanticipated Serious Adverse Device Effect (USADE):  Serious adverse effect which by its nature, 
incidence, severity or outcome has not been identified in the current risk assessment. 
 

 
  
 
 
 
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Note 1: Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, 
severity or outcome has been identified in the risk assessment. 
 
Device Deficiency:  Any inadequacy in the identity, quality, durability, reliability, safety or performance of 
an investigational device, including malfunction, use errors or inadequacy in information supplied by the 
manufacturer;. 
 
Note 1: Device deficiencies include malfunctions, use errors, and inadequacy in the information supplied by 
the manufacturer including labelling.  
Note 2: This definition includes device deficiencies related to the investigational medical device or the 
comparator. 
Use Error: User action or lack of user action while using the medical device that leads to a different result 
than that intended by the manufacturer or expected by the user. 
 
Note 1: Use error includes the inability of the user to complete a task.  
Note 2: Use errors can result from a mismatch between the characteristics of the user, user interface, task 
or use environment. 
Note 3: Users might be aware or unaware that a use error has occurred.  
Note 4: An unexpected physiological response of the patient is not by itself considered a use error.  
Note 5: A malfunction of a medical device that causes an unexpected result is not considered a use error. 
 
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 CIP, or IB. 
 
Incident: Any malfunction or deterioration in the characteristics or performance of a device made available 
on the market, including use-error due to ergonomic features, as well as any inadequacy in the information 
supplied by the manufacturer and any undesirable side-effect. 
 
Serious incident: Any incident that directly or indirectly led, might have led or might lead to any of the 
following: 
a) The death of a patient, user or other person,  
b) The temporary or permanent serious deterioration of a patient’s, user’s or other 
person’s state of health, 
c) A serious public health threat 
 
Serious public health threat: an event which could result in imminent risk of death, serious deterioration 
in a person’s state of health, or serious illness,  that may require prompt remedial action, and that may cause 
significant morbidity or mortality in humans, or that is unusual or unexpected for the given place and time..  
 
Note 1: This would include events that are of significant and unexpected nature such that they become 
alarming as a potential serious health hazard or possibility of multiple deaths occurring at short intervals. 
 
15.2 Causality/Relationship 
The investigator and the Sponsor will assess the causality of all adverse events in relation to the research, 
i.e., the relationship between the AE / SAE and the investigational treatment or any other study-related 
procedures.  
 

 
  
 
 
 
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Each SAE will be classified according to four different levels of causality (as per MDCG 2020:10/1): 
1) Not related: relationship to the device or procedures can be excluded when:  
 
the event has no temporal relationship with the use of the investigational device or the procedures;  
 
the serious adverse 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 adverse event;  
 
the event involves a body-site or an organ that cannot 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;  
 
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 adverse event. 
2) Possible: the relationship with the use of the investigational device, or the relationship with the procedure 
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.  
 
3) Probable: the relationship with the use of the investigational device or the relationship with the procedure 
seems relevant and/or the event cannot reasonably be explained by another cause, but additional 
information may be obtained.  
 
4) Causal relationship: the serious adverse 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 a) the investigational device or procedures are applied 
to or b) the investigational device or procedures have an effect on;  
 
the serious adverse 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 
adverse 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;  
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 adverse event. 

 
  
 
 
 
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15.3 Adverse Event Reporting 
The reporting requirements adopted in this study are derived from the international standard on clinical 
investigations ISO 14155:2020 (“Clinical investigation of medical devices for human subjects — Good 
Clinical Practice"), Article 80 of the EU MDR 2017/745, and MDCG-2020-10/1:  
 
 
15.3.1 Investigator reporting Responsibilities 
Investigators must report to the sponsor, without delay (immediately) and not later than 3 calendar days 
after his awareness, all adverse device effects (ADEs), device deficiencies and serious adverse events 
(SAEs) study subjects experience during participation in this investigation. 
Each reported event must be appropriately documented to include the event’s serious criterion, relatedness, 
treatment, and resolution. All reported events that remain unresolved should be re-assessed until the event 
resolves or the subject’s study participation is complete. In the event of subject death, the investigator will 
make reasonable effort to obtain a death summary, autopsy report, etc. 
15.3.2 Sponsor’s reporting Responsibilities  
1) The sponsor will be responsible for recording the following events which have been documented 
by the investigator:  
 
a) any adverse event critical to  the evaluation of the results of the clinical investigation: endpoint events 
(mortality, ICH, and device/procedure related events) and device deficiencies that adversely affect the 
subject. 
b) Any SAE (Serous Adverse Event) 
c) Any Device Deficiency that might have led to a serious adverse vent if appropriate action had not been 
taken, intervention had not occurred, or circumstances had been less fortunate 
d) Any new findings in relation to any event referred to in points (a) to (c) 
2) The sponsor will be responsible for reporting, without delay to all Member States in which the 
clinical investigation is being conducted, the following events: 
a) any serious adverse event that has a causal relationship with the investigational device, the comparator or 
the investigation procedure or where such causal relationship is reasonably possible 
b) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, 
intervention had not occurred, or circumstances had been less fortunate 
c) any new findings in relation to any event referred to in points (a) and (b). 
The sponsor will report to all NCAs where the clinical investigation is authorised to start: 
 
For all reportable events as described in section 2) above resulting in death or which indicate an 
imminent risk of death, serious injury, or serious illness and that requires prompt remedial action for 
other patients/subjects, users or other persons or a new finding to it:  

 
  
 
 
 
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=> Without delay (immediately, but not later than 2 calendar days after awareness by sponsor 
of a new reportable event or of new information in relation with an already reported event. 
 
 
Any other reportable events as described in section 2) above or a new finding/update to it:  
=> Without delay (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. 
 
It is the responsibility of sponsor to inform all investigators in writing within 10 working days if device 
deficiencies, adverse events, adverse device effects, near-incidents, serious adverse events, serious 
adverse device effects or unanticipated serious adverse device effects lead to corrective actions (e.g. 
change of IFU). 
3) Reporting of serious incidents to the relevant CAs  
 
 The manufacturer will report any serious incident immediately after they have established the causal 
relationship between that incident and their device or that such causal relationship is reasonably 
possible and not later than 15 days after they become aware of the incident.   
 In the event of a serious public health threat a report shall be provided immediately, and not later 
than 2 days after the manufacturer becomes aware of that threat. 
 In the event of death or an unanticipated serious deterioration in a person's state of health a report 
shall be provided immediately after the manufacturer has established or as soon as it suspects a 
causal relationship between the device and the serious incident but not later than 10 days after the 
date on which the manufacturer becomes aware of the serious incident. 
16. 
SAFETY MONITORING 
Synapse will designate a qualified physician to function as an independent Medical Monitor.  The Medical 
Monitor will not otherwise be involved with the study and will act in an advisory capacity to assist the sponsor 
in monitoring subject safety.  The Medical Monitor will review the available information (e.g., case report 
forms and source documentation) for site reported ADEs.  The Medical Monitor will review the investigator 
classification of whether the event was serious, related to the study device or the procedure, and 
unanticipated. 
17. 
STUDY EARLY TERMINATION 
Synapse will monitor the progression of the trial and may suspend or prematurely terminate either a clinical 
investigational site or the entire clinical investigation.   
Instances which warrant premature study termination or site closure may include: 
 
Suspicion of unacceptable risk to study subjects 
 
Serious or repeated deviations on the part of an investigator 
 
Inadequate subject enrollment or a decision by Synapse to suspend or discontinue development of 
the device 
In the event of suspension or premature termination, Synapse will notify the applicable regulatory authorities 
in accordance with the regulations and ensure that the EC is notified.    

 
  
 
 
 
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18. 
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Esteban A, Alia I, Gordo F et al. Extubation outcome after spontaneous breathing trials with T-tube 
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3. 
Levine S, Nguyen T, Taylor N et al. Rapid disuse atrophy of diaphragm fibers in mechanically 
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Jaber S, Jung B, Matecki S, Petrof BJ. Clinical review: Ventilator-induced diaphragmatic dysfunction 
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Shanely RA, Van Gammeren D, Deruisseau KC et al. Mechanical ventilation depresses protein 
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Levine S, Biswas C, Dierov J et al. Increased proteolysis, myosin depletion, and atrophic AKT-
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Tang H, Lee M, Budak MT et al. Intrinsic apoptosis in mechanically ventilated human diaphragm: 
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Onders R, Ponsky TA, Elmo MJ, Lidsky K, Barksdale E. First reported experience with 
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D'Agostino RS, Jacobs JP, Badhwar V et al. The Society of Thoracic Surgeons Adult Cardiac 
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Hessels L, Coulson TG, Seevanayagam S et al. Development and Validation of a Score to Identify 
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Suarez-Pierre A, Fraser CD, Zhou X et al. Predictors of operative mortality among cardiac surgery 
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Food and Drug Administration. Enrichment Strategies for Clinical Trials to Support Determination 
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Schoenfeld DA, Bernard GR, Network A. Statistical evaluation of ventilator-free days as an efficacy 
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