A Prospective, Multi-Center, Open Label, Single Arm Clinical Trial Evaluating the Safety and Efficacy of the Cordella™ Pulmonary Artery Sensor System in NYHA Class III Heart Failure Patients (PROACTIVE- HF Trial)
Phase: NA
Conditions: Heart Failure NYHA Class III
Sponsor: Endotronix, Inc.

Study Protocol 
 
Protocol Title: A Prospective, Multi-Center, Open Label, Single Arm Clinical Trial 
Evaluating the Safety and Efficacy of the Cordella™ Pulmonary Artery Sensor System 
in New York Heart Association (NYHA) Class III Heart Failure Patients 
 
Brief Title: PROACTIVE-HF IDE Trial Heart Failure NYHA Class III 
 
Unique Protocol ID: ETX-HFS-PA-03 
 
NCT04089059 
 
08 November 2023 

 
Study No: ETX-HFS-PA-03 
 
Version: 11.0 (Final) 
Cordella™ PA Sensor System 
 
Date:  08 Nov 2023 
 
Endotronix - Confidential 
 
Page 1 of 153 
 
Clinical Trial Protocol / Clinical Investigational Plan (CIP) 
Protocol Number/ CIP: 
 
 ETX-HFS-PA-03 IDE Trial 
Title: 
A Prospective, Multi-Center, Open Label, Single Arm 
Clinical Trial Evaluating the Safety and Efficacy of the 
Cordella™ Pulmonary Artery Sensor System in New York 
Heart Association (NYHA) Class III Heart Failure Patients  
(PROACTIVE- HF Trial) 
Investigational Product Name:  
Cordella Pulmonary Artery Sensor System 
 
Version: 
11.0 (Final) 
IDE Number: 
G190020 
Date: 
08 November 2023 
This protocol contains confidential information, which is the property of Endotronix, Inc. for 
use by the Principal Investigators, designated representatives and applicable ethics 
committee/institutional review board and regulatory authorities participating in this clinical 
investigation.  It should be held confidential and maintained in a secure location. It should not 
be copied or made available for review by any person or firm without the prior written consent 
of Endotronix, Inc. 
 

 
Study No: ETX-HFS-PA-03 
 
Version: 11.0 (Final) 
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Date:  08 Nov 2023 
 
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ADMINISTRATIVE INFORMATION 
Sponsor Contacts 
Medical, Clinical and Operational Support 
Sponsor Name: 
 
 
Endotronix Inc 
Sponsor Address: 
 
 
1415 West Diehl Road 
Suite #500W,  
Naperville, IL 6056 
3USA  
Sponsor Name (EU only): 
 
 
Endotronix, Ireland Limited 
Sponsor Address (EU only): 
 
 
DCU Alpha Innovation Center 
Old Finglas Road, Glasnevin 
Dublin 11, D11 KXN4 
Ireland  
 
Sponsor Responsible Medical Officer  
 
Peter Branecky, MD  
Telephone Number: 
 
 
+1 630 425 0049 
Email Address: 
 
 
peter.branecky@endotronix.com 
 
Sponsor Responsible Clinical Operational Support Andrea Sauerland 
Telephone Number: 
 
 
+1 630 599 7176/+353 1 571 0252 
Email Address: 
 
 
andrea.sauerland@endotronix.com 
 
Manufacturing 
Manufacturing Name: 
 
 
Endotronix Inc. 
Manufacturing Address: 
 
 
1415 West Diehl Road 
Suite #500W 
Naperville, IL 60563 

 
Study No: ETX-HFS-PA-03 
 
Version: 11.0 (Final) 
Cordella™ PA Sensor System 
 
Date:  08 Nov 2023 
 
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PROTOCOL ADMINISTRATIVE INFORMATION 
Protocol/ CIP Number:  
ETX-HFS-PA-03 
Revision Number: 
11.0 Final  
Protocol/ CIP Date: 
08 November 2023 
IDE Number: 
G190020 
Investigational Product: 
Cordella™ Pulmonary Artery (PA) Sensor System 

 
Study No: ETX-HFS-PA-03 
 
Version: 11.0 (Final) 
Cordella™ PA Sensor System 
 
Date:  08 Nov 2023 
 
Endotronix - Confidential 
 
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AMENDMENT HISTORY 
Date  
Amend
ment 
Number 
Amendment Type  
05 September 2019    2.0 
The following specific revisions made to the protocol 
sections are described below: 
- 
Section 8.1.21: Updated text to clarify that for each 
unscheduled call for a treatment subject an 
unscheduled call for a control subject needs to be 
performed   
- 
Section 10.3: Updated text to reflect the change in 
the primary analysis to negative binomial regression 
of events per unit time as a function of the 
Treatment Arm.    
In addition, TOC was updated to reflect the correct 
sections and page numbers. The headers and footers 
were updated to reflect the current revision number 
and the current version date. These changes are not 
specified individually as they are administrative or 
formatting only. 
15 October 2019 
3.0 
The following specific revisions made to the protocol 
sections are described below: 
- 
Sections 1.3 and 10.5 have been updated to reflect 
the correct Safety Endpoints at 12 month. 
- 
Section 6.3 has been updated to reflect the revised 
study start.  
- 
Section 8.17, 8.3.2, 8.3.3, 8.3.4, 8.3.5, 8.3.6, 8.3.7, 
8.3.8, 8.3.9 has been updated to clarify full and 
abbreviated physical examinations during the trial. 
- 
Section 8.1.9 has been updated to reflect the 
correct schedule of Assessment for NT-pro BNP. 
- 
Sections 8.1.10 and 14.1 have been updated to 
reflect the correct schedule of Assessment for 
Echocardiogram. 
- 
Sections 8.1.8, 8.3.3, 8.3.4, 8.3.5, 8.3.9 and 14.1: 
Updated to reflect the change that subjects in both 
Arms will be instructed to taking PAP measurements 

 
Study No: ETX-HFS-PA-03 
 
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Date:  08 Nov 2023 
 
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in supine position at all study visits. 
- 
Section 14.1 has been updated to reflect the correct 
schedule of Assessment for V2. 
In addition, TOC was updated to reflect the correct 
sections and page numbers. Some minor typos have 
been corrected. The headers and footers were updated 
to reflect the current revision number and the current 
version date. These changes are not specified 
individually as they are administrative or formatting 
only. 
11 February 2020 
4.0 
The following specific revisions made to the protocol 
sections are described below: 
- 
Appendix 14.5 has been updated to reflect a change 
in the mPAP target range  
In addition, TOC was updated to reflect the correct 
sections and page numbers. Some minor typos have 
been corrected. The headers and footers were updated 
to reflect the current revision number and the current 
version date. These changes are not specified 
individually as they are administrative or formatting 
only. 
13 May 2020 
5.0 
The following specific revisions made to the protocol 
sections are described below: 
- 
To align with updated labelling documentation the 
entire document has been updated as follows: 
o Change CHFS to Cordella System 
o Change myCordella Hub to myCordella 
Tablet 
- 
Protocol Synopsis, Section 6.5, 8.3.4 and Appendix 
14.1 have been updated to reflect that Study Visit 4 
will be performed as remote/ virtual Telemonitoring 
visit  
- 
Exclusion Criteria #3 has been updated in Protocol 
Synopsis and Section 7.5 
In addition, TOC was updated to reflect the correct 
sections and page numbers. Some minor typos have 
been corrected. The headers and footers were updated 

 
Study No: ETX-HFS-PA-03 
 
Version: 11.0 (Final) 
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Date:  08 Nov 2023 
 
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Page 6 of 153 
 
to reflect the current revision number and the current 
version date. These changes are not specified 
individually as they are administrative or formatting 
only. 
09 December 2020 
6.0 
The following specific revisions made to the protocol 
sections are described below: 
- 
Protocol Synopsis, Section 6.2, 6.4 and 7.6 have 
been updated to reflect that the number of sites has 
been updated to 90 sites in the United States and 
Europe 
- 
Protocol Sections 4.1 Potential Risks, 9.14 
Anticipated Adverse Events and 15 have been 
updated to align with the updated labeling  
- 
Protocol Section 6.3 to update the completion date 
of the Trial Enrollment 
- 
Sections 8.14 and 14.1 have been updated to reflect 
a change in collection of Health Economic Data 
In addition, TOC was updated to reflect the correct 
sections and page numbers. Some minor typos have 
been corrected. The headers and footers were updated 
to reflect the current revision number and the current 
version date. These changes are not specified 
individually as they are administrative or formatting 
only. 
11 November 2021 
7.0 
The following specific revisions made to the protocol 
sections are described below: 
- 
The trial design is being changed from a 
randomized- controlled trial design to an open-label 
single arm trial design, therefore the following 
sections have been updated accordingly: Protocol/ 
CIP Synopsis, Section 1.3, 5, 6, 7.2, 7.3, 7.6, 10, 
13.12 and 15 
- 
To reflect the change from randomized to an open-
label trial, trial procedures and methods have been 
updated in Protocol/ CIP Synopsis, Section 8.1.1, 
8.1.5,8.1.18, 8.1.20, 8.1.21, 8.3.2 and 8.3.6. 
Methods was updated to include 3 Cohorts. Cohort  
#1 will not be part of the primary endpoint analysis 

 
Study No: ETX-HFS-PA-03 
 
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as these patients have already had follow-up visits 
as patients in the previous Control Arm. To 
harmonize all patients in the study, data for the 
primary endpoints will only be collected for patients 
who receive treatment from onset (i.e., Cohorts #2 
and #3).  
- 
Updating ISO 14155-2011 to the new version 
14155:2020 
- 
Due to the fact that European sites are added to the 
trial the following sections have been updated to 
account for EU specific requirements: 
o Added European Contact Details  
o Adding Clinical Investigational Plan (CIP) 
throughout the document  
o Adding Competent Authority (CA) and 
Independent Ethics Committee (IEC)), 
throughout the document 
o Added section 8.1.4 on informing GPs 
o Updated Adverse Event sections 9.1, 9.1.4, 9.2 
and 9.3  
o Added section 9.3.2 on Regulatory Reporting 
Requirements 
o Added Appendix 14.7 
- 
Intended Use & Indications for Use have been 
revised in Protocol/ CIP Synopsis and section 1.4 
- 
Protocol/ CIP Synopsis, Section 6.2, 6.4 and 7.6 have 
been updated to reflect that the number of sites has 
been updated to 120 sites in the United States and 
Europe 
- 
Exclusion Criteria in Protocol/ CIP Synopsis and 
section 7.5 have been updated: 
o Exclusion Criteria 19- to provide more clarity  
o Added Exclusion Criteria 20 as per required by 
German Competent Authority (BfArM) 
- 
Section 1.2 and 15 have been updated to reflect 
recent updates and publications on Pulmonary 
Artery Pressure (PAP) 

 
Study No: ETX-HFS-PA-03 
 
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Date:  08 Nov 2023 
 
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- 
Section 3.2 and 15 to update on the progress of all 
ongoing clinical trials at Endotronix  
- 
Additional secondary efficacy endpoints have been 
added to Protocol/ CIP Synopsis, section 5.1 and 
10.4 
o Added new Secondary Efficacy Endpoints # 3, # 
4 and # 8 
o Updated Secondary Efficacy Endpoints # 11 
- 
Section 6.3 has been updated to reflect revised 
timelines 
- 
Subject compliance on the Cordella System is very 
satisfactory, therefore we updated sections 6.5, 
8.1.15, 8.1.20 and 8.3.2 to reflect that the Cordella 
System and Training will be provided at V2/ Implant 
Visit  
- 
Addition of an optional Subject Survey with new 
section 8.1.21 and update to section 8.4.4, 8.4.6, 
14.1 and new Appendices 14.7 and 14.8 
- 
Revision to section 8.1.21 and 14.1 with regards to 
subject contact schedule with addition of optional 
Subject and Site Surveys on PAP and new 
Appendices 14.8 and 14.9 
- 
Added section 9.1.3 Device Deficiency (DD) 
Definition for consistency 
- 
Appendix 14.5 Cordella PA Sensor Treatment 
Guidelines were updated to reflect the recent 
addition of the use of SGLT-2 inhibitors for HF 
Management 
- 
Small clarifications have been made to the following 
sections: 
o 6.2 to clarify total subject enrollment per site 
o 7.7.1 Screen Failure criteria was clarified 
o 8.1.9 BUN and Urea Laboratory Test can be 
performed 
o 8.1.16 additional PAP measurements may be 
taken seated/ supine within 24 hours after 
implant 

 
Study No: ETX-HFS-PA-03 
 
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o 8.1.18 PAP Measurements for FUP visits may 
also be taken at home by the subject 
o 8.3.2 follow-up for safety in case an implant 
was not completed  
o Throughout section 8 and 14.1 changed sitting 
to seated for clarification 
- 
In addition, TOC was updated to reflect the correct 
sections and page numbers. Some minor typos have 
been corrected. The headers and footers were 
updated to reflect the current revision number and 
the current version date. These changes are not 
specified individually as they are administrative or 
formatting only. 
08 June 2022 
8.0 
The following specific revisions made to the protocol 
sections are described below: 
- 
The Performance Goal (PG) for the primary and first 
secondary endpoint was revised for this trial and 
therefore the sample size increased to 450 
implanted subjects (Cohort #2 and Cohort #3). In 
the protocol the following sections have been 
updated accordingly: Protocol/ CIP Synopsis, Section 
6.1, 6.2, 6.5, 7.6, 10.3, 10.4 and 10.5. 
- 
Number of Cohort #1 subjects (cross- over from 
former Control Arm) was updated to 85 subjects in 
the following sections: Protocol/ CIP Synopsis, 
Section 6.1 and 6.2.  
- 
Protocol/ CIP Synopsis, section 6 and figure 8 have 
been updated to provide clarification with regards 
to timing of unblinding of Cohort #2 and Cohort #3 
subjects. 
- 
Protocol Sections 4.1 Potential Risks, 8.2 Device 
Explant and 9.14 Anticipated Adverse Events have 
been updated to provide clarification on one specific 
risk.  
- 
Section 6.2 has been updated to further specify 
subject disposition. 
- 
Enrollment will now finish in Q4 2022, section 6.3 
has been updated accordingly. 

 
Study No: ETX-HFS-PA-03 
 
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- 
Inclusion Criteria # 4 in Protocol/ CIP Synopsis and 
section 7.4 has been updated to reflect the inclusion 
of (European Society of Cardiology) ESC Guidelines 
for the EU part of the trial. 
- 
Protocol/ CIP Synopsis , section 7.6, 8.1.1, 8.1.13, 
8.1.15, 8.3.1 and 14.1 have been updated to 
indicate that subject training  on and distribution of 
the commercial Cordella System (myCordella™ 
Tablet & Peripherals) will occur at Screening Visit 
(Visit 1).   
- 
Baseline KCCQ will be performed as soon as the 
subject receives their Cordella System during the 
Screening Visit. Protocol/ CIP Synopsis, sections 6.5, 
7.6, 8.1.13, 8.1.15, 8.3.1, 8.3.2 and 14.1 have been 
updated to reflect this change. The threshold for 
chest circumference for providing a CT-scan for 
review has been reduced from 59 inch/ 1500 mm to 
55 inch /1400 mm, section 8.1.7 has been updated 
accordingly. 
- 
Section 8.3 has been updated to remove 
temperature collection as its not needed for safety 
purposes 
- 
Section 8.3.1 and 14.1 have been updated to add 
which study procedures have to be repeated in case 
a subject will be implanted > 30 days after visit 1 
- 
Further clarification has been made on the safety 
endpoints in section 10.5 
- 
Section 11.7.1.1 has been updated to provide 
further clarity on responsibilities on 
indemnification/ insurance. 
- 
For EU only, section 13.12 has been added to cover 
the end of the trial. 
- 
Small corrections have been made to sections 4.2 
and  14.5 
- 
Appendix 14.7 has been updated to add the 
following: 
o Added Adverse Event Causality Assessment for 
the EU 

 
Study No: ETX-HFS-PA-03 
 
Version: 11.0 (Final) 
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Date:  08 Nov 2023 
 
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o Added Safety Reporting Requirements for the 
EU as per EU (Medical Device Regulations) MDR. 
- 
Appendix 14. 9 Subject Survey was updated with 
small corrections 
In addition, TOC was updated to reflect the correct 
sections and page numbers. Some minor typos have 
been corrected. The headers and footers were updated 
to reflect the current revision number and the current 
version date. These changes are not specified 
individually as they are administrative or formatting 
only. 
01 September 2022 
9.0 
The following specific revisions made to the protocol 
sections are described below: 
- 
Protocol/ CIP Synopsis , section 5.2 and 10.5 have 
been updated to indicate that one (1) additional 
secondary safety endpoint has been added  
- 
The Performance Goal (PG) for the primary and first 
secondary efficacy endpoints was revised for this 
trial. In the protocol the following sections have 
been updated accordingly: Protocol/ CIP Synopsis, 
Section 10.3 and 10.4. 
- 
Primary Endpoint Analysis has been finalized for 
SIRONA 2; therefore Section 3.2 has been updated 
- 
Enrollment will now finish in Q4 2022, section 6.3 
has been updated accordingly. 
- 
Reference 52 and 53 have been added 
- 
Exclusion  # 6 in Protocol/ CIP Synopsis and section 
7.5 has been  changed to support the fact that F 
patients who have repaired congenital heart disease 
conditions would benefit from participating in the 
PROACTIVE-HF trial.  
- 
Sections 8.1.2, 8.1.10, 8.3.1 and 14.1 have been 
updated to change that the Screening 
Echocardiography may also be obtained within 6 
months of Study Visit 1 
- 
The timing of the initial NYHA Classification 
Assessment has been clarified in sections 8.31 and 
14.1. 

 
Study No: ETX-HFS-PA-03 
 
Version: 11.0 (Final) 
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In addition, TOC was updated to reflect the correct 
sections and page numbers. Some minor typos have 
been corrected. The headers and footers were updated 
to reflect the current revision number and the current 
version date. These changes are not specified 
individually as they are administrative or formatting 
only. 
16 December 2022 
10.0 
The following specific revisions made to the protocol 
sections are described below: 
- 
The responsible Medical Officer has been updated 
- 
Increase of FUP time for all subjects to Year 5, 
therefore the following sections have been updated 
accordingly: 
o CIP Synopsis 
o Section 6, 6.3 and 6.5 
o Sections 7.7.2 
o Sections 8.1, 8.1.7, 8.1.8, 8.1.9, 8.1.10, 8.1.12, 
8.1.22  
o Sections 8.3.8  
o Sections 10.4.1 and 10.4.2 
o Section 14.1 and 14.3 
In addition, TOC was updated to reflect the correct 
sections and page numbers. The headers and footers 
were updated to reflect the current revision number 
and the current version date. These changes are not 
specified individually as they are administrative or 
formatting only. 
08 November 2023 
11.0 
The following specific revisions made to the protocol 
sections are described below: 
- 
Change of sponsor/ manufacturing address to 1415 
West Diehl Road, Suite #500W, Naperville, IL 60563 
- 
A clarification has been made to Secondary Efficacy 
Endpoint #3; therefore the following sections have 
been updated accordingly: 
o CIP Synopsis 
o Section 5.1 and 10.4 

 
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In addition, TOC was updated to reflect the correct 
sections and page numbers. The headers and footers 
were updated to reflect the current revision number 
and the current version date. These changes are not 
specified individually as they are administrative or 
formatting only. 

Study No: ETX-HFS-PA-03
Version: 11.0 (Final)
Cordella™PA Sensor System
Date: 08 Nov 2023
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Page 14 of 153
SPONSOR PROTOCOL/ CIP APPROVAL
The study will be carried out in accordance with the highest respect for the individual 
participants in accordance with the requirements of this protocol/ CIP and also in accordance 
with the following:
The ethical principles that have their origin in the Declaration of Helsinki.
International Organization of Standardization (ISO) 14155:2020- Clinical investigation of 
medical devices for human subjects – Good Clinical Practice
All applicable local laws and regulations, including, without limitation, data privacy laws and 
regulations. 
SIGNATURES
Sponsor Signatory:
Signature:
Date:
Name & Title
Peter Branecky, MD, Sr. Medical Director, 
Endotronix Inc.
Name & Title
Andrea Sauerland, VP Clinical Operations 
Endotronix Inc.
Name & Title
Lisbert Avila- Yu, SVP Quality Affairs & 
Regulatory Endotronix Inc.

 
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INVESTIGATOR ACKNOWLEDGEMENT  
By signing this clinical protocol/CIP, I confirm that I have read the protocol/ CIP and agree that 
it contains all the necessary details for performing the study. I agree to conduct the study as 
outlined herein, complying with Good Clinical Practice, and all applicable regulatory 
requirements.  
I will provide copies of protocol/CIP and all pertinent documents to all members of the study 
team responsible to me who assist in the conduct of the study. I will discuss this material with 
them to assure that they are fully informed and trained on the study conduct as well as use of 
the Investigational Device. 
I will use only the informed consent form approved by the sponsor and the Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) or its representative.  
I also understand that this study will not be initiated without approval of the appropriate 
IRB/IEC, Competent Authority (CA) and that all administrative requirements of the governing 
body of the institution will be complied with fully.  
I will obtain written informed consent from all participating subjects as specified in ICH Guideline 
for Good Clinical Practice; Section 4.8 and will fulfill all responsibilities for submitting pertinent 
information to the IRB/IEC. 
I also agree to report all information or data in accordance with the protocol/CIP and, in 
particular, I agree to report without unjustified delay, all Adverse Events (Aes) and Serious 
Adverse Events (SAEs) that could have led to an Unanticipated Adverse Device Effect (UADE) or 
Unanticipated Serious Adverse Device Effect (USADE). 
I further agree that Endotronix and/or designee will have access to any original source 
documents from which electronic case report form (eCRF) information may have been 
generated.  
I also agree to have control over all clinical supplies (including investigational products) provided 
by Endotronix and/or designee and collect, account and handle all clinical specimens in 
accordance with the protocol/CIP. 
I further agree not to originate or use the name of Endotronix and/or Cordella™ Heart Failure 
System and Cordella™ Pulmonary Artery Sensor System, or any of its employees, in any publicity, 
news release or other public announcement, written or oral, whether to the public, press or 
otherwise, relating to this protocol/CIP, to any amendment hereto, or to the performance 
hereunder, without the prior written consent of Endotronix Inc. 
Investigator Acknowledgement Signature  
_____________________________________ 
 
______________ 
Signature 
 
 
 
 
 
 
Date 
 
Name (Print) 

 
Study No: ETX-HFS-PA-03 
 
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PROTOCOL/ CIP SYNOPSIS 
 
Protocol Title 
A Prospective, Multi-Center, Open- Label, Single Arm Clinical Trial Evaluating 
the Safety and Efficacy of the Cordella™ Pulmonary Artery Sensor System in 
New York Heart Association (NYHA) Class III Heart Failure Patients 
(PROACTIVE-HF Trial) 
Protocol Number 
ETX-HFS-PA-03/ IDE Trial 
Device Name 
Cordella™ Pulmonary Artery (PA) Sensor System (CorPASS) 
Device 
Description 
The Cordella PA Sensor System comprises seven (7) subsystems that operate 
together to take daily PA Pressure (PAP) readings at a patient’s home and 
transmit the results to a care provider for evaluation.    
1. Cordella Sensor 
2. Cordella Delivery System 
3. myCordella Patient Reader  
4. Reader Dock 
5. Cordella Calibration Equipment (CalEQ) 
6. myCordella Tablet* 
7. Cordella Data Analysis Platform (CDAP) 
For use in the proposed clinical trial, Endotronix intends to use the system in 
conjunction with Endotronix’s commercial Cordella Heart Failure System 
(Cordella System).  The Cordella System collects, records, and transmits 
physiologic data and communications from the patient at home to clinician(s) 
for assessment, patient communication, and patient-centered heart failure 
(HF) management.   
It contains the following components: 
1. myCordella Patient App 
2. myCordella Patient Management Portal (PMP) 
3. myCordella Tablet*, ** 
4. Up to Three (3) commercially available Medical Devices that 
patients use at home to collect data: weight, blood pressure 
(BP), heart rate (HR) and blood oxygen saturation (SpO2) 
* The myCordella Tablet for the Cordella System and CorPASS systems are one and 
the same.  
** not a medical device in accordance with the 21st Century Cures Act. 

 
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Intended Use & 
Indications for 
Use 
Cordella PA Sensor System  
The Cordella PA Sensor System is intended to measure, record, and 
transmit pulmonary artery pressure (PAP) data from NYHA Class III heart 
failure patients at home to clinicians for assessment and patient-
centered heart failure management, with the goal of reducing heart 
failure hospitalizations.   
Study Objectives 
To demonstrate safety and efficacy of the Cordella PA Sensor System.  
Study Design 
This is a prospective, open- label, single arm, multicenter clinical trial to 
evaluate the safety and effectiveness of the Cordella PA Sensor System in 
NYHA Class III Heart Failure Patients compared to a Performance Goal 
(PG). 
Study Duration  
Study Follow-Up Period: Follow up visits will be scheduled at 1, 3, 6, 12, 
18, and 24 months and year 3, 4 and 5 after the Cordella PA Sensor 
implant, or until study termination. 
Study Population 
Male and female subjects, ≥ 18 years of age with a diagnosis of NYHA 
Class III Heart Failure. 
Methods 
 Screening/ Enrollment into this trial will continue until at least 450 are 
enrolled and successfully implanted with the Cordella PA (consisting of 
subjects from Cohort #2 and Cohort #3 below). These subjects will be the 
basis for the primary study analysis. 
Additionally, up to 85 subjects (cross- over from former Control Arm) will 
continued to be followed in Cohort #1. 
With this amendment to the protocol/CIP, subjects will be categorized 
into three (3) different cohorts: 
1. Cohort #1- Previously enrolled Control Arm subjects  
• 
Subjects in this cohort will be unblinded to their PAP 
measurements and informed about their previous group 
assignment and continue their Follow-up visit schedule  
• 
Additionally, subjects will be asked, throughout the remaining 
Follow-up period, to complete a regular subject survey on their 
experience with PAP Measurements and PAP Values. 

 
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• 
Clinicians will be unblinded to their PAP measurements and start 
managing the patients to target PA pressures per protocol/ CIP 
and according to Guideline Directed Medical Therapy (GDMT) 
• 
Additionally, the clinical site will be asked to contact the subject 
on a regular basis to discuss their PAP values 
• 
Separate subgroup analysis (safety and effectiveness) will be 
performed  
2. Cohort #2- Previously enrolled Treatment Arm subjects 
• 
As of month 12 subjects in this cohort will be able to see their  
own PAP measurements for the remaining duration of the study.   
• 
Clinicians will continue to manage the patients to target PA 
pressures per protocol/CIP and according to GDMT 
• 
All primary and secondary safety and effectiveness analyses will 
be performed 
3. Cohort #3- Newly enrolled subjects 
• 
Subjects will participate in the Screening/ Enrollment Visit 
• 
 Cordella PA Sensor Implant Visit, and Follow-Up Visits. 
• 
Clinicians will manage the patients to target PA pressures per 
protocol/ CIP and according to GDMT 
• 
As of month 12 subjects in this cohort will  be able to see their 
own PAP measurements for the remaining duration of the study. 
• 
All primary and secondary safety and effectiveness analyses will 
be performed 
The Cordella PA Sensor will be implanted in conjunction with a right 
heart catheterization (RHC) procedure. During this visit, the Cordella PA 
Sensor, which is pre-mounted on a catheter Delivery System, will be 
introduced via percutaneous venous access to the pulmonary artery.  
Once deployed, the Sensor PAP will be calibrated using the Delivery 
System’s fluid-filled catheter for independent reference measurements.   
The calibration coefficients for that Sensor/Reader/ Subject will be stored 
in a database, allowing for consistent PAP calculations throughout the 
study duration.    
Also, at the Screening Visit, eligible subjects will be provided with the 
commercially available Endotronix Cordella System to measure BP, HR, 
SpO2 and weight. 

 
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Subjects will be observed until stable and discharged home with 
instructions to take their PAP measurements daily in addition to their    
weight, BP, HR and SpO2, which will all be wirelessly transmitted to a 
secure website for review using the myCordella Patient Management 
Portal (part of Endotronix’s commercially available  Cordella System).   
Visibility to patients’ daily data trends will enable the clinician to 
proactively manage the patients to target PA pressures per protocol and 
according to GDMT. 
The clinician will contact all subjects on a  regular basis to discuss their 
health status and all patients will be treated according to GDMT.   
All Subjects will return for follow up visits at 1, 6, 12, 18, 24 months, as 
well as at Year 3, 4 and 5, after the Cordella PA Sensor implant, or until 
study termination.   The 3 month follow-up visit will be performed as 
remote/ virtual Telemonitoring visit. 
At Month 6, the primary safety and efficacy endpoints will be assessed 
for subjects from Cohort #2 and #3. Additional monitoring of safety and 
efficacy assessments will be performed throughout the study duration, 
including evaluation of subject functional and health status, adverse 
events, Heart Failure (HF) related hospitalizations or equivalent (e.g., 
intravenous (IV) diuretics). 
Sites  
Up to 120 sites in the United States (US) and Europe 
Efficacy 
Endpoints 
Primary Efficacy Endpoint (through 6 months post- implant): 
The primary efficacy endpoint will be the 6 month incidence of HF 
related Hospitalizations (HFH) or all- cause mortality.  
Secondary Efficacy Endpoints: 
1. Incidence of HF Hospitalizations or all-cause mortality at 12 months 
2. Number of HF Hospitalizations at 6 and 12 months post-implant 
compared to the number of HF Hospitalizations in the 6 and 12 
months prior to implant 
3. Comparison of the number of HF Hospitalizations or Emergency 
Department/ Hospital Outpatient IV diuretic visits of Cohort #1 and 
Cohort #2 +#3 at 6 and 12 months post implant  
4. Change of N-terminal pro B-type Natriuretic Peptide (NT-pro BNP) 

 
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from Baseline through 6 and 12 months 
5. Combined outcome of  
a. First and recurrent HF Hospitalizations 
b. Emergency Department/ Hospital Outpatient IV diuretic visits 
c. all-cause mortality  
at 6 months, added together with equal weighting into a total 
number of events. 
6. Heart failure hospitalization or Emergency Department / Hospital 
Outpatient IV diuretic visits at 6 and 12 months 
7. Cardiac and all-cause mortality 
8. Days Alive and Out of Hospital (DAOH) 
9. Intravenous (IV) diuretic visits  
10. Heart failure related Medication changes 
11. Change in PAP: 
a. From Baseline through 6 and 12 months in subjects with a 
baseline mPAP 
i. above target range 
ii. within or below target range 
iii. Overall  
b. Before and after 6-Minute Walk Test 
12. Percentage of device success as documented by ability of the System 
to successfully transmit PAP data  
13. Patient Outcome Measures, measured by KCCQ  
14. Functional status improvement, as measured by NYHA and 6-Minute 
Walk Test 
15. Health Economic Analysis 
Safety Endpoints 
Primary Safety endpoints:  
1. Freedom from device/system related complication at 6 months  
2. Freedom from pressure sensor failure at 6 months 
Secondary safety endpoints:   
1. Pressure sensor failure rate throughout the study  

 
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2. Frequency of serious adverse events throughout the study 
3. Frequency of implant procedure and  procedure related adverse 
events and serious adverse events 
Sample Size 
Statistical 
Rationale 
Primary Efficacy Endpoint (at 6 months post- implant): 
The primary endpoint will be the 6 month incidence of HF related 
Hospitalizations or all-cause mortality, compared to a performance goal 
(PG).  
The statistical PG of 0.43 is derived from published results from clinically 
relevant, contemporary studies of NYHA class III HF subjects.   
For study success, the upper confidence bound of the observed event rate 
for the planned study must be less than the PG6. Additionally, we require 
the observed event rate to be less than 0.37. 
Evaluating the upper bound of the confidence interval for the rate, 
ensures that 1) the observed rate will be comparable to prior studies of 
active treatment (highest observed value = 0.44), 2) the observed rate 
will be less than the mean rate from meta- analysis of prior studies of 
treatment and control, and 3) the observed rate will be less than the 
lowest rate observed in the control studies (GUIDE-HF).  The added 
requirement for the observed rate to be less than 0.37 provides further 
assurance that results are comparable to studies of prior treatment. 
Based on this, the study will implant 450 subjects (single arm cohorts)  
leading to an expected evaluable cohort of 406 subjects. With a PG of 
0.43 and a one-sided 0.025 alpha level, the study will have greater than 
80% power assuming a population treatment rate of 0.34. Calculations 
are based on a one-sample Poisson rate test and were performed with 
PASS 2021. 
Primary Safety Endpoints 
There are two primary safety endpoints. 
Freedom from device or system related complications at 6 months will be 
tested against the null rate of 90%.   Based on a one sample test of a 
proportion, a sample size of 450 patients provides greater than 95% 
power assuming a population rate of 95% based on a two-sided Type I 
error rate of 5%.     
Similarly, Freedom from Pressure Sensor Failure at 6 months will be 
tested against the null rate of 95%.   Based on a one sample test of a 

 
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proportion, a sample size of 450 patients provides greater than 95% 
power assuming a population rate of approximately 98.4% based on a 
two-sided Type I error rate of 5%. 
Inclusion Criteria 
1. Subject has given written informed consent 
2. Male or female, at least 18 years of age 
3. Diagnosis and treatment of HF (regardless of left ventricular ejection 
fraction (LVEF)) for ≥ 3 months and NYHA Class III HF at time of 
Screening  
4. Subjects should be on stable, optimally titrated medical therapy for at 
least 30 days, as recommended according to current American Heart 
Association (AHA)/American College of Cardiology (ACC) guidelines as 
standard-of-care for HF therapy in the United States,  or current 
European Society of Cardiology (ESC ) guidelines for HF treatment  in 
Europe, with any intolerance documented. 
5. HF related hospitalization, HF treatment in a hospital day-care 
setting, or urgent outpatient clinic HF visit for IV diuretics within 12 
month (last hospitalization should be 30 days before Screening 
/Enrollment) and/or N-terminal pro B-type Natriuretic Peptide (NT-
proBNP) at time of Screening/ Enrollment defined as: 
a. Subjects with LVEF ≤ 50%: NT-proBNP ≥ 1500 pg/mL. 
b. Subjects with LVEF > 50%: NT-proBNP ≥ 800 pg/mL . 
Thresholds for NT-proBNP (for both LVEF ≤ 50% and LVEF > 50%) will 
be corrected for body mass index (BMI) using a 4% reduction per BMI 
unit over 25 kg/m2 
6. Subjects should be on diuretic therapy 
7. Subjects who are physically able to hold the myCordella™ Patient 
Reader unit (approximate weight 1.3lb) against the ventral thoracic 
surface for up to 2 minutes per day while in a seated position, as well 
as dock and undock the myCordella™ Patient Reader 
8. Subjects with sufficient eyesight, hearing, and mental capacity to 
respond to the myCordella™ Patient Reader’s audio/visual cues and 
operate the myCordella™ Patient Reader 
9. Subject has sufficient Cellular and/ or Wi- Fi Internet coverage at 
home 
10. Subject agrees to return to the treating Investigator for all scheduled 
follow up visits and can return to the hospital for follow up 
Exclusion Criteria 
1. Intolerance to all neuro-hormonal antagonists (i.e., intolerance to 

 
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angiotensin converting enzyme-inhibitors (ACE-I), angiotensin 
receptor blockers (ARB), angiotensin-neprilysin inhibitors (ARNI), and 
beta-blockers) due to hypotension or renal dysfunction 
2. ACC/AHA Stage D refractory HF (including having received or 
currently receiving pharmacologic circulatory support with inotropes) 
3. Subjects with history of recurrent pulmonary embolism ( ≥2 episodes 
within 5 years prior to Screening Visit) and/or deep vein thrombosis 
(< 3 month prior to Screening Visit) 
4. Subjects who have had a major cardiovascular (CV) event (e.g., 
myocardial infarction, stroke) within 3 months of the Screening Visit 
5. Unrepaired severe valvular disease 
6. Subjects with significant congenital heart disease  that has not been 
repaired and would prevent implantation of the Cordella PA Sensor  
or mechanical/tissue right heart valve(s) 
7. Subjects with known coagulation disorders 
8. Subjects with a hypersensitivity or allergy to platelet aggregation 
inhibitors including aspirin, clopidogrel, prasugrel, and ticagrelor; or 
patients unable to take dual antiplatelet or anticoagulants for one- 
month post implant 
9. Known history of life threatening allergy to contrast dye 
10. Subjects whereby RHC is contraindicated 
11. Subjects with an active infection at the Cordella PA Sensor Implant 
Visit 
12. Subjects with a Glomerular Filtration Rate (GFR) <25 ml/min or who 
are on chronic renal dialysis 
13. Implanted with Cardiac Resynchronization Therapy (CRT)-Pacemaker 
(CRT-P) or CRT-Defibrillator (CRT-D) for less than 90 days prior to 
screening visit 
14. Received or are likely to receive an advanced therapy (e.g., 
mechanical circulatory support or lung or heart transplant) in the 
next 12 months 
15. Subjects who are pregnant or breastfeeding 
16. Subjects who are unwilling or deemed by the Investigator to be 
unwilling to comply with the study protocol, or subjects with a history 
of non-compliance 
17. Severe illness, other than heart disease, which would limit survival to 

 
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<1 year 
18. Subjects whose clinical condition, in the opinion of the Investigator, 
makes them an unsuitable candidate for the study 
19. Subjects enrolled in another investigational trial with an active 
treatment arm 
20. Subject who is in custody by order of an authority or a court of law 

 
 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACC 
American College of Cardiology  
ACE-I 
Angiotensin Converting Enzyme-Inhibitors 
ADE 
Adverse Device Event 
AE 
Adverse Event 
AAHFN  
American Association of Heart Failure Nurses 
AHA 
American Heart Association 
ALT 
Alanine Aminotransferase 
ARB 
Angiotensin Receptor Blockers 
ARNI 
Angiotensin-Neprilysin Inhibitors 
AST 
Aspartate Aminotransferase 
AV 
Atrioventricular Block 
BARC 
Bleeding Academic Research Consortium 
BB 
Beta Blocker 
BMI 
Body Mass Index 
BP 
Blood Pressure  
BUN 
Blood Urea Nitrogen 
CABG 
Coronary Artery Bypass Grafting 
CalEQ 
Cordella™ Calibration Equipment 
CEC 
Clinical Events Committee 
CDAP 
CorPASS Data Analysis Platform 
CFR 
Code of Federal Regulations 
Cordella System 
Cordella™ Heart Failure System 
CI 
Cardiac Index 
CIP 
Clinical Investigational Plan 
CK-MB 
Creatinine Kinase-MB (isoenzymes CKM and CKB) 
cm 
Centimeters 
CO 
Cardiac Output 
CorPASS 
Cordella™ Pulmonary Artery Sensor System 
CPX 
Cardiopulmonary Exercise Testing 
CRO 
Contract Research Organization  
CRP 
C- Reactive Protein 
CRT 
Cardiac Resynchronization Therapy 
CV 
Cardiovascular 
DAOH 
Days Alive and Out of Hospital 
DD 
Device Deficiencies 
dl 
Deciliter 

 
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Abbreviation 
Definition 
DSRC 
Device System Related Complication 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
EDC 
Electronic Data Capture 
ESC 
European Society of Cardiology 
EU 
European Union 
FDA 
Food and Drug Administration 
FIH 
 First in Human 
GCP 
 Good Clinical Practice 
GDMT 
Guideline Directed Medical Therapy  
GFR 
Glomerular Filtration Rate 
HCP 
Health Care Provider 
HF 
Heart Failure 
HFH 
Heart Failure Hospitalizations 
HfpEF 
Heart Failure with preserved Ejection Fraction 
HfrEF 
Heart Failure with reduced Ejection Fraction 
HR 
Heart Rate 
ICD 
Internal Cardiac Defibrillator 
ICF 
Informed Consent Form 
ICH/GCP 
International Committee for Harmonization for Good Clinical Practices 
IEC 
International Electrotechnical Commission 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISO 
International Organization of Standardization 
ITT 
Intent to Treat 
IV 
Intravenous 
KCCQ 
Kansas City Cardiomyopathy Questionnaire  
kg 
Kilogram 
l 
Liter 
ITT 
Intent To Treat  
LBBB 
Left Bundle Branch Block 
LDH 
Lactate Dehydrogenase 
LVEDD 
Left Ventricular End Diastolic Diameter 
LVEF 
Left Ventricular Ejection Fraction 

 
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Abbreviation 
Definition 
m 
Meter 
MDCG 
Medical Device Coordination Group (Europe) 
MDR 
Medical Device Regulations (Europe) 
MEMS 
Microelectromechanical Systems 
mg 
Milligram 
MI 
Myocardial Infraction 
mITT 
modified Intent to Treat 
mL 
Milliliter 
mmol 
Millimole 
MRA 
Mineralocorticoid Receptor Antagonists 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
NP 
Nurse Practitioner 
NT- Pro BNP 
N-terminal pro B-type Natriuretic Peptide 
NYHA 
New York Heart Association 
PA  
Physician Assistant  
PA 
Pulmonary Artery 
dPAP 
Pulmonary Artery Pressure – Diastolic 
mPAP 
Pulmonary Artery Pressure – Mean 
PAP 
Pulmonary Artery Pressure 
PAPGHFM 
PAP Guided Heart Failure Management 
sPAP 
Pulmonary Artery Pressure – Systolic 
PCI 
Percutaneous Coronary Intervention 
PCWP 
Pulmonary Capillary Wedge Pressure 
PG 
Performance Goal 
pH 
Potential of Hydrogen 
PMA 
Pre -Market Approval 
PMP 
myCordella™ Patient Management Portal  
PP 
Per protocol 
PTT 
 Partial Thromboplastin Time 
RAP 
 Right Atrial Pressure 
RBC 
 Red Blood Cell 
RCT 
 Randomized Controlled Trial 
RGA 
 Return Goods Authorization 
RHC 
 Right Heart Catheterization 
RIM 
 Reader Integration Module 
RN 
 Registered Nurse 

 
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Abbreviation 
Definition 
RVP 
 Right Ventricular Pressure  
SADE 
 Serious Adverse Device Effect 
SAE 
 Serious Adverse Event 
SEV 
 Site Evaluation Visit 
SGOT 
 Serum Glutamic Oxaloacetic Transaminase 
SGPT 
 Serum Glutamic Pyruvic Transaminase 
SpO2 
 Blood Oxygen Saturation 
UADE 
 Unanticipated Adverse Device Effect 
URL 
 Upper Range Limit 
USADE 
 Unanticipated Serious Adverse Device Effect 
US 
 United States 

 
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TABLE OF CONTENTS 
ADMINISTRATIVE INFORMATION...................................................................................... 2 
PROTOCOL ADMINISTRATIVE INFORMATION .................................................................... 3 
AMENDMENT HISTORY ..................................................................................................... 4 
SPONSOR PROTOCOL/ CIP APPROVAL ............................................................................. 14 
INVESTIGATOR ACKNOWLEDGEMENT ............................................................................. 15 
PROTOCOL/ CIP SYNOPSIS .............................................................................................. 16 
LIST OF ABBREVIATIONS ................................................................................................. 25 
TABLE OF CONTENTS ...................................................................................................... 29 
1 
Background Information ........................................................................................... 35 
1.1 
Introduction ............................................................................................................................. 35 
1.2 
Pulmonary Artery Pressure (PAP) .............................................................................................. 36 
1.3 
Trial Rationale .......................................................................................................................... 39 
1.4 
Intended Use & Indications for Use ........................................................................................... 41 
2 
Investigational Device: Cordella™ PA Sensor System .....................................................42 
2.1 
Generalized System Operation and Subsystem Description ........................................................ 42 
2.2 
Use of CorPASS with the Commercially Available Endotronix Cordella Heart Failure System 
(Cordella System) Product ................................................................................................................... 47 
2.3 
Control Algorithm ..................................................................................................................... 49 
2.4 
Device Set Up and Maintenance ................................................................................................ 52 
2.5 
Device Accountability ............................................................................................................... 49 
3 
Preclinical and Clinical Studies of the CORDELLA PA SENSOR SYSTEM ..........................51 
3.1 
Pre-clinical Studies of the Cordella™ PA Sensor System .............................................................. 51 
3.2 
Clinical Studies of the Cordella PA Sensor System ...................................................................... 52 
4 
Potential Risks and Benefits .............................................................................................54 
4.1 
Potential Risks .......................................................................................................................... 54 
4.2 
Potential Benefits ..................................................................................................................... 55 
5 
Study Objectives and Endpoints ......................................................................................59 
5.1 
Efficacy Endpoints .................................................................................................................... 59 
5.2 
Safety Endpoints ....................................................................................................................... 60 

 
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6 
Study Design .....................................................................................................................61 
6.1 
Study Flow ............................................................................................................................... 62 
6.2 
Number of Clinical Sites and Subjects ........................................................................................ 64 
6.3 
Subject Participation and Study Duration .................................................................................. 64 
6.4 
Site Selection Criteria ................................................................................................................ 64 
6.5 
Study Visits............................................................................................................................... 65 
7 
Study Population and Enrollment ....................................................................................66 
7.1 
Study Population .............................................................................. Error! Bookmark not defined. 
7.2 
Special Efforts to Ensure Optimal Inclusion of Women and Minorities ........................................ 66 
7.3 
Optimal Heart Failure Medical Management ............................................................................. 67 
7.4 
Inclusion Criteria ...................................................................................................................... 67 
7.5 
Exclusion Criteria ...................................................................................................................... 68 
7.6 
Strategies for Recruitment and Retention ................................................................................. 69 
7.7 
Subject Withdrawal or Termination .......................................................................................... 70 
7.7.1 
Screening Failure and Documentation ........................................................................ 70 
7.7.2 
Reasons for Withdrawal or Termination ..................................................................... 70 
7.8 
Subject Follow- up after trial completion or early termination ................................................... 70 
8 
Study Procedures and Schedules .....................................................................................71 
8.1 
Study Procedures and Evaluations ............................................................................................. 71 
8.1.1 
Study Eligibility Review ................................................................................................ 71 
8.1.2 
Informed Consent Procedure ...................................................................................... 72 
8.1.3 
Point of Contact ........................................................................................................... 72 
8.1.4 
Informing the Subject’s General Practitioner (EU only) .............................................. 72 
8.1.5 
Subject Demographics ................................................................................................. 72 
8.1.6 
Cardiac/Medical and Surgical History ......................................................................... 73 
8.1.7 
Physical Examination and Vital Signs ........................................................................... 73 
8.1.8 
Electrocardiograms (ECG) ............................................................................................ 73 
8.1.9 
Clinical Laboratory Tests .............................................................................................. 74 
8.1.10 
Echocardiogram ........................................................................................................... 75 
8.1.11 
NYHA Functional Classification .................................................................................... 75 
8.1.12 
Six (6) Minute Walk ..................................................................................................... 75 
8.1.13 
Quality of Life Questionnaire....................................................................................... 76 
8.1.14 
Health Economic/ Operational Questionnaire ............................................................ 76 
8.1.15 
Subject Training & Use: Cordella PA Sensor and HF System ....................................... 76 

 
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8.1.16 
Cordella PA Sensor Implant Procedure ....................................................................... 76 
8.1.17 
Right Heart Catheter Procedure .................................................................................. 77 
8.1.18 
Cordella PA Sensor PAP Measurements ...................................................................... 77 
8.1.19 
Cordella PA Sensor and HF System Data Transmission & Compliance ....................... 77 
8.1.20 
myCordella™ Patient Management Portal (PMP) Data Review and Contact ............. 78 
8.1.21 
Subject Contact/ Subject Survey (Cohort #1 only) ...................................................... 79 
8.1.22 
Concomitant Medications ........................................................................................... 79 
8.2 
Device Explant .......................................................................................................................... 80 
8.3 
Schedule of Observations and Procedures ................................................................................. 80 
8.3.1 
Study Visit 1 (Screening/ Enrollment Visit).................................................................. 80 
8.3.2 
Study Visit 2 (Cordella PA Sensor Implant Visit: Admission & Implant) ...................... 82 
8.3.3 
Study Visit 3 (Month 1, ±7 days) .................................................................................. 82 
8.3.4 
Study Visit 4 (Month 3, ±7 days) .................................................................................. 83 
8.3.5 
Study Visit 5 (Month 6, ±14 days) ................................................................................ 83 
8.3.6 
Study Visit 6 (Month 12 ±30 days) ............................................................................... 83 
8.3.7 
Study Visit 7 to 8 (Month 18, 24, ±30 days) ................................................................ 84 
8.3.8 
Study Visits 9 to 11 (Years 3, 4, 5 ±30 days) ................................................................ 84 
8.3.9 
Early Termination Visit ................................................................................................ 85 
9 
Adverse Events .................................................................................................................86 
9.1 
Definition and Documentation of Adverse Events ...................................................................... 87 
9.1.1 
Adverse Events (AE) ..................................................................................................... 87 
9.1.2 
Serious Adverse Event (SAE): ....................................................................................... 87 
9.1.3 
Device or Procedure-Related Adverse Events ............................................................. 87 
9.1.4 
Anticipated/ Expected Adverse Events: ...................................................................... 88 
9.2 
Assessment of Causality ............................................................................................................ 90 
9.2.1 
Not related ................................................................................................................... 90 
9.2.2 
Unlikely related ............................................................................................................ 90 
9.2.3 
Possibly related ............................................................................................................ 90 
9.2.4 
Probably related .......................................................................................................... 90 
9.2.5 
Related ......................................................................................................................... 90 
9.3 
Adverse Event Reporting Requirements .................................................................................... 90 
9.3.1 
Investigator Reporting Requirements ......................................................................... 90 
9.3.2 
Regulatory Reporting Requirements ........................................................................... 91 
9.3.3 
Contacting Endotronix Regarding Safety ..................................................................... 92 
9.4 
Device/System-Related Complication (DSRC) ............................................................................ 92 
9.5 
Study Implant Card ................................................................................................................... 92 
10 Statistical Considerations .................................................................................................94 

 
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10.1 
General Statistical Considerations .......................................................................................... 94 
10.2 
Analysis Population ............................................................................................................... 94 
10.2.1 
Enrolled Set .................................................................................................................. 94 
10.2.2 
Intent-to- Treat Population (ITT) ................................................................................. 94 
10.2.3 
Modified Intent-to-Treat Population (mITT) ............................................................... 95 
10.2.4 
Per Protocol Population (PP) ....................................................................................... 95 
10.2.5 
Cohort #1- Previously enrolled Control Arm subjects- Population ............................. 95 
10.3 
Primary Efficacy Endpoint and Hypotheses ............................................................................ 95 
10.4 
Additional Secondary Efficacy Endpoints ................................................................................ 98 
10.5 
Safety Endpoints ................................................................................................................. 101 
10.6 
Analysis sites ....................................................................................................................... 102 
10.7 
Adverse Events and Other Safety Analyses ........................................................................... 103 
10.8 
Study Retention and Handling of Missing and Incomplete Data ............................................ 103 
11 Ethical Aspects ................................................................................................................104 
11.1 
Ethical Considerations ......................................................................................................... 104 
11.2 
Subject Information and Consent ......................................................................................... 104 
11.3 
Institutional Review Board (IRB)/Independent Ethic Committee (IEC) ................................... 105 
11.3.1 
Investigator Reports .................................................................................................. 106 
11.4 
Annual Report ..................................................................................................................... 107 
11.5 
Insurance ............................................................................................................................ 107 
11.6 
Regulatory Affairs ............................................................................................................... 107 
11.7 
Investigators and Trial Administrative Structure ................................................................... 107 
11.7.1 
Investigator ................................................................................................................ 107 
11.7.2 
Endotronix (Sponsor) ................................................................................................. 109 
11.7.3 
Contract Research Organization ................................................................................ 109 
11.7.4 
Endotronix (Device Support) ..................................................................................... 109 
12 Documentation of Trial Data ..........................................................................................110 
12.1 
Case Report Forms .............................................................................................................. 110 
12.2 
Data Management .............................................................................................................. 110 
12.2.1 
Data Management ..................................................................................................... 110 
12.2.2 
eCRFs.......................................................................................................................... 110 
12.2.3 
Coding ........................................................................................................................ 110 
12.2.4 
Source data ................................................................................................................ 111 

 
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12.3 
Data Review ........................................................................................................................ 111 
12.4 
Data Quality Assurance ....................................................................................................... 112 
12.5 
Database lock ...................................................................................................................... 112 
13 ADMINISTRATIVE REQUIREMENTS ................................................................................113 
13.1 
Monitoring of the Study ...................................................................................................... 113 
13.2 
Independent Data Review and Event Adjudication ............................................................... 113 
13.2.1 
DSMB and CEC Composition ...................................................................................... 113 
13.2.2 
DSMB ......................................................................................................................... 113 
13.2.3 
CEC ............................................................................................................................. 114 
13.3 
Quality System, Audit and Inspection .................................................................................. 114 
13.3.1 
Quality system ........................................................................................................... 114 
13.3.2 
Audit .......................................................................................................................... 114 
13.3.3 
Inspection .................................................................................................................. 115 
13.4 
Maintenance of Study Documentation ................................................................................. 115 
13.5 
Subject Data Protection ....................................................................................................... 115 
13.6 
Protocol/ CIP Modifications ................................................................................................. 116 
13.7 
Compliance/ Investigational Site Termination ...................................................................... 116 
13.7.1 
Compliance ................................................................................................................ 116 
13.7.2 
Investigational Site Termination ................................................................................ 117 
13.8 
Record Retention ................................................................................................................ 117 
13.9 
Site Training ........................................................................................................................ 117 
13.10 
Confidentiality of trial results .............................................................................................. 117 
13.11 
Publication policy ................................................................................................................ 118 
13.12 
End of Investigation /Premature Termination /Suspension ................................................... 118 
13.13 
Final report ......................................................................................................................... 118 
13.14 
Organization/ Site personnel ............................................................................................... 118 
14 Appendices ......................................................................................................................119 
14.1 
Time and Event Schedule ..................................................................................................... 119 
14.2 
New York Heart Association (NYHA) Functional Classification ............................................... 121 
14.3 
Procedure for 6 Minute Walk Test ....................................................................................... 122 
14.4 
Kansas City Cardiomyopathy Questionnaire ......................................................................... 124 
14.5 
Guidelines for managing HF using Pulmonary Artery Pressures ............................................. 126 

 
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14.6 
Adverse Event Definitions.................................................................................................... 128 
14.7 
Definition,  Documentation and Reporting of Adverse Events specific for EU sites ................. 137 
14.7.1 
Definitions .................................................................................................................. 137 
14.7.2 
Causality Assessment ................................................................................................ 138 
14.7.3 
Safety Reporting ........................................................................................................ 139 
14.8 
PROACTIVE-HF Site Survey (V1.0/ 09 Nov 2021) ................................................................... 144 
14.9 
PROACTIVE-HF Subject Survey (V2.0/ 11 Feb 2022) .............................................................. 146 
15 References ......................................................................................................................148 

 
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1 
BACKGROUND INFORMATION 
1.1 
Introduction  
Heart failure (HF) is a major public health problem that affects over 23 million people worldwide with 
approximately 2 million new cases diagnosed each year.1 HF is a complex clinical syndrome in which 
the ventricle’s ability to fill or eject blood is impaired, affecting delivery of oxygen- and nutrient-rich 
blood throughout the body.2 The body’s compensation mechanisms in the presence of HF include 
enlargement of the heart, a faster heart rate (HR), narrowing of blood vessels to maintain blood 
pressure (BP), and diversion of blood away from other vital tissues and organs. While these 
compensation mechanisms may decrease HF symptoms, their effects are only temporary and 
eventually, the heart fails to keep up with the body’s demands. Heart failure is chronic, worsens over 
time, and is characterized by acute exacerbations.1 These periodic exacerbations require treatment 
intensification most often in the hospital setting and are the single most frequent cause of 
hospitalization in persons aged ≥65 years.1 
After the diagnosis of HF, survival estimates are 50% and 10% at 5 and 10 years, respectively,3-5 and 
left ventricular dysfunction is associated with an increase in the risk of sudden death.6 There is no 
cure for HF, but treatment plan options consist of lifestyle changes, medications, implantable cardiac 
devices, and surgical procedures including heart transplants. Treatment goals for HF include 
targeting the underlying cause of the condition, reducing clinical symptoms and improving the 
patient’s quality of life, and preserving heart function. 
HF is associated with significant mortality, morbidity, and healthcare expenditures affecting patients, 
their families, care providers, and payers. The incidence of HF is on the rise and healthcare systems 
are grappling with the persistent burden of HF. Nearly 1 million hospitalizations for HF occur each 
year,1 and readmission rates are frequent.  
In 2012, total cost for HF was estimated to be $30.7 billion. Of this total, 68% was attributable to 
direct medical costs.9 Projections show that by 2030, the total cost of HF will increase almost 127% 
to $69.7 billion from 2012. This equals ≈$244 for every US adult.10 
Entire economic systems are impacted due to the aging global population, high cost of care, and 
limitations of existing solutions for HF 8. 
 
 

 
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1.2 
Pulmonary Artery Pressure (PAP) 
Given the many challenges of HF, traditional HF management must be reevaluated to include 
continuous physiologic monitoring, proactive clinical decisions prior to development of symptoms, 
reduced hospital readmission rates, and improved quality of life. Hemodynamics, and PAP, have 
been shown to be critical measurements in determining early signs of worsening HF.11 The precursor 
to clinically apparent congestion is an observed increase in PAP.  In patients with HF, as the blood 
pressure inside the heart and lungs increases, Cardiac Output (CO) decreases. The decrease in CO 
results in less oxygenated blood being pumped throughout the body which induces compensatory 
mechanisms in the body. Long-term hypo perfusion ultimately creates damage to vital organs and 
further exacerbates the deterioration of heart function. Eventually, the high levels of heart and lung 
pressures result in a buildup of fluid in the heart or the lungs (hemodynamic and/or pulmonary 
congestion) as well as peripheral edema. The majority of HF patients are hospitalized with signs and 
symptoms of fluid overload and congestion. 
Elevations in PAP as well as other hemodynamic measurements, which serve as surrogate indicators 
of PAP, are identified in the literature as associated with worse outcomes in HF patients and as 
predictors of adverse event outcomes (i.e., heart failure hospitalizations (HFH) and death). For 
example, pulmonary artery capacitance was found to be a strong independent predictor of 
mortality,12 pulmonary artery diastolic pressure, independent of other covariates, was a significant 
predictor of mortality in chronic HF patients,13 and a higher systolic PAP was independently 
associated with clinical status and outcomes of HF patients.14 
Secondary pulmonary hypertension is common among HF patients. Studies have reported  secondary 
pulmonary hypertension as an independent predictor of worse outcomes. A strong association 
between secondary pulmonary hypertension and an increased risk of mortality was found in several 
studies.14-19 In addition, HF patients with severe secondary pulmonary hypertension were at an 
increased risk of recurrent HFHs.15 
Direct PAP has been conventionally obtained via a RHC procedure in which a catheter inserted 
through a vein in the patient’s neck or groin is advanced to the pulmonary artery under fluoroscopic 
guidance. The complications associated with this invasive procedure limit its use as a long-term 
monitoring tool in HF patients. In addition, there are discomforts to the patient associated with this 
procedure, and possible risks of a RHC include bruising and excessive bleeding at the catheter 
insertion site, blood clots, damage to the vein, and cardiac arrhythmias or embolisms.  
Parallel to studies presenting the association between PAP and clinical outcomes, the evidence 
supporting the approach to patient treatment based on monitoring changes in PAP is also growing. 
Hemodynamic monitoring of HF patients utilizes PAP data obtained from implantable sensors. 

 
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The first PAP sensor, the CardioMEMS™ HF System, received CE Mark in 2010 followed by Premarket 
Approval by the U.S. Food and Drug Administration (FDA) in 2014. This system is an ambulatory PAP 
monitoring system in which a small PA sensor is permanently implanted in the pulmonary artery via 
a RHC procedure and provides PAP data on demand. This system allows for routine PAP monitoring 
and provides an alternative to repeated RHC procedures to monitor PAP.  
With this recent technology, daily measurement of PAP is the key metric for managing patients with 
HF. PAP monitoring is a recommended HF management tool added to the European Society of 
Cardiology (ESC) guidelines since 2016. Additionally, just recently, the elevated importance and 
recommendation of PAP guided HF management was incorporated into the 2021 Update to the ACC 
Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 
Pivotal Issues About Heart Failure with Reduced Ejection48.  
Longitudinal monitoring of PAP can allow for early detection of volume changes before the onset of 
fluid overload leads to deterioration of health status and decompensation. PAP awareness will allow 
for early detection of and rapid, proactive medical intervention to prevent worsening HF, ultimately 
leading to better patient outcomes. Long term results from the CardioMEMS™ CHAMPION-HF study 
demonstrated a 37% reduction in HF hospitalizations,19 and a 58% reduction in all-cause 30-day 
readmissions. In addition, the treatment group in this trial had a lower risk of death.20   These results 
were confirmed in real-world post market settings. Desai reported that the cumulative incidence of 
HFH was significantly lower in the period following device implantation (hazard ratio [HR]: 0.55; 95% 
confidence interval [CI]: 0.49 to 0.61; p < 0.001).21  Furthermore, PAP guided therapy has been shown 
to significantly improve outcomes in HF patients with comorbidities compared to the control group.22  
In a recent presentation, there was demonstrated a 30% reduction of mortality for the CardioMEMS 
treatment group compared to a control group.23 Lastly, results presented from a Post Approval Study 
with ambulatory HF patients showed at 1-year post-implant that HFH was reduced by 58%, compared 
to 1-year pre-implant and HFH/death was decreased by 44% at 1-year post-implant, compared to 1-
year pre-implant.42 These results are independent on geography as the results of the European post-
market study (MEMS-HF) 46 also showed similar reduction of HFH rates. 
The most contemporary randomized CardioMEMS study published, the GUIDE-HF study,51 evaluated 
PAP guided HF management in NYHA class patients II-IV and included patients that had elevated NT-
Pro-BNP/BNP and/or a recent HFH. Unfortunately, the study results were impacted by the COVID-19 
pandemic (28.3% of follow up conducted during the pandemic). Consequently, the overall study 
endpoint (12 months HFH/mortality) was not met but the prespecified pre-COVID analysis showed a 
significant reduction (28%) in the treatment arm compared to the control arm for the combined 
endpoint of HFH/mortality. Importantly, NYHA class II and II combined, showed a significant 
reduction of 17% in HFH (0.525 tx vs. 0.633 ctl, p=0.050) in the overall analysis. 

 
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Abundant evidence correlates long-term elevations in PAP with worse clinical outcomes related to 
HF.  Still more recent evidence demonstrates the immense value daily home PAP readings add to 
chronic HF management.  The field will require increasingly advanced diagnostic systems to safely, 
reliably, and efficiently deliver PAP data to clinical managers of HF, laying the foundation for a new 
era in the treatment of this ubiquitous and deadly pathology. 
The CorPASS is a second-generation PAP monitoring device and, as a part of the Cordella™ Heart 
Failure System, will allow for a well-rounded and proactive approach to improve HF patient 
management for the 21st century.  
 
 

 
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1.3 
Trial Rationale 
A PAP sensor is a diagnostic medical device with the sole purpose of providing real-time accurate 
pulmonary artery pressure (PAP) values when activated. A PAP sensor does not provide a direct 
therapeutic effect (as therapeutic medical devices do); however, the information it does provide, 
namely near real-time PAP, has important clinical implications. It is well established that increased 
PAP is a predictor for worse clinical outcomes in HF patients; thus, ongoing monitoring and 
consequently managing abnormal PAP is an important goal in guideline-directed medical therapy 
(GDMT). Increasing PAP is an early “warning sign” before any other clinical symptoms become 
apparent and if left untreated will likely lead to HF decompensation and rehospitalization. 
Rehospitalization in HF patients is a well-known clinical concern, and a large body of literature has 
described the HFH readmission rates and associated negative patient impact.   
Current landscape of Pulmonary Artery Pressure Guided HF management: Consistent, robust 
evidence of safety and effectiveness supports adoption in clinical practice  
Since PROACTIVE-HF IDE study (NCT04089059) submission and approval, evidence-based data 
supporting effectiveness of Pulmonary Artery Pressure (PAP) guided HF management has grown 
significantly and continues to build.  To-date, more than 20,000 CardioMEMS devices have been 
implanted demonstrating an excellent safety profile for PA sensors and improving outcomes for 
patients.19,21,24,44-47 The CardioMEMS post-approval studies, PAS44 (N=1200) and MEMS-HF46 
(N=234), both published in 2020, further confirmed that PAP guided HF management was associated 
with low adverse events, lower PA pressures, and reduced rates of heart failure hospitalization (HFH) 
& all-cause hospitalization in HF patients with NYHA class III.   To date, all published CardioMEMS 
studies (with more than 4,000 study subjects), have consistently demonstrated a clinically 
meaningful benefit for patients treated with PAP guided HF management. Of note, the observed 
clinical benefit following PA sensor implantation was sustained in more recent contemporary 
CardioMEMS studies,44,46,47despite leveraging newer HF drugs such as Angiotensin Receptor-
Neprilysin Inhibitors (ARNi). 
The publication of these study results has materially impacted clinical practice, as physicians have 
become significantly more convinced of the clinical benefits of PAP guided HF management over the 
last few years.  The effect of the increasing physician acceptance of PAP guided HF management can 
be seen by the removal of negative coverage policies of Medicare Administrative Contractors Novitas 
and First Coast in July 2020 50 resulting now in nation-wide Medicare reimbursement for PA sensor 
technology.  
Further, the elevated importance and recommendation of PAP guided HF management was 
incorporated into the 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for 
Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure with 
Reduced Ejection. 48  It was pointed out that in “well-selected patients with recurrent congestion, 

 
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this highly specialized monitoring strategy may guide therapeutic decision making” and ambulatory 
pulmonary artery pressure monitoring was incorporated in one of the guiding HF management 
principles: “diligent measurement of volume status will reduce patient symptoms”. 
The increasing acceptance of the clinical benefit of PAP guided HF management following the 
growing scientific evidence and acceptance by a variety of stakeholders has impacted enrollment in 
PROACTIVE-HF more than anticipated during the design of the study in late 2018.  A randomized 
study design may still be possible from an academic standpoint, but in practice is growing exceedingly 
difficult and practically impossible. With increasing acceptance and utilization of PAP guided HF 
management, several clinicians have declined the study or refer some patients to commercial use of 
CardioMEMS, as they are hesitant to refer a patient to PROACTIVE-HF enrollment that may delay 
utilization of PAP guided HF management in the control arm when there is an approved PAP guided 
HF management (CardioMEMS) available to benefit the patient immediately outside of the study.  
This impact to enrollment has been further exacerbated by the COVID-19 pandemic, as clinicians and 
patients have been hesitant to accept the elevated risks of exposure to COVID-19 for a procedure 
that may not lead to benefit to a patient in the control arm for 12 months (at the time of cross-over 
to active treatment).  A number of potential eligible study patients decided not to participate in 
PROACTIVE-HF as they were not willing to wait potentially for one year for therapy if the alternative 
commercial device is readily available. This issue may also lead to selection bias, as physicians may 
offer the study only to patients who they think can “wait” for PAP guided HF management, and 
therefore they are willing to randomize. 
Taking the above-described recent advancements of PAP guided HF management into account and 
the subsequent negative impact on trial enrollment, an Open- Label Single Arm study design, will 
eliminate these concerns and allows all study subject prompt access to PAPGHFM treatment. A single 
arm study is well suited to show comparable effectiveness performance to the commercially 
available device and thus, will provide reasonable assurance that the device is effective for use in the 
intended population.  
Single arm PROACTIVE -HF rationale  
As for any (diagnostic) medical device, safety and effectiveness must be proven to attain PMA 
approval. In evaluating the potential for a single-arm study, Endotronix evaluated whether there was 
adequate data in the published literature for a sufficiently similar device and study population to 
support establishment of an appropriate performance goal.  With respect to device similarity, both 
the CardioMEMS PA sensor and Cordella PA sensor are very similar in their diagnostic device 
properties. Both devices have the same mechanism of action, namely MEMS technology measuring 
pulmonary artery pressure, and both devices display PA pressure trends to the clinicians in a patient 
management portal.  Both devices are implanted in the pulmonary artery during a right heart 
catheterization. Both devices target the same NYHA class III patient population to be treated.  For 

 
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both devices, improved clinical outcomes (clinical effectiveness) relies heavily on the appropriate 
clinician’s interpretation and consequently pharmacological treatment based on the displayed PA 
pressure values. Thus, the clinical outcomes reported from CardioMEMS studies are well suited to 
be used as a comparison group to establish a Performance Goal (PG) for the evaluation of the 
Cordella PA sensor effectiveness.  
The safety profile of CardioMEMS and Cordella PA sensor 49 have been both excellent to date and 
there has not been any concern (with device or system related complications (DSRC) less than 
2%)19,24,44-47,49. Nonetheless, safety will be evaluated in the single arm study as a primary endpoint.   
1.4 
Intended Use & Indications for Use  
The Cordella PA Sensor System is intended to measure, record, and transmit pulmonary artery 
pressure data from NYHA Class III heart failure patients at home to clinicians for assessment and 
patient-centered heart failure management, with the goal of reducing heart failure hospitalizations.   

 
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2 
INVESTIGATIONAL DEVICE: CORDELLA™ PA SENSOR SYSTEM 
2.1 
Generalized System Operation and Subsystem Description 
The system consists of the following components:  
• 
Cordella PA Sensor  
• 
Cordella Delivery System  
• 
myCordella Patient Reader and Dock  
• 
Cordella Calibration Equipment (CalEQ)  
• 
myCordella Tablet* (running the myCordella Patient App) 
• 
Cordella Data Analysis Platform (CDAP)  
The Cordella PA Sensor System, schematized in Figure 1 and described in the paragraphs that 
follow, comprises eight subsystems that operate together to take daily PA Pressure (PAP) readings 
at a patient’s home and transmit the results to a care provider for evaluation.   
 
Figure 1:  Functional Block Diagram of the CorPASS  

 
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The heart of the CorPASS is an active implantable medical device, the Cordella PA Sensor, a 
permanent implant that resides inside a branch of the patient’s pulmonary artery.  The wireless 
Sensor, illustrated in Figure 2, has a glass body approximately 20 x 4 x 2 mm in size.  Nitinol anchors 
extend from either end to hold the Sensor body in place against a wall of the PA, such that the 
sensitive surface of the Sensor body faces away from the vessel wall and into the bloodstream.  The 
Sensor resonates electrically, changing its resonance frequency in proportion to the PAP.  The Sensor 
is shipped sterile to a hospital pre-attached to the distal end of the Cordella Delivery System, a 
custom catheter depicted in Figure 3.  Attachment wires in the Catheter hold the Sensor’s nitinol 
anchors flat during vascular ingress.  A physician uses the Delivery Catheter to place the Sensor in a 
pre-defined location in the PA, via percutaneous venous access.  Once placed, the physician uses the 
Delivery Catheter handle to retract the attachment wires and release the Sensor.  At this point, the 
Sensor’s nitinol anchors unfold and hold the device in place for the lifetime of the patient.  The 
Delivery System is removed and discarded.   The minimally invasive implant procedure is designed to 
resemble existing Right Heart Catheterization (RHC) procedures, and to be safe, simple, and brief.  
 
Figure 2:  Cordella PA Sensor 
  
 
Figure 3:  Cordella Delivery System 
 

 
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The myCordella Reader (Figure 4) is a handheld wireless device used for obtaining Sensor readings. 
Each day at home the patient acquires a PAP reading by holding their myCordella Reader against 
their chest. During the reading, the Reader powers the Sensor wirelessly and obtains the pressure 
reading by measuring the frequency transduced from the pressure on the Sensor.  The Reader 
transmits data to the myCordella Tablet (part of Cordella System), where the RIM* service 
transmits the data to the Cordella Data Analysis Platform (CDAP), a web-based application that 
stores configuration and calibration data, processes raw data from the daily readings, and makes 
the final PA pressure data available to clinicians through the Cordella Patient Management Portal 
(PMP) (part of Cordella System). The myCordella Dock connects to a wall plug and recharges the 
Reader’s battery. The entire home reading sequence is designed for patient convenience and is 
generally completed in less than one minute.  The Reader remains docked at all other times, when 
the patIent is not actively taking a reading. 
 
 
Figure 4:  Cordella Reader and Docking Station 
CDAP is a secure, cloud-based standalone app that collects and stores raw Reader data and 
processes it according to pre-defined algorithms to convert it into final-form PAP data. CDAP 
collects and stores data from the Reader’s daily readings, Endotronix manufacturing (Sensor and 
Reader characterization data) and calibration equipment (CalEQ) (in-situ calibration coefficients 
measured at the time of implant, Reader serial number, Sensor serial number, and patient ID#). All 
data is fed into CDAP’s processing engine to convert the Reader’s raw data into final-form PAP data 
(systolic, diastolic, mean pressures and a waveform). CDAP sends the PAP data to the responsible 
care providers.  
 
The Calibration Equipment (CalEq) supports the implantation procedure. CalEq facilitates the 
tracing of CorPASS component serial numbers to patient ID numbers, the calibration of the 
CorPASS to a reference pressure at the time of implantation, and the real time monitoring of PA 
Pressure. 

 
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The RIM* is a service within myCordella Patient App and has no user interface.   The RIM service only 
transports the data.  The myCordella Patient App is designed to operate on a commercially available 
tablet device running the Android operating system and connects to the internet via a cellular 
network and/or Wi-Fi. 
The RIM service carries out the following functions:  
• 
‘Listens’ for Bluetooth messages from the Reader, indicating new raw data is ready for upload 
• 
When requested by the Reader, receives the new raw data via Bluetooth  
• 
Stores the raw data in local Tablet memory as a backup  
• 
Uploads the new data to the Cordella Data Analysis Platform (CDAP), a secure, cloud-based 
standalone app that collects and stores raw Reader data, and processes it according to 
predefined algorithms to convert it into final-form PAP data  
• 
Obtains an updated local date and time from the web server  
• 
Transmits date and time to Reader, allowing it to update its internal Real Time Clock  
* not a medical device  
Figure 5 provides a functional illustration of the CDAP software.  The blocks in this diagram represent 
CDAP functions, not necessarily architectural elements, data structures, or software modules.  The 
arrows represent data flow between the functions.  CDAP functionality can be partitioned into two 
major functional groups:  a database, and a data processing computational engine.  The database 
functions collect and store data from Readers.  The processing function converts raw Reader data 
into final PAP data.  Within each group, a number of interrelated subordinate functions exist.   

 
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Figure 5:  Functional block diagram of the Cordella Data Analysis Platform (CDAP)  
Four (4) internet portals, shown in green at bottom, transfer data into and out of the CDAP:  
1. The RIM portal (within CDAP) connects to all myCordella Patient Apps in the field, generally 
located in patients’ homes.  It receives raw data from daily readings.  The database stores the 
raw data and transfers it to the algorithm for processing without performing an action on the 
data 
2. The Factory portal connects to Endotronix’s manufacturing facility, where authorized users (or 
automated test equipment) upload calibration data unique to each Reader and Implant.  The 
CDAP database stores this data, which will be used in the processing algorithm to convert the 
raw data to calibrated PAP data.  CDAP also downloads factory calibration data to the appropriate 
CalEq device for local processing  
3. The CalEq portal communicates with all Calibration Equipment hardware in the field – generally 
located at implanting hospitals or care providers’ clinics.  CalEq uploads two types of data to the 
CDAP: readings taken at hospitals/clinics and final in-situ calibration coefficients measured at the 
time of implant.  CalEq uploads the calibration coefficients it receives from its in-situ Cordella 
and reference readings.  CalEq uploads the association between Reader serial number, Sensor 
serial number, and patient ID#, recorded at the time of implant, for storage.  This association 
ensures that the correct factory and hospital coefficients are applied to the processing of each 
home reading 
4. The Clinic Portal interfaces with the entity receiving the final processed output of each PAP 
reading – usually an app used by the patient’s care provider (i.e., Cordella System Patient 

 
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Management Portal).   Each reading contains an 18 second PAP waveform, as well as the systolic, 
diastolic, and mean values for that waveform.  The Clinic portal connects to on-line apps 
accessible by staff at the clinics of care providers.  These apps are clinical information systems 
which store and display the data, as well as allow for simple searches of past data.  The Clinic 
portal’s other function involves upload of patient / clinic / hospital association to a CDAP 
database. 
The CDAP processing engine comprises five general steps:  
1. Filtering raw data to reduce noise and outliers 
2. Converting the raw frequency data to pressure data 
3. Applying the factory and in-situ generated calibration coefficients 
4. Subtracting the local ambient pressure (measured by an on-board sensor in the Reader at time 
of reading and uploaded via RIM) 
5. Determine systolic, diastolic, and mean pressures for the reading 
Not shown in Figure 6 are various functions supporting cybersecurity, patient privacy, diagnostics, 
and ‘sanity checks’ on incoming data.  Additionally, CDAP may send notifications to the Clinical 
portal regarding missing readings, failed reader self-tests, end-of-life for reader, etc.  CDAP may 
also record diagnostic Reader data for statistical analysis by Endotronix, to evaluate system 
performance.   
The CorPASS and each of its subsystems only support diagnostic functions.  Their purpose is to 
provide clinicians with accurate PAP data from patients’ daily home readings.  They do not 
recommend therapy or any other clinical action, nor do they draw conclusions from the data.  
2.2 
Use of CorPASS with the Commercially Available Endotronix Cordella Heart Failure System 
(Cordella System) Product   
The CorPASS is a standalone system.  For use in the proposed clinical trial, Endotronix intends to 
make it available to cardiologists in conjunction with Endotronix’s Cordella System.  The Cordella 
System collects, records, and transmits physiologic data and communications from the patient at 
home to clinician(s) for assessment, patient communication, and patient-centered heart failure 
management.  The system consists of the following components: 
• 
The myCordella™ Patient Management Platform (PMP) A clinic-facing, web-based 
database and communication portal, serving as an electronic patient record system for use 
by a clinician.  The streamlined PMP enables clinicians to: 
o review the data generated from each patient’s home use of the Cordella System 
Medical Devices 

 
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o record notes and actions taken during the care of the patient 
o communicate with the patient and other clinicians regarding the patient’s health 
status 
o access externally developed documentation (published referenced guides, etc.) 
• 
The myCordella™ Tablet is a commercial, off-the-shelf mobile platform on which the 
myCordella Patient App resides. The Patient App (see below) uses general platform 
functions, such as Bluetooth connectivity, internet connectivity, a touchscreen, audio 
output, and an operating system.  This is a tablet device running the Android operating 
system.  The tablet hardware and software (operating system and standard drivers) are 
intended by their manufacturer for general purposes, and not specifically intended to be 
used for a medical purpose. 
• 
myCordella Patient App:  A standalone application that resides on the Tablet. This patient-
facing app: 
o Reminds the patient at home, daily, to operate the Cordella System Medical 
Devices (see below) 
o Daily asks the patient several simple health-related questions using the Tablet’s 
touchscreen 
o Receives wireless (Bluetooth) output data from the Medical Devices 
o Securely transmits the Medical Devices’ generated data, and the patient’s 
responses to the health-related questions, to the myCordella Patient 
Management Portal 
o Allows the patient to review his/her past data from the Medical Devices, as well 
as past question responses 
o Allows the patient to communicate with health care providers, for example by 
email, text, phone, or videophone 
• 
Three (3) Original Equipment Manufacturer (OEM) Medical Devices:  Commercially 
available medical devices that patients use at home to collect data (weight, BP, HR and 
SpO2). Each Medical Device is a standalone, approved device.  Each retains its OEM labeling, 
packaging, and function. The Patient App prompts the patient to use each Device according 
to the Device’s original Instruction for Use (IFU).  After use, each Device uploads its output 
data to the myCordella Patient App via Bluetooth.   
The CorPASS i’ designed to operate with the Cordella System.  The two systems “touch” one another 
at two points:   
• 
The CorPASS Reader will interface with RIM service on the myCordella™ Tablet to send data 
from the Reader and the RIM service in turn will transport the data to CDAP.   

 
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• 
The CorPASS CDAP will transfer data to/from the myCordella™ Patient Management Portal, 
a cloud-based app that combines a simple database with a User Interface for use by clinicians.  
The connection point for the latter is the ‘Clinic Portal’ shown in Figure 6.  
 
Figure 6:  Interaction between CorPASS and Cordella System 
2.3 
Control Algorithm  
The myCordella PMP will be able to calculate simple trends in the mean PA pressure (mPAP) of a 
patient and identify the time-points when treatment needs to be adjusted for each patient based 
on a defined ruleset (Appendix 14.5 Guidelines for managing HF using Pulmonary Artery Pressures). 
The goal for all the patients (HFrEF and HFpEF) is to adjust and maintain their mPAP within the 
normal range of 10-25 mmHg, adjusted for the seating position, which will be achieved at 
increments of 10mmHg until desired mPAP goal has been reached.  After each patient receives the 
sensor their baseline pressure will be defined a few days after the implant procedure based on the 
initial home readings. The myCordella PMP will notify the physician to modify treatment based on 
the 7-day moving average trends and thresholds defined in the Guidelines in Appendix 14.5. 
2.4 
Device Accountability 
The Cordella PA Sensor Systems are investigational devices. The Investigator is responsible for 
ensuring that only study participants utilize the device, and all Endotronix Cordella PA Sensor Systems 
must be stored in a location that is accessible only by authorized personnel.   The disposition of all 

 
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Cordella PA Sensor System components must be maintained by serial number or lot number and 
must be accounted for in the Device Accountability Log. All unused product will be returned to 
Endotronix.  
All components of the Cordella PA Sensor System must be kept by the Investigator for future 
Endotronix inspection including used catheter-based delivery systems after each Cordella PA Sensor 
implant procedure. Endotronix will provide the Investigator instructions to pack and ship the used 
delivery systems as biohazards. 

 
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3 
PRECLINICAL AND CLINICAL STUDIES OF THE CORDELLA PA SENSOR 
SYSTEM 
3.1 
Pre-clinical Studies of the Cordella™ PA Sensor System 
The Cordella PA Sensor System consisting of the Cordella™ Delivery System, Cordella PA Sensor, 
myCordella™ Patient Reader, CalEq and CDAP have been evaluated in bench, acute and chronic 
preclinical testing and found to meet performance specifications for clinical use.  The below table 
outlines a summary of the Pre-Clinical Verification testing: 
Pre-Clinical Verification Testing 
System Level Testing 
Biocompatibility testing  
Pass 
In-vivo animal studies (Acute and Chronic) 
Pass 
Sterilization Validation 
Pass 
Implantable Sensor 
Sensor Bench Performance for overall safety 
• Simulated Conditions 
• Mechanical / Electrical Accelerated 
Lifecycle 
• Structural Integrity and functionality 
Pass 
Magnet Resonance Imaging (MRI) Safety 
Evaluation and Performance 
Pass 
Ultrasound testing 
Pass 
Defibrillator-safe Testing 
Pass 
Safety testing per ISO 14708-1:2014 
Pass 
Delivery System 
Visual and Dimensional Inspection 
Pass 
Simulated Use testing 
Pass 
Resistance to Torsional Forces 
Pass 
Pressure Leak Test 
Pass 
Tensile Strength 
Pass 
Compatibility with ISO 594 (Fluid-
Communicating Port) 
Pass 
Corrosion resistance 
Pass 
 
 

 
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Reader and Docking Station 
Essential Performance and Safety 
Pass 
Safety with Pacemaker / Internal Cardiac 
Defibrillator (ICD) 
Pass 
Safety in accordance with International 
Electrotechnical Commission (IEC) 60601-1 
(General Safety) and IEC 60601-11 (Home 
Use) 
Pass 
Electromagnetic Compatibility per IEC 60601-
1-2 
Pass 
Shock and Vibration per ISTA-2A 
Pass 
Repeatability and Accuracy over time 
Pass 
Power and battery  
Pass 
Software Verification / Validation 
Pass 
Calibration Equipment 
Unit Level Testing 
Pass 
Integration testing 
Pass 
System Level Testing 
Pass 
Safety in accordance with IEC 60601-1 
(General Safety) 
Pass 
CDAP 
Integration testing 
Pass 
System Level Testing 
Pass 
Packaging 
Pouch Integrity 
Pass 
3.2 
Device Set Up and Maintenance 
The subjects will be trained at the clinical site by a trained Clinical Site Delegate or Endotronix 
representatives on the set up and use of the Cordella System during the Screening/ Enrollment Visit 
and for the Cordella PA Sensor System at the Implant Visit. Visits to the subject’s home by an 
Endotronix Representative may be required throughout the study to provide troubleshooting, 
servicing, and maintenance of the system. 
3.3 
Clinical Studies of the Cordella PA Sensor System 
In the US, no prior clinical studies have been performed to evaluate the Cordella™ Heart Failure 
system with the Cordella PA Sensor System.   

 
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In Europe, Endotronix has currently two studies ongoing: 1. SIRONA (NCT03375710), a First in Human 
(FIH) study and 2. SIRONA 2 (NCT04012944) study, our CE mark study.  
1. SIRONA 1: The FIH study is ongoing at 2 centers in Europe. Overall, 15 patients have been 
implanted. The primary safety endpoint is freedom from adverse events associated with the 
use of the Cordella™ Heart Failure System through 30 days post index procedure. The primary 
efficacy endpoint is measurement of the correlation of Cordella PA Sensor pressure 
measurements compared with pressure measurements (Swan Ganz) obtained by standard 
RHC at 90-day post index procedure. In this FIH study, the patients use the Cordella PA Sensor 
System in combination with the Cordella™ HF System. All patients were successfully 
implanted with the Cordella PA Sensor without device system related complication or sensor 
failure. The primary efficacy endpoint of a mean PAP was met in all patients with a cohort 
difference of 2.7 mmHg (Cordella PA Sensor 22.5 mmHg +/-11.8, Swan-Ganz 25.2 mmHg 
+/8.5). Patient adherence to daily measurement and transmission of vital signs was 99% and 
Cordella PA Sensor readings compliance was 99% 45. This study is ongoing and in long- term 
follow up, to date no safety or efficacy concerns have been reported. 
2. SIRONA 2: This CE-Mark study is ongoing in 8 European centers in Europe (Belgium, Ireland, 
Germany).  SIRONA 2 is a prospective, multi-center, open-label, single-arm CE-Mark trial to 
assess device safety and efficacy of the Cordella PA Sensor System in up to 85 NYHA Class III 
HF patients who received the Cordella PA Sensor implant. Enrollment is finalized and the PA 
sensor was successfully implanted in 70 patients. The primary efficacy endpoint was the 
accuracy of PA sensor mean PAP measurements, compared with fluid-filled catheter mean 
PAP measurements obtained by standard RHC at 90 days post-implant, assessed in all 
patients with a successful implant. The primary safety endpoint was freedom from adverse 
events associated with use of the Cordella PA Sensor System through 30 days post-implant, 
assessed in all patients who entered the Cath Lab for a PA sensor implant. Equivalence 
between the PA sensor and RHC for mean PA pressures was within the equivalence bounds 
of - 4.0 to 4.0 mmHg (mean PAP: 0.0 to 2.9 mmHg, P = 0.003), therefore the primary efficacy 
endpoint was met. The device safety profile was excellent with 98.6% freedom from Device 
System Related Complications, defined as invasive treatment, device explant or death and 
with no pressure sensor failures. This study is ongoing and in long- term follow up, to date 
no safety or efficacy concerns have been reported. 

 
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4 
POTENTIAL RISKS AND BENEFITS 
4.1 
Potential Risks  
There is extensive clinical experience with respect to right heart cardiac catheterization and 
interventional procedures, and it is expected that these acute procedural risks will not be significantly 
different with the Cordella PA Sensor System.  Possible adverse events associated with cardiac 
catheterization and/or the implantation of the Cordella PA Sensor System may include, but are not 
limited to, the following:  
• 
Allergic reaction 
• 
Arrhythmias 
• 
Bleeding complications (which may require transfusion) 
• 
Cardiac arrest 
• 
Chest pain 
• 
Death 
• 
Device embolization/migration 
• 
Device explant 
• 
Emergent or urgent cardiac, vascular, and/ or other surgery necessitated by the device or 
implant procedure (e.g., coronary sinus lead revision) 
• 
Endocarditis or device infection 
• 
Entry site complications (e.g., hematoma, dissection)  
• 
Fracture of a component of the device/system that may or may not lead to serious injury or 
surgical intervention 
• 
Gastrointestinal bleed (antiplatelet therapy) 
• 
Hemoptysis 
• 
Hypo or hypertension 
• 
Infection or fever   
• 
Peripheral embolism/thrombus 
• 
Pulmonary embolism/pulmonary occlusion 
• 
Pseudoaneurysm of the vein  
• 
Radiation exposure 
• 
Reaction to contrast media/ medication 
• 
Renal insufficiency or failure 
• 
Respiratory distress or failure (breathing problems)  
• 
Sepsis 
• 
Valvular injury (tricuspid and/or pulmonary)  
• 
Vascular complications (e.g., venous dissection, perforation, rupture, arteriovenous fistula) 
• 
Vessel trauma which may require surgical repair 

 
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• 
Worsening heart failure 
When used in accordance with the clinical protocol, risks associated with commercially available 
Cordella System are considered low. To ensure proper use of the myCordella™ Tablet and 
Peripherals, subjects will be trained in accordance with the manufacturer’s instructions for use. 
Potential risks of the commercially available Cordella System include the following: 
• Temporary arm discomfort/pressure from the blood pressure cuff 
• Skin irritation or petechia at the site of the blood pressure cuff placement 
• Loss of balance while standing on scale 
• Inaccurate measurements or measurement errors 
In addition, there may be unknown or unforeseen adverse effects due to the CorPASS investigational 
device. All effort will be made to minimize these risks by selecting investigators who are experienced 
and skilled in catheterization procedures, conducting appropriate training on the use of the device, 
clearly defining Inclusion/Exclusion criteria to ensure that only appropriate patients are enrolled, and 
by ensuring that the treatment and follow-up of the patient are consistent with current medical 
practices. 
4.2 
Potential Benefits 
It is hoped that the information collected will provide the clinicians with a better understanding of 
the Cordella PA Sensor System as a potential solution for proactive HF management, early detection 
of fluid overload, and ultimately prevention of worsening HF symptoms. Studies of other similar 
devices (Abbott’s CardioMEMS) have shown the benefit of monitoring PAP as it relates to reduction 
of HF hospitalizations19,20,42.   
The Cordella PA Sensor System and the CardioMEMS™ systems are substantially equivalent in their 
intended use, technological characteristics, and risk profiles.  
The Cordella PA Sensor System is a further refinement in remote PAP monitoring technology and 
combines clinical benefits of remote PAP management (i.e., proactive continuous PAP monitoring/ 
management over time without ongoing RHC risks, increased life span with improved quality of life) 
with its own system-specific benefits.  
Benefits of the Cordella PA Sensor System over the CardioMEMS include an optimized system design 
for improved PA sensor positioning and anchoring within the vessel, reduced system components 
size resulting in better ease of use for the patient, and increased system versatility to provide a more 
comprehensive picture of the patient’s overall health status.  

 
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In addition to collecting PAP, the Cordella PA Sensor System interacts with the commercially 
available Cordella™ HF System which has an interactive platform that incorporates collection of 
clinical information including weight, BP, HR, SpO2and patient feedback as part of the data 
communicated to clinicians. This platform also facilitates direct communications between the 
patient and their clinicians, which enhances the exchange of relevant clinical information and 
patient-clinician interactions that are important during the HF management process. 
Despite their similarities, the Cordella PA Sensor System is differentiated from the Abbott 
CardioMEMS product by several advantageous features.  These potential benefits include: 
Implantation.   Like CardioMEMS™, the Cordella PA Sensor provides a custom catheter assembly, 
pre-fitted with a sensor, as well as a dedicated hospital-use reader unit to facilitate the process of 
initial calibration against a reference reading.  But unlike CardioMEMS™, Cordella PA Sensor’s nitinol 
anchors are designed to hold the Sensor in the same anatomical PA target location for every patient.  
Anatomical features in the PA common to all patients facilitate quick and reliable mapping of the 
location with nonquantitative angiography.  The Cordella PA Sensor anchors hold the Sensor’s body 
in a known position against the vessel wall, eliminating errors due to the sensor surface contacting a 
wall.  Cordella PA Sensor’s standard location is proximal and more deterministic than that of 
CardioMEMS, reducing risks associated with going too distal into smaller branches, such as vessel 
obstruction, clotting, vessel damage, or Sensor migration after implant.  The Cordella PA Sensor 
catheter features a softer tip to reduce vessel damage risk.  Further, the catheter provides a built-in 
port for connecting a fluid-filled reference catheter for calibration and contrast dye injection for 
mapping of the pulmonary tree under fluoroscopy, requiring fewer intraprocedural catheter 
exchanges than the CardioMEMS™.  The ‘one location for all patients’ design frees Cordella™ 
implanters from complicated and sometimes intractable rule sets involving vessel sizes, branches, 
and angles deep in the PA.   Finally, doctors and nurses in the implantation environment will benefit 
from the efficient workflow afforded by CorPASS’s ‘Calibration Equipment’ device.  CardioMEMS’ 
pencil-and-paper based calibration procedure is replaced by automated entry, data integrity checks, 
and secure cloud-based servers for recording, uploading, authenticating, and storing essential 
configuration and calibration data.  Automation contributes to ease of use and allows catheter lab 
staff to calibrate Cordella PA Sensors efficiently. It also reduces potential for human error in data 
association, data entry, authentication, and cybersecurity. 
Home Readings.  Both the Cordella PA System and CardioMEMS ™ require the implanted patient to 
make bodily contact with a ‘Reader’ device to take a daily 18-second PAP reading and upload it to a 
secure website for clinician access.  Patented Cordella™ technology sharply differentiates the two 
user experiences.  CardioMEMS’ reader requires the patient to lie supine on a bulky mattress-like 
electronics unit, which must plug into wall power.    The CardioMEMS™ patient must remain in the 
supine position until data is uploaded, which can take up to several minutes.  The Cordella™ Reader, 

 
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in contrast, is handheld and cordless.  The patient undocks it, holds it against his chest with one hand 
for 18 seconds while seated, and re-docks in response to an audio cue. 
The highly portable CorPASS hardware allows the patient to travel away from home and still receive 
uninterrupted HF management.  Its physical size facilitates packing and transport in a small travel 
bag.  The CardioMEMS™ device ships with its own full-sized roller bag and requires a dedicated bed 
or sofa at the destination to set the device up.  Cordella™’s inherent portability also facilitates 
bringing Readers to and from the patient’s cardiology clinic for any needed replacement, additional 
training, or troubleshooting. 
Finally, the handheld reader allows caregivers to instruct patients to take PAP measurements before, 
after, or during exercise (e.g., 6-minute walk test), if desired. 
Data-Driven Management.  The CardioMEMS™ system processes reader data (filtering, signal 
strength analysis, application of calibration coefficients, etc.) locally in each of its Reader units, only 
uploading the final result to the remote database.  It relies on human operators to set up initial 
calibration data and associations manually in the reader during the implant procedure.  Cordella™ 
readers only upload raw, unprocessed pressure data, along with data indicative of signal strength for 
each reading.  Cordella™ data processing is all carried out automatically with carefully maintained 
and monitored software on a secure cloud server.  Besides enhancing cybersecurity, this 
arrangement allows Endotronix to update and improve algorithm accuracy, and more closely 
monitor the system for functionality and re-process raw data using different methods for new 
applications. 
As a 21st Century digital health product, CorPASS’s data management architecture emphasizes 
flexibility and interoperability with the myriad of third-party Electronic Medical Record (EMR) 
management systems in use by clinics today, without compromising availability, integrity, or 
confidentiality of data.  Unlike CardioMEMS™, whose data interface is limited to St Jude’s legacy 
Merlin system, CorPASS features a relatively simple data i/o stream that will be amenable to direct 
integration with current and future EMR products, by establishment of simple APIs with target EMR 
systems as needed. 
Although CorPASS can function as a standalone system, it is typically most effective when used with 
Endotronix’s Cordella System a separate commercial product.  The Cordella System furnishes 
implanted or non-implanted HF patients with simple noninvasive devices: a BP cuff, weight scale, 
and pulse oximeter.  It also provides each patient with a tablet for aggregating Bluetooth data from 
these devices and uploading it to the secure PMP database.  The tablet also transfers secure, private 
communications between patient and caregiver.  The PMP provides the cardiology staff with an easy-
to-use yet powerful tool that ensures efficient workflow during the patient management process.  
Unlike the numerous other telehealth systems on the market, Cordella System focuses exclusively 
on heart failure, and was designed specifically to optimize productive workflow for cardiology 

 
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practices.  With Cordella System, a cardiologist can manage all HF patients, from any NYHA class, and 
readily identify those that would benefit from the addition of a Cordella PA System Sensor (typically 
NYHA Class III).  The new Reader PA data seamlessly integrates with the PMP data structures already 
established for the patient.  In this trial, the new CorPASS patient and patient’s cardiologist’s staff 
will typically already have experience in use of the Cordella System for at approximately one week 
prior to getting the Cordella PA Sensor implant – adding the CorPASS measurement to the daily 
reading routine will be an incremental change in behavior for both patient and clinician. 
A flexible, yet powerful and robust telehealth system that focuses exclusively on Heart Failure, while 
offering the option to obtain critical PAP data for specific patients, is unique in the market.  It 
represents a major step away from legacy or fragmented ‘all purpose’ data systems, and towards 
efficient yet comprehensive management of HF.  The table below demonstrates perceived 
advantages of the CorPASS compared to the CardioMEMS system. 
 
Figure 7:  Comparison CorPASS and CardioMEMS 
 

 
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5 
STUDY OBJECTIVES AND ENDPOINTS 
The objective of this IDE study is to demonstrate the safety and effectiveness of the Cordella PA 
Sensor System. 
Safety will be measured as described in Section 5.2.  Efficacy will be measured by the primary and 
secondary endpoints as described in Section 5.1.  In addition, subjects enrolled in this trial will be 
monitored for safety and adverse events, for device failures, Health Status and functional status 
improvement. 
5.1 
Efficacy Endpoints 
Primary Efficacy Endpoint through 6 months post- implant): 
The primary efficacy endpoint is the 6 month incidence of HF related Hospitalizations or all-cause 
mortality.  
Secondary Efficacy endpoints include:  
1. Incidence of HF Hospitalizations or all-cause mortality at 12 months 
2. Number of HF Hospitalizations at 6 and 12 months post-implant compared to the number of HF 
Hospitalizations in the 6 and 12 months prior to implant 
3. Comparison of the number of HF Hospitalizations or Emergency Department/ Hospital 
Outpatient IV diuretic visits of Cohort #1 and Cohort #2+#3 at 6 and 12 month post implant   
4. Change of NT-proBNP from Baseline through 6 and 12 months 
5. Combined outcome of: 
a. First and recurrent HF Hospitalizations 
b. Emergency Department/ Hospital Outpatient IV diuretic visits 
c. all-cause mortality  
at 6 months, added together with equal weighting into a total number of events. 
6. Heart failure hospitalization or Emergency Department / Hospital Outpatient IV diuretic visits at 
6 and 12 month 
7. Cardiac and all-cause mortality 
8. Days Alive and Out of Hospital (DAOH) 
9. IV diuretic visits  
10. Heart failure related Medication changes 
11. Change in PAP: 

 
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a. From Baseline through 6 and 12 months in subjects with a baseline mPAP 
i. above target range 
ii. within or below target range 
iii. overall 
b. Before and after 6-Minute Walk Test 
12. Percentage of device success as documented by ability of the System to successfully transmit PAP 
data  
13. Patient Outcome Measures, measured by KCCQ  
14. Functional status improvement, as measured by NYHA and 6-Minute Walk Test 
15. Health Economic Analysis 
5.2 
Safety Endpoints 
Primary Safety endpoints include:  
1. Freedom from device/system related complication at 6 months  
2. Freedom from pressure sensor failure at 6 months 
Secondary Safety endpoints include:   
1. Pressure sensor failure rate throughout the study  
2. Frequency of serious adverse events throughout the study 
3. Frequency of implant procedure and procedure related adverse events and serious adverse 
events 

 
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6 
STUDY DESIGN 
This is a prospective, open-, single arm, multi-center clinical trial to evaluate the safety and 
effectiveness of the Cordella PA Sensor System in NYHA Class III Heart Failure Patients.  
Subjects will be categorized into three (3) different cohorts, with subjects from Cohort #2 and 
Cohort #3 below serving as the basis for the primary study analysis: 
1. Cohort #1- Previously enrolled Control Arm subjects 
• 
Subjects in this cohort will be unblinded to their PAP measurements and informed about 
their previous group assignment and continue their Follow-up visit schedule  
• 
Additionally, subjects will be asked, throughout the remaining Follow-up period, to 
complete a regular subject survey on their experience with PAP Measurements and PAP 
Values. 
• 
Clinicians will be unblinded to their PAP measurements and start managing the patients to 
target PA pressures per protocol/ CIP and according to GDMT 
• 
Additionally, the clinical site will be asked to contact the subject on a  regular basis to 
discuss their PAP values 
• 
Separate subgroup analysis (efficacy and safety) will be performed 
2. Cohort #2- Previously enrolled Treatment Arm subjects 
• 
As of month 12 subjects in this cohort will be able to see their own PAP measurements for 
the remaining duration of the study. 
• 
Clinicians will continue to manage their patients to target PA pressures per protocol/ CIP 
and according to GDMT 
• 
All primary and secondary safety and effectiveness analyses will be performed 
3. Cohort #3- Newly enrolled subjects 
• 
will participate in the Screening/ Enrollment Visit Cordella PA Sensor Implant Visit, and 
Follow-Up Visits 
• 
Clinicians will manage the patients to target PA pressures per protocol/CIP and according 
to GDMT  
• 
As of month 12 subjects in this cohort will be able to see their own PAP measurements for 
the remaining duration of the study.    
• 
All primary and secondary safety and effectiveness analyses will be performed 
All subjects will receive a Cordella PA Sensor Implant and will be followed for 6 month for the 
Primary Efficacy Endpoint, 6 months for the Safety Endpoints, and will be continued to be followed 
up to 5 years post implant. 

 
 
 
 
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Figure 8:  Study Design 
6.1 
Study Flow 
The study will implant up to 535 subjects. Assuming a dropout rate of approximately 10% by 6 months, this study will implant a 
maximum of 450 patients in Cohort #2 and Cohort #3.  This is to achieve at least 406 implanted patients with complete follow-up at 6 
months. After completion of enrollment and as soon all 406 subjects reach their 6 month follow- up visit, the 6 month primary endpoint 
data will be used for Premarket Approval (PMA) submission. Up to 85 subjects (cross- over from former Control Arm) will continued 
to be followed in Cohort #1. 
  
 

 
 
 
 
 
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Figure 9:  Study Flow

 
 
 
 
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6.2 
Number of Clinical Sites and Subjects 
The trial will be conducted at up to hundred-twenty (120) sites in the US and Europe.  Screening will 
continue until a maximum of 535 subjects are successfully implanted (all Cohorts).  
Of these 535 subjects, up to 85 subjects (cross- over from former Control Arm) will continued to be 
followed in Cohort #1. 
At least 50% of the total subjects will be enrolled in the US. No single clinical site will be allowed to 
enroll more of 20% of the total subjects into the study. In addition, clinical sites are not allowed to 
implant more than thirty (30) subjects into the study without prior written approval from 
Endotronix. 
6.3 
Subject Participation and Study Duration  
Subjects will participate in the study for a total of 5 years. 
The study started in the Fourth Quarter 2019 (First Implant) and enrollment (Last Implant) is 
estimated to be completed by First Quarter 2023.  
6.4 
Site Selection Criteria  
The trial will be conducted at up to 120 clinical centers in the US and Europe (EU).  A site evaluation 
visit (SEV) will be conducted to confirm that all participating centers meet the following criteria: 
• Center having interventional cardiology (or access to) and Heart Failure teams and an 
established research group structure. 
• Center needs to be Heart Failure Board Certified with at least 300 HF visits/ year 
• American Association of HF Nurses (AAHFN) certified Nurse Practitioner (NP) & HF Nurses (US 
only) 
• Each institution must have access to the necessary equipment and supplies that are needed 
to gather the data at baseline, implant and follow-up evaluations. 
• Accredited laboratory or laboratories for the evaluation of blood chemistry and hematology.  
• Clinical research study experience and resources that demonstrate good compliance with 
study requirements and timely, complete documentation of subject follow-up.  Investigative 
teams must designate a study coordinator to manage the study. 
• Ability to adhere to the standards of Good Clinical Practice (GCP).  
• Agree to comply with data collection requirements and data input timelines. 
• Centers will respond to queries from Endotronix in a timely fashion. 
• Willingness to allow personnel from Endotronix (or its designate) access to the hospital 
records, investigator’s study records, data and subject files as they pertain to the study. 

 
 
 
 
 
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6.5 
Study Visits  
Subjects will participate in the Screening/ Enrollment Visit, the Sensor Implant Visit, and Follow-Up 
Visits for a total study duration of up to 5 years.   
At the Screening/ Enrollment Visit, subjects will review and sign the informed consent form prior to 
any study-related procedures performed. Based on Screening Visit results, the Investigator will 
confirm and document study eligibility for each subject. As part of the study screening process, all 
subjects will be trained on and instructed to use the commercially available Cordella System at home. 
As part of the study screening process, subjects will be scheduled for a RHC and PA Sensor Implant 
procedure.  
At the Implant Visit, the Cordella PA Sensor, which is pre-mounted on a catheter Delivery System, 
will be delivered according to the system’s Instructions for Use. Once deployed, the Sensor PAP 
readings will be calibrated using the system’s fluid-filled catheter.  The calibration coefficients for 
that Sensor/subject will be stored in a database, allowing for consistent PAP calculations throughout 
the study duration.  
Subjects will be observed until stable, trained on and instructed to use the Cordella PA Sensor System 
and discharged home with instructions to take their PAP measurements daily (same time each 
morning) along with their weight, BP, HR and SpO2, which will all be wirelessly transmitted to a 
secure website. Subjects will also be given a Cordella™ PA Sensor System implant card, a Patient 
User’s Manual, and a Technical Support number to contact Endotronix representatives with any 
questions. 
Subjects will return for follow up visits at 1, 6, 12, 18, and 24 months and Year 3, 4 and 5 after the 
Cordella PA Sensor implant, or until study termination. The 3 month follow-up visit will be performed 
as remote/ virtual Telemonitoring visit.  
When at least 406 implanted subjects (Cohort #2 and Cohort #3) completed their study visit 5 (Month 
6) , the primary efficacy endpoint will be assessed to demonstrate durability of the treatment effect. 
Assessments to be performed at follow up visits include echocardiograms, physical examinations, 
cardiac medication assessment, clinical laboratory assessments, vital signs, review of Cordella PA 
Sensor PAP readings, NYHA Functional Classification, KCCQ, 6-Minute Walk and adverse events 
assessment. 

 
 
 
 
 
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7 
STUDY POPULATION AND ENROLLMENT 
7.1 
Study Population 
Subjects in this study will be male or female NYHA Class III heart failure patients at least 18 years of 
age. Subjects must be diagnosed with heart failure for a minimum of 3 months, are clinically stable, 
have an increase of NT-proBNP and a HF related hospitalization, HF treatment in a hospital day-care 
setting, or urgent outpatient clinic HF visit for IV diuretics within 12 month (last hospitalization should 
be 30 days before Screening /Enrollment). Subjects must also meet certain physical requirements 
necessary for the Cordella PA Sensor implant and functionality of the Cordella System as outlined in 
the study Inclusion/Exclusion Criteria. 
7.2 
Special Efforts to Ensure Optimal Inclusion of Women and Minorities 
Discrepancies in HF management for women are apparent not only in clinical trials, but also in 
clinical practice. β-blockers, which have supportive data for men and women, are used less 
frequently in women with HF.  In a European population-based study, women with HF and reduced 
ejection fraction were 25% less likely to receive Beta Blockers (BB) than men27.  The CHARM study 
confirmed these findings, with women being 17% less likely than men to receive BBs28.  Clinical 
practice also appears to vary in a gender-based fashion for ACE inhibitors.  A British study found 
that women were 24% less likely to receive ACE inhibitors than men, while the National Heart 
Failure Project and the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in 
the Outpatient Setting (IMPROVE HF) trial found that older women with HF were less likely to 
receive guideline-recommended treatments compared with men29,30. 
The recent published results from CHAMP-HF31 showed that 99% of cardiologists are not following 
guidelines.  In general, they are prescribing the right meds, but are being too conservative and 
under-medicating.  Our system's constant feedback from the patient will enable them to titrate 
meds more confidently and thus better follow guidelines.  This is especially true for women, since:  
(i) they tend to be smaller mass, and thus are more sensitive to overmedication and side effects;  
(ii) they may experience different side effects from men and thus the physician may not be as 
familiar with these side effects;  (iii) they may be on different meds than men are typically (e.g. 
hormones) for other conditions, and so drug interactions may be different - physician will need 
extra feedback if these require special attention. 
Major factors that might exclude women from receiving a Pulmonary Artery Sensor: 1) small PA 
size and 2) Inadequate social support for those women without a regular caregiver.  Severe illness, 
other than heart disease, which would limit survival to < 3 years, could in theory limit the screening 
and enrollment of women with HF, who tend to be older and may have a larger burden of 
concomitant illnesses.  
We believe that the proposed trial will recruit more women for several reasons:  

 
 
 
 
 
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• The Cordella PAP system is more suitable for smaller patients;  
• Our anchoring system is a 'one size fits all' that depends on a universal anatomical feature 
• Patients are expected to be older (mean > 65 years), where women with HF constitute a 
larger clinical population.  
Endotronix believes that women should constitute ideally at least 35% of the population.   
To ensure robust enrollment of women, we will (or already have):  
1. Select sites that have Women’s’ Heart Clinics,  
2. Make an appeal in all training materials and at investigator meetings for recruitment of 
women as subjects; and  
3. Recruit leadership for the clinical trial and steering committee that includes women 
physicians.  
In the CHAMPION HF trial 19 and GUIDE-HF trial 51, 73% of subjects and 81% respectively were 
White.  The African-American population of the US is approximately 13%.  According to American 
Heart Association statistics, the annual incidence of heart failure in whites is approximately 6 per 
1,000 person-years, while in African Americans it is 9.1 per 1,000 person-years 33. Endotronix 
believes the recruitment of African-American patients will be representative and will exceed 13% to 
approximately 20%. The location of many study sites in urban areas that serve larger African-
American populations assumes adequate participation of this minority group. It is also expected 
that other minorities (e.g., Hispanics) will represent at least an additional 10%. 
7.3 
Optimal Heart Failure Medical Management 
To be enrolled into the study, subjects must be receiving stable GDMT for HF per current AHA/ACC 
guidelines as standard-of-care for HF therapy in the United States and Europe, with any intolerance 
documented for at least 30 days. This will be verified by the trial specific PROACTIVE-HF Clinical 
Eligibility Committee. Throughout the study duration, all subjects will continue to receive 
appropriate medical management for their heart failure, including cardiac medication optimization 
as well as dietary and fluid restrictions. In addition, subjects will receive Treatment Optimization to 
target PA pressures, per the Project Specific Guidelines and GDMT considering daily PAP 
measurements and vital signs collected by Cordella System. 
The clinician will contact all subjects on a regular basis to discuss their health status and all patients 
should be treated according to GDMT.   
7.4 
Inclusion Criteria  
In order to be eligible to participate in this study, each subject must meet all of the following criteria: 
1. Subject has given written informed consent 

 
 
 
 
 
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2. Male or female, at least 18 years of age 
3. Diagnosis and treatment of HF (regardless of left ventricular ejection fraction (LVEF)) for ≥ 3 
months and NYHA Class III HF at time of Screening  
4. Subjects should be on stable, optimally titrated medical therapy for at least 30 days, as 
recommended according to current American Heart Association (AHA)/American College of 
Cardiology (ACC) guidelines as standard-of-care for HF therapy in the United States, or current 
European Society of Cardiology (ESC ) guidelines for HF treatment  in Europe, with any intolerance 
documented. 
5. HF related hospitalization, HF treatment in a hospital day-care setting, or urgent outpatient clinic 
HF visit for IV diuretics within 12 month (last hospitalization should be 30 days before Screening 
/Enrollment) and/or N-terminal pro-Brain Natriuretic Peptide (NT-proBNP)) at time of Screening/ 
Enrollment defined as: 
a. Subjects with LVEF ≤ 50%: NT-proBNP ≥ 1500 pg/mL. 
b. Subjects with LVEF > 50%: NT-proBNP ≥ 800 pg/mL. 
Thresholds for NT-proBNP (for both LVEF ≤ 50% and LVEF > 50%) will be corrected for body mass 
index (BMI) using a 4% reduction per BMI unit over 25 kg/m2 
6. Subjects should be on diuretic therapy 
7. Subjects who are physically able to hold the myCordella™ Patient Reader unit (approximate 
weight 1.3lb) against the ventral thoracic surface for up to 2 minutes per day while in a seated 
position, as well as dock and undock the myCordella™ Patient Reader 
8. Subjects with sufficient eyesight, hearing, and mental capacity to respond to the myCordella™ 
Patient Reader’s audio/visual cues and operate the myCordella™ Patient Reader 
9. Subject has sufficient Cellular and/ or Wi- Fi Internet coverage at home 
10. Subject agrees to return to the treating Investigator for all scheduled follow up visits and can 
return to the hospital for follow up 
7.5 
Exclusion Criteria  
A potential subject who meets any of the following criteria will be excluded from participation in this 
study: 
1. Intolerance to all neuro-hormonal antagonists (i.e., intolerance to ACE-I, ARB, ARNI, and beta-
blockers) due to hypotension or renal dysfunction 
2. ACC/AHA Stage D refractory HF (including having received or currently receiving pharmacologic 
circulatory support with inotropes) 

 
 
 
 
 
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3. Subjects with history of recurrent pulmonary embolism (≥ 2 episodes within 5 years prior to 
Screening Visit) and/or deep vein thrombosis within 3 months of the Screening Visit 
4. Subjects who have had a major CV event (e.g., myocardial infarction, stroke) within 3 months of 
the Screening Visit 
5. Unrepaired severe valvular disease 
6. Subjects with significant congenital heart disease that has not been repaired and would prevent 
implantation of the Cordella PA Sensor or mechanical/tissue right heart valve(s) 
7. Subjects with known coagulation disorders 
8. Subjects with a hypersensitivity or allergy to platelet aggregation inhibitors including aspirin, 
clopidogrel, prasugrel, and ticagrelor; or patients unable to take dual antiplatelet or 
anticoagulants for one- month post implant 
9. Known history of life threatening allergy to contrast dye. 
10. Subjects whereby RHC is contraindicated 
11. Subjects with an active infection at the Sensor Implant Visit 
12. Subjects with a GFR <25 ml/min or who are on chronic renal dialysis 
13. Implanted with CRT-P or CRT-D for less than 90 days prior to screening visit 
14. Received or are likely to receive an advanced therapy (e.g., mechanical circulatory support or 
lung or heart transplant) in the next 12 months 
15. Subjects who are pregnant or breastfeeding 
16. Subjects who are unwilling or deemed by the Investigator to be unwilling to comply with the 
study protocol, or subjects with a history of non-compliance 
17. Severe illness, other than heart disease, which would limit survival to <1 year 
18. Subjects whose clinical condition, in the opinion of the Investigator, makes them an unsuitable 
candidate for the study 
19. Subjects enrolled in another investigational trial with an active Treatment Arm 
20. Subject who is in custody by order of an authority or a court of law 
7.6 
Strategies for Recruitment and Retention  
A total of 535 subjects can be enrolled under this clinical protocol/CIP at up to 120 sites in the US 
and Europe. Potential subjects will be identified by the Investigator and research staff with the study 
Inclusion and Exclusion criteria in mind. At Screening, subjects will be fully informed on what to 
expect with study participation to maintain a high study participation retention rate. Subjects will 

 
 
 
 
 
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also undergo a training on the at-home use of the commercial Cordella System to ensure compliance 
with the web-based clinical care management component of the Cordella™ Heart Failure System, as 
part of their study screening/ enrollment visit.  Throughout the study, subjects will continue to be 
followed closely to ensure study compliance as well as continued study participation. 
7.7 
Subject Withdrawal or Termination   
7.7.1 Screening Failure and Documentation 
Subjects who sign the Informed Consent, but do not meet the inclusion criteria or subjects 
who meet an exclusion criterion and are not enrolled into the study are considered screening 
failures.  Information on screening failure subjects will be captured on a Screening Failure log 
and will include demographic information and the primary reasons for Screen Failures will 
not be recorded in the electronic Case Report Form (eCRF). 
7.7.2 Reasons for Withdrawal or Termination   
A subject may discontinue his or her participation without giving a reason at any time during 
the study.  Should a subject’s participation be discontinued, the primary reason for 
termination must be recorded in the eCRF. In addition, efforts should be made to perform all 
procedures scheduled for the Month 6 visit if discontinuation is prior to that visit, or the year 
5 visit if discontinuation is after year 4 but before year 5.  Subjects who are withdrawn may 
be replaced with new subjects for evaluation upon Sponsor approval.  
 
The primary reason for discontinuation or withdrawal of the subject from the study should 
be noted using the following categories:  
• Lost to follow-up.  The subject did not return to the clinic and attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented 
• Voluntary withdrawal.  The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the eCRF.  NOTE: All attempts should be 
made to determine the underlying reason for the withdrawal and, where possible, the 
primary underlying reason should be recorded 
• Principal Investigator withdrawal due to failure to comply with trial requirements or 
subject is uncooperative or refuses to continue in the trial 
• Study termination. The sponsor, IRB/ IEC, or regulatory agency terminates the study 
• Other (NOTE: The specific reasons should be recorded in the eCRF) 
7.8 
Subject Follow- up after trial completion or early termination 
After completion of the last study visit, the subject will continue to participate in the site-specific 
Heart Failure Follow-up program.  

 
 
 
 
 
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8 
STUDY PROCEDURES AND SCHEDULES 
8.1 
Study Procedures and Evaluations 
The following sections describe the procedures to be completed throughout the conduct of the 
study.  Subjects are to be assessed by the same Investigator or site personnel whenever possible.  
The Schedule of Study Procedures is described here in Section 8 and in Appendix 14.1. Every 
attempt should be made to perform evaluations at the designated time points. However, for visits 
conducted at Month 1 and 3 there is a window of +7 days, for visits at Month 6 there is a window 
of +14 days and after Month 6 (Month 12, 18, 24 and Year 3, 4 and 5) there is a window of +30 
days. 
8.1.1 Study Eligibility Review 
Inclusion and exclusion criteria will be reviewed during the Screening period for all subjects 
to determine study participation eligibility using the following process: 
 
 
 
Figure 10:  Enrollment Process 
 
 

 
 
 
 
 
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8.1.2 Informed Consent Procedure 
Before enrolling the subject in the trial, i.e., before any trial-related examination is 
performed, a written Informed Consent Form (ICF) must be obtained. Each potential 
participant shall be informed of the aim of the trial and what participation entails. They shall 
be supplied with an Information Sheet summarizing the details of the trial. Ample time should 
be given to the subjects to consider their participation. Agreement to participate in the trial 
is to be confirmed by the subject and the Principal Investigator (or authorized designee) by 
signing and dating the consent form. Documentation of this procedure is required in the 
medical record. 
Standard-of-care assessments obtained within the 30 days prior to consent for screening may 
be used: 1) to confirm eligibility; and 2) for screening measurements, if the subject meets 
eligibility criteria and signs the ICF. Echocardiograms obtained within 3 or 6 months prior to 
ICF may be used for screening measurements.  
Vulnerable populations will not be included in this trial. 
8.1.3 Point of Contact 
A point of contact of where to obtain additional information on the trial, on the rights of the 
subject and whom to contact in the event of trial-related injury will be provided to each 
subject. This information will be specified in the ICF. 
8.1.4 Informing the Subject’s General Practitioner (EU only) 
In certain applicable countries, and in cases where the subject is typically treated by a general 
practitioner or other equivalent Health Care Provider (HCP), then with the subject’s 
agreement this HCP is to be informed of the subject’s participation in the trial at enrollment. 
The provider should be informed of the title of the trial, date of enrollment into the trial, and 
the dates of the outstanding visits. The communication with the general practitioner should 
be documented in the subject’s medical record. 
8.1.5 Subject Demographics 
Subject demographics will be collected and identified by a non-identifying number on the 
eCRF including sex, gender, year of birth, weight, height, race, and ethnicity. Subject BMI will 
also be recorded. 
 
 

 
 
 
 
 
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8.1.6 Cardiac/Medical and Surgical History 
Medical and surgical history, including cardiac history, will be obtained at Screening and 
updated at the Cordella PA Sensor Implant Visit prior to the implant procedure as follows: 
• General medical history 
• Primary cardiac diagnosis (ischemic cardiomyopathy/ nonischemic cardiomyopathy) 
• Previous cardiac history incl.: 
o Coronary Artery Bypass Grafting (CABG) 
o Percutaneous coronary intervention (PCI) 
o Hypertension 
o Ventricular Tachycardia 
o Atrial Fibrillation 
o ICD / CRT  
• Duration of Heart Failure/ NYHA class 
• Cardiopulmonary Exercise Testing (CPX) Results (if available) 
• Number of hospitalizations in past year for cardiac reasons and HF 
• Smoking, Alcohol, Drug Use 
 
With co-morbidities to be identified as:     
• Diabetes (diet, oral, insulin) 
• COPD 
• Chronic Kidney Disease 
• Carotid artery disease, Peripheral vascular disease 
8.1.7 Physical Examination and Vital Signs 
A full physical examination including chest circumference* will be obtained at Screening.   An 
abbreviated physical examination will be obtained at the Cordella PA Sensor Implant Visit 
prior to the implant procedure and at Month 1, 6, 12, 18, 24 and Year 3, 4 and 5. All physical 
examinations will be conducted by a licensed physician, NP, registered nurse (RN), or 
physician assistant (PA) in accordance with local laws and regulations. 
Vital signs via Cordella System will be obtained at all study visits. BP, HR, arterial oxygen 
saturation (SpO2) level, and weight. Height and BMI will be measured at Screening only. 
*If chest circumference is above 55 inch/ 1400 mm please provide CT scan in Screening 
Package for PROACTIVE-HF Clinical Eligibility review. If a preexisting CT exists, which was 
taken within the last 12 months, the CT does not have to be repeated at the time of screening. 
8.1.8 Electrocardiograms (ECG)  
A 12-lead electrocardiogram (ECG) will be obtained at Screening, Month 6, 12, 24 and Year 3, 
4 and 5.  For all ECGs, the Investigator will write their findings on the ECG as either: 

 
 
 
 
 
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• “Normal ECG" 
• "Abnormal ECG, Clinically Significant" 
• "Abnormal ECG, Not Clinically Significant”  
Subsequent ECGs may be obtained at the discretion of the Investigator.  ECGs will be signed 
and dated by the Investigator. The original ECG tracing will be retained in the subject's records 
at the study site and a copy will be provided to the Sponsor if requested.  
8.1.9 Clinical Laboratory Tests 
Blood samples will be obtained for local clinical laboratory tests (hematology and serum 
chemistry) at Screening, Month 6, 12, 24 and Year 3, 4 and 5. Additionally, urine samples will 
be obtained for testing, including pregnancy tests for females at Screening. Appropriate 
accreditation for all laboratories as well as the reference ranges for each of the laboratory 
parameters measured with a description of the methods to be used in the study must be 
provided to Endotronix prior to initiation of the study. Changes in the reference ranges or in 
the methodology during the trial are to be communicated to Endotronix or representative. 
 
Hematology 
Biochemistry 
Urinalysis (Screening only) 
Hemoglobin 
NT-pro BNP* 
 CRP 
Glucose 
Hematocrit  
Sodium  
SGOT (AST) 
Protein 
Leucocytes 
Potassium 
SGPT (ALT) 
Specific gravity 
Platelets 
Creatinine 
Cholesterol 
pH 
Lymphocytes 
Total Bilirubin 
Uric Acid 
Ketones 
aPTT** 
Blood Urea Nitrogen 
(BUN)/ Urea 
 
Bilirubin 
INR** 
Total Protein 
 
Urobilinogen 
 
Albumin 
 
Nitrite 
* also captured at Month 1, 3 and 18 
** if indicated  
 
Blood 
Leukocytes 
Urine Pregnancy Test 
(females) 
The results of laboratory tests will be returned to the investigator, who is responsible for filing 
and reviewing these results together with the data in the eCRF.  The investigator is 
responsible for transcribing laboratory results to the eCRF.  The investigator will maintain a 
copy of the laboratory accreditation and the reference ranges for each laboratory used. 
The total amount of blood per subject for laboratory tests will be approximately 100 mL. 

 
 
 
 
 
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8.1.10 Echocardiogram 
Echocardiograms will be performed at Screening, Month 12 and Year 3, 4 and 5. 
Echocardiograms will determine the following parameters: 
• LVEF 
• Left ventricular mass 
• Left ventricular volume 
• Left Ventricular End Diastolic Diameter (LVEDD) 
• Systolic pulmonary artery pressure (sPAP) 
• Mean pulmonary artery pressure (mPAP) 
• Diastolic pulmonary artery pressure (dPAP) 
• Right atrial pressure (RAP) 
• Left atrial size 
• Left atrial volume 
• Mitral regurgitation  
• Tricuspid regurgitation 
If an echocardiogram has been performed within 3  months of Screening, that LVEF may be 
acceptable to determine study eligibility. While an echocardiogram within 3 months of the 
screening visit date is preferable. In case this is not possible, Endotronix will accept an 
echocardiogram from within 6 months of Screening provided the patient does not have a standard 
of care indication for an echocardiogram during this interval.  
8.1.11 NYHA Functional Classification 
AHA/ACC and NYHA classification guidelines can be found in Appendix 14.2.  The NYHA 
Functional classification categorizes the extent of HF by placing patients in one of four 
categories based on how much they are limited during physical activity and symptoms of 
shortness of breath and/or angina. Determination of NYHA classification will be performed 
by an independent assessor (defined as a physician or qualified PA, RN or NP not directly 
involved with this clinical trial).  
NYHA Functional Classification will be obtained at all study visits and must be NYHA Class III 
for study entry. 
8.1.12 Six (6) Minute Walk 
Subjects will complete a six (6) minute walk test at Screening, Month 6, 12 and 24 as well as 
at Year 3, 4 and 5. In addition, PAP Measurements will be obtained before and after 6-minute 
walk test after unblinding at Month 12, 24 and Year 3, 4 and 5.  
If the Subject is unable or unwilling to perform the 6-minute walk test, the distance recorded 
should be left blank. Instructions for the procedure are found in Appendix 14.3. 

 
 
 
 
 
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8.1.13 Quality of Life Questionnaire  
The KCCQ are measures of health-related quality of life and can be found in Appendix 14.4 
respectively. These questionnaires will be administered to subjects at screening visit  as soon 
they receive the Cordella System and at all follow up visits. Subjects will be instructed to 
perform the KCCQ via the myCordella™ Patient App. 
The KCCQ is a 23-item, self-administered instrument that quantifies physical function, 
symptoms (frequency, severity and recent change), social function, self-efficacy and 
knowledge, and quality of life related to HF.  
8.1.14 Health Economic/ Operational Questionnaire  
Subject related health economic or operational data may be collected throughout the study 
to provide an aggregated summary of case data to include, but not limited to Cordella Sensor 
procedural status (Inpatient/Outpatient), implant procedure complications, patient 
compliance to remote management schedule, readmissions during the study and care 
management experience feedback.  
8.1.15 Subject Training & Use: Cordella PA Sensor and HF System 
At the Screening/Enrollment Visit (Visit 1), subjects will be trained on the set up and use of 
the commercial Cordella System, on how to collect their weight, BP, HR and SpO2 and how 
to transmit their data daily for review.  
During the Implant Visit (Visit 2), subjects will also be trained to use the Reader while seated 
at the same time each day (i.e., morning) and will be instructed to collect PAP information 
together with the other vital signs and transmit the data daily for review. This training will be 
performed prior to the subject’s discharge from the implant visit hospitalization. 
If the subject is unable to use the Reader to collect PAP data, an Endotronix representative 
will be available by phone or in person to assist. Subjects will be instructed to collect this 
information daily throughout the study. Subject compliance will be defined as at least 5 days 
of data collection/transmissions. The 5 days of data collection/transmissions do not have to 
be consecutive days. 
8.1.16 Cordella PA Sensor Implant Procedure  
At the Cordella PA Sensor Implant Visit, the Sensor, which is pre-mounted on a catheter 
Delivery System, will be delivered according to the system’s IFU. Once deployed, the Sensor 
PAP will be calibrated using the systems fluid-filled catheter as part of an RHC.  The calibration 
coefficients for that Sensor/subject will be recorded in the CalEQ and stored in the CDAP, 
allowing for consistent PAP calculations throughout the life of the Sensor.  

 
 
 
 
 
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Subjects will be observed until stable (per clinicians’ discretion) and discharged home with 
post-RHC instructions and instructions to take their PAP measurements daily, which will be 
wirelessly transmitted to a secure website. Additional PAP measurements (seated and 
supine) will be performed within 24 hours of discharge. The study site should also instruct 
subjects to return for a catheter insertion site check per their standard-of-care. Before 
discharge, seated Cordella PA Sensor PAP will be measured via CalEQ.  
8.1.17 Right Heart Catheter Procedure  
A RHC procedure using percutaneous venous access will be performed at the Cordella PA 
Sensor Implant Visit, at Year 3 and as needed for Re-calibration purposes at the clinician’s 
discretion. The RHC should be performed per the site’s standard-of-care and subjects should 
also be asked by the site to return per their standard-of-care for a post-procedure catheter 
insertion site evaluation. 
The following measurements will be obtained from the RHC: 
• RAP 
• Right ventricular pressure (RVP): systolic, diastolic, end diastolic 
• PAP: systolic, diastolic, mean 
• Pulmonary Capillary Wedge Pressure (PCWP) 
• Heart Rate 
• CO 
• Cardiac Index (CI) 
8.1.18 Cordella PA Sensor PAP Measurements 
In addition, to daily PAP measurements transmitted by the subject, seated and supine PAP 
measurements are to be obtained at all Follow-up Visits* including systolic (sPAP), diastolic 
(dPAP), and mean (mPAP).  
* PAP measurements can also be performed by the subject at home at the Follow- up visit day.  
PAP readings from the Cordella PA Sensor will be accessible to the subjects and clinicians after 
the Cordella PA Sensor Implant Visit.  PAP changes from baseline will be assessed and 
notification limits need to be set for the subjects so that out of range PAP readings are flagged 
for the Investigator’s prompt review and appropriate HF management as per the guidelines 
in Appendix 14.5.  
8.1.19 Cordella PA Sensor and HF System Data Transmission & Compliance 
All subjects will be instructed to transmit their clinical data daily (PAP data and vital signs) 
using the myCordella™ Tablet during the study. Subjects will be asked to transmit their clinical 
data at approximately the same time each day (typically in the morning). Subjects will also be 
given a pre-set time window to make their daily transmission. 

 
 
 
 
 
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Use of the Cordella System and PAP Measurements will be monitored, and compliance will 
be measured by tracking the number of transmitted data occurrences. For study purposes, 
compliance will be defined as subjects transmitting at least 5 days of myCordella™ clinical 
data per week (does not need to be consecutive days). If a subject does not transmit at least 
5 days per week, Endotronix will notify the study site on a regular basis on their subject’s 
compliance.  
Subjects will then be notified by the study site to review system use expectations and any 
other user issues will be addressed.  
To help subjects with data transmission compliance during the study, the myCordella™ Tablet 
will be programmed with daily reminders to transmit data, successful transmission indicators, 
and flags to transmit data if a transmission is missed. 
8.1.20 myCordella™ Patient Management Portal (PMP) Data Review and Contact 
Following the Cordella PA Sensor implant, clinical data from the Cordella™ Heart Failure 
System including PAP sensor data will be continuously transmitted by all subjects and 
monitored by clinicians at the study site. Clinicians will be trained by an Endotronix 
representative on how to use the myCordella™ PMP to review data transmissions.   
For all subjects’ mandatory reviews and acknowledgements of all subject’s vital signs is 
required as per the table below to assure optimal hemodynamic PAPGHFM in addition to 
GDMT HF management for all patients:   
Data Review Schedule 
Comments 
Recommended Cordella System 
At least 2 times per week 
 
Mandatory PAP Sensor Data 
2 times per week 
maximum of 4 days between 
data reviews  
Regular review of the patient’s data will allow proactive heart failure management. It is 
assumed that post sensor implant, more intense HF management is needed to optimize the 
patient’s HF treatment for a period of 1-3 months, as the patient is treated to target 
pressures per the guidelines in Appendix 14.5 and GDMT.  Data displayed at the 
myCordella™ PMP will enable clinicians to effectively adjust medication dosages (e.g., drug 
titration) during this “optimization” period.  In the following “stabilization” phase, the 
clinician will be able to quickly assess the patient daily health status via the myCordella™ 
PMP and take action as needed.  As it is the nature of this particular disease, even under 
optimal treatment, HF patients are likely to worsen again over time.  Regular review of the 
patient PAP trends, in addition to other data provided by the Cordella System, will allow the 
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When worsening occurs, the patient will undergo again the “optimization” phase, followed 
by the “stabilization” phase as per the guidelines in Appendix 14.5. 
8.1.21 Subject Contact/ Subject Survey (Cohort #1 only) 
Subject Contact 
After unblinding subjects from Cohort #1 will be contacted by the clinical site as per the 
following schedule to discuss their PAP values:  
Time Point 
(Post unblinding) 
Contact via scheduled 
Phone Call or Cordella® System Messaging 
1 month 
X 
Quarterly 
X 
 
Additionally, a short optional site survey will be administered for those Cohort #1 subjects. 
This survey can be found in Appendix 14.8. 
Subject Survey 
A subject survey will be collected to evaluate the subjects experience on visibility of their PAP 
Measurements. This survey can be found in Appendix 14.9. 
This survey is optional and will be administered to all Cohort #1 subjects after the first month 
and then on a quarterly basis after unblinding/ cross-over.  
8.1.22 Concomitant Medications 
Administration of beta blockers (BB), ACE-I, ARB, ARNI, mineralocorticoid receptor 
antagonists, (MRA), nitrates, hydralazine, inotropes, anticoagulants, anti-arrhythmics, 
antiplatelet medications, antibiotics, diuretics and antihypertensive medications, and any 
other cardiac medications at all study visits between screening and year 5 will be recorded.  
Information collected at time of visit will include: 
• Drug 
• Dose 
• Route of administration 
Adverse Events 
Any Concomitant Medications taken prior, up to onset and to treat an Adverse Event will be 
collected at the time of each event. 
 
 

 
 
 
 
 
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Anticoagulation 
For subjects who are not being treated with chronic anticoagulant therapy, it is 
recommended to use dual antiplatelet therapy with aspirin and clopidogrel, (or prasugrel, 
ticagrelor) for 30 days post implant.   
Subjects who are currently on anticoagulant therapy, or those in which chronic anticoagulant 
therapy is indicated for HF treatment should discontinue use of anticoagulant therapy 1-2 
days prior to the Cordella Sensor implant and restart treatment post- implant. An INR of <1.5 
is recommended prior to sensor implant for subjects who were previously on anticoagulant 
therapy. The standard of care as bridge therapy to Cordella Sensor placement should be used 
in patients who were on anticoagulant therapy. 
Post 30 days, continuous single antiplatelet therapy with aspirin indefinitely is recommended. 
It is important to resume or initiate antiplatelet or anticoagulant therapy post-implant to 
reduce the likelihood of thrombotic events. 
8.2 
Device Explant 
In the event that the Cordella PA sensor is explanted (i.e., death or intervention to explant) the 
Cordella PA sensor should be returned to Endotronix for analysis. Endotronix will provide an Explant 
Kit that is designed for transportation of used health care products. Explant, packaging and shipping 
instructions will be included in each Explant Kit. In addition, a Return Goods Authorization (RGA) 
number must be obtained from Endotronix prior to shipment of the Cordella PA Sensor and 
associated components.  
8.3 
Schedule of Observations and Procedures  
8.3.1 Study Visit 1 (Screening/ Enrollment Visit) 
Subjects will be screened against entry criteria, and if confirmed to meet all requirements for 
enrollment and sign/date the current IRB approved consent, will be eligible for implant and 
enrollment into the study. The screening log will be maintained per Section 8.3.2 
Written ICF must be provided by the subject prior to any study procedures being conducted, 
including screening labs or tests of any kind. Subjects will be screened against the inclusion 
and exclusion criteria and, if confirmed to meet all requirements, will then be enrolled into 
the study. 
The following study procedures will be performed during this visit: 
• Informed Consent  
• Subject Demographics 

 
 
 
 
 
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• Study Eligibility Review 
• Cardiac/Medical & Surgical History 
• Physical Examination 
• Height, Weight and BMI 
• Vital Signs: BP, HR, SpO2 
• 12-Lead ECG  
• Safety Labs (Chemistry & Hematology & Urinalysis) 
• Urine Pregnancy Test (female), if applicable 
• Serum NT-pro BNP 
• aPTT/INR (if indicated) 
• Echocardiogram (may be obtained within 3  months of Screening)* 
• NYHA Functional Classification (may be obtained within the 30 day Study Visit 1 window) 
• 6-Minute Walk Test  
• KCCQ Quality of Life Questionnaires 
• Concurrent/Cardiac Medications  
• Set Up/Subject Training: Cordella™ HF System (myCordella™ Tablet & Peripherals)* 
*While an echocardiogram within 3 months of the screening visit date is preferable.  In case this is 
not possible, Endotronix will accept an echocardiogram from within 6 months of Screening provided 
the patient does not have a standard of care indication for an echocardiogram during this interval. 
After the subject has been approved by the PROACTIVE-HF Clinical Eligibility Committee, they 
will be enrolled into the study and can be scheduled for Study Visit 2 (Implant Visit). 
In case a subject will be implanted >30 days after Study Visit 1, the following study procedures 
will need to be repeated and results obtained prior to implant: 
• Reconfirm Study Eligibility Review 
• Any changes in Health Status 
• Any changes in concomitant medications  
•  Repeat  selected Safety Labs  
Hematology 
Biochemistry 
Urinalysis  
Hemoglobin 
Sodium  
Glucose 
Nitrite 
Hematocrit  
Potassium 
Protein 
Blood 
Leucocytes 
Creatinine 
Specific gravity 
Leukocytes 
Platelets 
BUN 
pH 
 
Lymphocytes 
SGOT (AST) 
Ketones 
 
aPTT/ INR 
SGPT (ALT) 
Bilirubin 
 
INR 
GFR 
Urine Pregnancy Test (females) 
* Subject training  on and distribution of the commercial Cordella™ System (   

 
 
 
 
 
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8.3.2 Study Visit 2 (Cordella PA Sensor Implant Visit: Admission & Implant) 
Before the subjects return for the Cordella PA Sensor Implant Visit, they will be instructed by 
the Investigator to discontinue use of anticoagulation therapy 1-2 days prior to the 
procedure.  The investigator should consider utilizing another anticoagulant per the site’s 
standard-of-care as bridge therapy to Cordella PA Sensor placement in subjects who were on 
anticoagulation therapy.  
Implant procedures for the Cordella PA Sensor are described in detail in section 6 of the IFU, 
which will be provided to each site at study start.  
Implants may be performed via RHC using percutaneous venous access. 
In case the Cordella PA Sensor Implant is attempted but not completed, subjects will be 
followed through 30 days for safety purposes. 
It is critical that accountability of the device is maintained for research records.  Federal 
regulations require that the lots / ID number of the device are appropriately noted and 
tracked (please also see Section 2.4). 
The following study procedures will be performed during this visit: 
• Cordella PA Sensor implant 
• RHC PAP: diastolic, systolic, mean, HR, RAP, Pulmonary Capillary Wedge Pressure (PCWP), 
CO, Cardiac Index (CI), RVP: diastolic, systolic, end diastolic  
• Cordella PA Sensor PAP: diastolic, systolic, mean, pulse (via CalEQ): 
  after calibration 
 seated and supine before discharge or at home (within 24 hours) 
• Set Up/Subject Training: Cordella™ HF System (myCordella™ Tablet & Peripherals) 
• Subject Training/Subject Use: CorPASS (myCordella ™ Patient Reader and Dock)  
• Abbreviated Physical Examination 
• Concurrent/Cardiac Medications  
• Adverse Event 
8.3.3 Study Visit 3 (Month 1, ±7 days) 
The following study procedures will be performed prior/ during this visit: 
• Abbreviated Physical Examination 
• Vital Signs: weight, BP, HR and SpO2 (via myCordella™ Patient App) 
• Serum NT-pro BNP  
• Cordella PA Sensor PAP (seated and supine): diastolic, systolic, mean, pulse (via 
myCordella™ Patient App) 
• Subject Status 
• NYHA Functional Classification 
• KCCQ Quality of Life Questionnaire 

 
 
 
 
 
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• Concurrent/Cardiac Medications  
• Adverse Event  
8.3.4 Study Visit 4 (Month 3, ±7 days) 
This visit should be performed as remote/ virtual Telemonitoring Visit and the following study 
procedures will be performed prior/during this visit: 
• Vital Signs: weight, BP, HR and SpO2 (via myCordella™ Patient App) 
• Serum NT-pro BNP (if available) 
• Cordella PA Sensor PAP (seated and supine): diastolic, systolic, mean, pulse (via 
myCordella™ Patient App) 
• Subject Status 
• NYHA Functional Classification 
• KCCQ Quality of Life Questionnaire 
• Concurrent/Cardiac Medications  
• Adverse Event  
8.3.5 Study Visit 5 (Month 6, ±14 days) 
The following study procedures will be performed prior/ during this visit: 
• Abbreviated Physical Examination 
• Vital Signs: weight, BP, HR and SpO2 (via myCordella™ Patient App) 
• 12-Lead ECG  
• Safety Labs (Chemistry & Hematology) 
• Serum NT-pro BNP  
• Cordella PA Sensor PAP (seated and supine): diastolic, systolic, mean, pulse (via 
myCordella™ Patient App) 
• Subject Status* including question on assigned treatment 
• 6-Minute Walk Test 
• NYHA Functional Classification 
• KCCQ Quality of Life Questionnaire 
• Concurrent/Cardiac Medications  
• Adverse Event  
8.3.6 Study Visit 6 (Month 12 ±30 days) 
The following study procedures will be performed prior/ during this visit: 
• Abbreviated Physical Examination 
• Vital Signs: weight, BP, HR and SpO2 (via myCordella™ Patient App) 
• 12-Lead ECG  
• Safety Labs (Chemistry & Hematology) 

 
 
 
 
 
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• Serum NT-pro BNP  
• Cordella PA Sensor PAP (seated and supine): diastolic, systolic, mean, pulse (via 
myCordella™ Patient App ) 
• Echocardiogram  
• Subject Status* including question on assigned treatment 
• 6-Minute Walk Test (additional PAP Measurements will be obtained before and after 6-
minute walk test via myCordella™ Patient App) 
• NYHA Functional Classification 
• KCCQ Quality of Life Questionnaire 
• Concurrent/Cardiac Medications  
• Adverse Event 
8.3.7 Study Visit 7 to 8 (Month 18, 24, ±30 days) 
The following study procedures will be performed prior/ during this visit: 
• Abbreviated Physical Examination 
• Vital Signs: weight, BP, HR andSpO2 (via myCordella™ Patient App) 
• 12-Lead ECG (Visit 8 only) 
• Safety Labs (Chemistry & Hematology) (Visit 8 only) 
• Serum NT-pro BNP  
• Cordella PA Sensor PAP (seated and supine): diastolic, systolic, mean, pulse (via 
myCordella™ Patient App) 
• Subject Status 
• 6-Minute Walk Test (additional PAP Measurements will be obtained before and after 6-
minute walk test via myCordella™ Patient App) (Visit 8 only) 
• NYHA Functional Classification 
• KCCQ Quality of Life Questionnaire 
• Concurrent/Cardiac Medications  
• Adverse Event 
• Health Economic Questionnaire/Cost-Effectiveness Analysis (Visit 8 only) 
8.3.8 Study Visits 9 to 11 (Years 3, 4, 5 ±30 days) 
The following study procedures will be performed prior/during these visits: 
• Abbreviated Physical Examination 
• Vital Signs: weight, BP, HR and SpO2(via myCordella™ Patient App) 
• 12-Lead ECG  
• Safety Labs (Chemistry & Hematology) 
• Serum NT-pro BNP  

 
 
 
 
 
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• RHC PAP: diastolic, systolic, mean, HR, RAP, Pulmonary Capillary Wedge Pressure (PCWP), 
CO, Cardiac Index (CI), RVP: diastolic, systolic, end diastolic * 
• Cordella PA Sensor PAP (seated and supine): diastolic, systolic, mean, pulse (via 
myCordella™ Patient App) 
• Echocardiogram 
• Subject Status 
• 6-Minute Walk Test (additional PAP Measurements will be obtained before and after 6-
minute walk test via myCordella™ Patient App) 
• NYHA Functional Classification 
• KCCQ Quality of Life Questionnaire 
• Concurrent/Cardiac Medications  
• Adverse Event 
*Visit 9/ Year 3 only 
8.3.9 Early Termination Visit 
The following study procedures will be performed prior/during this visit: 
• Abbreviated Physical Examination 
• Vital Signs: weight, BP, HR andSpO2 (via myCordella™ Patient App) 
• 12-Lead ECG  
• Safety Labs (Chemistry & Hematology) 
• Serum NT-pro BNP  
• Cordella PA Sensor PAP (seated and supine): diastolic, systolic, mean, pulse 
• Subject Status 
• 6-Minute Walk Test 
• NYHA Functional Classification 
• KCCQ Quality of Life Questionnaire 
• Concurrent/Cardiac Medications  
• Adverse Event 
 

 
 
 
 
 
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9 
ADVERSE EVENTS 
From the time of enrollment, at each evaluation of a subject enrolled in the trial, the investigator or 
site staff determines whether any adverse events (AE) have occurred and determines their 
relationship to the study devices or procedures. All adverse events, study device malfunctions and 
other product issues must be recorded in the appropriate eCRF section(s). 
Safety will be assessed throughout the study by the frequency of Adverse Events (AEs), pressure 
sensor failure rate, and device/system-related complications by relationship to the device and 
severity. Additional emphasis on safety for the primary safety endpoint will be placed through 6 
month following the Cordella PA Sensor Implant procedure to capture any adverse events 
associated with use of the Cordella PA Sensor. 
Adverse events may be volunteered spontaneously by the subject, or discovered as a result of 
general, non-leading questioning.  If it is determined that an AE has occurred, the investigator 
should obtain all the information required to complete the AE page of the eCRF, in accordance with 
the guidelines that accompany it. The investigator must submit to sponsor (or designee) any UADEs, 
and SAEs occurring during the study within 24 hours after being notified of the event and provides 
additional information, if required by Endotronix. 
All AEs must be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained or is judged by the investigator to be no longer clinically significant, or until the subject is 
lost to follow-up.  The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations necessary to elucidate as completely as practical the nature and/or 
causality of the AE.  This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
Investigators are not obligated to actively seek AEs in former study participants. However, if the 
investigator learns of any SAE, including a death, at any time after a subject has been discharged 
from the study, and he/she considers the event reasonably related to the investigational product or 
study participation, the investigator should promptly notify Endotronix. 
All AEs will be collected until a subject’s participation in the trial is considered complete.  
 
 

 
 
 
 
 
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9.1 
Definition and Documentation of Adverse Events  
Adverse Event definitions specific to the EU sites can be found in Appendix 14.7. 
9.1.1 Adverse Events (AE) 
An adverse event is any undesirable clinical occurrence in a subject whether it is considered 
to be device related or not. 
9.1.2 Serious Adverse Event (SAE): 
The event is serious when the patient outcome is: 
• Death 
• Life-threatening 
• Hospitalization (initial or prolonged) 
• Disability or permanent change 
• Congenital Anomaly/Birth Defect 
• Required Intervention to Prevent Permanent Impairment or Damage 
• Other Serious (Important Medical Events) 
A planned hospitalization for a pre-existing condition, or a procedure required by the 
protocol, without a serious deterioration in health, is not considered to be a serious adverse 
event. 
9.1.3 Device or Procedure-Related Adverse Events 
9.1.3.1 
Device deficiency (DD) 
Inadequacy of a medical device related to its identity, quality, durability, reliability, safety 
or performance, such as malfunction, misuse or use error, and inadequate labeling.  
9.1.3.2 
Unanticipated Adverse Device Effect (UADE)  
Any serious adverse effect on health or safety, any life threatening problem or death 
caused by, or associated with a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or 
application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects (21CFR812.3).   

 
 
 
 
 
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9.1.4 Anticipated/ Expected Adverse Events:  
An anticipated/expected event by its nature, incidence, severity or outcome has been 
previously identified in the risk analysis report and is included into the table below.  
Anticipated Adverse Events include those that are reasonably expected to occur in 
association with the use of any RHC and the use of the result of implanting an investigational 
medical device. The anticipated/ expected adverse events that will be collected are: 

 
 
 
 
 
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Potential Event 
Overall Incidence % 
overall 
Allergic reaction 33 
3% 
Arrhythmias 34-36 
< 1% 
Bleeding complications which may require transfusion 
< 1% 
Cardiac arrest 34 
< 1% 
Chest pain 34,36 
< 1% 
Death 34,36 
< 1% 
Device embolization/migration 
Not Available 
Device explant 
< 1% 
Emergent or urgent cardiac, vascular, and/or other surgery necessitated 
by the device or implant procedure 
Not Available 
Endocarditis or device infection 36 
< 1% 
Entry site complications (e.g., hematoma, dissection) 34,36 
< 1% 
Fracture of a component of the device/system that may or may not lead 
to serious injury or surgical intervention 
Not Available 
Gastrointestinal bleed 36 
3% 
Hemoptysis24,43 
< 1% 
Hypo or hypertension 34,36 
6% 
Infection 36,37 
< 1% 
Peripheral embolism/thrombus 
Not Available 
Pulmonary embolism/pulmonary occlusion 36 
< 1% 
Pseudoaneurysm of the vein 38-40 
< 2% 
Radiation exposure 
Not Available 
Reaction to contrast media/ medication 33 
3% 
Renal insufficiency or failure 41 
10% 
Respiratory distress or failure (breathing problems) 
Not Available 
Sepsis 
< 1% 
Valvular injury (tricuspid and/or pulmonary) 
Not Available 
Vascular complications (e.g., venous dissection, perforation, rupture, 
arteriovenous fistula) 35 
< 1% 
Vessel Trauma which may require surgical repair 35,36 
< 1% 
Worsening heart failure 
< 30%36 
 
 

 
 
 
 
 
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9.2 
Assessment of Causality 
The likely relationship of each adverse event to the investigational medical device will be assessed 
according to the definitions below: 
9.2.1 Not related 
 
Is defined as an AE which is not related to the use of the investigational medical device. 
9.2.2 Unlikely related  
The relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
9.2.3 Possibly related  
 
Is defined as an AE which might be due to the use of the investigational device. An alternative 
explanation (e.g., concomitant drug(s), concomitant disease(s)) is inconclusive. The 
relationship in time is reasonable; therefore, the causal relationship cannot be excluded. 
9.2.4 Probably related 
The relationship with the use of the investigational device seems relevant and/or the event 
cannot reasonably be explained by another cause, but additional information may be 
obtained.  
9.2.5 Related  
Data demonstrating clear evidence for a causal relationship (i.e., a clinical event, including 
laboratory test abnormality, occurring in a plausible time relationship to the investigational 
medical device, which cannot be explained by concurrent disease or other factors.)  
9.3 
Adverse Event Reporting Requirements 
9.3.1 Investigator Reporting Requirements 
All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, must 
be recorded using medical terminology in the source document and in the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
"upper respiratory infection"). Investigators must record in the eCRF their opinion concerning 
the relationship of the AE to study therapy. All measures required for AE management must 
be recorded in the source document and reported according to Endotronix instructions. 

 
 
 
 
 
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All events will be classified per Adverse Event definitions as documented in Appendix 14.7.  
Additionally, the date of the event, seriousness criteria and outcome should also be recorded.   
Laboratory and clinical parameters will be followed to evaluate the safety and performance 
of the Cordella PA Sensor System; these include adverse event reporting and monitoring, 
routine clinical laboratory tests (hematology, biochemistry, and urinalysis), vital signs, review 
of concomitant medications and echocardiogram. 
It is the responsibility of the investigators to inform their IRB/IEC of adverse events as 
required by their local IRB procedures.  
Investigators must notify Endotronix (or designee) within 24 hours of discovering any 
Unanticipated Adverse Device Effects (UADE)/ Unanticipated Serious Adverse Device Effect 
(USADE).  Investigators are required to submit a report of a UADE/ USADE to the reviewing 
IRB/ IEC as soon as possible, but in no event later than 10 working days after the investigator 
first learns of the event.  UADEs/USADEs must be documented on the appropriate eCRF.   
9.3.2 Regulatory Reporting Requirements 
UADE/ USADE: 
Endotronix’s evaluation of the UADE/ USADE must be reported to the FDA/CAs, all reviewing 
IRBs/IECs, and participating investigators within 10 working days of knowledge of the event 
by Endotronix.  All UADE/ USADEs will be reported to the FDA/CAs according to regulatory 
reporting requirements found in CFR 812.46 (US) and MDCG 2020-10/1 under Directive 
Regulation 2017/ 745 on Medical Device Regulations (MDR) (EU). Contacts for SAE/ UADE/ 
USADE receipt can be found on the Endotronix/Medical Monitor Contact Information page in 
the Site File. 
AEs/ DDs 
Endotronix Inc. is required to expedite to worldwide regulatory authorities reports of AEs and 
DDs as applicable for each region and in line with the relevant legislation including Safety 
21CFR 812.3, CFR 812.46 (US) as well as in MDCG 2020-10/1 under Directive Regulation 
2017/745 on MDR (EU). 
All investigators will receive a safety letter notifying them of relevant reports.  In accordance 
with the applicable national regulations, Endotronix or designee will notify the relevant IRBs/ 
IECs of applicable reports as individual notifications or through a periodic line listing as 
defined in the region’s applicable Safety Plan. 
Endotronix or its designee will submit to the regulatory authorities all safety updates and 
periodic reports, as required by applicable regulatory requirements.  

 
 
 
 
 
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Endotronix authorized a CRO to perform the processing (receipt/triage/reporting) of SAEs 
within this clinical trial. The responsible vigilance contact person is:  
Iva Penava, Safety Projects Manager,  
Syneos Health  
Email: safetyreporting@syneoshealth.com 
Details and Instructions on the procedures for the documentation, evaluation and reporting 
of SAEs occurring in this clinical trial to the German Federal Institute for Drugs and Medical 
Devices (BfArM) can be found on www.bfarm.de and in the study specific Safety Management 
Plan. 
9.3.3 Contacting Endotronix Regarding Safety 
Contacts for SAE/ USADE receipt can be found on the Sponsor/Medical Monitor Contact 
Information page in the Site File. 
9.4 
Device/System-Related Complication (DSRC) 
Any suspected Cordella PA Sensor System malfunction will be reported to Endotronix and recorded 
on the eCRF.  Any potentially affected component(s) will be returned to Endotronix for evaluation 
upon request by Endotronix. A DSRC is defined as an adverse event that is, or is possibly, related to 
the device/system (Cordella PA Sensor System or electronic components) and is either treated 
invasively (other than intramuscular medication or diagnostic RHC) or results in patient death or 
explant of the device.  
Pressure Sensor Failure is assumed when the sensor malfunctions and no readings can be obtained.  
All attempts to troubleshoot (including recalibration) should be exhausted including ruling out any 
problems with the electronic components, prior to determining that a Pressure Sensor Failure has 
occurred. 
9.5 
 Study Implant Card 
As the subjects are not under 24-hour supervision of the Investigator or site staff, they must be 
provided with a "study/implant card" indicating the following: 
• Investigational device name/model 
• Investigational device identifiers (serial numbers, etc.…) 
• Study number 
• Investigator's name 
• 24-hour emergency contact number 

 
 
 
 
 
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• Warnings or precautions 
• Expected lifetime of the investigational device 
• Any other information to ensure safe use of the investigational device 

 
 
 
 
 
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10 
STATISTICAL CONSIDERATIONS 
10.1 
General Statistical Considerations 
All data collected in this study will be documented using summary tables and subject data listings.  
For categorical variables, frequencies and percentages will be presented.  For continuous variables, 
descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will be 
presented.  
Demographic data, including sex, gender, race, age, weight, height, race, ethnicity, BMI, and 
screening assessments (e.g., primary cardiac diagnosis, previous cardiac history, duration of HF, 
number of hospitalizations in past year for cardiac) will be summarized using frequencies and 
percentages, or descriptive statistics, as applicable.  
Any deviations from the planned statistical analyses will be reported with proper justification as a 
protocol deviation. 
Statistical analysis will be performed using SAS version 9.3 or higher. 
10.2 
Analysis Population 
The focus of analyses will be on treated subjects from Cohort #2 and #3 (previously enrolled 
Treatment Arm subjects and Newly Enrolled subjects). Unless otherwise specified, the sets defined 
below are based only on these two treated cohorts. 
10.2.1 Enrolled Set 
The Enrolled Set will include all subjects enrolled from Cohort #2 and #3. Screen failures are not 
entered into the database and are therefore not included in this set.  
10.2.2 Intent-to- Treat Population (ITT) 
The Intent-to-Treat Population (ITT) will include all enrolled subjects intended to receive the 
Cordella PA Sensor who entered the Cath Lab, including those in whom Implant Procedure is not 
attempted for whatever reason (e.g., Cordella PA Sensor Implant cannot be performed due to 
anatomical reasons) from Cohort #2 and #3.  Subjects in this population in whom the Cordella PA 
Sensor Implant is not attempted will be followed through 30 days for safety purposes. The ITT will 
be used for all analyses of safety endpoints. Effectiveness analysis will not be performed on the ITT 
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10.2.3 Modified Intent-to-Treat Population (mITT) 
The Modified Intent-to-Treat Population (mITT) will include all implanted subjects form Cohort #2 
and Cohort #3. All primary and secondary effectiveness analyses will be performed on the mITT. 
10.2.4 Per Protocol Population (PP) 
The Per Protocol Population (PP) will include all mITT subjects without any major protocol 
deviations. All primary and secondary safety and effectiveness analyses will be performed in 
addition on PP population. If PP and mITT populations will be identical, analysis will be performed 
based on mITT only. 
10.2.5 Cohort #1- Previously enrolled Control Arm subjects- Population  
This subgroup will include all Cohort #1 (previously enrolled Control Arm) subjects and will be 
reported separately for all endpoints. 
10.3 
Primary Efficacy Endpoint and Hypotheses 
To meet the objectives of the study, observed event rates in the single arm PROACTIVE-HF should 
be similar to observed event rates in the treatment arm of CardioMEMS studies.  Furthermore, 
observed event rates in the single arm PROACTIVE-HF should be lower than observed event rates in 
the control arm of CardioMEMS studies.   
Thus, we set the performance goal (PG) as the LOWER of 1) the meta-analysis upper bound 
confidence interval of CardioMEMS treated patients, and 2) the meta-analysis estimate of 
CardioMEMS control patients, further adjusted down by potential impact of SGLT2i. 
Furthermore, we also require that the single arm PROACTIVE-HF observed event rate is LOWER 
than both 1) the meta-analysis estimate of CardioMEMS treatment patients, and 2) the lowest 
observed event rates of CardioMEMS control patients, further adjusted down by potential impact 
of SGLT2i. 
The primary endpoint will be the 6 month incidence of HF related Hospitalizations (HFH) or all-cause 
mortality compared to a PG.  
Meta-analysis of treatment and control event rates were considered in determining the Primary 
Endpoint PG. Meta-analyses were based on a random effects meta-analysis for the log-transformed 

 
 
 
 
 
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incidence rate fit via restricted maximum likelihood. Results are back transformed to the rate scale. 
Calculations were performed in R version 3.6.3 with the “metafor” package. 
The mean 6 month event rate from the meta-analysis of prior control studies is 0.46, or 0.43 on an 
adjusted basis to account for SGLT2i inclusion in the guidelinesa.  A 6 month event rate of 0.43 also 
represents a value just below both the highest event rate observed across the CardioMEMS 
treatment studies (0.44 in MEMS-HF) and the upper bound of the overall meta-analytic treatment 
estimate (0.44).  Taking the totality of results from the meta-analysis of active treatment trials, 
individual results of active treatment trials, as well as the meta-analysis of control trials, we set the 
primary endpoint performance goal (PG6) at 0.43.   
Furthermore, the mean 6 month event rate from the meta-analysis of prior treatment studies is 
0.38, with both the CHAMPION (0.37) and GUIDE-HF (0.31, NYHA class III) treatment groups with 
event rates lower than the mean.  The lowest 6 month event rate across CardioMEMS control 
studies of 0.39 occurred in GUIDE-HF (NYHA class III), where modest use of SGLT2i occurred during 
the trial.  We conservatively adjust this lowest observed control event rate down to 0.37 to account 
for increased SGLT2i utilization. 
The table below outlines the data sources used to derive a PG for this endpoint. 
Since patient level data was not available and summary data was limited in scope, analysis was 
based on the numbers of events reported from each study and the number of enrolled subjects 
was for denominator, assuming all subjects were followed for the corresponding time period. 
Accordingly, the estimates are likely conservative underestimates of true rates since complete 
follow-up on all subjects was unlikely. 
For studies reporting only 12 month rates, estimates of 6 month rates were estimated via an 
exponential distribution. For example, for a study with a reported 12 month rate, r12, we calculated 
the 6 month rate, r6, as: 
r6 = 1-exp(logn(1- r12)/2) 
where the division by two (2) accounts for a calculation of the rate for half the follow-up time (i.e. a 
linearized rate). When possible, events of each type (HF related hospitalization and death) were 
 
 
 
a Adjustment applied assuming 50% use of SGLT2i at the average hazard ratio observed across EMPEROR 
Preserved, EMPEROR REDUCED, DAPA-HF for NYHA III subjects. 

 
 
 
 
 
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calculated separately and summed to produce the composite event counts and the corresponding 
composite rate. Rates are calculated as numbers of events over numbers of subjects. 
Active Treatment - updated 6 Month Rates with calculation details 
Study/Publication 
Number of 
Subjects1 
Events 
Rate2 
Details 
CHAMPION19 
270 
99 
0.37 
- 
6 month HFH rate reported as 0.31, yielding approx. 84 events 
- 
15 deaths reported 
- 
Adding calculated 6 month HFH events and deaths yields 99 
events 
MEMS PAS44 
1200 
493 
0.41 
- 
6 month rate calculated via reported 12 month rate of 0.54  
- 
Calculated 6 month HFH rate of 0.32, yielding 386 events 
- 
107 deaths reported 
- 
Adding calculated 6 
- 
month HFH events and deaths yields 493 events 
MEMS-HF 46 
234 
102 
0.44 
- 
6 month HFH calculated via reported 12 month rate of 0.60 
- 
Calculated 6 month HFH rate of 0.37, yielding 86 events 
- 
16 deaths reported 
- 
Adding calculated 6 month HFH and deaths yields 102 events 
GUIDE-HF 52 – NYHA 
class III only 
322 
100 
0.31 
- 
Reported 12 month rate of  0.431/0.089 for HFH/D, for 
composite of 0.52.  
- 
Assuming exponential rate, calculated 6 month rate (events) is 
0.31 (100) 
- 
Events calculated as 322 subjects x 0.31 
Estimate (CI) 
0.38 (0.33, 0.44) 
1 Numbers of subjects are those treated subjects estimated to be followed for 6 month events.  
2 Estimates for events are based on either reported results or are estimated from published figures. For studies reporting 12 month 
results, 6 month rates were estimated based on exponential rates.  
Altogether, for study success, the upper confidence bound of the observed event rate for the 
planned study must be less than the PG6 (0.43) and the observed event rate must be less than 0.37.  
Evaluating the upper bound of the confidence interval for the rate ensures that 1) the observed 
rate will be comparable to prior studies of active treatment (highest observed value = 0.44), 2) the 
observed rate will be less than the meta-analytic value derived from prior studies of treatment and 
control, and 3) the observed rate will be less than the lowest rate observed in the control studies 
(GUIDE HF).  The added requirement for the observed event rate to be less than 0.37 provides 
further assurance that results are comparable to studies of prior CardioMEMS treatment. 
The assumed PROACTIVE-HF population event rate is expected to be 0.34.  This assumed event rate 
is lower than all prior active CardioMEMS treatment rates except for GUIDE-HF.  While the 

 
 
 
 
 
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contemporary GUIDE-HF study observed an event rate of 0.31 (NYHA Class III), PROACTIVE-HF has 
higher NTproBNP thresholds than the GUIDE-HF cohort and we expect subjects with higher 
NTproBNP levels to more closely align with subjects with a recent hospitalization, which have 
higher event rates.   
The mathematical statement of the null and alternative hypothesis is as follows: 
𝐻𝐻𝑂𝑂: r6 ≥ PG6 
𝐻𝐻𝐴𝐴: r6 < PG6 
where r6 is the 6 month rate of primary endpoint events and PG6 is the performance goal. A value 
of 0.43 will be used for the goal. The null hypothesis will be rejected if the upper confidence bound 
for the rate is less than the performance goal, or equivalently, that the corresponding p-value from 
the hypothesis test is less than 0.025. An observed rate of less than 0.37 and rejection of the null 
hypothesis indicate that the observed rate is statistically less than the performance goal, indicating 
clinically acceptable results and study success. Analysis will be based on a Poisson regression 
approach for the number of events, with the log follow-up time as an offset term. Sensitivity 
analyses using a negative binomial approach to capture within-subject correlation will be 
performed.  
The study will implant 450 subjects (combined in Cohort #2 and Cohort #3) leading to an expected 
evaluable cohort of 406 subjects. With a goal of 0.43 and a one-sided 0.025 alpha level, the study 
will have greater than 80% power assuming a population treatment rate of 0.34. Calculations are 
based on a one-sample Poisson rate test and were performed with PASS 2021.  
10.4 
Additional Secondary Efficacy Endpoints 
The first secondary efficacy endpoint is incidence of HF Hospitalizations or all-cause mortality at 12 
months compared to a PG. 
The mean 12 month event rate from the meta-analysis of prior control studies is 0.75, or 0.70 on an 
adjusted basis to account for SGLT-2i inclusion in the guidelinesb.  A 12 month event rate of 0.70 
represents a value just below the highest event rate observed across the CardioMEMS treatment 
studies (0.73 in MEMS-HF) and the upper bound of the overall meta-analytic treatment estimate 
(0.74). Taking the totality of results from the meta-analysis of active treatment trials, individual 
 
 
 
b Adjustment applied assuming 50% use of SGLT2i at the average hazard ratio observed across EMPEROR 
Preserved, EMPEROR REDUCED, DAPA-HF for NYHA III subjects. 

 
 
 
 
 
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results of active treatment trials, as well as the meta-analysis of control trials, we set the secondary 
endpoint performance goal (PG12) at 0.70.   
Furthermore, the mean 12 month event rate from the meta-analysis of prior treatment studies is 
0.64, with both the CHAMPION (0.6) and GUIDE-HF (0.52, NYHA class III) treatment groups with 
event rates lower than the mean.  The lowest 12 month event rate across CardioMEMS control 
studies of 0.63 occurred in GUIDE-HF (NYHA class III only), where modest use of SGLT2i occurred 
during the trial.  We conservatively adjust this lowest observed control event rate down to 0.59 to 
account for increased SGLT2i utilization. 
The table below outlines the data sources used to derive a PG for this endpoint. 
Active Treatment - updated 12 Month Rates with calculation details  
Study/Publication 
Number of 
Subjects1 
Events 
Rate2 
Details 
CHAMPION53 
270 
162 
0.60 
- 
HFH rate of 0.46, yielding approx. 124 events 
- 
Mortality rate of 0.14, yielding approx. 38 
events 
- 
Total events = 124 + 38 
MEMS PAS44 
1200 
840 
0.70 
- 
HFH rate of 0.54, yielding 648 events 
- 
Mortality rate of 0.16, yielding 192 events 
- 
Total events = 648 + 192 
MEMS-HF 46 
234 
171 
0.73 
- 
HFH rate of 0.60, yielding 140 events 
- 
Mortality rate of 0.13, yielding approx. 30 
events 
- 
Total events = 140 + 31 
GUIDE-HF 51 – NYHA 
class III only 
 
322 
167 
0.52 
- 
 
- 
HFH rate of 0.431 + plus death rate of 0.0897 
- 
Composite rate = 0.52 
- 
Total events = 322 subjects x 0.52 
Estimate CI 
0.64 (0.55, 074) 
Altogether, for study success, the upper confidence bound of the observed event rate for the 
planned study must be less than the PG12 (0.70) and the observed event rate must be less than 
0.59.  Evaluating the upper bound of the confidence interval for the rate ensures that 1) the 
observed rate will be comparable to prior studies of active treatment (highest observed value = 
0.74), 2) the observed rate will be less than the meta-analytic value derived from prior studies of 
treatment and control, and 3) the observed rate will be less than the lowest rate observed in the 

 
 
 
 
 
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control studies (GUIDE HF).  The added requirement for the observed rate to be less than 0.59 
provides further assurance that results are comparable to studies of prior treatment. 
The assumed PROACTIVE-HF population event rate is expected to be 0.55.  This assumed event rate 
is lower than all prior active CardioMEMS treatment rates except for GUIDE-HF.  While the 
contemporary GUIDE-HF study (NYHA class III only) observed an event rate of 0.52, PROACTIVE-HF 
has higher NTproBNP thresholds than the GUIDE-HF cohort and we expect subjects with higher 
NTproBNP levels to more closely align with subjects with a recent hospitalization, which have 
higher event rates.  The mathematical statement of the null and alternative hypothesis for the first 
secondary efficacy is as follows: 
𝐻𝐻𝑂𝑂: r12 ≥ PG12 
𝐻𝐻𝐴𝐴: r12 < PG12 
where r12 is the 12 month rate of secondary endpoint events and PG12 is the performance goal. A 
value of 0.70  will be used for the goal. The null hypothesis will be rejected if the upper confidence 
bound for the rate is less than the performance goal, or equivalently, that the corresponding p-
value from the hypothesis test is less than 0.025. An observed value of less than 0.59 and rejection 
of the null will indicate that the observed rate is statistically less than the performance goal, 
indicating clinically acceptable results. Analysis will be based on a Poisson regression approach for 
the number of events, with the log follow-up time as an offset term. Sensitivity analyses using a 
negative binomial approach to capture within-subject correlation will be performed. 
Sample size calculations for the first secondary endpoint were performed in PASS 2021 and based 
on an assumed population event rate of 0.55, the sample size of 450 subjects would provide 
approximately 95% power for the secondary endpoint based on a one-sided 0.025 alpha level. If 
406 subjects are followed for 12 months, approximately 95% power will be provided, so that the 
planned sample size is sufficient in light of potential attrition.  
Formal hypothesis testing for the purposes of labeling claims for the first secondary efficacy 
endpoint will only be performed if the null hypothesis for the primary efficacy endpoint is 
successfully rejected.  
This gatekeeping approach preserves the overall type I error rate. Any other calculated P-values 
and confidence intervals for secondary endpoints will be nominal, without adjustment for multiple 
comparisons. 
The remaining secondary efficacy endpoints are as follows: 
1. Number of HF Hospitalizations at 6 and 12 months post-implant compared to the number of HF 
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2. Comparison of the number of HF Hospitalizations or Emergency Department/ Hospital 
Outpatient IV diuretic visits of Cohort #1 and Cohort #2+#3 at 6 and 12 month post implant   
3. Change of NT-pro BNP from Baseline through 6 and 12 months 
4. Combined outcome of: 
a. First and recurrent HF Hospitalizations 
b. Emergency Department/ Hospital Outpatient IV diuretic visits 
c. all-cause mortality  
at 6 months, added together with equal weighting into a total number of events 
5. Heart failure hospitalization or Emergency Department / Hospital Outpatient IV diuretic visits at 
6 and 12 months 
6. Cardiac and all-cause mortality 
7. Days Alive and Out of Hospital (DAOH) 
8. IV diuretic visits 
9. Heart failure related Medication changes 
10. Change in PAP: 
a. From Baseline through 6 and 12 months in subjects with a baseline mPAP 
i. above target range 
ii. within or below target range 
iii. Overall 
b. Before and after 6-Minute Walk Test 
11. Percentage of device success as documented by ability of the System to successfully transmit PAP 
data  
12. Patient Outcome Measures, measured by KCCQ  
13. Functional status improvement, as measured by NYHA and 6-Minute Walk Test 
14. Health Economic Analysis 
10.5 
Safety Endpoints 
There are two primary safety endpoints, Freedom from device/system related complication at 6 
months and Freedom from pressure sensor failure at 6 months.  Freedom from device or system 
related complications at 6 months will be tested against the null rate of 90%.  Freedom from 
Pressure Sensor Failure at 6 months will be tested against the null rate of 95%.  
Mathematical statements of the null and alternative hypothesis for each test are as follows: 
𝐻𝐻𝑂𝑂: S1 ≤ PGS1 

 
 
 
 
 
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𝐻𝐻𝐴𝐴: S1 > PGS1 
and 
𝐻𝐻𝑂𝑂: S2 ≤ PGS2 
𝐻𝐻𝐴𝐴: S2 > PGS2 
where S1 and S2 represent the freedom-from-event rates for device/system related complication 
at 6 months, and pressure sensor failure at 6 months respectively, and PGS1 and PGS2 represent the 
corresponding performance goals with values expressed as a proportion of 0.90 and 0.95 
respectively. 
Each of these will be assessed within among all patients who underwent a device implant by 
estimating freedom from the event of interest at 6 months by the Kaplan-Meier method.  The 
proportion event free at 6 months and the corresponding two-sided 95% confidence interval will be 
compared to the null rate. We use a one-sample test of binomial proportions with a two-sided Type 
I error rate of 5% to estimate the power available for these analyses.   
A sample size of 450 patients provides greater than 95% power assuming a population rate of 95% 
for the freedom-from-event rates for device/system related complication at 6 months. Power would 
still be maintained at this level for an evaluable sample size of 406.   
Similarly, a sample size of 450 patients provides approximately greater than 95% power  assuming 
a population rate of approximately 98.4%, for the pressure sensor failure at 6 months endpoint. 
Power would still be maintained at this level for an evaluable sample size of 406. 
Primary Safety Endpoints: 
1. Freedom from device/system related complication at 6 months  
2. Freedom from pressure sensor failure at 6 months 
In addition to the two (2) primary safety endpoints with hypothesis tests, the following secondary 
safety endpoints will be summarized. 
Secondary Safety Endpoints: 
1. Pressure sensor failure rate throughout the study  
2. Frequency of serious adverse events throughout the study 
3. Frequency of implant procedure and procedure related adverse events and serious adverse 
events 
10.6 
Analysis sites 
The study will be conducted such that: 1) the same protocol will be used at each study site; 2) site 
investigators and personnel will receive uniform training; and 3) central data management, and 

 
 
 
 
 
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monitoring will be applied with equal rigor at all sites.  The diversity of hospital and clinical practice 
settings will add to the scientific validity and generalizability of the findings.  
Subjects will be pooled across sites for analysis of study endpoints.  
Sites with at least 20 subjects will retain their identities.  Smaller sites will be ranked in decreasing 
order of size (site identification numbers, smallest first, will be used to break ties) and cumulatively 
pooled until pooled sites of no less than 10 subjects are achieved. After this pooling process, we will 
test for homogeneity in the treatment effects across site with a likelihood ratio test of the 
hypothesis that all sites have the same rate.  The homogeneity test will be conducted at the 0.15 
level based on Fisher’s exact test.   
10.7 
Adverse Events and Other Safety Analyses 
Adverse events and other safety analyses will also be assessed.  No formal statistical hypothesis 
tests will be conducted.  Analyses will involve Kaplan-Meier curves for time to event outcomes, 
descriptive statistics (n, mean, standard deviation, median, minimum and maximum) for 
quantitative outcomes, and count and frequency results for categorical outcomes. 
10.8 
Study Retention and Handling of Missing and Incomplete Data 
Every effort will be made to collect all data points in the study.  Endotronix plans to minimize the 
amount of missing data by appropriate management of the prospective clinical trial, proper 
screening of study subjects, and training of participating investigators, monitors and study 
coordinators.  The primary efficacy analysis will be based on the mITT population and the primary 
safety analyses will be based on the population of patients who underwent a device implant.    The 
primary analysis methods naturally handle missing data by censoring patients who have dropped 
out.   Sensitivity analyses to missing data will be conducted.  For the primary safety analyses, the 
endpoints can be considered as dichotomous and the extreme cases as well as a tipping point 
analysis can be presented.  Reasons for missing data (e.g., patient withdrawal of consent, death, 
etc.) will be captured and summarized. 

 
 
 
 
 
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11 
ETHICAL ASPECTS 
11.1 
Ethical Considerations 
This trial is to be conducted according to the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with ISO 14155:2020, ICH GCP and applicable 
regulatory requirement(s) including the Code of Federal Regulations (CFR) 21CFR Part 812, 21CFR 
Part 54 and 21CFR Part 56.  
The Investigator is responsible for ensuring that the clinical trial is performed in accordance with 
the protocol/ CIP, current ISO 14155:2020, ICH guidelines on GCP, and applicable regulatory 
requirements. 
Good Clinical Practice is a standard for the design, conduct, performance, monitoring, auditing, 
recording, analyses and reporting of clinical trials that provides assurance that the data and reported 
results are credible and accurate, and that the rights, integrity and confidentiality of the trial 
subjects are protected. 
The medical care given to, and medical decisions made on behalf of subjects should always be the 
responsibility of a qualified physician. Each individual involved in conducting the trial should be 
qualified by education, training and experience to perform his or her respective task(s). 
The trial can only start at the Investigator’s site when the relevant IRBs/ IECs have given signed and 
dated approval of the protocol/CIP, written ICFs and other written information to be provided to 
the subjects (e.g., questionnaires). 
11.2 
Subject Information and Consent 
All subjects will be informed that participation is voluntary and that they can cease participation at 
any time without necessarily giving a reason and without any penalty or loss of benefits to which 
they are entitled. However, the Investigator should try to exclude an adverse event as the reason 
for withdrawing voluntarily. 
With the help of the Information Sheet, the subject will be informed about the device and 
anticipated effects, and the reason, design and implication of the trial. The subject must give 
consent to participate prior to enrollment in the trial. This consent must be given in writing or orally 
in the subject’s native non-technical language that is understandable to the subject if witnessed by 
a third party due to the subject’s condition if allowed for by local legislation. The witness must sign 
the consent form. The person who conducted the ICF discussion must also sign. With consent, the 

 
 
 
 
 
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subject will confirm that his participation is voluntary and that they will follow the instructions of 
the Investigator and answer the questions asked. Signatures must be personally dated. 
Prior to participation in the trial, the subject, should receive a copy of the signed and dated written 
ICF and any other pertinent written information. 
The ICF and Information Sheet must include all elements required by law, local regulations and ICH 
GCP guidelines, and CA requirements as well as trial specific items. 
The subject must be informed that it may be necessary for the analysis of certain data that their 
name will remain visible whilst the analysis is performed. The results of the analysis will be 
processed so that the confidentiality of the subject is maintained. 
Neither the Investigator, nor the trial staff, should coerce or unduly influence a subject to participate 
or to continue to participate in the trial. The Investigator should not include themselves, their 
relatives, and members of their clinical team or their relatives in the trial. Ample time must be 
allowed for the subject to make his or her decision, and to make further enquiries about the trial. 
The signed and dated consent form will be kept by the Investigator. 
Should new information become available during the course of the trial that may be relevant to the 
subject’s consent, the Information Sheet will be revised. The revised version will be submitted for 
IRB/IEC approval before use. The subject must be informed as soon as possible if new information 
becomes available that may be relevant to the subject’s willingness to continue participation in the 
trial. The communication of this information should be documented. The subject should receive a 
copy of any updates to the signed and dated written ICF or other pertinent written information. 
11.3 
Institutional Review Board (IRB)/Independent Ethic Committee (IEC)  
An Institutional Review Board (IRB)/ Independent Ethic Committee (IEC) will safeguard the rights, 
safety, and well-being of all trial subjects. This study will be undertaken only after full approval of 
the protocol addenda, and ICFs have been obtained from an IRB/ IEC and a copy of this approval has 
been received by Endotronix.  
The IRB/ IEC must be informed of all subsequent protocol amendments issued by Endotronix.  
Reports on, and reviews of, the study and its progress will be submitted to the IRB/ IEC by the 
investigator at intervals stipulated in their guidelines.  
At study termination, a Final Report must be submitted by the Investigator to their respective IRB/ 
IEC.   

 
 
 
 
 
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Copies of all submissions to and correspondence (approvals and disapprovals) from the IRB must be 
maintained on file at the study site. 
11.3.1 Investigator Reports 
Investigators are required to prepare and submit the following complete, accurate and timely 
reports on this investigation to Endotronix Clinical Operations or designee. 
Responsibilities for Preparing and/or Submitting Reports  
 
Type of Report 
 
Submit to 
 
Time of Notification to 
Endotronix  
Time of 
Notification to IRB/ 
IEC 
Suspected Device 
Malfunction or 
problem 
Endotronix, IRB, 
IEC 
Within 5 working days of 
knowledge 
As required  
Device Failure 
Endotronix, IRB, 
IEC 
Within 72 hours of 
knowledge 
As required 
Unanticipated Adverse 
Device Event  
Endotronix, IRB, 
IEC 
Within 24 hours of 
knowledge 
Within 10 days 
Subject death during 
study 
Endotronix, IRB, 
IEC 
Within 24 hours of 
knowledge 
As required 
Subject withdrawal 
Endotronix, IRB, 
IEC 
Within 72 hours of 
knowledge 
As required 
Withdrawal of IRB 
approval 
Endotronix, IRB, 
IEC 
Within 72 hours of 
knowledge 
Not Applicable 
Serious deviations 
from the protocol/CIP 
Endotronix, IRB, 
IEC 
Within 5 working days  
As required  
ICF not obtained  
Endotronix, IRB, 
IEC 
Within 5 working days 
As required 
Progress Reports 
Endotronix, IRB, 
IEC 
At least annually 
At least annually 
Final summary report  
Endotronix, IRB, 
IEC 
≤6 months of study 
completion 
≤6 months of study 
completion 
Other information as 
requested by 
Endotronix, IRB and/or 
regulatory bodies 
As appropriate 
As requested 
As requested 

 
 
 
 
 
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11.4 
Annual Report  
Endotronix will provide the FDA/ CAs with an Annual Progress Report, where applicable.  
Investigators must provide their annual progress reports to Endotronix in a timely fashion to allow 
compliance with this requirement.  Individual IRBs/ IEC will be provided with copies of the annual 
progress reports, where applicable.  
11.5 
Insurance 
Insurance for the subjects participating in this trial which will provide compensation to subjects for 
clinical investigation related injuries will be arranged by Endotronix. 
A copy of the insurance certificate will be held in the central or the country specific parts of the Trial 
Master File at Endotronix. 
The insurance regulations will be handed over to the subjects upon request. 
11.6 
Regulatory Affairs 
This trial will be carried out in compliance with legal regulations. Before initiating the trial 
Endotronix and/or the Investigator, if required by the applicable regulatory requirement(s), will 
submit any required application(s) to the appropriate authorities for review, acceptance, and/or 
permission to begin the trial. A copy of the submission will be held in the central files. 
The Investigator will be informed by Endotronix when new information about the Device and 
adverse events due to the Device becomes available. 
11.7 
Investigators and Trial Administrative Structure  
11.7.1 Investigator 
The Investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, Declaration of Helsinki, ISO 14155:2020, ICH GCP Guidelines, and 21CFR 
Part 812, 21CFR Part 54 and 21CFR Part 56, and any country laws, as applicable. 
If the trial is conducted by a team of individuals at the trial site, the Investigator is the 
responsible leader of the team and may be called the Principal Investigator.  
A Sub-Investigator (e.g., associates, residents, research fellows) is any individual member of 
the clinical trial team designated and supervised by the Principal Investigator at a trial site to 
perform critical trial-related procedures and/or to make important trial-related decisions.  

 
 
 
 
 
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The Investigator must maintain a signed list of appropriately qualified persons to whom they 
have delegated significant trial-related duties which must be specified. A copy is held in the 
site files at Endotronix and the Contract Research Organization (CRO).  
Trial-related medical decisions are the responsibility of a qualified physician (the Investigator 
or delegate).  
Curricula vitae and/or other relevant documents confirming the qualifications of the 
Investigator and Sub-Investigators are required by Endotronix/the CRO. Any previous training 
in the principles of GCP or experience obtained from work with clinical trials and subject care 
should be described in the curriculum vitae. When personnel changes are made, the relevant 
documentation must be updated before a new member of the team can perform critical 
and/or significant trial-related activities.  
The Investigator has to comply with the local legal requirements concerning reporting of 
information relevant for the trial conduct. The standard requirements for IRB review, ICF, 
subject data protection, investigator agreements and financial disclosures will apply. 
11.7.1.1 
Investigator Agreement 
Prior to study initiation, the Investigator must sign an Investigator Agreement (Endotronix 
to provide Investigator Agreement template to sites).  The Investigator Agreement 
identifies the Investigator’s legal and ethical commitments with respect to the conduct of 
the clinical study as defined in Practice 21 CFR Part 812, Part 56, Part 50, and Part 54 and 
ISO 14155:2020. 
In addition, responsibility for insurance or indemnity to cover any liability of the 
Investigator which may arise directly or indirectly from his participation in the trial will be 
specified in a contract between the Investigator and / or Institution and Endotronix. 
11.7.1.2 
Financial Disclosure 
A Financial Disclosure Form must be reviewed and signed by the Investigator and sub-
investigator(s) prior to study initiation.  Endotronix or designee will provide Financial 
Disclosure Form to sites.  Updates to financial disclosure will be made during the course 
of the study and for 1 year following completion of the study (21 CFR Part 54).  
The Financial Disclosure form is required to record the Investigator’s and Sub-
Investigator’s financial interests in Endotronix which may be a potential source of bias in 
the outcome of the clinical study. 
11.7.1.3 
Protocol/ CIP Deviations and Medical Emergencies  
The Investigator will not deviate from the protocol without the prior written approval of 
Endotronix except in medical emergencies or in unforeseen, isolated instances where 

 
 
 
 
 
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minor changes are made that will not increase the subject’s risk or affect the validity of 
the study.  In addition, Endotronix will not allow any deviations/waiver from the Inclusion 
and Exclusion Criteria.  
In medical emergencies, prior written approval for protocol deviations will not be 
required, but Endotronix personnel must be notified via telephone within 24 hours of 
occurrence. 
If there are any circumstances during the clinical trial which can affect the safety of the 
subjects, users or third person, Endotronix and the investigator will take all necessary 
security measures immediately to protect the subjects, users and third persons against 
direct or indirect risk. Endotronix and the investigator must inform FDA/CA and the 
responsible IRB/IEC immediately about these new circumstances and the measures taken. 
However, in case of any deviation for a scheduled assessment e.g., out of window 
assessment, missing laboratory sample, and prior approval from Endotronix is required in 
advance for changes in or deviations from the protocol. 
11.7.2 Endotronix (Sponsor) 
Endotronix accepts the responsibilities of the Sponsor. 
11.7.3 Contract Research Organization 
 
A CRO (Syneos Health) has been employed by Endotronix to perform 1 or more of its trial-
related duties and functions. The extent of the delegation must be specified in a contract 
between the involved parties. The CRO should implement quality assurance and quality 
control but Endotronix will have the right to supervise the implementation of the methods 
for quality assurance and quality control. 
11.7.4 Endotronix (Device Support) 
Endotronix Device Support involved in many trial-related duties and functions in cooperation 
with Endotronix Clinical Operations. Their tasks include but are not limited to: 
• Training the Investigator and site staff in the use of the Cordella™ Heart Failure System 
including CorPASS 
• Ongoing education 
• Implant support 
• On-Call clinical and technical support 
• Assist with subject training 
• Device inventory and replacement 
• Complaints (Cordella System only) 
• Device Deficiencies (DD) 
This will be specified case by case before actions for the trial are taken and documented in 
the trial documentation.  

 
 
 
 
 
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12 
DOCUMENTATION OF TRIAL DATA  
12.1 
Case Report Forms  
An Electronic Data Capture (EDC) system will be utilized to collect all subject data during the course 
of the study.  Data must be entered into eCRFs in English. The eCRFs are to be completed within 72 
hours of the subject's visit, with the exception of results from tests performed outside the 
investigator's office, so that they always reflect the latest observations on the subjects participating 
in 
the 
study. 
This 
includes 
all 
medication 
changes 
in 
between 
study 
visits. A 
predetermined/designated individual(s) will be responsible for completion of the Electronic Case 
Report Forms (eCRFs).  The PI will ultimately be responsible for the review, completion and accuracy 
of data entered into the eCRF.  
Completed eCRFs will be verified by a Sponsor monitor at the site at regular intervals throughout 
the study. The Investigator will allow the monitor and the regulatory bodies (Competent Authorities 
(CAs)) to review the study files, subject eCRFs, medical records and other study-related documents. 
12.2 
Data Management 
12.2.1 Data Management 
Data Management will be coordinated by Endotronix or their assigned designee. 
12.2.2 eCRFs 
During data entry in the eCRF, queries will be directly issued to clarify missing data, 
inconsistencies and incorrect values. After completion of the eCRF, further queries will be 
issued to the Investigator to clarify (e.g., inconsistencies resulting out of the medical and 
manual review). Resolutions of queries will be made by the Investigator or the trial site’s 
designated persons. The query is answered directly in the eCRF system and the original value 
is changed, if necessary. 
12.2.3 Coding 
Medication names will be coded using the World Health Organization Drug Dictionary. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  The 
version most currently implemented when the first subject is enrolled will be used through 
the study. Coding will be reviewed by an Endotronix Medical Monitor. 

 
 
 
 
 
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12.2.4 Source data 
Source data is all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents 
which comprise clinical documentation, data and records (e.g., hospital records, clinical and 
office charts, laboratory notes, memoranda, evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments and data and records arising from other 
departments such as the pharmacy, laboratory and medico-technical departments).  
Clinical documentation relevant to the trial includes all records in any form including, but not 
limited to: 
• Medical history/physical condition of the subject before enrollment sufficient to verify  
• Protocol entry criteria 
• Dated and signed notes for specific results of procedures and exams 
• Laboratory reports 
• Concomitant Medications incl. changes 
• Information related to adverse events 
• Notes on subject’s condition with device implanted and when explanted 
• Quality of Life studies 
• Discharge Summaries/Procedure reports 
• Autopsy reports 
All clinical documentation and data arising from the trial are to be kept by the Investigator 
who must provide direct access for trial-related monitoring, audits, IRB/IEC review, and 
regulatory inspection. 
In certain circumstances, data may only be recorded in the trial specific eCRF and not in other 
documents. When this occurs, the eCRF is considered to be the source document.  
At the end of the trial, the Investigator will receive a certified copy of all data captured for 
their subjects, in human readable form, on a read-only CD-ROM. Data captured of all subjects 
will be sent to the sponsor in human readable form, on a read-only CD-ROM for archiving. 
12.3 
Data Review  
All eCRFs will be reviewed for completeness and clarity.  Missing data will be investigated by the 
monitor and clarified by study personnel as necessary. Endotronix may request additional 
documentation such as physician procedure notes or written summaries relating to adverse events 
or procedures. Endotronix will be responsible for the quality control of the database and confirming 
the overall integrity of the data. 
 

 
 
 
 
 
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12.4 
Data Quality Assurance 
Steps to be taken to assure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers, review of protocol/ CIP procedures with the 
investigator and associated personnel prior to the study and periodic monitoring visits by the 
sponsor. eCRFs will be reviewed for accuracy and completeness by the sponsor during on-site 
monitoring visits and after their return to Endotronix and any discrepancies will be resolved with 
the investigator or designees, as appropriate. The data will be entered into the clinical study 
database and verified for accuracy. 
12.5 
Database lock 
When all data are received, all data checks and quality control checks have been performed, and a 
final data review meeting has been held, the trial database is considered clean and can be locked. 

 
 
 
 
 
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13 
ADMINISTRATIVE REQUIREMENTS 
13.1 
Monitoring of the Study 
Endotronix contracted a CRO who will perform on-site monitoring visits as frequently as necessary. 
Visits are usually made at intervals of at least four to twelve weeks. The dates of the visits will be 
recorded by the monitor in a study center visit log to be kept at the site. The first post initiation visit 
will usually be made as soon as possible after enrollment has begun. At these visits the monitor will 
compare the data entered into the eCRFs with the hospital or clinic records (source documents). At 
a minimum, source documentation must be available to substantiate proper ICF procedures, 
adherence to protocol/ CIP procedures, adequate reporting and follow-up of AEs, administration of 
concomitant medication and device receipt/ return records. Specific items required as source 
documents will be reviewed with the investigator prior to the study. Findings from this review of 
eCRFs and source documents will be discussed with the investigator. The sponsor expects that, 
during monitoring visits, the investigator (and as appropriate the study coordinator) will be 
available, the source documentation will be available, and a suitable environment will be provided 
for review of study-related documents. 
13.2 
Independent Data Review and Event Adjudication 
To meet the trial’s ethical responsibility to its subjects, results will be monitored by two independent 
groups that have no formal involvement with the subjects or the investigation, as follows: 
1. 
DSMB- Data Safety Monitoring Board. 
2. 
CEC- Clinical Events Committee. 
The members of these committees shall function independently of Endotronix and the CRO.   
13.2.1 DSMB and CEC Composition 
These two committees will include a Data Safety Monitoring Board (DSMB) and Clinical Events 
Committee (CEC).  Each committee will be composed of at least three or more members (at 
least two physicians from the fields of HF cardiology and Interventional Cardiology) who are 
not directly involved in the conduct of the trial.  A semi-annual report will be provided to the 
FDA, which will include the names of each DSMB and CEC member. 
13.2.2 DSMB 
The DSMB will review the study at key points during the conduct.  
The first DSMB safety review will take place after the first 50 subjects which have been 
implanted with the Cordella PA Sensor reached their Month 3 follow-up. The next DSMB 

 
 
 
 
 
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safety will then take place after the first 100  implanted subjects reached their 30-day follow- 
up.  
Periodic safety review of study data every six months from the date of the first Cordella PA 
Sensor implant.  Members will be provided data summaries (listings) from the clinical study 
in a blinded fashion without site or physician identification.  Based on the safety data, the 
DSMB may recommend that the trial be modified or stopped.  No formal statistical rule will 
be defined for stopping the trial for safety reasons.  
The DSMB process (including their ability to stop an ongoing study due to safety concerns) is 
documented in the study specific DSMB Charter.   
13.2.3 CEC 
The CEC will adjudicate all events including device malfunctions dynamically. Each event will 
be adjudicated by an independent CEC committee (at least 3 reviewers) with the final 
adjudicated result being a consensus of the committee. 
The CEC process is documented in the study specific CEC Charter.   
13.3 
Quality System, Audit and Inspection 
13.3.1 Quality system 
Endotronix is responsible for implementing and maintaining quality assurance and quality 
control systems with written Standard Operating Procedures. Endotronix/the CRO is 
responsible for ensuring that all parties involved with the trial agree to direct access to all 
trial-related sites, source data and documents, and reports for the purposes of monitoring 
and auditing by Endotronix/the CRO, and inspection by domestic and foreign regulatory 
authorities. 
The documentation of the trial should be adequate for reconstruction of the course of events 
(audit trail). 
13.3.2 Audit  
An audit is the systematic and independent examination of trial-related activities and 
documents to determine whether the evaluated trial-related activities were conducted, and 
the data recorded, analyzed and accurately reported according to the protocol/ CIP, 
Endotronix /the CRO’s Standard Operating Procedures, GCP and applicable regulatory 
requirements.  

 
 
 
 
 
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The Investigator will permit an appointed person by the Quality Assurance Unit of 
Endotronix/the CRO to audit the facilities and documentation at agreed times. Auditors are 
independent of the clinical trial and its performance. 
13.3.3 Inspection  
Inspection is the act by regulatory authorities of conducting an official review of the 
documents, facilities, records and other resources that are deemed by the authorities to be 
related to the clinical trial and that may be located at the trial site, at Endotronix, at the CRO, 
or at other facilities deemed appropriate by the regulatory authorities. The Investigator is 
obliged to cooperate with any inspection. 
13.4 
Maintenance of Study Documentation 
The Investigator must maintain the following documents throughout the study: 
• Protocol/ CIP 
• IRB/ IEC Approvals and Correspondence 
• IRB/ IEC Approved ICF 
• Correspondence with Endotronix 
• Electronic Signature Authorization Form Device Accountability 
• Investigator Agreements 
• Curriculum Vitae 
• Financial Disclosure Forms 
• Telephone Logs 
• Screening Logs 
• eCRFs 
• Monitoring Visit Log 
• Laboratory Accreditation and Normal Values 
• Site Delegation and Responsibility log 
• Source Documents supporting information on eCRFs 
• Any other study specific documents  
13.5 
Subject Data Protection 
Subjects will be identified on the eCRF by a subject identification number.  The investigator will 
maintain a confidential subject identification list separate from investigational files to link medical 
records and subject identification numbers. 
All information and data sent to Endotronix or their authorized representative, concerning subjects 
or their participation in this study, will be considered confidential.  All data used in analysis and 

 
 
 
 
 
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reports will be used without identifiable reference to the subject.  At all times throughout the study, 
confidentiality shall be observed by all parties involved.  All data shall be secured against 
unauthorized access.  
All subjects consented for this study will be informed and must agree to the use and disclosure of 
their study information by the institution and investigators to Endotronix, their agents and 
representatives, the Competent Authorities (CAs) or other government agencies or review boards.     
13.6 
Protocol/ CIP Modifications 
Changes to the protocol/ CIP during the trial will be documented as amendments. The amended 
protocol will be signed by the relevant personnel at Endotronix, and by the Investigator(s).  
Depending on the contents of the amendment and local legal requirements, the amendment will 
be submitted to the relevant IRBs/ IECs and, where necessary, to the FDA/ national CAs of the 
participating EU member states. 
The Investigator should not implement any deviation from, or changes to the protocol, without 
agreement by Endotronix and the CRO and prior review and documented approval/favorable 
opinion of the appropriate IRB/ IEC and, if legally required, the FDA/ CA, except where necessary to 
eliminate an immediate hazard to the subjects, or when the change(s) involve only logistical or 
administrative aspects of the trial.  
If an amendment substantially alters the trial design, increases the potential risk to the subjects or 
affects the treatment of the subject, then the Information Sheet must be revised and submitted to 
the relevant IRB/ IEC and, where necessary, to the FDA/ national CAs of the participating EU member 
states, for review and approval. When a subject is currently undergoing trial procedures and is 
affected by the amendment, then the subject must be asked to consent again using the new 
Information Sheet. The new Information Sheet must be used to obtain consent from new subjects 
before enrollment.  
In general, any substantial amendment to the CIP will be approved by the relevant IRB/IEC and, 
where necessary, by the FDA / national CAs of the participating EU member states before it can be 
implemented. 
13.7 
Compliance/ Investigational Site Termination 
13.7.1 Compliance 
Compliance is the adherence to all trial-related requirements, to Good Clinical Practice (GCP) 
and to regulatory rules and regulations. 

 
 
 
 
 
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13.7.2 Investigational Site Termination  
An initiative for center closure or study termination can be taken at any time either by the 
sponsor or by the investigator, provided there is reasonable cause and sufficient notice is 
given in advance of the intended termination. Endotronix reserves the right to terminate an 
investigational site from the study for any of the following reasons: 
• Repeated failure to complete case report forms 
• Failure to obtain ICF 
• Failure to report SAEs and UADEs/ USADEs 
• Loss of or unaccountable investigational device inventory 
• Repeated protocol/ CIP violations 
• Failure of investigator to comply with training or Instructions for Use 
• Failure to screen and/or enroll an adequate number of subjects 
• Insufficient subject and caregiver/Companion training 
13.8 
Record Retention  
Endotronix and all participating Investigators must establish and maintain records and reports.  The 
Investigator must maintain the signed ICFs, eCRFs, study documentation (listed above) and source 
documents for at least 15 years from the date of the manufacture of the last product in agreement 
with the local regulations. Endotronix should be contacted if the Principal Investigator plans to leave 
or otherwise absent themselves from the investigational site.   
In the event of an FDA/ CA audit, the Investigator must allow FDA/ CA access to the study records 
for inspection and copying.  The Investigator must inform Endotronix of any FDA/ CA audit and 
provide Endotronix with a copy of Form FDA 483/ List of Observations, if issued. 
The trial master file, the eCRFs, and other material supplied for the performance will be retained by 
Endotronix according to applicable regulations and laws. 
13.9 
 Site Training 
Sites will be trained by Endotronix on the device usage and on implant technique as appropriate.  
Training on GCP, protocol required procedures and data collection will be provided by the vendor(s). 
13.10 Confidentiality of trial results 
The results of this trial are confidential and are not to be transmitted to a third party in any form or 
fashion. All persons involved in the trial are bound by this confidentiality clause.  

 
 
 
 
 
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13.11 Publication policy  
The results of the trial will be published as soon as the data for the primary endpoint is available, 
initially as a poster/presentation at a congress, and then as a full publication in an international 
cardiology/heart failure journal. Draft manuscripts of publications will be prepared in co-operation 
between Endotronix and the Coordinating Investigator/Investigator(s). Joint publications are only 
possible if all parties agree. All editorial decisions will be made jointly by Endotronix and the 
Coordinating Investigator/Investigator(s). 
Endotronix reserves the right to review any publication pertaining to the trial before it is submitted 
for publication. Neither party has the right to prohibit publication unless publication can be shown 
to affect possible patent rights or regulatory submission requirements. 
In case of discrepancies with other contracts, the provisions of the protocol shall prevail.  
13.12 End of Investigation /Premature Termination /Suspension 
For EU only: In accordance with the Article 77(1) the end of this trial or, if applicable, a temporary 
halt or early termination of the trial will be reported to the national CAs of the participating European 
member states within the timelines stipulated in Article 77(3 and 4) of the MDR (Regulation (EU) 
2017/745). 
13.13 Final report 
A final report, integrating medical and statistical aspects, will be prepared. This will be authorized 
by the relevant personnel of Endotronix, and the Investigators. The Investigator(s) will be provided 
with a copy of the summary of the final report. Endotronix will provide the FDA/ CAs and IRBs/ IECs 
with the complete clinical trial report within 1 year after the end of the trial or on request, where 
required. 
13.14 Organization/ Site personnel 
It may be necessary to define additional site personnel (e.g., doctors, nurses, technicians) who have 
a special responsibility for the performance of portions of the trial at a site under the auspices of 
the Investigator. The information regarding all site personnel taking part in the trial will be 
documented and stored in the Investigator’s site file. 

 
 
 
 
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14 
APPENDICES 
14.1 
Time and Event Schedule 
Assessment 
V1: 
Screening/ 
Enrollment 
(30 days)15 
 
V2: 
Cordella PA 
Sensor 
Implant Visit 
V3: 
Month 
1 
(±7 days) 
V4 11: 
Month 
3 
(±7 days) 
V5: 
Month 
6 
(±14 days) 
V6: 
Month 
12 
(±30 days) 
V7 to V8: 
Months 18, 
24 
(±30 days) 
V9 to V11 
Year 
3, 4, 5 
(±30 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
Subject Demographics 
X 
 
 
 
 
 
 
 
Study Eligibility Review and Committee Approval 
X 
 
 
 
 
 
 
 
Cardiac/Medical & Surgical History 
X 
 
 
 
 
 
 
 
Physical Exam, height, weight, and vital signs 1, 5 
X 
X 
X12 
X 
X 
X 
X 
12-Lead ECG with Interpretation 
X 
 
 
 
X 
X 
X4 
X 
Urinalysis 2 
X 
 
 
 
 
 
 
 
Safety Labs (Chemistry/Hematology/ aPTT/ INR)  
X 
 
 
X 
X 
X4 
X 
Serum NT-pro BNP  
X 
 
X 
X12 
X 
X 
X 
X 
aPTT/ INR (if indicated) 
 
 
 
 
 
 
 
 
Echocardiogram 3 
X 
 
 
 
X  
 
X 
Subject Training: Cordella™ HF System 14 
X 
 
 
 
 
 
 
Subject Training: CorPASS 
 
X 
 
 
 
 
 
 
Cordella™ PA Sensor Implant  
 
X 
 
 
 
 
 
 
Cordella System Use (daily)  
X 
X 
X 
X 
X 
X 
X 
X 
Cordella™ PAP – dia/sys/mean/pulse  
 
X9 
X5,6 
X5,6 
X5,6 
X5,6 
X5,6 
X6 
RHC PAP / RAP/ PCWP/ CO/ CI/ RVP8 
 
X 
 
 
 
 
X17 
Subject Status 
X 
 
X 
X 
X10 
X10 
X 
X 
6- Minute Walk Test  
X 
 
 
 
X 
X7 
X4,7 
X7 
NYHA Functional Classification 
X16 
 
X 
X 
X 
X 
X 
X 
KCCQ Quality of Life Questionnaires 5 
X 
 
X 
X 
X 
X 
X 
X 
Concurrent/Cardiac Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Health Economic Questionnaire 
 
 
 
 
 
 
X4 
 
Subject Survey (optional)/ Cohort #1 only13 
1. Month 1 after Unblinding  
2. Quarterly until V11 / Year 5 
Site Survey (optional)/ Cohort #1 only13 
1. Month 1 after Unblinding  
2. Quarterly until V11 / Year 5 

 
 
 
 
 
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1. 
Full Physical Examination and Height performed at Screening Visit only 
2. 
Urine (V1) pregnancy test for females 
3. 
Echo may be obtained within 3 or 6 months of Screening details are in section 8.1.10 
4. 
At Month 24 only  
5. 
via myCordella™ Patient App at home prior to visit. Baseline KCCQ will be completed on 
myCordella tablet following Cordella System distribution at Screening Visit        
6. 
via myCordella™ Patient App seated and supine 
7. 
Additional PAP Measurements will be obtained before and after 6-minute walk test  
8. 
Additional RHC as needed for Re-calibration purposes at the clinician’s discretion 
 
9. 
Via CalEQ 
10. Incl. question on assigned treatment at Visit 5 and 6 
11. Visit should be completed remote/ virtually 
12. If available 
13. After subject gets unblinded to PAP Pressures at V6 or cross-over whatever comes first  
14. Subject training  on and distribution of the commercial Cordella™ System (should occur at 
Screening Visit (Visit 1).   
15. Some study procedures need to be repeated in case a subject is implanted >30 days after Visit 
1, details are in section 8.3.1. 
16. may be obtained within the 30 day Study Visit 1 window 
17. At V9/ Year 3 only 
 
 
 

 
 
 
 
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14.2 
New York Heart Association (NYHA) Functional Classification 
The subject’s functional status will be assessed by a qualified individual at the institution (who is 
not associated with the trial) by utilizing the NHYA functional classification below: 
 
ACC/AHA vs. NYHA Classification of Heart Failure 
 
ACC/AHA Stage 
NYHA Functional Class 
Stage 
Description 
Class 
Description 
A 
Patients at high risk of developing HF because of 
the presence of conditions that are strongly 
associated with the development of HF. Such 
patients have no identified structural or 
functional abnormalities of the pericardium, 
myocardium, or cardiac valves and have never 
shown signs or symptoms of HF. 
No  
comparable 
functional  
class 
NA 
B 
Patients who have developed structural heart 
disease that is strongly associated with the 
development of HF but who have never shown 
signs or symptoms of HF. 
I 
(Mild) 
No limitation of physical activity. 
Ordinary physical activity does not 
cause undue fatigue, palpitation, 
or dyspnea. 
C 
Patients who have current or prior symptoms of 
HF associated with underlying structural heart 
disease. 
II 
(Mild) 
Slight limitation of physical activity. 
Comfortable at rest, but ordinary 
physical activity results in fatigue, 
palpitation, or dyspnea. 
III 
(Moderate) 
Marked limitation of physical 
activity. Comfortable at rest, but 
less than ordinary activity causes 
fatigue, palpitation, or dyspnea. 
D 
Patients with advanced structural heart disease 
and marked symptoms of HF at rest despite 
maximal medical therapy and who require 
specialized interventions. 
IV 
(Severe) 
Unable to carry out any physical 
activity without discomfort. 
Symptoms of cardiac insufficiency 
at rest. If any physical activity is 
undertaken, discomfort is 
increased. 
ACC/AHA = American College of Cardiology/American Heart Association; HF = heart failure; NYHA = New York Heart 
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14.3 
Procedure for 6 Minute Walk Test 
Location 
The 6-minute Walk test (6MWT) should be performed indoors, along a long, flat, straight, 
enclosed corridor with a hard surface that is seldom traveled.  The distance should be 
reported in meters walked. The walking course must be 30 meters in length.  A 35-meter 
hallway is required.  The length of the corridor should be marked every 3 meters.  The 
turnaround point should be marked with a cone (such as an orange traffic cone).  A starting 
line which marks the beginning and end of each 60-meter lap should be marked on the floor 
using brightly colored tape. 
Patient Preparation 
1. Comfortable clothing should be worn 
2. Appropriate shoes for walking should be worn 
3. Patients should use their usual walking aids during the test (cane, walker, etc.) 
4. The patients’ usual medical regimen should be continued 
5. A light meal is acceptable before early morning or early afternoon tests 
6. Patients should not have exercised vigorously within 2 hours of beginning the test 
Measurements 
1. Repeat testing should be performed at about the same time of day to minimize intraday 
variability. 
2. A warm up period before the test should not be performed. 
3. The patient should sit at rest in a chair located near the starting position for at least 10 
minutes before the test starts.  During this time, check for contraindication, measure 
pulse and blood pressure, and make sure clothing is appropriate. 
4. At the Month 12, 24 and Year 3, 4 and 5 visits, perform a PAP Measurement with the 
myCordella™ Reader and Tablet before start of the test. 
5. Set the lap counter to zero and the timer to 6 minutes.  Assemble all necessary equipment 
(lap counter, timer, clipboard, worksheet) and move to the starting point. 
6. Instruct the patient as follows: “The object of this test is to walk as far as possible for 6 
minutes.  You will walk back and forth in this hallway.  Six minutes is a long time to walk, 
so you will be exerting yourself.  You will probably get out of breath or become exhausted.  
You are permitted to slow down, to stop, and to rest as necessary.  You may lean against 
the wall while resting but resume walking as soon as you are able. 

 
 
 
 
 
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You will be walking back and forth around the cones.  You should pivot briskly around the 
cones and continue back the other way without hesitation.  Now I’m going to show you.  
Please watch the way I turn without hesitation.” 
Demonstrate by walking one lap yourself.  Walk and pivot around the cone briskly. 
“Are you ready to do that?  I am going to use this counter to keep track of the number of 
laps you complete.  I will click it each time you turn around at this starting line.  Remember 
that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run or jog. 
Start now or whenever you are ready: 
1. Position the patient at the starting line.  You should also stand near the starting line 
during the test.  Do not walk with the patient.  As soon as the patient starts to walk, 
start the timer. 
2. Do not talk to anyone during the walk.  Use an even tone of voice when using the 
standard phrases of encouragement.  Watch the patient.  Do not get distracted and 
lose count of the laps.  Each time the participant returns to the starting line, click 
the lap counter once.  Let the participant see you do it.   
3. After the first minute, tell the patient the following (in even tones): “You are doing 
well.  You have five minutes to go.”  Repeat after each minute. 
When the timer is 15 seconds from completion say this: “In a moment I’m going to 
tell you to stop.  When I do, just stop right where you are, and I will come to you.” 
When the timer rings, say this: “Stop!”  Walk over to the patient.  Consider taking 
a chair if they look exhausted.  Mark the spot where they stopped by placing a bean 
bag or piece of tape on the floor. 
4. At the Month 12, 24 and Year 3, 4 and 5 visit, perform a PAP Measurement with 
the myCordella™ Reader and Tablet right after the patient finished the test. 
5. Record the number of laps from the counter. 
6. Record the additional distance covered using the markers on the wall as distance 
guides.  Calculate the total distance walked, rounding to the nearest meter and 
record it on the worksheet. 
7. Congratulate the patient on good effort and offer a drink of water.  
 
*Excerpted from the American Thoracic Society, ATS Statement: Guidelines for the 
 
Six-Minute Walk Test, March 2002. 
 
 

 
 
 
 
 
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14.4 
Kansas City Cardiomyopathy Questionnaire 
 
 

 
 
 
 
 
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14.5 
Guidelines for managing HF using Pulmonary Artery Pressures  
These guidelines are required for clinicians for managing HF to allow for proactive heart 
failure management, if clinically tolerated by patient.  It is mandatory to use them for all 
patients in Cohort #2 and Cohort #3 after the implant of the Cordella PA Sensor and for 
subjects in Cohort #1 as soon they have been unblinded. 
Deviations from the Treatment Guidelines have to be justified. 
In addition, Data and Reminders will be provided by the myCordella™ PMP to support the 
clinician and team to facilitate following these guidelines. 
 
 

 
 
 
 
 
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14.6 
Adverse Event Definitions 
Adverse event definitions continue to evolve.  The adverse event definitions below may be 
revised according to the published adverse event definitions as determined by following 
references. 
 
References: 
Kappetein et al. Updated standardized endpoint definitions for transcatheter aortic valve 
implantation: The Valve Academic Research Consortium-2 consensus document,  
European Heart Journal (2012) 33, 2403-2418  
Rao SV et al. Standardized reporting of bleeding complications for clinical investigations in acute 
coronary syndromes: a proposal from the Academic Bleeding Consensus (ABC) multidisciplinary 
working group.  
Am Heart J. 2009;158:881–886.e1.   
Hicks et al.  2014 ACC/ AHA Key Data Elements and Definitions for Cardio Vascular Endpoint Events in 
Clinical Trials  
JACC VOL. 66, NO. 4, 2015 July 28, 2 0 1 5  : 4 0 3 – 6 9438 
ACUTE KIDNEY INJURY (AKIN CLASSIFICATION a) 
Stage 1: Increase in serum creatinine to 150–199% (1.5–1.99 × increase compared with 
baseline) OR increase of ≥0.3 mg/dl (≥26.4 mmol/l) OR Urine output <0.5 ml/kg/h for >6 but 
<12 h. 
Stage 2: Increase in serum creatinine to 200–299% (2.0–2.99 × increase compared with 
baseline) OR Urine output <0.5 ml/kg/h for >12 but <24 h 
Stage 3bb: Increase in serum creatinine to ≥300% (>3 × increase compared with baseline) OR 
serum creatinine of ≥4.0 mg/dl (≥354 mmol/l) with an acute increase of at least 0.5 mg/dl (44 
mmol/l) OR Urine output <0.3 ml/kg/h for ≥24 h OR Anuria for ≥12 h 
The increase in creatinine must occur within 48 h. 
a Metha et all; Acute Kidney Injury N. Acute Kidney Injury Network:  Report of an initiative to improve 
outcomes in acute kidney injury. Crit Care 2007;11: R31. 
b Patients receiving renal replacement therapy are considered to meet Stage 3 criteria irrespective of 
other criteria. 
 
 

 
 
 
 
 
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BLEEDING 
Life-threatening or disabling bleeding 
• Fatal bleeding (BARC type 5)  
OR 
• Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial 
necessitating peri cardiocentesis, or intramuscular with compartment syndrome (BARC 
type 3b and 3c). 
OR 
Bleeding causing hypovolemic shock or severe hypotension requiring vasopressors or surgery 
(BARC type 3b). 
OR 
• Overt source of bleeding with drop in hemoglobin ≥5 g/dl or whole blood or packed red 
blood cells (RBCs) transfusion ≥4 units a (BARC type 3b). 
Major bleeding (BARC type 3a) 
• Overt bleeding either associated with a drop in the hemoglobin level of at least 3.0 g/dl 
or requiring transfusion of two (2) or three (3) units of whole blood/RBC, or causing 
hospitalization or permanent injury, or requiring surgery.  
AND 
• Does not meet criteria of life-threatening or disabling bleeding 
 Minor bleeding (BARC type 2 or 3a, depending on the severity) 
• Any bleeding worthy of clinical mention (e.g. access site hematoma) that does not qualify 
as life-threatening, disabling, or major 
a Given that one unit of packed RBC typically will raise the hemoglobin concentration by 1 g/dl, an 
estimated decrease in hemoglobin will be calculated. 
*BARC: Bleeding Academic Research Consortium  
 
 

 
 
 
 
 
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CONDUCTION DISTURBANCES AND ARRHYTHMIAS 
Data elements to be collected should include 
• Baseline conduction abnormalities, paroxysmal or permanent atrial fibrillation (or 
flutter), and the presence of permanent pacemakera. 
• Implant-related new or worsened cardiac conduction disturbance (new or worsened first-
degree atrioventricular (AV) block, second-degree AV block (Mobitz I or Mobitz II), third-
degree AV block, incomplete right bundle branch block, right bundle branch block, 
intraventricular conduction delay, left bundle branch block, left anterior fascicular block, 
or left posterior fascicular block, including block requiring a permanent pacemaker 
implant. 
• Persistent or transient high-degree AV block. High-grade AV block is persistent if it is 
present every time the underlying rhythm is checked. 
• New permanent pacemaker implantation, with precision of the indication and the 
number of days post-implant of the placement of new permanent pacemaker. 
• New-onset atrial fibrillation (or flutter)b                
• Any new arrhythmia resulting in hemodynamic instability or requiring therapyc. 
a Type of permanent pacemaker should be recorded (e.g. defibrillator, single vs. dual 
chamber, biventricular). 
b New-onset atrial fibrillation (or flutter) is diagnosed as any arrhythmia within hospitalization that 
has the ECG characteristics of atrial fibrillation (or flutter) and lasts sufficiently long to be recorded on 
a 12-lead ECG, or at least 30 s on a rhythm strip. 
c Therapy includes electrical/medical cardioversion or initiation of a new medication (oral 
anticoagulation, rhythm, or rate controlling therapy). 
DEATH 
Cardiovascular (CV) death  
Cardiovascular death includes death resulting from an acute myocardial infarction (MI), 
sudden cardiac death, death due to HF, death due to stroke, death due to CV procedures, 
death due to CV hemorrhage, and death due to other CV causes. 
Non-cardiovascular death 
Any death in which the primary cause of death is clearly related to another condition (e.g. 
trauma, cancer, suicide). 
 
 

 
 
 
 
 
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DEVICE / SYSTEM-RELATED COMPLICATION  
A Device /system related complication is an adverse event that is, or is possibly, related to 
the system (wireless pressure sensor or external electronics) and at least one the following:  
• 
is treated with invasive means (other than intramuscular medication or a right heart 
catheterization with a Swan-Ganz measurement which is used for diagnostic 
purposes)  
• 
results in the death of the subject  
• 
results in the explant of the device 
HEART FAILURE (HF) 
A HF Event includes hospitalization for HF and may include urgent, unscheduled outpatient 
office/practice or Emergency Department (ED) visits. 
• A HF Hospitalization is defined as an event in which the patient is admitted to the hospital 
with a primary diagnosis of HF, the length of stay is at least 24 h, the patient exhibits new 
or worsening symptoms of HF on presentation, has objective evidence of new or 
worsening HF, and receives initiation or intensification of treatment specifically for HF. 
• An Urgent HF Visit is defined as an event in which the patient has an urgent, unscheduled 
office/practice or ED visit for a primary diagnosis of HF but is not admitted to the hospital 
and exhibits new or worsening symptoms of HF on presentation, has objective evidence 
of new or worsening HF, and receives initiation or intensification of treatment specifically 
for HF. Note that changes to oral diuretic therapy do not qualify as initiation or 
intensification of treatment.  
HEMOPTYSIS  
Spitting up blood or blood-tinged sputum from the respiratory tract. Hemoptysis occurs when 
tiny blood vessels that line the lung airways are broken. 
MYOCARDIAL INFARCTION (MI) 
Peri-procedural MI (≤72 h after the index procedure) 
• New ischemic symptoms (e.g. chest pain or shortness of breath), or new ischemic signs 
(e.g. ventricular arrhythmias, new or worsening HF, new ST-segment changes, 
hemodynamic instability, new pathological Q-waves in at least two contiguous leads, 
imaging evidence of new loss of viable myocardium or new wall motion abnormality). 
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• Elevated cardiac biomarkers (preferable CK-MB) within 72 h after the index procedure, 
consisting of at least one sample post-procedure with a peak value exceeding 15× as the 
upper reference limit for troponin or 5× for CK-MB. If cardiac biomarkers are increased at 
baseline (>99th percentile), a further increase in at least 50% post-procedure is required 
AND the peak value must exceed the previously stated limit. 
Spontaneous MI (>72 h after the index procedure) 
Any one of the following criteria: 
• Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one 
value above the 99th percentile URL, together with the evidence of myocardial ischemia 
with at least one of the following: 
o Symptoms of ischemia 
o ECG changes indicative of new ischemia [new ST-T changes or new left bundle 
branch block (LBBB)]. 
o New pathological Q-waves in at least two contiguous leads 
o Imaging evidence of a new loss of viable myocardium or new wall motion 
abnormality. 
o Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST 
elevation, or new LBBB, and/or evidence of fresh thrombus by coronary 
angiography and/or at autopsy, but death occurring before blood samples could 
be obtained, or at a time before the appearance of cardiac biomarkers in the 
blood. 
o Pathological findings of an acute myocardial infarction. 
PRESSURE SENSOR FAILURE  
A pressure sensor failure occurs when the sensor malfunctions to the point that no readings 
can be obtained from it after all attempts are exhausted including troubleshooting the system 
to rule out any problems with the electronic components.  
NOTE: Recalibration of CorPASS via RHC will be performed as deemed necessary by Sponsor. 
PULMONARY EMBOLISM 
Pulmonary embolism (PE) is a sudden blockage of an artery in the lungs. The blockage usually 
is caused by a blood clot that travels to the lung from a vein in the leg. 
A PE assessment requires the diagnosis of a PE. Subjects will be assessed for signs and 
symptoms of PE – including, but not limited to any sudden onset of dyspnea, tachypnea, 

 
 
 
 
 
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worsening hypoxemia, unexplained tachycardia or sustained hypotension, chest pain, 
syncope, or shock.  
If signs or symptoms are present, unless an alternative diagnosis is suspected, assess the 
results of AT LEAST ONE of the following diagnostic examination to confirm or rule out the 
presence of a PE: 
1. Spiral multi-detector CT (MDCT) scan 
2. Pulmonary angiogram 
3. Ventilation perfusion (V/Q) scan 
4. A cardiac ECHO will be considered as a diagnostic option only in study subjects with 
clinical diagnosis of PE who:  
Are considered at High Risk of Mortality or Massive PE  
Are hypotensive and/or in shock 
Diagnosis of PE is confirmed when: 
1. An intraluminal filling defect in multiple (>1) segmental or more proximal branches 
on spiral multi-detector CT (MDCT) scan AND not seen in previous spiral MDCT.  
2. An intraluminal filling defect or an extension of an existing defect or a new sudden 
cutoff of multiple (>1) segmental or more proximal branches on the pulmonary 
angiogram AND not seen in a previous pulmonary angiogram.  
3. A perfusion defect of at least multiple (>1) segment with a local normal ventilation 
result (high-probability) AND not seen in a previous ventilation perfusion scan.  
4. There is evidence of right ventricular dysfunction AND visualization of a mobile 
thrombi in the right heart cavities and/or in the pulmonary arteries with the ECHO 
images. 
PULMONARY OCCLUSION 
A blockage of an artery in the lung causing hemodynamic compromise. 
RENAL DYSFUNCTION 
Two categories of renal dysfunction will be identified: 
Acute Renal Dysfunction 
Abnormal kidney function requiring dialysis (including hemofiltration) in patients who did not 
require this procedure prior to implant, or a rise in serum creatinine of greater than 3 times 
baseline or greater than 5 mg/dL  sustained for over 48 hours. 

 
 
 
 
 
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Chronic Renal Dysfunction 
An increase in serum creatinine of 2 mg/dl or greater above baseline, or requirement for 
hemodialysis sustained for at least 90 days. 
STROKE AND TRANS ISCHEMIC ATTACK (TIA) 
Diagnostic criteria: Acute episode of a focal or global neurological deficit with at least one of 
the following: change in the level of consciousness, hemiplegia, hemiparesis, numbness, or 
sensory loss affecting one side of the body, dysphasia or aphasia, hemianopia, amaurosis 
fugax, or other neurological signs or symptoms consistent with stroke. 
Stroke: duration of a focal or global neurological deficit ≥24 h; OR <24 h if available 
neuroimaging documents a new hemorrhage or infarct; OR the neurological deficit results in 
death. 
TIA: duration of a focal or global neurological deficit <24 h, any variable neuroimaging does 
not demonstrate a new hemorrhage or infarct. 
No other readily identifiable non-stroke cause for the clinical presentation (e.g. brain tumor, 
trauma, infection, hypoglycemia, peripheral lesion, pharmacological influences), to be 
determined by or in conjunction with the designated neurologista. 
Confirmation of the diagnosis by at least one of the following: 
• Neurologist or neurosurgical specialist. 
• Neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed on clinical 
grounds alone. 
 Stroke classification: 
• Ischemic: an acute episode of focal cerebral, spinal, or retinal dysfunction caused by 
infarction of the central nervous system tissue. 
• Hemorrhagic: an acute episode of focal or global cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular, or subarachnoid hemorrhage. 
A stroke may be classified as undetermined if there is insufficient information to allow 
categorization as ischemic or hemorrhagic. 
Stroke definitions b: 
• Disabling stroke: a modified Rankin Scale (mRS) score of 2 or more at 90 days and an 
increase in at least one mRS category from an individual's pre-stroke baseline. 
• Non-disabling stroke: an mRS score of <2 at 90 days or one that does not result in an 
increase in at least one mRS category from an individual's pre-stroke baseline. 

 
 
 
 
 
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a Patients with non-focal global encephalopathy will not be reported as a stroke without unequivocal 
evidence of cerebral infarction-based upon neuroimaging studies (CT scan or brain MRI). 
b mRS assessments should be made by qualified individuals according to a certification process. 
VASCULAR ACCESS SITE AND ACCESS-RELATED COMPLICATIONS 
Major vascular complications 
• Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or new 
apical aneurysm/pseudo-aneurysm  
OR 
• Access site or access-related vascular injury (dissection, stenosis, perforation, rupture, 
arterio-venous fistula, pseudo aneurysm, hematoma, irreversible nerve injury, 
compartment syndrome, percutaneous closure device failure) leading to death, life-
threatening or major bleeding, visceral ischemia, or neurological impairment  
OR 
• Distal embolization (non-cerebral) from a vascular source requiring surgery or resulting in 
amputation or irreversible end-organ damage  
OR 
• The use of unplanned endovascular or surgical intervention associated with death, major 
bleeding, visceral ischemia or neurological impairment  
OR 
• Any new ipsilateral lower extremity ischemia documented by patient symptoms, physical 
exam, and/or decreased or absent blood flow on lower extremity angiogram OR 
• Surgery for access site-related nerve injury  
OR 
• Permanent access site-related nerve injury  
Minor vascular complications 
• Access site or access-related vascular injury (dissection, stenosis, perforation, rupture, 
arterio-venous fistula, pseudo aneurysms, hematomas, percutaneous closure device 
failure) not leading to death, life-threatening or major bleeding a, visceral ischemia, or 
neurological impairment.  
OR 

 
 
 
 
 
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• Distal embolization treated with embolectomy and/or thrombectomy and not resulting 
in amputation or irreversible end-organ damage. 
OR 
• Any unplanned endovascular stenting or unplanned surgical intervention not meeting the 
criteria for a major vascular complication. 
OR 
• Vascular repair or the need for vascular repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, or stent-graft). 
a as per Bleeding definition 
VESSEL TRAUMA  
Any injury to a blood vessel – an artery, which carries blood to an extremity of an organ, or a 
vein, which returns blood to the heart. Causes for this type of trauma are: 1. blunt or 2. 
penetrating injury.  
1. A blunt injury can occur when a blood vessel is crushed or stretched.    
2. A penetrating injury can occur when a blood vessel is punctured, torn or severed.    
Either type of vascular trauma can cause the blood vessel to clot (thrombosis) and interrupt 
blood flow to an organ or extremity, or cause bleeding which can lead to life-threatening 
hemorrhage. 
OTHER 
An event that causes clinically relevant changes in the patient’s health (e.g. cancer). 
 
 
 

 
 
 
 
 
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14.7 
Definition,  Documentation and Reporting of Adverse Events specific for EU sites   
14.7.1 Definitions 
Adverse Events (AE) 
An adverse event is any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other 
persons, in the context of a clinical investigation, whether it is considered to be device related 
or not. 
Serious Adverse Event (SAE): 
Any adverse event that led to any of the following: 
• Death 
• Serious deterioration in the health of the subject, that resulted in any of the following: 
 life-threatening illness or injury 
 permanent impairment of a body structure or a body function 
 hospitalization or prolongation of patient hospitalization 
 medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
 chronic disease 
• fetal distress, fetal death or a congenital physical or mental impairment or 
birth defect 
Adverse Device Effect (ADE)  
Adverse event related to the use of an investigational medical device. This includes any 
adverse event resulting from insufficiencies or inadequacies in the instructions for use, the 
deployment, the implantation, the installation, the operation, or any malfunction of the 
investigational medical device. This includes any event that is a result of a use error or 
intentional misuse. 
Serious Adverse Device Effect (SADE) 
A SADE is one that has resulted in any of the consequences characteristic of a serious adverse 
event. 
Unanticipated Serious Adverse Device Effect (USADE) 
A USADE which by its nature, incidence, severity or outcome has not been identified in the 
current Risk Management section of the Investigator’s Brochure (IB) and IFU. 

 
 
 
 
 
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Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with the Cordella PA Sensor System, that was not previously 
identified in nature, severity, or degree of incidence in the CIP, IB or IFU or any other 
unanticipated serious problem associated with the study device that relates to the rights, 
safety, or welfare of subjects. 
An unanticipated event is one where the nature or intensity is not consistent with the 
information in the current Risk Management section of the CIP, IB and IFU. 
Furthermore, reports which add significant information on specificity or severity of a known, 
already documented adverse effect constitute unanticipated events. For example, an event 
more specific or more severe than described in the IB would be considered ‘unexpected’.  
14.7.2 Causality Assessment  
The  relationship  between  the  use  of  the  medical  device  (including  the  medical  -  
surgical  procedure)  and  the  occurrence  of  each  adverse  event shall be  assessed  and 
categorized as follows: 
• Not related 
Relationship  to  the  device,  comparator  or  procedures can  be  excluded when:  
- 
the  event  has  no  temporal  relationship  with  the  use  of  the  investigational  
device,  or  the  procedures  related  to  application  of  the investigational  device;  
- 
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 adverse  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. 
• Possible 

 
 
 
 
 
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The  relationship  with  the  use  of  the  investigational  device  or  comparator,  or  the  
relationship  with  procedures,  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  where  
relatedness  cannot  be  assessed,  or  no  information  has  been  obtained should  also  
be classified  as possible.  
• Probably related 
The  relationship  with  the  use  of  the  investigational  device  or  comparator,  or  the  
relationship  with  procedures,  seems relevant  and/or  the  event  cannot  be  reasonably  
explained  by  another  cause.  
• Causal Relationship 
the  serious  adverse  event  is  associated  with  the  investigational  device,  comparator  
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  
o the  investigational device  or  procedures  are  applied  to;  
o 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;  
- 
the  event  depends  on  a  false  result  given  by  the  investigational  device  used  
for  diagnosis10,  when  applicable; 
14.7.3 Safety Reporting  
Regulations 
Safety reporting will be performed in line with the requirements of the Regulation (EU) 
2017/745 –Medical Device Regulation (MDR) Article 80(2) and MDCG 2020-10-1. 

 
 
 
 
 
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The sponsor will report, without delay to all Member States in which the clinical 
investigation is being conducted, all of the following (reportable 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)  
All causality assessments will be made as described in the section 9.2.2 of the CIP.  Only 
causality level 1 (i.e. “not related”) is excluded from reporting. If either the sponsor or 
the investigator has assigned a higher causality level than "not related", the event 
should be reported. 
Safety reporting-Investigator: 
As indicated in the section 9 of the CIP, the investigator must submit to sponsor (or 
designee) any UADEs and SAEs occurring during the study within 24 hours after being 
notified of the event and provide additional information, if required by Endotronix. In 
addition, any new finding regarding such events must be reported to the sponsor 
within the same time window (24 hours). 
Germany: The reporting timelines for the investigator or principal investigator are in 
accordance with the requirements of Section 63 of the German Medical Device Law 
Implementation Act (MPDG). 
For further information regarding the safety reporting by investigators please refer to 
the sections 9 and 11.3.1 of the CIP. 
Reporting method: 
A template for the Summary Reporting Form will be used for the safety reporting 
(please refer to the Appendix of MDCG 2020-10-01) 
Report to whom 
Reportable events must be reported all at the same time to all national competent 
authorities where the clinical investigation is authorized to start or has commenced. 
Reportable events occurring in the USA 
Reportable events occurring in the USA will be reported to the NCA(s) of the 
participating EU member states. 

 
 
 
 
 
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• The NCA will start receiving the reportable events occurring in the USA as 
soon as the clinical investigation is authorized to start in the participating EU 
Member State 
• Events occurring in the USA after the participating European sites have 
closed will continue to be reported

 
 
 
 
 
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Country Specific reporting timelines requirements 
 
Country / 
Authority 
Specific requirement to be met 
Process to meet this 
requirement 
Ireland/ 
Belgium 
For all reportable events 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: 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 or a new finding/update to it: Immediately, but not later than 7 calendar 
days following the date of awareness by the sponsor of the new reportable event or of new information 
in relation with an already reported event. 
The safety reports will be sent to: 
Belgium:  ct.rd@fagg-afmps.be Ireland: mailto:devices@hpra.ie  
All reportable SAEs will be 
processed in 2- day timeline (for 
SAEs which indicates an 
imminent risk of death, serious 
injury, or serious illness) and 7- 
day timeline for all other SAEs 
 
 
 

 
 
 
 
 
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Country / 
Authority 
Specific requirement to be met 
Process to meet this 
requirement 
Germany 
A causal relationship between the SAEs and 
the investigational medical device, a 
comparator device, diagnostic or 
therapeutic procedures performed as part of 
the clinical trial or other conditions of the 
trial conduct cannot be excluded 
To be reported immediately 
Germany 
German SAE Report Form to: 
MPSAE@bfarm.de  
All reportable SAEs will be 
processed in 2 day timeline (for 
SAEs which indicates an 
imminent risk of death, serious 
injury, or serious illness 
requiring immediate corrective 
action) and 7 day timeline for all 
other SAEs. 
New findings regarding an event 
will be reported within the 
original ridge requirement for 
that event. 
All other countries 
where the clinical 
trial is performed 
-Summary table 
-Clinical Investigation Summary 
Safety Reporting form   
A causal relationship between the SAE and 
the investigational medical device, a 
comparator device, diagnostic or 
therapeutic procedures performed as part 
of the clinical trial or other conditions of the 
trial conduct can be excluded 
To be reported quarterly 
All countries where 
the clinical trial is 
performed 
-Summary table 
-Clinical Investigation Summary 
Safety Reporting form   
SAE summary evaluation and 
cumulative Clinical Investigation 
Summary Safety Reporting form 
will be sent on a quarterly basis 
on predefined intervals 
All SAEs 
All countries where 
the clinical trial is 
performed 
-SAE summary evaluation  
-Annex 3.1 complication rate 
 
Further guidance as well as a link to the aforementioned reporting forms can be found under the following link: 
https://www.bfarm.de/EN/Medical-devices/Applications-and-reports/SAE-report/_node.html 

 
 
 
 
 
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14.8 
PROACTIVE-HF Site Survey (V1.0/ 09 Nov 2021) 
 

 
 
 
 
 
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14.9 
PROACTIVE-HF Subject Survey (V2.0/ 11 Feb 2022) 
 

 
 
 
 
 
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15 
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