A Prospective, Single-Arm, Nonrandomized, Observational Study of Cardiac Output Monitoring in Pediatric Patients
Conditions: Pediatric ALL
Sponsor: Edwards Lifesciences

 
 
 
 
 
 
 
 
 
 
 
 
NCT04465370 
 
 
 
 Pediatric Cardiac Output MonitorinG Observational Study  
 
 (POGO Study) A Prospective, Single-Arm, Nonrandomized, 
Observational Study of Cardiac Output Monitoring in 
Pediatric Patients 
 
 
Clinical Trial Protocol and Statistical Analysis Plan 
 
 
Clinical Trial Protocol version: November 20, 2022 
Statistical Analysis Plan version: December 2, 2020 
 
 
 

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
Page 1 of 52
CONFIDENTIAL
Pediatric Cardiac Output MonitorinG Observational Study
(POGO Study)
A Prospective, Single-Arm, Nonrandomized, Observational Study 
of Cardiac Output Monitoring in Pediatric Patients 
Clinical Study Protocol
Study Number: 2019-08
IDE Number: G190308
Revision: E
Date: November 20, 2020
Edwards Lifesciences LLC
One Edwards Ways
Irvine, CA 92614 USA

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
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CONFIDENTIAL
Revision B Change Summary
Please note: Punctuation, formatting or clerical changes are not included in the table.
Section 
(Page)
Change and Reason for Change
Synopsis & Study Design
(7 & 17)
Updated number of sites to up to 5
Reason: To meet enrollment goal within 12 months of commencement 
Schedule of Events & Procedures
(26)
Removed reference of thermodilutions analyses
Reason: SAP provides details of analysis
Independent Safety Committees 
(36)
Clarified the structure of the DSMB meetings
Reason: To ensure it is clear that efforts to mitigate operational bias are in 
place
Revision C Change Summary
Please note: Punctuation, formatting or clerical changes are not included in the table.
Section 
(Page)
Change and Reason for Change
Synopsis, Study Objective & 
Statistical Methods
(8, 16 & 22)
Limited secondary effectiveness endpoint to a single focus on CO, as 
determined by the Critchley and Critchley method of percent error 
calculation. Also added exploratory analyses comparisons of CI, as 
determined by the Critchley and Critchley method of percent error 
calculation and CI as determined by the Bland-Altman method of bias.
Reason: To align with revised statistical analysis plan
Data Safety Monitoring Board
(37)
Updated to indicate DSMB’s role in study oversight 
Reason: Clarified that DSMB will solely evaluate study safety and base its 
recommendation to continue the study on this assessment.  There is no 
planned interim analysis, thus DSMB will not assess effectiveness.

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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Lifesciences Corporation.
2019-08
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CONFIDENTIAL
Revision D Change Summary
Please note: Punctuation, formatting or clerical changes are not included in the table.
Section 
(Page)
Change and Reason for Change
Synopsis, Subject Selection and 
Withdrawal
(8, 19)
Edited inclusion criteria #4 to read “For those Subjects who have had a 
cardiac transplant, Subjects must be at least two weeks post cardiac 
transplantation.”
Reason: To qualify and better clarify that pre-transplant cardiac 
catherization evaluations are allowable.  For only those Subjects who have 
undergone cardiac transplantation, those Subjects will need to wait at 
least 2 weeks after the transplant to be eligible for the study.
Revision E Change Summary
Please note: Punctuation, formatting or clerical changes are not included in the table.
Section 
(Page)
Change and Reason for Change
Synopsis, Subject Selection and 
Withdrawal
(8, 19)
Edited exclusion criteria to include the following additional exclusions: 
6. Documented ≥ moderate pulmonary hypertension (PAPm > 25 mmHg, 
PVRI > 3.0 WUxm2)
7. Presence of intracardiac shunting (i.e., ASD, VSD)
8. Aorto-pulmonary collaterals 
9. ≥ Moderate tricuspid regurgitation, per echocardiogram criteria
10. > Moderate Aortic or pulmonary regurgitation, per echocardiogram 
criteria
11. Persistent cardiac arrythmias during the cardiac catheterization period 
(> 3min)
12. Vascular abnormalities of the arterial system (i.e., connective tissue 
disorders, mid-aortic syndrome)
Reason: Additional clarity to ensure intended exclusion of patients whose 
pathophysiologic state may result in intermittent and/or prolonged states 
in which the cardiac output from the right side of the heart may differ 
from the cardiac output from the left side of the heart.

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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Lifesciences Corporation.
2019-08
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CONFIDENTIAL
INVESTIGATOR’S SIGNATURE PAGE
This study will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and 21 CFR Parts 11, 50, 54, 56 and 812.
I will provide copies of the protocol to the Institutional Review Board and all members of the Study team 
responsible to me who participate in the Study.  I will discuss this material with them to ensure that all 
participating personnel at the Study site are fully informed regarding the conduct of the protocol.
Once the Institutional Review Board approves the protocol, I will not modify this protocol without obtaining 
the prior approval of both the Sponsor and the Institutional Review Board.  I will submit the protocol 
modifications and/or any informed consent modifications to the Sponsor and the Institutional Review Board, 
as applicable, and approval will be obtained before any modifications are implemented.
I will conduct the study as detailed in the protocol and in accordance with conditions of the approval imposed 
by the Institutional Review Board and all applicable regulations. I will maintain adequate source 
documentation records throughout the study and make them available as requested during monitoring visits.  
I will maintain device accountability records and will supervise the used of the device involving human 
subjects.
In addition, I will provide all the information requested in the electronic Case Report Forms 
presented to me by the Sponsor in a manner to assure completeness and accuracy.
I will ensure that the requirements for obtaining informed consent are met. Additionally, I will disclose 
financial interests in accordance with 21 CFR 54, and certify that such financial interests, if any, will not 
interfere with my responsibilities as an investigator or influence study outcomes under my supervision.
I have read the attached protocol and hereby agree that it contains all the necessary details for performing 
the Study. 
Investigator's Signature
Date
Investigator’s Printed Name
Study Site Name

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
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CONFIDENTIAL
Table of Content
Synopsis ...................................................................................................................................................... 8
1. Introduction ......................................................................................................................................... 10
Background .....................................................................................................................................................................10
2. Medical Devices .................................................................................................................................. 12
Device Names.................................................................................................................................................................12
Device Descriptions, Contraindications and Intended Uses....................................................................................12
Swan-Ganz Technology ....................................................................................................................................................12
FloTrac Technology............................................................................................................................................................13
ClearSight Technology.......................................................................................................................................................14
ForeSight Elite Technology ...............................................................................................................................................15
3. Study Objective................................................................................................................................... 17
Study Endpoints .............................................................................................................................................................17
4. Study Design ....................................................................................................................................... 18
General Design...............................................................................................................................................................18
5. Subject Selection and Withdrawal................................................................................................... 19
General Characteristics of the Proposed Subject Selection ....................................................................................19
Informed Consent...........................................................................................................................................................19
Inclusion Criteria .................................................................................................................................................................19
Exclusion Criteria................................................................................................................................................................19
Subject Screening ..........................................................................................................................................................20
Early Withdrawal of Subjects ............................................................................................................................................20
6. Statistical Methods ............................................................................................................................. 21
Primary Effectiveness Endpoint ...................................................................................................................................21
Sample Size Justification ..............................................................................................................................................21
Primary Safety Endpoint................................................................................................................................................23
Analysis Populations......................................................................................................................................................23
Analysis Methods ...........................................................................................................................................................23
Secondary Effectiveness Endpoint..............................................................................................................................23
Additional Evaluations ...................................................................................................................................................23

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
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CONFIDENTIAL
7. Receiving, Storage, and Return of devices.................................................................................... 25
Receipt of Device Supplies...........................................................................................................................................25
Storage ............................................................................................................................................................................25
Device Accountability.....................................................................................................................................................25
Return of Device .................................................................................................................................................................25
8. Schedule of Events & Procedures................................................................................................... 26
Schedule of Events ........................................................................................................................................................26
Intermittent Thermal Dilution Assessment(s) .............................................................................................................27
Clinical Study Completion or Early Termination ........................................................................................................27
Protocol Deviation ..........................................................................................................................................................27
Changes to the Protocol................................................................................................................................................29
9. Risk Analysis....................................................................................................................................... 30
Anticipated Risks............................................................................................................................................................30
Risk Management ..........................................................................................................................................................32
Benefits ................................................................................................................................................................................32
10.Reportable Events .............................................................................................................................. 33
Recording and Reporting of Adverse Events.............................................................................................................33
Recording and Reporting of Adverse Device Effects................................................................................................33
Recording and Reporting of Serious Adverse Event ................................................................................................34
Recording and Reporting of Serious Adverse Device Effects .................................................................................34
Recording and Reporting of Unanticipated Adverse Device Events ......................................................................34
Recording and Reporting of Deaths ............................................................................................................................35
Recording and Reporting of Adverse Events Associated with Commercial Components ..................................35
Recording and Reporting of Pre-Existing Conditions................................................................................................35
Reporting Adverse Events to the FDA ........................................................................................................................35
Reporting Adverse Events to the Responsible IRB...................................................................................................36
11.Independent Safety Committees...................................................................................................... 37
Clinical Events Committee............................................................................................................................................37
Data Safety Monitoring Board ......................................................................................................................................38
Stopping Rules....................................................................................................................................................................38
12.Data Handling and Record Keeping ................................................................................................ 39
Confidentiality .................................................................................................................................................................39
Source Documents.........................................................................................................................................................40
13.Data Collection Methods ................................................................................................................... 41
14.Record Retention................................................................................................................................ 42
15.Study Documentation ........................................................................................................................ 43

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
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CONFIDENTIAL
Study Records ................................................................................................................................................................43
Study Reports .................................................................................................................................................................43
Communication Procedures .........................................................................................................................................45
16.Study Monitoring, Auditing and Inspecting ................................................................................... 46
Site Selection ..................................................................................................................................................................46
Study Monitoring Plan....................................................................................................................................................46
Interim Monitoring Activities ..............................................................................................................................................46
Site Close-Out Visit ............................................................................................................................................................46
Auditing and Inspecting .................................................................................................................................................47
17.Ethics .................................................................................................................................................... 48
Ethical and Scientific Conduct of the Clinical Research Study................................................................................48
18.Financial Disclosures......................................................................................................................... 49
19.Publications ......................................................................................................................................... 50
20.Acronyms and Abbreviations........................................................................................................... 51
21.References ........................................................................................................................................... 52

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
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CONFIDENTIAL
SYNOPSIS
Title: 
Pediatric Cardiac Output MonitorinG Observational Study
Short Title:
POGO Study
Study 
Objective:
The primary objective of the study is to assess Cardiac Output Monitoring in 
pediatric subjects by comparing FloTrac and ClearSight system to 
intermittent thermodilution Swan-Ganz, in order to expand the indications 
of FloTrac, ClearSight and Swan-Ganz thermodilution pulmonary artery 
catheter to the pediatric population 12 to 18 years of age.  
Study Devices:
HemoSphere advanced monitoring platform, intermittent thermodilution 
Swan-Ganz, FloTrac, ClearSight system, ForeSight Elite sensors
Overall Design:
A prospective, single-arm, nonrandomized, observational study to assess the 
cardiac output (CO) monitoring methods in pediatric subjects.
Study 
Population:
Up to 108 eligible Subjects in a single arm
Males and Females, 12 to 18 years of age at the time of screening.
Number of 
Sites:
Up to five (5) U.S. sites
Study 
Duration:
Total of 9 to 12 months
Participation
Duration:
Screening/Baseline; Procedure; 30-day Telephone Follow-Up Visit
Inclusion/ 
Exclusion 
Criteria:
Inclusion Criteria
1.
Subjects who are 12 to 18 years of age
2.
Subjects who have signed the Informed Consent Form
3.
Subjects who are projected to receive Swan-Ganz catheter as part of 
procedure/standard of care with intermittent cardiac output measures
4.
For those Subjects who have had a cardiac transplant, Subjects must 
be at least two weeks post cardiac transplantation
5.
Subjects with planned pressure monitoring with an arterial line  
Exclusion Criteria
1.
Subjects with contraindications for Pulmonary Artery Catheters 
Placement and monitoring (recurrent sepsis, or with 
hypercoagulopathy);
2.
Subjects with contraindications for Arterial Line Placement;
3.
Subjects with an extreme contraction of the smooth muscle in the 
arteries and arterioles in the lower arm and hand (i.e., Raynaud’s 
Disease).
4.
Subjects with a physical site area too limited for proper Sensor 
placement
5.
Subjects with finger size less than the smallest finger cuff size

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
Page 9 of 52
CONFIDENTIAL
6.
Documented ≥ moderate pulmonary hypertension (PAPm > 25mmHg, 
PVRI > 3.0 WUxm2)
7.
Presence of intracardiac shunting (i.e., ASD, VSD)
8.
Aorto-pulmonary collaterals 
9.
≥ Moderate tricuspid regurgitation, per echocardiogram criteria
10. > Moderate Aortic or pulmonary regurgitation, per echocardiogram
criteria
11. Persistent cardiac arrythmias during the cardiac catheterization 
period (> 3min)
12. Vascular abnormalities of the arterial system (i.e., connective tissue 
disorders, mid-aortic syndrome)
Primary 
Effectiveness 
Endpoint:
Demonstrate that monitoring of cardiac output with Swan-Ganz, FloTrac, 
and ClearSight system is comparable as determined by the Bland-Altman 
method of bias.
Primary Safety 
Endpoint:
The primary safety endpoint is to assess all serious intraoperative and post-
operative adverse events through 30 days, including serious device-related 
events.
Secondary
Effectiveness 
Endpoint:
Demonstrate that monitoring of cardiac output with Swan-Ganz, FloTrac, and 
ClearSight system is comparable as determined by the Critchley and Critchley 
method of percent error calculation.
Study Sponsor:
Edwards Lifesciences LLC
One Edwards Way
Irvine, CA 92614 USA
Study Director:
 
 
Study 
Manager:
 

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
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CONFIDENTIAL
1.
INTRODUCTION
Background
In the critically ill, traditional vital signs may be late indicators of compromised or inadequate oxygen delivery 
to the tissues, potentially delaying intervention and putting the patient at greater risk. The ability to monitor 
blood oxygenation early is critical. The pursuit of measuring blood flow through the heart has resulted in the 
development of different techniques for its quantification. The three main methodologies to measure cardiac 
output are the Fick method, dye dilution, and thermodilution techniques [9]. The Fick method is the “gold 
standard” for cardiac output determinations in adults and is based on the principles developed by Adolph Fick 
in the 1870’s. Fick’s concept proposes that the uptake or release of a substance by an organ is the product of 
blood flow through that organ and the difference between the arterial and venous values of the same 
substance. The Fick principle reflects the extraction of oxygen through the systemic circulation and is 
dependent on arterial and pulmonary arterial oxygen levels, hemoglobin and the maximum amount of oxygen 
consumption by the body in a given period (VO2 max).  Thus, the Fick principle involves the blood oxygenation 
process through the lungs and oxygen delivery to the tissues, where it is added and removed by a flow limited 
mechanism.  By measuring the amount of oxygen carried by the blood, the total amount of blood needed to 
carry oxygen through the lungs could be calculated.  This value then reflects the output of the heart [9].
An intermittent thermodilution method applies the Steward Hamilton indicator dilution principles, using
temperature change as the indicator. A known amount of solution with a known temperature is injected into 
the right side of the circulation and continuously withdrawn and measured at a constant rate from the arterial 
side. This resultant curve is plotted against time and cardiac output is calculated using the Stewart-Hamilton 
Equation. This curve is similar to the one produced by the indicator dilution method. A modified Stewart-
Hamilton equation is used to calculate the cardiac output, taking into consideration the change in temperature 
as the indicator. Modifications include the measured temperature of the injectate and the patient’s blood
temperature, along with the specific gravity of the solution injected [9].
Minimally invasive technologies have been developed to monitor CO. FloTrac is a minimally invasive solution 
for advanced hemodynamic monitoring that automatically calculates key flow parameters every 20 seconds. 
Continuous clarity provided by the FloTrac system offers proactive decision support to manage hemodynamic 
instability and ensure adequate perfusion. In addition to minimally invasive technologies, noninvasive 
technologies such as the ClearSight system offer proactive decision support to optimize perfusion. The 
ClearSight system provides advanced hemodynamic parameters and continuous noninvasive blood pressure 
(BP) from a finger cuff and extends the benefits of continuous hemodynamic monitoring to a broad patient 
population, including patients in whom an arterial line would not typically be placed [10].
The Swan-Ganz pulmonary artery catheter (PAC) is considered the gold standard to validate new CO monitoring 
devices. The Swan-Ganz PAC consists of an intravenous device placed in the pulmonary artery allowing 
measurement of cardiac output, pulmonary artery pressures [1] as well as cardiac filling pressures. Since its 
initial presentation by Swan in 1970 [2], several modifications were made on the initial catheter that allowed 
for intermittent monitoring of cardiac output, stroke volume (SV), systemic vascular resistance (SVR) and mixed 
venous saturation (SvO2) [1,3]. Technology for cardiac output (CO) and blood volume measurements has been 
developed using existing central venous
and peripheral arterial catheters (PAC),
such that 

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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Lifesciences Corporation.
2019-08
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CONFIDENTIAL
transcardiopulmonary thermodilution of blood with a small saline bolus is detected with ultrasound sensors 
attached to an extracorporeal arteriovenous loop [4].  
There is an unmet need in the pediatric population, as there are currently no clinically practical, accurate or
precise methods for measuring cardiac output (CO).  During his research in 1920, Alfred Blalock, M.D., a pioneer 
of pediatric congenital cardiac surgery found that “the repeated removal of blood is usually associated with a 
decline in the cardiac output from 30 to 50% below the normal level before a marked diminution in the mean 
blood pressure occurs” [4,5].  Even though it has been nearly 100 years since Dr. Blalock demonstrated the 
importance of cardiac output in global cardiovascular circulation, even with its shortcomings, blood pressure 
remains the gold standard for hemodynamic monitoring of cardiovascular function in critically ill pediatric 
patients [6]. Cardiac output is measured very rarely in the pediatric population; however, it is vital for oxygen 
delivery.  In this population, the methods used for cardiac output monitoring continue to be a poor surrogate, 
not validated or inaccurate. Cardiac output measurement is an essential part of hemodynamic monitoring and 
management of all critically ill patients, including pediatric patients of all ages and sizes [7].  
The primary objective of the study is to assess Cardiac Output Monitoring in pediatric subjects by comparing 
FloTrac, ClearSight system to intermittent thermodilution Swan-Ganz, in order to expand the indications of 
FloTrac, ClearSight and Swan-Ganz thermodilution pulmonary artery catheter to the pediatric population 12 to 
18 years of age.  The study population will be children ages 12 to 18 who are at least 2 weeks post cardiac 
transplant.
The ForeSight Elite sensors, which are cleared for pediatric use, will be used in this study with the HemoSphere 
advanced monitoring platform to collect additional data on tissue oximetry. The ForeSight Elite Sensors provide 
the benefit of continually monitoring oxygen saturation of tissue with accuracy and precision.

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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Lifesciences Corporation.
2019-08
Page 12 of 52
CONFIDENTIAL
2.
MEDICAL DEVICES
Device Names
x
HemoSphere Advanced Monitoring Platform (including ClearSight Module)
x
Swan-Ganz thermodilution pulmonary artery catheter
x
FloTrac Sensor
x
ClearSight System (includes pressure controller/wrist unit, Heart Reference Sensor and finger cuff)
x
ForeSight Elite Sensors (commercially available in adults and pediatric populations)
Device Descriptions, Contraindications and Intended Uses
Swan-Ganz Technology
Description
The Swan-Ganz thermodilution catheters provide diagnostic information to rapidly determine 
hemodynamic pressures and cardiac output when used with a compatible cardiac output computer. The 
Swan-Ganz technology will be used for the intermittent cardiac output measurements. There will be two 
sets of four repeated intermittent cardiac output measurements.
x
Swan Ganz Thermodilution Catheters: K160084 cleared in adults. Devices are investigational in 
pediatric population.
Swan-Ganz Thermodilution Pulmonary Artery Catheter Cleared Indications
The Swan-Ganz thermodilution catheters are indicated for the assessment of a patient’s hemodynamic 
condition through direct intracardiac and pulmonary artery pressure monitoring, cardiac output 
determination, and for infusing solutions.
The distal (pulmonary artery) port also allows sampling of mixed venous blood for the assessment of 
oxygen transport balance and the calculation of derived parameters such as oxygen consumption, oxygen 
utilization coefficient, and intrapulmonary shunt fraction.
Swan-Ganz Thermodilution Pulmonary Artery Catheter Proposed Indications
Swan-Ganz thermodilution catheters are indicated for the assessment of a patient’s hemodynamic 
condition through direct intracardiac and pulmonary artery pressure monitoring, cardiac output 
determination, and for infusing solutions.
The distal (pulmonary artery) port also allows sampling of mixed venous blood for the assessment of 
oxygen transport balance and the calculation of derived parameters such as oxygen consumption, oxygen 
utilization coefficient, and intrapulmonary shunt fraction.  Indicated for use in adults and pediatric patients 
12-18 years of age.
Contraindications

     
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2019-08
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CONFIDENTIAL
No absolute contraindications to the use of flow-directed pulmonary artery catheters exist. However, a 
patient with a left bundle branch block may develop a right bundle branch block during catheter insertion, 
resulting in complete heart block.
HemoSphere Advanced Monitor with HemoSphere Swan-Ganz Module Cleared Indications
The HemoSphere advanced monitor when used with the HemoSphere Swan-Ganz module and Edwards 
Swan-Ganz catheters is indicated for use in adult and pediatric critical care patients requiring monitoring of 
cardiac output (continuous [CO] and intermittent [iCO]) and derived hemodynamic parameters in a 
hospital environment. It may be used for monitoring hemodynamic parameters in conjunction with a 
perioperative goal directed therapy protocol in a hospital environment.
The are no changes to the HemoSphere Advanced Monitor with HemoSphere Swan-Ganz Module since the 
specific patient population indications are provided as part of the Swan-Ganz catheter IFU (see below).
FloTrac Technology
Description
The FloTrac sensor is a sterile, single use kit that monitors pressures when attached to pressure monitoring 
catheters. When connected to a compatible monitor, the FloTrac sensor minimally-invasively measures 
cardiac output and key hemodynamic parameters, which assist the clinician in assessing the patient’s 
physiologic status and support clinical decisions related to hemodynamic optimization. The disposable 
sterile cable with a red connector interfaces exclusively with an Edwards cable that is specifically wired for 
the pressure monitor being used. The disposable sterile cable with a green connector interfaces exclusively 
with the Edwards cables for use with the Edwards arterial pressure based cardiac output monitoring 
devices or hardware. The cardiac output measurements from the FloTrac technology will be compared to 
the intermittent cardiac output measurements from the Swan-Ganz technology.
The FloTrac sensor has a straight, flow-through design across the pressure sensors with an integral flush 
device.
x
FloTrac Sensors (classic): K152980 are cleared in adults. Devices are investigational in pediatric 
population.
FloTrac Sensor Cleared Indications
The FloTrac sensor is indicated for use in intravascular pressure monitoring. It is also indicated for use with 
the Edwards arterial pressure based cardiac output monitoring devices or hardware to measure cardiac 
output. 
FloTrac Sensor Proposed Indications
The FloTrac sensor is indicated for use in intravascular pressure monitoring. It is also indicated for use with 
the Edwards arterial pressure based cardiac output monitoring devices or hardware to measure cardiac 
output. Indicated for adult and pediatric patients 12-18 years of age.

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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Lifesciences Corporation.
2019-08
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CONFIDENTIAL
Contraindications
There are no absolute contraindications for using the FloTrac sensor in patients requiring invasive pressure 
monitoring.
The FloTrac Sensors are cleared for use with the HemoSphere Advanced Monitor with HemoSphere 
Pressure Cable (K180881).
HemoSphere Advanced Monitor with HemoSphere Pressure Cable Cleared Indications (For Use with 
FloTrac)
The HemoSphere advanced monitor when used with the HemoSphere pressure cable is indicated for use in 
critical care patients in which the balance between cardiac function, fluid status, vascular resistance and 
pressure needs continuous assessment. It may be used for monitoring of hemodynamic parameters in 
conjunction with a perioperative goal directed therapy protocol in a hospital environment.
The are no changes to the HemoSphere Advanced Monitor with HemoSphere Pressure Cable since the 
specific patient population indications are provided as part of the FloTrac sensor IFU (see below).
ClearSight Technology
Description
The ClearSight finger cuffs, when used with an appropriate Edwards monitoring system, provide 
continuous, noninvasive hemodynamic monitoring. The ClearSight finger cuffs utilize the volume-clamp 
method to measure blood pressure with an inflatable bladder wrapped around the middle phalanx of the 
finger. The cardiac output measurements from the ClearSight technology will be compared to the 
intermittent cardiac output measurements from the Swan-Ganz technology.
x
ClearSight Finger Cuffs: K190130 are cleared in adults for use with EV1000NI. Investigational device 
for use with HemoSphere Advanced Monitoring Platform.
The ClearSight technology is not cleared in the US for use with the HemoSphere Advance Monitor 
Platform. The non-invasive ClearSight technology is currently available in the US on a different Edwards’ 
platform (EV1000NI - K160552) but is investigational on the HemoSphere advanced monitor.
Contraindications
In some patients with extreme contraction of the smooth muscle in the arteries and arterioles in the lower 
arm and hand, such as may be present in patients with Raynaud’s disease, blood pressure measurement 
can become impossible.

     
POGO Study
Study #2019-08
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Lifesciences Corporation.
2019-08
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CONFIDENTIAL
HemoSphere Advanced Monitor with HemoSphere ClearSight Module Proposed Indications
The HemoSphere advanced monitor when used with the HemoSphere ClearSight module, pressure 
controller and a compatible Edwards finger cuff are indicated for adult patients over 18 years of age and 
pediatric patients 12-18 years of age in which the balance between cardiac function, fluid status and 
vascular resistance needs continuous assessment. It may be used for monitoring hemodynamic 
parameters in conjunction with a perioperative goal directed therapy protocol in a hospital environment. 
In addition, the noninvasive system is indicated for use in patients with co-morbidities for which 
hemodynamic optimization is desired and invasive measurements are difficult. The HemoSphere advanced 
monitor and compatible Edwards finger cuffs noninvasively measures blood pressure and associated 
hemodynamic parameters.
ClearSight Finger Cuff Proposed Indications
The ClearSight finger cuffs are indicated for adult patients over 18 years of age and pediatric patients 12-
18 to noninvasively measure blood pressure and associated hemodynamic parameters when used with 
EV1000 clinical platform NI or HemoSphere advanced monitoring platform.
The HemoSphere Advanced Monitoring Platform is a multi-parameter, multi-technology, hemodynamic 
platform. The goal of this platform is to provide users with a single point in which they can utilize any of 
Edwards’ hemodynamic disposables. The HemoSphere advanced monitoring platform is composed of a 
primary HemoSphere Monitor.  The HemoSphere advance monitoring platform interfaces with external 
technology specific modalities in the form of modules or Smart-Cables. Each modality is designed to 
connect to a specific type of Edwards disposable product as discussed above, and interface to the 
HemoSphere Monitor via a digital interface.  The commercially available HemoSphere Advanced 
Monitoring Platform is cleared for use with the disposables presented above.
ForeSight Elite Technology
Description
The Sensor, when used in combination with the ForeSight Elite tissue oximeter module or in combination 
with the ForeSight Elite absolute tissue oximeter, is a single use applied part that measures hemoglobin 
allowing the clinician to continuously and accurately determine absolute levels of blood oxygenation 
saturation in the tissue (StO2).
x
ForeSight Elite Sensors:  K180003, in both pediatric and adult population on the HemoSphere 
Advanced Monitoring Platform (not seeking expansion, only included to obtain additional 
information under its current indications)
ForeSight Elite Sensors (Medium) Cleared Indications
When used in conjunction with the ForeSight Elite absolute tissue oximeter or FORE-SIGHT ELITE tissue 
oximetry module: The medium Sensor is indicated for monitoring of absolute regional hemoglobin oxygen 
saturation of blood under the sensor in individuals at risk for reduced flow or no-flow ischemic states. It is 
intended for use on pediatric subjects ≥ 3 kg.

     
POGO Study
Study #2019-08
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CONFIDENTIAL
ForeSight Elite Sensors (Large) Cleared Indications
When used in conjunction with the FORE-SIGHT ELITE absolute tissue oximeter or FORE-SIGHT ELITE tissue 
oximetry module: The large Sensor is indicated for monitoring of absolute regional hemoglobin oxygen 
saturation of blood under the sensor in individuals at risk for reduced flow or no-flow ischemic states. It is 
intended for use on pediatric subjects ≥ 40 kg.
There are no proposed indications for ForeSight Elite technology since Edwards is not seeking indications 
expansion. It is included in the study only to obtain reference information under its currently cleared 
indications for pediatric patients.
Contraindications
The ForeSight Elite sensor is contraindicated for use on patients:
•
With a physical site area too limited for proper Sensor placement
•
With allergic reactions to Sensor adhesive
•
Undergoing an MRI scan because of associate risk of injury
The ForeSight sensors are cleared for use with the HemoSphere Advanced Monitor with HemoSphere 
Tissue Oximetry Module (K190205) in both pediatric and adult population on the HemoSphere Advanced 
Monitoring Platform (not seeking expansion, only included to obtain additional information under its 
current indications)
HemoSphere Advanced Monitor with HemoSphere Tissue Oximetry Module Cleared Indications
The noninvasive ForeSight Elite tissue oximeter module is intended for use as an adjunct monitor of 
absolute regional hemoglobin oxygen saturation of blood under the sensors in individuals at risk for 
reduced-flow or no-flow ischemic states. The ForeSight Elite tissue oximeter module is intended to allow 
for the display of StO2 on the HemoSphere advanced monitor.  It is indicated for use as follows:
•
When used with large sensors, the ForeSight Elite tissue oximeter module is indicated for use on adults 
and transitional adolescents ≥40 kg.
•
When used with medium sensors, the ForeSight Elite tissue oximeter module is indicated for use on 
pediatric subjects ≥3 kg.
•
When used with small sensors, the ForeSight Elite tissue oximeter module is indicated for cerebral use 
on pediatric subjects <8 kg and non-cerebral use on pediatric subjects <5kg.
HemoSphere Advanced Monitor with HemoSphere Oximetry Cable Cleared Indications
The HemoSphere advanced monitor when used with the HemoSphere oximetry cable and Edwards
oximetry catheters is indicated for use in adult and pediatric critical care patients requiring monitoring of
venous oxygen saturation (SvO2 and ScvO2) and derived hemodynamic parameters in a hospital
environment. Refer to the Edwards oximetry catheter indications for use statement for information on 
target patient population specific to the catheter being used.  Refer to the Intended Use statement for a 
complete list of measured and derived parameters available for each patient population.

     
POGO Study
Study #2019-08
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2019-08
Page 17 of 52
CONFIDENTIAL
3.
STUDY OBJECTIVE
The primary objective of the study is to assess Cardiac Output Monitoring in pediatric subjects by 
comparing FloTrac, ClearSight and the Fick principle (using Swan Ganz) to intermittent thermodilution 
Swan-Ganz, in order to expand the indications of  FloTrac, ClearSight and Swan-Ganz thermodilution
pulmonary artery catheter to the pediatric population 12 to 18 years of age.  
Study Endpoints
The primary effectiveness endpoint is to demonstrate that monitoring of cardiac output (CO) with Swan-
Ganz, FloTrac, and ClearSight is comparable as determined by the Bland-Altman method of bias.
The primary safety endpoint is to assess all serious intraoperative and post-operative adverse events 
through 30 days, including serious device-related events.
The secondary effectiveness endpoint is to demonstrate that monitoring of cardiac output (CO) with Swan-
Ganz, FloTrac, and ClearSight is comparable as determined by the Critchley and Critchley method of 
percent error calculation.

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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2019-08
Page 18 of 52
CONFIDENTIAL
4.
STUDY DESIGN
General Design
This study is an observational study in the U.S. Up to 108 eligible Subjects will be enrolled at up to five (5) 
study sites. A subject will be considered enrolled in the study once the subject has signed the informed 
consent and a Swan-Ganz thermodilution pulmonary artery catheter has been deployed, a FloTrac has been 
connected, the ClearSight finger cuff has been attached or ForeSight Elite sensors have been placed. The Study 
ID will be a 6-digit number, the first three numbers will identify the site, and the second set of numbers will 
identify the subject identification number. 
A Swan-Ganz catheter, FloTrac transducer, ClearSight finger cuff and ForeSight Elite sensors will be placed 
prior to the start of the catheterization procedure. Intermittent cardiac output and other hemodynamic
parameters will be collected throughout the duration of the procedure and analyzed according to the 
Statistical Analysis Plan.
Data collected in this study will support in expanding the current indications of Swan-Ganz, FloTrac and 
ClearSight into the pediatric population.
This study will be conducted in a manner that is consistent with the applicable regulations and in accordance 
with current Good Clinical Practice (GCP).

     
POGO Study
Study #2019-08
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2019-08
Page 19 of 52
CONFIDENTIAL
5.
SUBJECT SELECTION AND WITHDRAWAL 
General Characteristics of the Proposed Subject Selection
Subjects 12 to 18 years of age, with planned catheterization procedure, at least 2 weeks post cardiac 
transplantation, who are projected to receive an arterial line and a Swan-Ganz catheter as part of the 
procedure/standard of care with intermittent cardiac output measures will be screened for inclusion into 
the Study.  Only subjects meeting all inclusion criteria will be enrolled.  
Prior to any Study procedures, an IRB approved informed consent form must be signed and dated by the 
subject or legal guardian.  Subjects who have been screened but do not sign an informed consent form will 
not be considered enrolled and will not have any eCRFs (electronic Case Report Forms) completed.  
Informed Consent
Before a subject undergoes any Study procedures, an informed consent will be obtained utilizing the IRB 
approved consent form.  All consent procedures will be conducted in a manner that is consistent with the 
applicable regulations and in accordance with Good Clinical Practice (GCP).
During the consent procedure, each potential subject will be given ample time to discuss participation in the 
Study and to have any questions or concerns addressed by the Principal Investigator or Investigator.  Each 
subject will be provided with a copy of the IRB approved consent.
Inclusion Criteria
Exclusion Criteria
4.
Subjects with a physical site area too limited for proper Sensor placement
5.
Subjects with finger size less than the smallest finger cuff size
6.
Documented ≥ moderate pulmonary hypertension (PAPm > 25mmHg, PVRI >3.0 WUxm2)
7.
Presence of intracardiac shunting (i.e., ASD, VSD)
8.
Aorto-pulmonary collaterals 
9.
≥ Moderate tricuspid regurgitation, per echocardiogram criteria
10. > Moderate Aortic or pulmonary regurgitation, per echocardiogram criteria
11. Persistent cardiac arrythmias during the catheterization period (> 3min)
1.
Subjects who are 12 to 18 years of age
2.
Subjects who have signed the Informed Consent Form
3.
Subjects who are projected to receive Swan-Ganz catheter as part of procedure/standard of care 
with intermittent cardiac output measures
4.
For those Subjects who have had a cardiac transplant, Subjects must be at least two weeks post 
cardiac transplantation
5.
Subjects with planned pressure monitoring with an arterial line
1.
Subjects with contraindications for Pulmonary Artery Catheters placement and monitoring 
(recurrent sepsis, or with hypercoagulopathy);
2.
Subjects with contraindications for Arterial Line Placement;
3.
Subjects with an extreme contraction of the smooth muscle in the arteries and arterioles in the 
lower arm and hand (i.e., Raynaud’s Disease).

     
POGO Study
Study #2019-08
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Lifesciences Corporation.
2019-08
Page 20 of 52
CONFIDENTIAL
12. Vascular abnormalities of the arterial system (i.e., connective tissue disorders, mid-aortic 
syndrome)
Subject Screening
All eligible subjects should be screened for Study eligibility.  The Investigator and/or Designee(s) at the Study 
site shall review the candidate’s eligibility. The Study site should maintain a cumulative log of all screened 
subjects that are eligible in participating.
Early Withdrawal of Subjects
Subjects may voluntarily withdraw consent at any time during the study with no loss of benefit or penalty. 
The Investigator may withdraw any subject if they determine that continued participation in the study may 
be detrimental to the subject’s safety and welfare. Each subject withdrawal will be documented on the 
appropriate eCRF. 

     
POGO Study
Study #2019-08
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Lifesciences Corporation.
2019-08
Page 21 of 52
CONFIDENTIAL
6.
STATISTICAL METHODS
Primary Effectiveness Endpoint
The primary objective of this study is to demonstrate that monitoring of cardiac output with Sawn-Ganz, 
FloTrac, and ClearSight system is comparable as determined by the Bland-Altman method of bias.
Sample Size Justification
Sample size consideration for bias
The bias between the matched pairs of CO measurements, as determined by the Bland-Altman method, 
must be smaller than the minimum clinical difference δ, which is the value that is large enough to claim 
difference. 
The hypothesis for bias is:
  H0:  bias <-δ or bias >δ 
  H1: -δ≤ bias ≤δ 
H0 is the null hypothesis (i.e. the difference between matched pairs of CO values of the two systems is 
larger than δ), H1 is the alternative hypothesis (i.e. the difference between matched pairs of CO values of 
the two systems is within the range of δ).  A meta-analysis conducted a comprehensive search of 21 
published medical literature to assess the accuracy and precision of minimally invasive CO monitoring 
systems used in children when compared with CO monitoring reference methods [8]. Among the 21 
studies, 19 studies (90%) showed a bias range of -0.5 to 0.5 L/min. Based on these data, the clinical 
minimum difference δ was set at 0.5 L/min, i.e. bias is expected to be -0.5< bias < 0.5 l/min. This value is 
smaller in magnitude than the 0.8 l/min floor that the US FDA had previously considered for CO 
comparisons. The meta-analysis also shows that 19 out of 21 published studies had standard deviation (SD) 
no more than 1.0 L/min.  
In this study eight repeated measurements (m=8 sub samples) or sub sample sections will be taken during 
the cardiac catherization case, thus intra-cluster correlation ecoefficiency ICC is a factor to be considered 
in sample size estimation. Here ܫܥܥ=
ఋೞమ
ఋೞమାఋೞೞ
మ. ߜ௦ଶis the variance component of study subject. ߜ௦௦
ଶis the 
variance component of sum sample. By literature the ICC in children ranges from 0.94 to 0.98. The 
variation of study subject is dominant. Fixed the study subjects, the more sub-samples taken the less 
ߜ௦௦
ଶwill be by a factor 1/m. This will reduce the total variance applied in sample size calculation. Using 
ICC=0.98, and SD=1 (Variance=1) as an example, for m=8, as an example, for m=8,  the stand deviation 
used in sample size estimation is ܵܦ= ට0.98 ∗1 +
ଵି଴.ଽ଼
଼
= 0.991211..
The sample size calculation for this hypothesis is based on the one-sample t-test for equivalence. The 
desired outcome is to reject the null hypothesis at the 0.05 significance level.  For this equivalence test of
bias, two comparisons will be performed: FloTrac vs Swan-Ganz and ClearSight vs Swan-Ganz. In order to 
preserve the overall type 1 error rate at 0.05, the Bonferroni Correction will be used to adjust for multiple 
comparisons. 

     
POGO Study
Study #2019-08
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2019-08
Page 22 of 52
CONFIDENTIAL
Assuming a true mean bias of 0.0 and a SD of 1.0 l/min in the cardiac output, the sample size required for 
δ=0.5, alpha=0.05, and power=90% to reject the null hypothesis is 45, ignoring the ICC. After considering 
ICC for eight repeated measures (m=8), a sample size of 54 Subjects in needed. After considering a 34.5% 
rejection rate for hemodynamic instability, 10% lost to follow-up rate and 6 Roll-in Subjects for the 
learning curve, a total of 102 (96 evaluable Pivotal Subjects and 6 Roll-in Subjects) will be enrolled.
Adjusting for multiple comparisons, considering there will be two target devices and a reference device 
pairs, simultaneously, 108 total Subjects will be enrolled in this study.
Sample size consideration for percent error
The Critchley and Critchley method of percent error (PE) calculation will be compared to 30%. The 
Precision will be considered as acceptable if PE is less than 30 %. 
The hypothesis for PE is a one-sided test: 
H0: PE > 30%
H1: PE ≤ 30% 
The sample size calculation for this hypothesis was based on the one-sided T-test. The desired outcome is 
to reject the null hypothesis at the 0.05 significance level. Assuming a true mean of 30% and a conservative 
SD assumption of 70%, the sample size required for power=90% to reject the null hypothesis is 49. 
Because the study is designed with sub samples (repeated measurements) or sub sample sections (m= 8), 
ICC is a factor needing to be considered in the sample size estimation.  When eight repeated measures
(m=8) are performed, the SD=69.38%.  The corresponding sample size necessary is 49.
For PE, a sample size of n=60 will be used in the study design, after considering two pairwise 
comparisons between 2 devices with a reference device. In addition, after considering a 34.5% rejection 
rate for hemodynamic instability, 10% lost to follow-up rate, 102 evaluable subjects will be targeted.  To 
account for the learning curve and 6 additional Roll-in Subjects will be enrolled, totaling 108 Subjects 
enrolled in the study.
Calculation of Cardiac Index (CI)
Adjusting cardiac output (CO) with study subject body surface area (BSA) results in the derivation of 
cardiac index (CI). This adjustment for body surface area, in the study pediatric population (12 to 18 years 
old), will result in a smaller bias and percent error between test device and reference device. The standard 
deviation estimate will also be smaller, at the same scale, thus, the sample size estimate decreases.  
Sample size estimates for bias and percent error for CI is detailed in the SAP.

     
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CONFIDENTIAL
Primary Safety Endpoint
The primary safety endpoint is to assess all serious intraoperative and post-operative adverse events 
through 30 days, including serious device-related events.
Analysis Populations
All enrolled subjects with evaluable data will be included in the analysis of effectiveness endpoint, and all 
enrolled subjects will be included in the analysis of safety endpoint.
  
The analysis set is composed of all evaluable subjects with valid CO matched pair measurements from the 
target medical device system (FloTrac and ClearSight systems) and the reference medical device system (the
Swan-Ganz thermodilution pulmonary artery catheter).  
Evaluable subjects are those with non-rejected intermittent thermodilutions who have completed the 30-
day telephone follow up period.
Analysis Methods
The primary effectiveness endpoints will be accessed using the testing method described in the Sample Size 
Justification section. Additionally, descriptive statistics will be used to summarize data. Mean, SD, median, 
25th (Q1) and 75th (Q3) percentiles, minimum, and maximum will be reported for continuous variables;
frequency and percentage of subjects will be reported for categorical variables. Further details of the analysis 
method will be described in the Statistical Analysis Plan for this study.
Secondary Effectiveness Endpoint
The secondary effectiveness endpoint is to demonstrate that monitoring of cardiac output (CO) with Swan-
Ganz, FloTrac and ClearSight is comparable, as determined by the Critchley and Critchley method of percent 
error.  
Additional Evaluations
The following additional evaluations will be included and considered exploratory:
x
Comparison analysis of CI as determined by the Bland-Altman method of bias calculation with 
confidence intervals
x
Comparison analysis of CI as determined by the Critchley and Critchley method of percent error 
calculation with confidence intervals
x
Subgroup analysis of primary and secondary endpoint by age stratification
x
Subgroup analysis of primary and secondary endpoint by gender
x
Subgroup analysis of primary and secondary endpoint by race
x
Subgroup analysis of primary and secondary endpoint by site

     
POGO Study
Study #2019-08
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2019-08
Page 24 of 52
CONFIDENTIAL
x
Comparison of cardiac output from FloTrac, ClearSight and Swan-Ganz technologies to the Fick 
principle
x
Evaluation of hemodynamic parameters that are collected by the FloTrac, ClearSight, Swan-Ganz
technologies, including:
o
Cardiac Output (CO)
o
Cardiac Index (CI)
o
Pulse Rate (PR)
o
Stroke Volume (SV)
x
Evaluation of other hemodynamic parameters that will be collected during the catherization 
procedure, as prespecified in the SAP

     
POGO Study
Study #2019-08
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2019-08
Page 25 of 52
CONFIDENTIAL
7.
RECEIVING, STORAGE, AND RETURN OF DEVICES
Receipt of Device Supplies
A packing list will accompany all device shipments.  This list will include the inventoried product with receipt 
date and investigator and/or designee signature.  
Storage
The HemoSphere advanced monitoring platform and all investigational devices for use in this study shall be 
stored in a secure and clean area complying with the storage instructions provided in the labeling.  
Device Accountability
The Investigator and/or delegated-study personnel shall keep records documenting the receipt, use, return, 
and disposal of the devices.  Only the Investigator, delegated-Study Personnel and/or designee(s) (i.e., 
Assisting Clinician(s)) may use the devices.  The Investigator will supervise the used of the device in Study 
subjects.  The Study site shall account for which system/device was used for which subject as well as for the 
return of the system/device.  
Return of Device
The Principal Investigator is responsible for returning the unused product back to the Sponsor.

     
POGO Study
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CONFIDENTIAL
8.
SCHEDULE OF EVENTS & PROCEDURES 
Schedule of Events
The following matrix shows the scheduled assessments through the end of the Study (30-Day Follow Up).
The duration of individual study participation is expected to be 30 days (±14 days) after procedure. 
Data collection will occur during the study via the HemoSphere platform and electronic case report forms
(eCRFs). The 30-day follow-up phone contact will be recorded on the applicable eCRF.
1 Medical History / Subject Demographics / Surgical and Clinician Demographics can be obtained prior to procedure, either at the 
screening visit or on the day of procedure.
2 Can be collected via the hospital record system anytime on the day of procedure or thereafter.
Study Procedure / Exam
Subject 
Screening
Procedure
Discharge
30-Day Follow Up
(±14 Days)
Obtain Informed Consent
X
Perform Inclusion / 
Exclusion Evaluation
X
Obtain Medical History / 
Subject Demographics1
X
Assign Subject ID
X
Enter Subject Data into 
Monitor
X
Vital Signs
X
Monitoring Duration
X
Data download from 
Monitor
X
Obtain Fluid and Vasoactive 
Medication Administration 
Record2
X
Complete eCRFs
X
X
X
X
Record Adverse Events, if 
applicable
X
X
X
Phone Contact 30-day 
follow up / Mortality 
Determination
X

     
POGO Study
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CONFIDENTIAL
Intermittent Thermal Dilution Assessment(s)
Using the Swan-Ganz thermodilution pulmonary artery catheter, two series of four (4) intermittent dilutions 
should be administered by the Investigator while in the cath lab.  The dilution curves are analyzed and 
averaged to give one (1) CO value.  
CO measured by the ClearSight and FloTrac systems will be simultaneously compared with the CO measured 
by the Swan-Ganz catheter using the thermodilution method. There will be 2 sets of 4 measurements 
recorded over a 30-second interval, during the Swan-Ganz thermodilution bolus injection. Those 4 
measurements will be pair-matched by time in the ClearSight and FloTrac systems. The same number of 
measurements that will be recorded during the Swan-Ganz thermodilution will be recorded for the 
ClearSight and FloTrac devices.  The following thermodilution procedure will be used:
A 10 ml sample of iced glucose solution (5%) will be drawn through an iced injectate container (CO-SET+ or 
any other container that meets the requirements, as determined by the investigator) and injected in a 
steady manner. Four TD CO determinations will output, preferably within 5 minutes.  From there, three 
values, will be averaged to obtain one single value. Each thermodilution curve will be visually checked 
before acceptance. The dilution curve will be automatically corrected for the temperature of the blood and 
of the injectate measured at the entrance of the catheter lumen. Values for temperatures will be stored 
together with the thermodilution values. The entire series of four thermodilution estimates will be rejected 
if, during an injection, the HemoSphere advanced monitor displays an alert signal, if the injectate 
temperature is above 10 °C, or when the curve of the dilution is abnormal. In case of rejection, the entire 
series of four thermodilutions will be repeated.
Hemodynamics and respiratory rate must be stable during the TD series, since variability violates the 
assumption of stability that is required for the TD technique.   Sponsor-instream review of the TD series will 
occur after each catheterization to determine if hemodynamic variability occurred and the site team will be 
retrained on the importance of conducting the TD technique during hemodynamic stability.  
Clinical Study Completion or Early Termination
The IRB will be notified upon completion or premature termination of the study. Edwards retains the right to 
suspend or prematurely terminate this clinical study at any time.
If suspicion of an unacceptable risk to subjects arises during the clinical investigation, or when so instructed 
by the IRB or regulatory authorities, Edwards shall suspend the study while the risk is assessed by the Data 
Safety Monitoring Board (DSMB). Edwards shall terminate the clinical investigation if an unacceptable risk is 
confirmed.
Protocol Deviation
Any deviations from the protocol will be documented on the protocol deviation eCRF. The Investigator/or 
Designee shall be responsible for the reporting of any deviations deemed reportable to the IRB.

     
POGO Study
Study #2019-08
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Lifesciences Corporation.
2019-08
Page 28 of 52
CONFIDENTIAL
Deviations shall be reported to the Sponsor, regardless of whether they are medically justifiable, pre-approved 
by the sponsor, or taken to protect the subject in an emergency. Subject-specific deviations will be reported 
on the appropriate eCRF.
Non-subject specific deviations (e.g. unauthorized use of a device outside the study, etc.) will be reported in 
writing. The investigator will also adhere to procedures for reporting study and subject specific deviations to 
their IRB in accordance with their specific IRB’s reporting policies and procedures.

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
Page 29 of 52
CONFIDENTIAL
Changes to the Protocol 
Changes to the research covered by this protocol must be implemented by formal protocol amendment. All 
amendments to the protocol must be initiated by the Sponsor.
Protocol amendments must not be implemented without prior IRB approval. Documentation of amendment 
approval by the Investigator and IRB or IEC must be provided to the Sponsor or its authorized representative. 
When the change(s) involve only logistic or administrative aspects of the study, the IRB only needs to be 
notified.

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
Page 30 of 52
CONFIDENTIAL
9.
RISK ANALYSIS
Anticipated Risks
Edwards will monitor for safety which include those potentially associated with use of the devices and its 
components.  There may be additional risks and discomforts that are not known at this time.
Any events associated with a commercially available study device (Fore-Sight Elite Tissue Oximetry Sensors)
will be reported in accordance with the Medical Device Reporting (Complaints) regulation (21 CFR Part 803), 
while events associated with the investigational devices (remainder of devices in this study) will be reported 
under the IDE program (812.150).
Below is a list of general anticipated risks associated with the type of surgeries and procedures, which may 
be conducted as standard of care.
x
Risks related to transplantation of donor organ:
o
Death
o
Explant of donor organ
o
Hemorrhage
o
Organ transplant failure
o
Respiratory Failure
o
Sepsis/Infection
x
Risks related to other surgical or patient factors:
o
30-day mortality
o
Cardiac arrest
o
Cardiac arrhythmia
o
Hemorrhage
o
Ileus
o
Nausea and vomiting
o
Pneumonia
o
Prolonged Hospital length of stay
o
Prolonged ICU length of stay
o
Pulmonary embolism
o
Sepsis
o
Transfusion need
o
Wound infection
Below is a list of anticipated risks that may be associated with the use of Swan-Ganz thermodilution 
pulmonary artery catheter:
x
Allergic reaction to latex
x
Cardiac arrhythmias
x
Complete heart block

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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2019-08
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CONFIDENTIAL
x
Knotting
x
Nitroglycerin absorption
x
Perforation of the pulmonary artery
x
Pneumothorax
x
Pulmonary infarction
x
Thrombocytopenia
x
Thrombophlebitis
x
Thrombosis
x
Tricuspid and pulmonic valve damage
x
Right bundle branch block
x
Sepsis/Infection
Below is a list of anticipated risks that may be associated with the use of the FloTrac Sensor:
The vascular access obtained is standard clinical care for the adult population and the addition of the FloTrac 
sensor is and is not expected to impose any additional risk to the patient. There is no measurable increased 
infectious risk with the temporary use of the FloTrac sensor.
Below is a list of anticipated risks that may be associated with the use of the ClearSight finger cuff:
x
Discoloration of digit distal to the cuff
x
Discomfort where the cuff is applied
x
Pain associated with inflation of the cuff
x
Slight numbness of the fingertip
Below is a list of anticipated risks that may be associated with the use of ForeSight Elite Sensors:
x
Allergic reaction to adhesive on sensors
x
Skin irritation

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
Page 32 of 52
CONFIDENTIAL
Risk Management 
The study devices have been tested to an established regimen of safety and performance testing and, with 
the exception of the ClearSight Module used in the HemoSphere platform, have been cleared by the US FDA
in adults.  The ClearSight technology has been cleared for use in adults with the EV1000 Monitor; however, 
it has not been cleared for use with the HemoSphere advanced monitoring platform. 
The current risks identified for using these products do not outweigh the benefit the patient will receive.   
Furthermore, this study is: 
1)
Being conducted on patients who are already planned to receive an arterial line and a Swan Ganz 
catheter and the addition of FloTrac and ClearSight do not add to the invasiveness of the study,
2)
Being conducted on patients who are already planned to receive thermodilutions 
3)
An observational study as opposed to an interventional study
4)
Not relying on the data obtained from the FloTrac and ClearSight to treat patients
Collecting data does not introduce any new risks in relation to these products. Regarding the ClearSight 
Module used in the HemoSphere platform, thorough testing has been performed to show that this system 
functions as intended. As such collectively, the risks do not outweigh the benefits.
  
Benefits
There are no guaranteed benefits from a subject’s participation in this study.  However, the ForeSight Elite 
Sensors are cleared for pediatric use and provide the benefit of continually monitoring oxygen saturation 
of tissue with accuracy and precision.  When desaturation of tissue occurs, the following may occur:
x
Cognitive disfunction
x
Extended time on mechanical ventilation
x
Extra days spent in the hospital or intensive care unit (ICU)
x
Increased post-operative nausea and vomiting

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
Page 33 of 52
CONFIDENTIAL
10.
REPORTABLE EVENTS
Recording and Reporting of Adverse Events
The Investigator and/or Designee(s) will determine whether any adverse events (AEs) have occurred.  An 
AE is defined as any untoward medical occurrence in a clinical Study of an Investigational Device regardless 
of the causal relationship of the problem with the device or, if applicable, other Study treatment or 
diagnostic product(s).  Information for AEs with the study devices will be collected from the time a subject 
begins the study procedure and is exposed to Study products.  AEs will also be collected during surgical 
intervention, post intervention, discharge and through the 30-day follow-up.  AEs may be volunteered by 
subjects, clinicians, elicited from questioning by Investigator and/or Designee(s), or collected via 
observation.  When a device or study related AE is suspected all available event information and will be 
provided to the Clinical Events Committee. 
Once an AE/SAE/UADE is confirmed as such, event, date of onset, severity, duration, treatment (if 
required), resolution (or ongoing), assessment of seriousness, relationship to Study procedure and 
relationship to device will be recorded on the appropriate eCRF or SAE Report Form and submitted as 
necessary by the Investigator and/or Designee(s).  Any suspected AEs related to the Investigational Device 
or Study procedure must be reported to the Sponsor or designee within 5 working days of first awareness 
of the event.  
Recording and Reporting of Adverse Device Effects
An adverse device effect (ADE) is defined as an AE related to the use of an investigational medical device.  
This definition includes AEs resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation or operation, or any malfunction of the investigation device.  It also includes any 
AE resulting from use error or from intentional misuse of the Investigational Device.  
Causality of relationship to the Investigational Device will be judged by the Investigator, and reviewed
independently by the Clinical Events Committee, as follows:
Not related: 
x
An event is clearly not and cannot be related to the Investigational Device.  Reporting is not 
required per protocol unless the event was related to the Investigational Device or Study.
Possibly Related:
x
A relationship may exist but could have been produced by another cause (e.g., treatment, 
condition).
Related:
x
A relationship can be directly attributed to the use of the Investigational Device.
ADEs must be reported to the Sponsor or designee, within 24 hours of first awareness of the event.  
Notification should be done via email, fax, telephone or direct communication followed by direct entry of 
AE/SAE data into the eCRF.  In addition, the Study site will report confirmed ADEs related to their IRB in 
accordance with the IRB’s requirements.  ADEs will also be reported to the FDA, as required.

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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Lifesciences Corporation.
2019-08
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CONFIDENTIAL
Recording and Reporting of Serious Adverse Event
A serious adverse event (SAE) is defined as an AE that results in any of the following outcomes: death, a 
life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital anomaly/birth defect.
Recording and Reporting of Serious Adverse Device Effects
A serious adverse device effect (SADE) is an ADE that has resulted in any of the consequences or 
characteristics of a SAE.  
SADEs must be reported to the Sponsor or designee, within 24 hours of first awareness of the event.  
Notification should be done via email, fax, telephone or direct communication followed by direct entry of 
AE/SAE data into the eCRF.  In addition, the Study site will report confirmed SADEs their IRB in accordance 
with the IRB’s requirements.  SADEs will also be reported to the FDA, as required.
Recording and Reporting of Unanticipated Adverse Device Events
Unanticipated adverse device effect (UADE) is defined in 21 CFR 812 as any serious adverse effect on 
health or safety or 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 supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. In contrast, an anticipated adverse device effect is an effect which by its nature, incidence, 
severity, or outcome has been identified in the risk analysis report.
UADEs must be reported to the Sponsor or designee within 24 hours and submitted to the reviewing IRB as 
soon as possible, but in no event later than 10 working days after the Investigator first learns of the effect.
All AEs related to the Investigational Device or Study will be reviewed by the Investigator and/or 
Designee(s) and Sponsor.  These AEs will be followed until they are adequately resolved, explained by the 
Investigator and/or Designee(s), until subject has completed follow-up or been withdrawn from the Study.  

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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Lifesciences Corporation.
2019-08
Page 35 of 52
CONFIDENTIAL
Recording and Reporting of Deaths
Events resulting in death during the subject’s enrollment in this Study are not expected to occur as a result 
of participation in the Study.  In the event of subject death; however, every reasonable effort should be 
made to obtain a copy of the autopsy report and/or death summary.  Information on the date and cause of 
death and its relationship to the Study device will be determined by the Investigator and/or Designee and 
recorded on the appropriate AE eCRF and submitted on an SAE Report Form as necessary.
Recording and Reporting of Adverse Events Associated with Commercial Components
Any adverse event associated with an FDA cleared component will be recorded as a device complaint and 
reported via the MDR program (21 CFR Part 803).  Complaints will also be reported to the IRB in 
accordance with each IRB’s requirements.  Device complaints should be reported to the Sponsor as soon as 
the site becomes aware of the complaint.
Recording and Reporting of Pre-Existing Conditions
Pre-existing medical conditions and symptoms due to pre-existing medical conditions, surgery or 
admission to ICU will not be recorded as adverse events. The admission of a critically ill patient in the 
intensive care unit is commonly due to one or several serious medical conditions and/or a major surgery, 
which may cause changes and abnormalities of blood chemistry, diagnostic and physiological parameters.  
In the event there is a deterioration of a pre-existing medical condition or symptoms due to the use of the 
Study products or a Study related procedure, then the review of the event will be initiated, and an AE will 
be recorded if it meets the definition.  Any events occurring prior to the study procedure will be recorded 
as medical history. 
Reporting Adverse Events to the FDA
Confirmed UADEs will be evaluated by the Clinical Events Committee.  The FDA, all participating principal 
investigators and their reviewing IRBs will be informed no later than 10 working days after Edwards 
Lifesciences or designee first becomes aware of the effect.

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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Lifesciences Corporation.
2019-08
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CONFIDENTIAL
Reporting Adverse Events to the Responsible IRB
In accordance with applicable policies of the IRB, the Investigator will report, any observed or volunteered 
confirmed adverse event that is determined to be (1) unexpected; (2) related or possibly related to the 
research; and/or (3) involves increased or greater risk of harm to participant(s) or others than was 
previously known or approved by the IRB.  AE reports will be submitted to the IRB in accordance with the 
IRB policies and procedures.
Confirmed UADEs will be evaluated and the reviewing IRB will be informed of the results of the Study no 
later than 10 working days after Edwards or when the designee first becomes aware of the effect.

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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Lifesciences Corporation.
2019-08
Page 37 of 52
CONFIDENTIAL
11.
INDEPENDENT SAFETY COMMITTEES 
Clinical Events Committee
An independent (3-Member) Clinical Events Committee (CEC) will be established to oversee the safety 
progress. Members of the CEC must be free of significant conflicts of interest (e.g. Financial, intellectual, 
professional, or regulatory), and are experts in all scientific disciplines needed to interpret the data and 
ensure study participant safety. The CEC will meet via teleconference a minimum of two (2) times over the 
course of the study. The CEC may also meet for an ad hoc review of data in the event that a UADE is 
reported. The CEC charter will be maintained by the Sponsor as part of the clinical study project plan. The 
CEC charter will outline membership and voting procedures as well as CEC Meeting documentation and 
communication.
The CEC will perform the following activities:
x
Adjudicate all adverse events based on whether the events were:
o
Serious/Non-Serious
o
Anticipated/Unanticipated
o
Related to procedure and/or device
x
The CEC will convene to provide an immediate adjudication [within 48 hours] of unanticipated adverse 
device effects [UADE] in terms of anticipation, severity and relatedness to study devices.

     
POGO Study
Study #2019-08
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Lifesciences Corporation.
2019-08
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CONFIDENTIAL
Data Safety Monitoring Board
An independent (4-Member) Data Safety Monitoring Board (DSMB) will be established to oversee the Study 
outcome. Members of the DSMB must be free of significant conflicts of interest (e.g. Financial, intellectual, 
professional, or regulatory) and are experts in all scientific disciplines needed to interpret the data and 
ensure study participant safety, including an independent biostatistician. The DSMB will meet via 
teleconference a minimum of one (1) time over the course of the study. The DSMB manual of operation 
(MOP) will be maintained by the Sponsor as part of the clinical study project plan. The DSMB MOP will 
outline membership and voting procedures as well as DSMB Meeting documentation and communication.  
The DSMB meetings will include an open session where the Sponsor will present study updates, review 
trends for device malfunctions, protocol deviations and subject withdrawal reasons to communicate study 
progress.  The Investigators may attend the open session.  
In addition to the open portion of the DSMB meetings, there will be closed sessions that will only be
attended by the DSMB members.
The DSMB will perform the following activities during the closed session of the meetings:
x
Assess primary safety endpoint 
x
Assess participant risk versus benefit, performance of study sites, and other factors that can affect 
study safety outcome
x
Review factors external to the study when interpreting the data, such as scientific or therapeutic 
developments that may have an impact on the safety of the participants or the ethics of the study
x
Make recommendations to Edwards Lifesciences, IRB, and investigators concerning continuation 
or conclusion of the study based solely on safety evaluation
x
Protect the confidentiality of the study data and the results of monitoring
To mitigate any potential release of study results, the analysis of safety endpoint will be led by the 
independent biostatistician serving on the DSMB.  The biostatistician will have no contact with the Sponsor 
or any study sites.  Furthermore, the identification of the other DSMB members will not be shared with the 
sites during the conduct of the study.  
Stopping Rules
Continuation or discontinuation of the study will be based upon the DSMB’s evaluation of study safety.  
The DSMB may recommend stopping the study based solely on any safety concerns. 

     
POGO Study
Study #2019-08
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Lifesciences Corporation.
2019-08
Page 39 of 52
CONFIDENTIAL
12.
DATA HANDLING AND RECORD KEEPING
Confidentiality 
Information about Study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Consistent with these regulations, 
a signed authorization will be obtained that informs each subject of the following:
x
What protected health information (PHI) will be collected from subjects in this Study 
x
Who will have access to that information and why
x
Who will use or disclose that information
x
The rights of a research subject to revoke their authorization for use of their PHI 
No subject demographic data or medical information will be used or shared outside the Sponsor and site 
staff unless an unanticipated adverse device effect (UADE) is reported. If a UADE is reported, all efforts will 
be made to keep subject information confidential. The Sponsor is dedicated to maintaining the 
confidentiality and privacy of subjects who volunteer to participate in the Study.  The Study Investigator and 
the Study site personnel are responsible for maintaining confidentiality throughout the clinical Study. The 
Sponsor and Sponsor designated Study personnel will have access to the data collected.  The hard copies of 
the source documentation are to be maintained in a secure area with limited access.
To protect subject confidentiality, the subject’s name must not appear anywhere on CRFs, or supporting 
documentation removed from the site.  All subject identifiers (e.g., social security number) will be 
obliterated from all photocopies of source documents that have been removed from the site.  All Study 
documents will identify the subject by a subject Study identification number and Protocol number assigned 
by the Sponsor (if applicable).
In the event that a subject revokes authorization to collect or use PHI, the Investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e. that the subject is alive) at the end of their scheduled Study period.

     
POGO Study
Study #2019-08
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Lifesciences Corporation.
2019-08
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CONFIDENTIAL
Source Documents
Source data are all information, original records of clinical findings, observations, or other activities in a 
study necessary for the reconstruction and evaluation of the study.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, source worksheets that have been certified as source, and records kept at the pharmacy, at the 
laboratories, and at medical-technical departments involved in the study.
Required data for this Study are to be recorded in the subject’s file and/or in worksheets, certified as source, 
for source documentation and data verification unless otherwise specified.  Protocol deviation information 
can be recorded directly on the Protocol Deviation eCRF.  Some of the source documentation generated 
during the Study may be either a worksheet, the electronic data from the Monitor, laboratory data, or 
printout from Radiometer and YSI.  It is recommended that electronic case report forms (eCRFs) be 
completed within 24 hours of data availability, but not more than 10 working days after completion of 
assessments. Because of the potential for errors, inaccuracies, and illegibility in transcribing data onto 
eCRFs, the Investigator must permit inspection of the source documents.

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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Lifesciences Corporation.
2019-08
Page 41 of 52
CONFIDENTIAL
13.
DATA COLLECTION METHODS
Study data will be captured utilizing electronic Case Report Forms (eCRFs) including the 30-day follow-up call
as well as downloaded files captured directly via the use of the HemoSphere advanced monitor. Data collected 
from the HemoSphere advanced monitor will be downloaded at the end of each catheterization procedure
and stored on a USB stick. USBs will be stored in a secure location at the site, accessible only to Study site 
personnel. The HemoSphere data on USBs may be shipped to the Sponsor at any point in time of the study
per the request of the Sponsor.

     
POGO Study
Study #2019-08
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Lifesciences Corporation.
2019-08
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CONFIDENTIAL
14.
RECORD RETENTION 
It is the Investigator’s responsibility to retain Study essential documents during the investigation and for a 
minimum period of two (2) years after the investigation is terminated or completed, or the records are no longer 
required for the purposes of supporting a premarket approval application or a notice of completion of a product 
development protocol.  These documents should be retained for a longer period if required by an agreement with 
the Sponsor. In such an instance, it is the responsibility of the Sponsor to inform the Investigator/institution as to 
when these documents no longer need to be retained.

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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Lifesciences Corporation.
2019-08
Page 43 of 52
CONFIDENTIAL
15.
STUDY DOCUMENTATION 
Study Records 
Edwards will maintain accurate, complete, and current records relating to the conduct of the study.
Records to be maintained by Edwards Lifesciences and the study site include but are not limited to:
x
Study protocol and all amendments, if applicable
x
IRB approved Informed Consent
x
IRB approval letter, including informed consent form
x
IRB membership list, or alternative notification of IRB being duly constituted or Department of Health 
and Human Services Multiple Projects AssuranceNumber
x
IRB correspondences
x
Study training logs
x
Device accountability records 
x
Required reports, if applicable
The following records must be maintained for each subject enrolled in the study:
x
Signed informed consent form
x
All completed eCRFs
x
Supporting documentation of any adverse events
Study Reports
Designated site personnel shall prepare and submit the following accurate and complete reports in a timely 
manner to the IRB and FDA, if applicable:
x
Report of an Unanticipated Adverse Device Effects (UADEs) as soon as possible, but in no event later 
than 10 working daysafter thefirstawarenessoftheevent.After an internal evaluation, Edwardsshall 
report the results of such evaluation to FDA and to all reviewing IRBs and participating investigators 
within 10 working days after receipt of notice of the effect. 
x
Withdrawal of IRB approval within 5 working days to Edwards. Thereafter, Edwards shall notify FDA 
and all reviewing IRBs and participating investigators of any withdrawal of approval of an investigation 
or a part of an investigation by a reviewing IRB within 5 working days after receipt of the notification 
of withdrawal of approval.
x
Progress reports will be submitted to the IRB as required and no less than yearly.
x
Deviation from the study protocol to protect the subject’s life or physical well-being in an emergency 
will be reported to Edwards as soon as possible, but in no event later than 5 working days after the 
emergency occurred. Non-emergency deviations will be reported to the IRB, as required. If deviations 
may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, FDA 
and IRB shall be notified.
x
A final written report is submitted to the IRB within 6 months after completion or termination of the 
study as required.
x
Upon request by the reviewing IRB or FDA, Edwards will provide accurate, complete, and current 
information about any aspect of the investigation.

     
POGO Study
Study #2019-08
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Lifesciences Corporation.
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CONFIDENTIAL
x
Use of the study device without informed consent will be reported to Edwards and the IRB within 5 
working days after the use occurs. Thereafter, Edwards shall notify FDA within 5 days of receipt of 
notice.

     
POGO Study
Study #2019-08
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Lifesciences Corporation.
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CONFIDENTIAL
Communication Procedures
Edwards will utilize an electronic regulatory binder to maintain required study documentation including 
applicable correspondences during the course of the study. 

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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CONFIDENTIAL
16.
STUDY MONITORING, AUDITING AND INSPECTING 
Site Selection
The Study site(s) for this Study will be pre-screened by the Sponsor.  The Principal Investigator will be 
selected based on their training and experience with this type of research activity and available subject 
population.  The Sponsor will provide the Investigator with information, Study specific training, and 
supplies necessary to conduct the Study.
Study Monitoring Plan
A Monitoring Plan will be created to address monitoring arrangements and the extent of source data 
verification.  A Study monitor will be assigned to monitor the progress of the Study by the Sponsor.  The 
Study monitor may be either an employee of the Sponsor or contracted.  The Study monitor will be 
responsible for reviewing eCRFs and monitoring the Study site routinely to observe Study progress and 
compliance with Study Protocol.  The Investigator must permit inspection of the source documents, 
regulatory binders and other Study related documents provided by the Sponsor.  
Study monitoring visits will be scheduled throughout the duration of the Study between the Study monitor 
and the Investigator and/or Designee at a mutually convenient and available time.  These visits will assure 
that the facilities are still acceptable, the Protocol and investigational plan are being followed, the IRB has 
been notified of approved Protocol changes as required, complete records are being maintained, 
appropriate timely reports have been made to the Sponsor and the IRB, device and device inventory are 
secure and the Investigator is carrying out all agreed activities.  Any personnel changes must be reported 
to the Study monitor immediately.  
All eCRFs will be maintained in a validated EDC system and missing or unclear data will be queried as 
necessary throughout the Study.  The Sponsor may request further information and documentation when 
complications and/or malfunctions are observed and reported.
Interim Monitoring Activities 
The Sponsor has the obligation to monitor the conduct of this study to ensure that the study is conducted 
in accordance with the protocol, Edwards Lifesciences procedures and 21 CFR 812.46 Monitoring 
Investigations.  
Interim monitoring visits (onsite or remote) will be conducted to evaluate the progress of the study, verify 
the rights, well-being, and protection of the patients, and verify that the reported clinical study data is 
accurate, complete and verifiable from the electronic medical records and source documents.  Monitoring 
visits will be made in accordance with the Monitoring Plan.   
Site Close-Out Visit
The Investigator will be notified in writing upon termination or completion of the Study.  The Sponsor 
retains the right to suspend or prematurely terminate this clinical investigation at any time.  Upon 
completion or premature termination of the Study, the Study monitor will perform a close-out visit.

     
POGO Study
Study #2019-08
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DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
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Lifesciences Corporation.
2019-08
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CONFIDENTIAL
A site will be considered closed when the following criteria are met:
x
Last subject completes 30-day follow-up
x
All data queries are resolved
x
A site closeout visit is completed
x
The IRB is notified in writing of site and study closure in accordance with their requirements
Auditing and Inspecting 
In the event that audits are initiated by the Sponsor or national/international regulatory authorities, the 
Investigator shall allow access to the original medical records and provide all requested information, as 
applicable.  The Investigator will permit Study-related monitoring, audits, and inspections by the Research 
Quality Assurance Office, IRB, the Sponsor, and government regulatory bodies, of all Study related 
documents (e.g. source documents, regulatory documents, data collection instruments, Study data etc.).  
The Investigator will ensure the capability for inspections of applicable Study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.).

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
Page 48 of 52
CONFIDENTIAL
17.
ETHICS
Ethical and Scientific Conduct of the Clinical Research Study 
The Study may only commence once IRB approval and regulatory approval, as applicable, are received.  This 
Study will be conducted in compliance with the Protocol approved by the IRB, the relevant federal 
regulations, and IRB policies and procedures and according to Good Clinical Practice standards.
The Investigator shall ensure that all work and services described herein, or incidental to those described 
herein, shall be conducted in accordance with the highest standards of medical and clinical research practice 
and the applicable regulations.  The Investigator will provide copies of the current Study Protocol to all Study 
site personnel responsible for Study conduct.
As the Sponsor of this clinical Study, Edwards Lifesciences has the overall responsibility for the conduct of 
the Study, including assurance that the Study meets the regulatory requirements of the pertinent regulatory 
agencies.  Edwards Lifesciences will also ensure compliance with the signed clinical agreement, the Protocol, 
the requirements of applicable regulations, and any conditions of Study approval by the IRB.
The Sponsor may transfer study related duties and functions to a CRO.  Transferred duties and functions will 
be specified in a written agreement.  Ultimate responsibility for the quality and integrity of the Study resides 
with the Sponsor.

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
Page 49 of 52
CONFIDENTIAL
18.
FINANCIAL DISCLOSURES
Appropriate financial disclosures will be obtained from all Principal Investigators and Sub-Investigators and 
additional personnel listed on the Statement of the Investigator.  The Investigator will provide sufficient and 
accurate financial disclosure information to the Sponsor.

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
Page 50 of 52
CONFIDENTIAL
19.
PUBLICATIONS 
At the conclusion of the Study, a manuscript may be prepared for publication in a scientific journal.  The Sponsor 
reserves the right to review any manuscripts prior to submission.  The Study will be entered into a clinical trial 
registry databank such as clinicaltrials.gov.

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
Page 51 of 52
CONFIDENTIAL
20.
ACRONYMS AND ABBREVIATIONS
Acronym
Entire Word
ADE
Adverse Device Effect
AE
Adverse Event
ASA
American Society of Anesthesiologists
BP
Blood Pressure
CI
Cardiac Index
CCO
Continuous Cardiac Output
CO
Cardiac Output
CEC
Clinical Events Committee
CRF
Case Report Form
DSMB
Data Safety Monitoring Board
FDA
Food and Drug Administration
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
GCP or gCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
HR
Heart Rate
Hr
Hour
ICC
Intra-Cluster Correlation
ICF
Informed Consent Form
ICO
Intermittent Cardiac Output
ICU
Intensive Care Unit
IRB
Institutional Review Board
ITT
Intent-to-Treat
mL
Milliliters 
mITT
Modified Intent-to-Treat
N
Total Sample Size
NCT
National Clinical Trial
PAC
Pulmonary Artery Catheters
PI
Principal Investigator 
PR
Pulse Rate
SADE
Serious Adverse Device Effect
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SpO2
Peripheral Capillary Oxygen Saturation
Sub-I
Sub-Investigator 
SV
Stroke Volume
SVI
Stroke Volume Index
SVV
Stroke Volume Variation
SVR
Systemic Vascular Resistance
UADE
Unanticipated Adverse Device Effect

     
POGO Study
Study #2019-08
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION OF EDWARDS LIFESCIENCES, LLC.  IT MAY NOT BE REPRODUCED OR 
DISCLOSED WITHOUT PRIOR WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES, LLC.
Edwards Lifesciences, Edwards, the stylized E logo, HemoSphere, Swan-Ganz, FloTrac, ClearSight and ForeSight Elite are trademarks of Edwards 
Lifesciences Corporation.
2019-08
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CONFIDENTIAL
21.
REFERENCES
1.
Richard C, Monnet X, and Teboul JL. Pulmonary artery catheter monitoring in 2011. Current opinion in 
critical care 2011; 17: 296-302.
2.
Swan HJ, et al. Catheterization of the heart in man with use of a flow-directed balloon-tipped catheter. 
The New England journal of medicine 1970; 283: 447-451.
3.
Mehta Y, and Arora D. Newer methods of cardiac output monitoring. World journal of cardiology 2014;
6: 1022-1029.
4.
Sigurdsson, TS., et al. Extracorporeal arteriovenous ultrasound measurement of cardiac output in small 
children. Anesthesiology 2019; 130:712-8.
5.
Blalock A.  Mechanism and treatment of experimental shock: Shock following hemorrhage. Arch Surg
1927; 15:762–98.
6.
Guyton AH and Hall JE. Overview of the circulation: Medical physics of pressure, flow, and resistance. In 
Textbook of Medical Physiology, 11th edition, Edited by S. Elsevier, Elsevier, Inc., Philadelphia, pp 161–
170
7.
Trieu,  C, et al.  Babies and children at last - Pediatric cardiac output monitoring in the twenty-first 
century. Anesthesiology 2019; 130:712.
8.
Suehiro K, et al. Accuracy and precision of minimally-invasive cardiac output monitoring in children: a 
systematic review and meta-analysis. J Clin Monit Comput 2016; 30:603–620.
9.
Argueta, E and Paniagua, D. Thermodilution cardiac output: A concept over 250 years in the making. 
Cardiology in Review 2019; 27: 138-144.
10. Martina, JR, et al. Noninvasive continuous arterial blood pressure monitoring with Nexfin®. 
Anesthesiology 2012; 116:1092-103.

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DOC-0089208 Rev A (This Template is required by DOC-0089206) 
 
Revision Date: December 2, 2020 
Rev B 
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Page 1 
Title 
Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
Protocol Title: 
A Prospective, Single-Arm, Nonrandomized, Observational Study of 
Cardiac Output Monitoring in Pediatric Patients 
Protocol Number: 
#2019-08 
SAP Version: 
B 
SAP Date: 
December 2, 2020 
SAP Author: 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 

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PRIOR WRITTEN PERMISSION OF EDWARDS LIFESCIENCES, LLC. 
DOC-0089208 Rev A (This Template is required by DOC-0089206) 
 
 
 
Revision Date: December 2, 2020 
 
Rev 
 
B 
For Use Only by 
Affiliates of 
Edwards 
Lifesciences 
 
Page 3 
Title 
Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
 
 
TABLE OF CONTENTS 
 
 
1. 
INTRODUCTION 
5 
2. 
STUDY DESIGN 
5 
2.1 Study Objectives 
5 
2.2 Overall Study Design and Plan 
5 
2.3 Sample Size Consideration 
7 
3. 
STUDY ENDPOINTS 
12 
3.1 Primary effectiveness endpoint 
12 
3.2 Secondary effectiveness endpoints 
13 
3.3 Explatory analyses 
13 
3.4 Explatory analyses 
14 
4. 
ANALYSIS POPULATIONS 
15 
5. 
DEFINITIONS 
15 
6. 
DATA AND ANALYSIS CONVENTIONS 
16 
6.1 General Conventions 
16 
6.2 Handling of Missing 
16 
6.3 Handling of Invalid Data 
16 
7. SUMMARY OF BASELINE INFORMATION 
17 
7.2 Demographics and Baseline Characteristics 
18 
7.3 Medical History 
18 
8.  STATISTICAL ANALYSIS OF STUDY ENDPOINTS 
21 
8.1 Primary Endpoint 
21 
8.1.1 Summary statistics and statistical comparison 
21 
8.1.2 Primary endpoint analysis with Bias calculated by CO 
21 
8.1.3Limits of Agreement 
Error! Bookmark not defined. 
8.2 
Secondary Endpoint 
22 
8.3 
Sensitivity Analysis 
22 
8.4 
Exploratory Analyses 
22 
8.5 
Interim analysis 
23 
8.6 
Analysis of other hemodynamic parameters 
23 
9. 
ANALYSIS OF SAFETY 
25 
9.1 
Deaths 
25 
9.2 
Adverse Events 
Error! Bookmark not defined. 
11. REFERENCES 
26 
12. APPENDIX 
27 
13. LITERATURE SEARCH/REVIEW 
27 
14. PEER REVIEW REQUEST, PER SAP INSTRUCTION (DOC-0089205) 
28 
 

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Page 4 
Title 
Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
 
 
Glossary of Terms 
 
 
ABBREVIATION 
DEFINITION OR DESCRIPTION 
  ABP 
Arterial Blood Pressure 
  AE 
Adverse Event 
  ADE 
Adverse Device Effect 
  Alpha 
Type I error in hypothesis test 
  Beta 
Type II error in hypothesis test 
  BSA 
Body Surface Area 
  CEC 
Clinical Events Committee  
  CI 
Cardiac Index 
  CI 
Confidence Intervals 
  CO 
Cardiac Output 
  CSR 
Clinical study report  
  eCRF 
Electronic Case Report Form 
  GCP 
Good Clinical Practice 
  H0 
Null hypothesis 
  H1 
Alternative hypothesis 
  MAP 
Mean Arterial Pressure 
  ICC 
Intra-cluster correlation coefficient 
  IRB 
Institutional Review Board 
  PAC 
Pulmonary Artery Catheter 
  PE 
Percent Error 
  SAE 
Serious Adverse Event 
  SAP 
Statistical Analysis Plan 
  SD 
Standard Deviation 
  SV 
Stroke Volume 
  TD 
Thermodilution 
 

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Page 5 
Title 
Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
 
1. 
INTRODUCTION 
 
This statistical analysis plan (SAP) specifies the statistical methods to be implemented for the analysis of data 
collected within the scope of Edwards Lifesciences’s Protocol #2019-08, “A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output Monitoring in Pediatric Patients”, and provides 
detailed instructions as to how each analysis will be performed. 
 
Results obtained from the analyses specified in the SAP will become the basis of the clinical study report (CSR) 
for this protocol.  Any deviations from the SAP must be documented in the CSR. 
 
2. 
STUDY DESIGN 
 
2.1 Study Objectives 
 
The primary objective of the study is to assess Cardiac Output Monitoring in pediatric subjects by comparing 
FloTrac™ and ClearSight™ to intermittent thermodilution Swan-Ganz™, in order to expand the indications of  
FloTrac™, ClearSight™ and Swan-Ganz Intermittent Thermodilution Catheter to the pediatric population 12 to 
18 years of age.  
 
2.2 Overall Study Design and Plan 
 
This is an observational study in the U.S.  A subject will be considered enrolled in the study once the subject has 
signed the informed consent, a Swan-Ganz catheter has been deployed, a FloTrac has been connected, a 
ClearSight finger cuff has been attached and ForeSight Elite sensors have been placed.  The Study ID will be a 6-
digit number, the first three numbers will identify the site, and the second set of numbers will identify the subject 
identification number. Subjects will be enrolled in age group, 12 to 18 years of age.  
 
A Swan-Ganz catheter, FloTrac transducer, ClearSight finger cuff and ForeSight Elite sensors will be placed prior 
to the start of the surgery.  There will be 2 sets of 4 intermittent cardiac output measurements recorded, each 
over a 30 second interval during the bolus injection. Measures for FloTrac and ClearSight will be retrospectively 
matched by time point to the Swan-Ganz catherization data. Intermittent cardiac output and other 
hemodynamic parameters will be collected throughout the duration of the surgery.  For each study subject two 
sets of four repeated measurements will be taken in the cardiac catherization lab.  Data collected in this study 
will support in expanding the current indications of Swan-Ganz, FloTrac and ClearSight into the pediatric 
population.  
 
In order to avoid a learning curve bias, up to 6 roll-in subjects will be enrolled, which is counted in the final 
sample size in study.  The collected data from the roll-in cohort will be analyzed separately from the pivotal 
study subjects. 
 
 
 

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Title 
Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
A modified intent-to-treat (mITT) principle will be applied. Through investigator professional judgement and 
statistical principles, this study will be conducted in a manner that is consistent with the applicable regulations 
and in accordance with current Good Clinical Practice (GCP). 
 
All methods of measurements will be recorded for all devices and included as part of the data set. Edwards will 
conduct analyses both with and without observations that are determined to be outliers.  Once outliers are 
identified, the Principal Investigator will assess the validity of the data.   
 
2.2.1 Cardiac Output 
 
Cardiac output will be continuously measured by FloTrac and ClearSight, while cardiac output will be 
intermittently measured by the Swan-Ganz catheter, using the thermodilution method.  During a 5- minute 
period of thermodilution and cardiac output determination, each subject will be assessed for hemodynamic 
stability. Should there be any instability, the bolus will be rejected. All data will be recorded and any rejected 
values will be clearly identified in the eCRF.  
 
The rejection criteria that will be used to determine hemodynamic instability are detailed below: 
 
 
 
x 
FloTrac and ClearSight will display mean arterial pressure (MAP).  If MAP varies  > 15% during the 
30-sec period of each intermittent thermodilution, the bolus will be rejected. 
i. If more than 1 result is greater than 15% of the mean or the prespecified rejection criteria 
is met, discard the entire series, and repeat the series of four thermodilutions. 
o Note: The likely cause for 2, 3 or 4 results being greater than 15% of the mean is 
technique dependent, i.e., shooting the thermodilution either fast, slow or drawing up 
the incorrect amount of fluid. 
ii. If none the results are greater than 15% of the mean or the prespecified rejection criteria 
is not met, discard one result that is furthest from the mean. 
x 
FloTrac and ClearSight will also display Pulse rate.  If Pulse varies > 15% during the 30-sec period of 
each ITD, the bolus will be rejected. 
i. If more than 1 result is greater than 15% of the mean or the prespecified rejection criteria 
is met, discard entire series, and repeat the series of four thermodilutions. 
o Note: The likely cause for 2, 3 or 4 results being greater than 15% of the mean is 
technique dependent, i.e., shooting the thermodilution either fast, slow or drawing up 
the incorrect amount of fluid. 
ii. If none the results are greater than 15% of the mean or the prespecified rejection criteria 
is not met, discard one result that is furthest from the mean. 
x 
ClearSight will display Physiocal.  If Physiocal is not at least 30 beats, the bolus will be rejected.  
 
For Cardiac Output comparisons of FloTrac and ClearSight to Swan-Ganz ITD, all hemodynamic monitors will be 
time aligned.   
 
The CO values from ClearSight and FloTrac for the analyses will be prepared as follows:   
 
x 
Determine the averaging window corresponding with each bolus injection  

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Title 
Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
 
x 
Average the CO over the 30 second period  
 
x 
Determine the average of 3 of 4 CO values 
 
The CO values from Swan-Ganz ITD for analyses will be prepared as follows: 
 
x 
Determine the CO from each of the 3 of 4 accepted bolus injections  
 
x 
Determine the average of 3 of 4 CO values 
 
 The CO values from Swan-Ganz ITD for analyses will be prepared as follows: 
x 
Determine the CO from each of the 3 of 4 accepted bolus injections 
x 
Determine the average of 3 of 4 CO values 
 
2.3 Sample Size Consideration 
 
2.3.1 Sample size consideration for bias 
 
The bias between the matched pairs of CO measurements, as determined by the Bland-Altman method, must be 
ƐŵĂůůĞƌ ƚŚĂŶ ƚŚĞ ŵŝŶŝŵƵŵ ĐůŝŶŝĐĂů ĚŝĨĨĞƌĞŶĐĞ ɷ͕ ǁŚŝĐŚ ŝƐ ƚŚĞ ǀĂůƵĞ ƚŚĂƚ ŝƐ ůĂƌŐĞ ĞŶŽƵŐŚ ƚŽ ĐůĂŝŵ ĚŝĨĨĞƌĞŶĐĞ͘The 
hypothesis for bias is: 
 
  H0:  bias <-ɷ Žƌ ďŝĂƐ хɷ  
  H1: -ɷч ďŝĂƐ чɷ  
 
H0 is the null hypothesis (i.e. the difference between matched pairs of CO values of the two systems is larger than 
ɷͿ͕ ,ϭ ŝƐ ƚŚĞ ĂůƚĞƌŶĂƚŝǀĞ ŚǇƉŽƚŚĞƐŝƐ ;ŝ͘Ğ͘ ƚŚĞ ĚŝĨĨĞƌĞŶĐĞ ďĞƚǁĞĞŶ ŵĂƚĐŚĞĚ ƉĂŝƌƐ ŽĨ K ǀĂůƵĞƐ ŽĨ ƚŚĞ ƚǁŽ ƐǇƐƚĞŵƐ ŝƐ
ǁŝƚŚŝŶ ƚŚĞ ƌĂŶŐĞ ŽĨ ɷͿ͘  ŵĞƚĂ-analysis conducted a comprehensive search of 21 published medical literature to 
assess the accuracy and precision of minimally-invasive CO monitoring systems used in children when compared 
with CO monitoring reference methods [8]. Among the 21 studies, 19 studies (90%) showed a bias range of -0.5 to 
0.5 L/min. Based on ƚŚĞƐĞ ĚĂƚĂ͕ ƚŚĞ ĐůŝŶŝĐĂů ŵŝŶŝŵƵŵ ĚŝĨĨĞƌĞŶĐĞ ɷ ǁĂƐ ƐĞƚ Ăƚ Ϭ͘ϱ >ͬŵŝŶ͕ ŝ͘Ğ͘ ďŝĂƐ ŝƐ ĞǆƉĞĐƚĞĚ ƚŽ ďĞ
-0.5< bias < 0.5 l/min. This value is smaller in magnitude than the 0.8 l/min floor that the US FDA had previously 
considered for CO comparisons. The meta-analysis also shows that 19 out of 21 published studies had standard 
deviation (SD) no more than 1.0 L/min.   
 

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Title 
Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
In this study eight repeated measurements (m=8 sub samples) or sub sample sections will be taken during the 
cardiac catherization case, thus intra-cluster correlation ecoefficiency ICC is a factor to be considered in sample 
size estimation. Here ܫܥܥ=
ఋೞమ
ఋೞమାఋೞೞ
మ. ߜ௦ଶis the variance component of study subject. ߜ௦௦
ଶis the variance component 
of sum sample. By literature the ICC in children ranges from 0.94 to 0.98. The variation of study subject is dominant. 
Fixed the study subjects, the more sub-samples taken the less ߜ௦௦
ଶwill be by a factor 1/m. This will reduce the total 
variance applied in sample size calculation. Using ICC=0.98, and SD=1 (Variance=1) as an example, for m=8,  the 
stand deviation used in sample size estimation is ܵܦ= ට0.98 כ 1 +
ଵି଴.ଽ଼
଼
= 0.991211. 
 
The sample size calculation for this hypothesis is based on the one-sample t-test for equivalence. The desired 
outcome is to reject the null hypothesis at the 0.025 significance level. For this equivalence test of bias, two 
comparisons will be performed: FloTrac vs Swan-Ganz and ClearSight vs Swan-Ganz.  In order to preserve the 
overall type 1 error rate at 0.05, the Bonferroni Correction will be used to adjust for multiple comparisons.  
ƐƐƵŵŝŶŐ Ă ƚƌƵĞ ŵĞĂŶ ďŝĂƐ ŽĨ Ϭ͘Ϭ ĂŶĚ Ă ^ ŽĨ ϭ͘Ϭ ůͬŵŝŶ ŝŶ ƚŚĞ ĐĂƌĚŝĂĐ ŽƵƚƉƵƚ͕ ƚŚĞ ƐĂŵƉůĞ ƐŝǌĞ ƌĞƋƵŝƌĞĚ ĨŽƌ ɷсϬ͘ϱ͕
alpha=0.025, and power=90% to reject the null hypothesis is 45, ignoring the ICC.  After considering ICC for eight 
repeated measures (m=8), adjusting for multiple comparisons, considering comparisons of between two target 
devices and a reference device pairs, simultaneously, a sample size of 60 Subjects is needed. After considering a 
34.5% rejection rate for hemodynamic instability, 10% lost to follow-up rate, and 6 roll-in Subjects for the learning 
curve, up to 108 (102) evaluable Pivotal Subjects and 6 Roll-in Subjects) will be enrolled into the study.  
 
By simulating the study results with a mixed effect model, using repeated measurement data collected from a 
similar study, although the sample size estimate from this approach is conservative, it is reasonable and rational. 
 
2.3.2 Sample size consideration for percent error  
 
The Critchley and Critchley method of percent error (PE) calculation will be compared to 30%. The Precision will 
be considered as acceptable if PE is less than or equal to 30%.  
The hypothesis for PE is a one-sided test:  
H0: PE > 30% 
,ϭ͗ W ч ϯϬй  
 
In a meta-analysis paper published in 2010, Peyton and Chong suggested that acceptable agreement should be a 
percentage error of 30% or less, which has become a widely quoted criterion.  
 
In a paper published by Odor, Bampoe, and Cecconi, “PE is calculated by dividing the limits of agreement by the 
mean value of measurements taken using the reference method of CO monitoring in the required population. A 
W ĐƵƚ ŽĨ ц ϯϬй ŚĂƐ ďĞĞŶ ƐƵŐŐĞƐƚĞd as a pragmatic guide for clinicians to determine whether a new measurement 
technique represents a good alternative to the reference standard. The basis of this approach is that the level of 
precision should be at least equivalent to the reference standarĚ ŝ͘Ğ͘ ƚŚĞƌŵŽĚŝůƵƚŝŽŶ͕ ǁŚŝĐŚ ŝƐ ц ϮϬй͘ ^ŝŶĐĞ ƌĂŶĚŽŵ
ĞƌƌŽƌ ŝŶ ŵĞĂƐƵƌĞŵĞŶƚ ŝƐ ĐŽŵƉŽƵŶĚĞĚ ĚƵƌŝŶŐ ĐŽŵďŝŶĂƚŝŽŶ ŽĨ ƚǁŽ ƉƌĞĐŝƐŝŽŶƐ͕ ǁŝƚŚ ƚǁŽ ŵĞĂƐƵƌĞŵĞŶƚƐ Ăƚ ц ϮϬй
ĞƋƵĂƚŝŶŐ ƚŽ Ă ƚŽƚĂů ĞƌƌŽƌ ŽĨ ц Ϯϴ͘ϯй͕ ƚŚĞ ƚŽƚĂů W ŝƐ ĐŽŵŵŽŶůǇ ƌŽƵŶĚĞĚ ƚŽ ц ϯϬй͘ dŚƵƐ͕ ĨŝŶĚŝŶŐ Ă ƉĞƌcentage error 

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Title 
Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
ŽĨ ůĞƐƐ ƚŚĂŶ ц ϯϬй ĞƋƵĂƚĞƐ ƚŽ ƚŚĞ ŶĞǁ ƚĞƐƚĞĚ ƚĞĐŚŶŝƋƵĞ ŚĂǀŝŶŐ ĂŶ ĞƌƌŽƌ ƐŝŵŝůĂƌ ƚŽ ƚŚĞ ƌĞĨĞƌĞŶĐĞ ƐƚĂŶĚĂƌĚ͕ ǁŚŝĐŚ
should therefore be considered acceptable.” 
 
The sample size calculation for this hypothesis was based on the one-sided T-test. The desired outcome is to reject 
the null hypothesis at the 0.025 significance level. Assuming a true mean of 30% and a conservative SD assumption 
of 70%, the sample size required for power=90% to reject the null hypothesis is 49.  With Bonferroni adjustment 
for two comparison between three target device systems, enrollment of 60 subjects is required.  
 
Additionally, in the paper "A meta-analysis of studies using bias and precision statistics to compare cardiac output 
measurement techniques,” Critchley LA and Critchley JA constructed an error gram from the percentage errors 
from the test and reference methods to determine acceptable limits between methods. They graphically showed 
that limits of agreement of up to +/-30% were acceptable for PE. 
 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
Because the study is designed with sub samples (repeated measurements) or sub sample sections (m=8), ICC is a 
factor needing to be considered in the sample size estimation. By similar assumption and calculation in section 
2.3.1, for m=8, the SD=69.38%, the corresponding sample size necessary is 49. For PE, a sample size of n=60 will 
be used in the study design, after considering two pairwise comparisons between 2 devices with a reference 
device.  In addition, after considering a, 34.5% rejection rate for hemodynamic instability, 10% lost to follow-up 
rate, up to 102 evaluable subjects will be targeted. To account for the learning curve, 6 additional roll-in subjects 
will be enrolled (up to 3 at each site), totaling 108 Subjects enrolled in the study.  
 
2.3.3 Sample size consideration for bias calculated with cardiac index 
 
The bias between the matched pairs of CI measurements, as determined by the Bland-Altman method, must be 
ƐŵĂůůĞƌ ƚŚĂŶ ƚŚĞ ŵŝŶŝŵƵŵ ĐůŝŶŝĐĂů ĚŝĨĨĞƌĞŶĐĞ ɷ͕ ǁŚŝĐŚ ŝƐ ƚŚĞ ǀĂůƵĞ ƚŚĂƚ ŝƐ ůĂƌŐĞ ĞŶŽƵŐŚ ƚŽ ĐůĂŝŵ ĚŝĨĨĞƌĞŶĐĞ͘  
 
The hypothesis for bias is: 
  H0:  bias <-ɷ Žƌ ďŝĂƐ хɷ  
  H1: -ɷч ďŝĂƐ чɷ  
 
Because there are no valid publications found through internet searching to design the settings in sample size 
estimation based on CI, the relation between CI and CO is used in sample size estimation here. Cardiac index (CI) 
is defined as cardiac output (CO)/body surface area (BSA).  By the results from Cattermole G. N., Leung P. Y. M., 
Mak P. S. K. et al. 2010 and Cattermole G. N., Leung P. Y. M., Ho G. Y. L. et al. 2017, the BSA value for kid with age 
൒8 is greater than 1, target on Chinese population in Hong Kong.  For the age group from 12 to 18 years, it is 
around 1.5. If the study subjects are from developed country the BSA value possibly will be larger. If the study 
targets at developing country population, this value possibly will be smaller. By this consideration BSA=1.2 is used 
in bias adjustment and the SD adjustment. The SD used in sample size estimation for CI will be 0.85 (ܵܦ஼ூൎ
ௌ஽಴ೀ
஻ௌ஺ൎ
0.85).  
 
In this study eight repeated measurements or sub sample sections for each study subject will be taken during the 
cardiac catherization case, thus intra-cluster correlation ecoefficiency ICC is a factor to be considered in sample size 
estimation. Here ܫܥܥ=
ఋೞమ
ఋೞమାఋೞೞ
మ. ߜ௦ଶis the variance component of study subject. ߜ௦௦
ଶis the variance component of sum 
sample. By literature the ICC in children ranges from 0.94 to 0.98. The variation of study subject is dominant. Fixed 
the study subjects, the more sub-samples taken the less ߜ௦௦
ଶwill be by a factor 1/m. This will reduce the total 
variance applied in sample size calculation. Using ICC=0.98, and SD=1 (Variance=1) as an example, as an example, 
for m=8, the adjusted variance will be 0.98 כ 0.7225 + (1 െ0.98) כ
଴.଻ଶଶହ
଼
= 0.70985 and the SD=0.8425. 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
 
3. 
STUDY ENDPOINTS  
 
The primary effectiveness endpoint is to demonstrate that monitoring of cardiac output (CO) with Swan-Ganz, 
FloTrac, and ClearSight is comparable as determined by the Bland-Altman method of bias.   
 
The secondary endpoint analyses will include: 
x 
CO, assessed using include using the Critchley and Critchley method of percent error calculation 
 
Two comparisons will be performed for each of three endpoints described above: FloTrac vs Swan-Ganz and 
ClearSight vs Swan-Ganz.    
 
The primary and secondary efficacy endpoints will be analyzed using the evaluable analysis set as defined in Section 
5.  
 
The primary safety endpoint is to assess all serious intraoperative and post-operative adverse events through 30 
days, including serious device-related events. The safety endpoint will be analyzed using the safety analysis set as 
defined in Section 5.  
  
3.1 Primary effectiveness endpoint 
 
By the CO measurement from Swan-Ganz, FloTrac, and ClearSight, and Fick principle, the variable bias (X) is derived 
for statistical analysis: 
 
 
ݔ௜௝= ܥܱ௧௜௝െܥܱ௥௜௝ 
 
Where ݔ௜௝ is the bias of ݅ݐ݄ subject and ݆ݐ݄ matched pair repeated measurements, ܥܱ௧௜௝ is CO measurement of 
the ݅ݐ݄ subject at ݆ݐ݄ repeated measurement of test device, such as Swan-Ganz, FloTrac, and ClearSight, ܥܱௗ௜ is 
the CO measurement of ݅ݐ݄ subject at ݆ݐ݄ repeated measurement of reference device the Swan-Ganz 
thermodilution pulmonary catheter. Here ݅= 1, … , ݊ (the estimated sample size, 102), ݆= 1, … . , ݉ (the planned 
repeated measurements, 8). 
 
3.1.2 97.5% Confidence Intervals for bias using bootstrap and limit of agreement methods 
 
Bootstrap method will be used to estimate two-sided 97.5% confidence intervals for all CO and CI bias measures 
under study. This will be performed for all analysis datasets as well as those data with rejected data. Results will 
be compared. 
 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
 
3.2 Secondary effectiveness endpoints 
ܲܧ௜௝= 100 כ หܥܱ௧௜௝െܥܱ௥௜௝ห
ܥܱ௥௜௝
= 100 כ หݔ௜௝ห
ܥܱ௥௜௝
 
3.2.1 PE derived by CO 
 
The percent error is derived as follow: 
 
ܲܧ௜௝= 100 כ หܥܱ௧௜௝െܥܱ௥௜௝ห
ܥܱ௥௜௝
= 100 כ หݔ௜௝ห
ܥܱ௥௜௝
 
 
where ܲܧ௜௝ is the percent error of ݅ݐ݄ subject at ݆ݐ݄ repeated measurement of FloTrac and ClearSight with CO 
measurements from the Swan-Ganz thermodilution pulmonary catheter, as the reference. 
 
3.3 Explatory analyses 
 
 
3.3.1 Bias derived by CI 
 
By the CI measurement from Swan-Ganz, FloTrac, and ClearSight, the variable bias (X) is derived for 
statistical analysis: 
 
ݔ௜௝= ܥܫ௧௜௝െܥܫ௥௜௝= (ܥܱ௧௜௝െܥܱ௥௜௝)/ܤܵܣ 
 
Where ݔ௜௝ is the bias of ݅ݐ݄ subject and ݆ݐ݄ matched pair repeated measurements of CI, ܥܫ௧௜௝ is CI 
measurement of the ݅ݐ݄ subject at ݆ݐ݄ repeated measurement by FloTrac and ClearSight, ܥܫ௥௜௝ is the CI 
measurement of ݅ݐ݄ subject at ݆ݐ݄ repeated measurement of reference device, Swan-Ganz ITD, on the 
same study subject. Here ݅= 1, … , ݊ (the estimated sample size, 102), ݆= 1, … . , ݉ (the planned repeated 
measurements, 8). And ܤܵܣ is the body surface area of this study subject. 
 
ܲܧ௜௝= 100 כ หܥܱ௧௜௝െܥܱ௥௜௝ห
ܥܱ௥௜௝
= 100 כ หݔ௜௝ห
ܥܱ௥௜௝
 
3.3.2 PE derived by CI 
 
The percent error of CI is derived as follow: 
ܲܧ௜௝= 100 כ หܥܫെܥܫ௥௜௝ห
ܥܫ௥௜௝
= 100 כ หݔ௜௝ห
ܥܫ௥௜௝
= 100 כ
ฬܥܱ௧௜௝
ܤܵܣെܥܱ௥௜௝
ܤܵܣฬ
ܥܱ௥௜௝
ܤܵܣ
= 100 כ ඃܥܱ௧௜௝െܥܱ௥௜௝ඇ
ܥܱ௥௜௝
 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
where ܲܧ௜௝ is the percent error of CI measurement of ݅ݐ݄ subject at ݆ݐ݄ repeated measurements by FloTrac and 
ClearSight, using Swan-Ganz ITD CI measurement as the reference. ܤܵܣ is the body surface area of this study 
subject. Here the PE calculated by CI is the same as calculated by CO. Therefore, this fact will be noted and present 
in the final report.        
   
                        ݔ௜௝= ܥܱ௧௜௝െܥܱ௥௜௝ 
 
3.4 Explatory analyses 
 
3.4.1 98.75% Confidence Intervals for PE using bootstrap method (derived by CO and CI)  
 
Bootstrap method will be used to estimate one-sided confidence for PE, CO and CI measures under study. This will 
be performed for all analysis datasets as well as those datasets with rejected data. Results will be compared. 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
4. 
ANALYSIS POPULATIONS 
 
The analysis set is composed of all evaluable subjects with valid CO matched paired measurements from 
the target medical device system (Swan-Ganz™, FloTrac™, and ClearSight™), the Fick principle and the 
reference medical device system (a Swan-Ganz thermodilution catheter).  Evaluable subjects are those 
with non-rejected intermittent thermodilutions who have completed the 30-day telephone follow up period. 
 
5. 
DEFINITIONS 
 
5.1. 
Enrolled Subject 
 
A subject will be considered enrolled in the study once the subject has signed the informed consent, 
a Swan-Ganz catheter has been deployed, a FloTrac has been connected, a ClearSight finger cuff 
has been attached and/or ForeSight Elite sensors have been placed. 
 
5.2. 
Evaluable Subject 
 
An evaluable subject is one who has valid CO pair measurements that were not rejected and also 
has completed the 30-Day follow up. 
 
5.3. 
Modified Intent-to-treat (mITT) 
 
Modified Intent-to-treat (mITT) is defined as the study subjects who were exposed to the study 
product and will therefore be included in the effectiveness and safety analysis datasets.   
 
5.4. 
Per Protocol Analysis 
 
A per protocol analysis is defined as a dataset of subjects who completed the cardiac catherization 
as written in the protocol.  No protocol deviations occurred during the cardiac catherization 
procedure. 
  
5.5. 
Pivotal Cohort 
 
The pivotal cohort are subjects who were enrolled after the roll-in period.  The pivotal cohort will be 
analyzed separately from the roll-in cohort. 
 
 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
5.6. 
Roll-in Cohort 
 
The roll-in cohort are the first 1-3 subjects enrolled at the site that the study investigator uses to 
confidently perform the intermittent thermodilution. This group of patients will analyze separately 
from the pivotal subjects. 
 
5.7. 
Screen Failure 
 
A screen failure is a study subject who does not meet all inclusion criteria or fails at least one of 
exclusion criteria. 
 
6. 
DATA AND ANALYSIS CONVENTIONS 
 
6.1 General Conventions 
 
The baseline characteristics and demographics of each study subject will be collected during the 
subject screening process.  The subject’s medical historical data will be recorded on an electronic 
case report form (eCRF).  The CO measurement data will be downloaded from hemodynamic 
monitor (Hemosphere advanced monitoring platform). The Roll-in cohort data will be analyzed 
separately. 
 
The data analyses will be conducted with SAS 9.4 software system. Bland Altman analyses will be 
performed for bias and precision measures. Limits of agreement will be calculated. 
 
6.2 Handling of Missing Data  
 
Missing data are defined as those instances in which data collection was attempted yet failed for 
some reason (i.e. due to technological, procedural, and/or subject constraints). Demographic and 
baseline characteristics are collected from the study subjects as part of screening.  If missing data 
are not related to the subject’s eligibility criteria, missing data will be presented by the valid sample 
size in the demographic and baseline characteristics summary statistics table.  Subjects with 
missing data will be included in the final analysis.  However, if the missing data are related to the 
subject’s eligibility, this will be considered a protocol deviation, and in this case, the study data from 
this subject will be reviewed internally, to determine if the subject should be excluded from the final 
analysis set.  
 
The CO measurements are downloaded from the hemodynamic monitor. Theoretically, there should 
be no missing data. For data that are missing as defined above, statistical imputation using the SAS 
imputation method will be utilized.   
 
6.3 Handling of Invalid Data 
 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
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Monitoring in Pediatric Patients 
 
 
After downloading the data from the hemodynamic monitors, abnormal observations will be checked 
and evaluated for hemodynamic stability.   Should there be any instability, the result will be rejected.  
All data will be recorded, and any rejected values will be clearly identified in the eCRF.  
 
The rejection criteria that will be used to determine - hemodynamic instability are detailed below: 
x 
Mean arterial pressure (MAP):  If MAP varies > 15% during the 30-sec period of each 
intermittent thermodilution, the bolus will be rejected. 
x 
Pulse rate:  If Pulse varies > 15% during the 30-sec period of each ITD, the bolus will be 
rejected. 
x 
PhysioCal:  If PhysioCal is not at least 30 beats, the bolus will be rejected. 
x 
 
Upon taking four (4) thermodilution measurements and given the above criteria for classifying data 
as invalid, Edwards proposes to remove the one measurement that is the greatest outlier of the 
four.  If upon the rare occasion two or more outliers measure greater than 15% from the mean, 
within a series of measurements, or hemodynamic instability results when these observations are 
taken, the clinician will repeat the series.  If this scenario of repeating the series is missed by the 
clinican during the clinical procedure and discovered by the statisticians during data review, the 
outliers will be analyzed separately. In addition to the results for the collected parameters, the 
number of subjects with less than 3 and number of subjects with at least 3 valid values, and 
results of subjects will be tabulated separately, and reported.  Those subjects who have less than 
3 valid measurements and were missed for repeated testing by the clinician performing the 
thermodilutions will be considered as protocol deviations or protocol violations.  
Additionally, a supplementary exploratory analysis will be reported using all the recorded values 
(valid and invalid) to assess the impact of the excluded values. 
 
7. SUMMARY OF BASELINE INFORMATION 
 
7.1 Subject Eligibility Criteria 
 Inclusion Criteria 
1. Subjects who are 12 to 18 years of age 
2. Subjects who have signed the Informed Consent Form 
3. Subjects who are projected to receive Swan-Ganz catheter as part of procedure/standard of care with 
intermittent cardiac output measures  
4. For those Subjects who have had a cardiac transplant, Subjects must be at least two weeks post   
cardiac transplantation Subjects     
5. Subjects with planned pressure monitoring with an arterial line   
   Exclusion Criteria 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
1. Subjects with contraindications for Pulmonary Artery Catheters Placement and monitoring (recurrent 
sepsis, or with hypercoagulopathy); 
2. Subjects with contraindications for Arterial Line Placement; 
3. Subjects with an extreme contraction of the smooth muscle in the arteries and arterioles in the lower 
arm and hand (i.e., Raynaud’s Disease). 
4. Subjects with a physical site area too limited for proper Sensor placement 
5. Subjects with finger size less than the smallest finger cuff size 
6. ŽĐƵŵĞŶƚĞĚ ш ŵŽĚĞƌĂƚĞ ƉƵůŵŽŶĂƌǇ ŚǇƉĞƌƚĞŶƐŝŽŶ ;WWŵ х Ϯϱ ŵŵ,Ő͕ WsZ/ х ϯ͘Ϭ thǆŵϮͿ 
7. Presence of intracardiac shunting (i.e., ASD, VSD) 
8. Aorto-pulmonary collaterals  
9. ш DŽĚĞƌĂƚĞ ƚƌŝĐƵƐƉŝĚ ƌĞŐƵƌŐŝƚĂƚŝŽŶ͕ ƉĞƌ ĞĐŚŽĐĂƌĚŝŽŐƌĂŵ ĐƌŝƚĞƌŝĂ 
10. > Moderate Aortic or pulmonary regurgitation, per echocardiogram criteria 
11. Persistent cardiac arrythmias during the cardiac catheterization period (> 3min) 
12. Vascular abnormalities of the arterial system (i.e., connective tissue disorders, mid-aortic syndrome)” 
 
 
7.2 Demographics and Baseline Characteristics 
 
The baseline characteristics and demographics of each study subject will be collected during the subject 
screening process.   
 
7.3 Medical History 
 
The subject’s medical historical data will be recorded on an electronic case report form (eCRF).  The CO 
measurement data will be downloaded from hemodynamic monitor (Hemosphere advanced monitoring 
platform). 
 
7.4 Risk Assessments 
 
Any events associated with a commercially available study device will be reported in accordance with the 
Medical Device Reporting (Complaints) regulation (21 CFR Part 803), while events associated with the 
investigational device will be reported under the IDE program (812.150). .  
 
Below is a list of anticipated risks that may be associated with the use of Swan-thermodilution pulmonary 
artery catheter. 
 
x 
Perforation of the pulmonary artery 
x 
Pulmonary infarction 
x 
Cardiac arrhythmias 
x 
Knotting 
x 
Sepsis/Infection 
x 
Right bundle branch block 
x 
Complete heart block 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
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Monitoring in Pediatric Patients 
 
 
x 
Tricuspid and pulmonic valve damage 
x 
Thrombocytopenia 
x 
Pneumothorax 
x 
Thrombophlebitis 
x 
Nitroglycerin absorption 
x 
Thrombosis 
x 
Allergic reaction to latex 
 
FloTrac sensor 
The vascular access obtained is standard clinical care and the addition of the FloTrac arterial transducer is 
standard procedure and does not impose any additional risk to the patient. There is no measurable increased 
infectious risk with the temporary use of the FloTtrac sensor. 
 
Below is a list of anticipated risks that may be associated with the use of the ClearSight finger cuff. 
x 
Discomfort where the cuff is applied 
x 
Discoloration of digit distal to the cuff 
x 
Pain associated with inflation of the cuff 
x 
Slight numbness of the fingertip 
 
Below is a list of anticipated risks that may be associated with the use of ForeSight Elite Sensors. 
x 
Allergic reaction to sensors 
x 
Skin irritation 
 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
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Monitoring in Pediatric Patients 
 
 
8.  STATISTICAL ANALYSIS OF STUDY ENDPOINTS 
 
8.1 Primary Endpoint  
 
The primary objective of this study is to demonstrate that monitoring of cardiac output with Sawn-Ganz, 
FloTrac, and ClearSight is comparable as determined by the Bland-Altman method of bias. To demonstrate 
this comparability, the bias calculation will be assessed separately. 
 
Summary statistics and statistical comparison 
 
The CO measurements from both investigational and reference device systems will be summarized using 
descriptive statistics including mean, median, minimum, maximum, standard deviation, Q1 (first quantile), 
and Q3 (third quantile).  Additionally, p values from paired t-test will be provided to test the difference.  
 
8.1.2 Primary endpoint analysis with Bias calculated by CO  
The primary endpoint of the bias between the matched pairs of CO measurements as determined by the Bland-
Altman method will be tested as below using the one sample t-test.  
 
The hypothesis for bias is: 
 
H0:  bias <-0.5 or bias >0.5  
H1: -Ϭ͘ϱч ďŝĂƐ чϬ͘ϱ  
See section 3.1 for details. 
 
8.1.3 Limits of Agreement  
Limits of agreement will be computed using Bland-Altman methods. Components of the one-way analysis of 
variance will be used to estimate variance of multiple between-device differences for the same subject. These 
components of variance measures include the mean square for subjects (SS), and residual mean square (RMS). 
The differences between the average difference across subjects will be estimated from the difference between 
SS and RMS.  This difference will be divided by M=;;єmi)2 - є mi2)/(n-1)*( єmi), where n = total number of 
subjects, and mi is the number of pairwise difference measurements for the ŝƚŚ subject. The estimated 
component of variance, which represents the heterogeneity, is estimated as (SS – RMS)/M. The total variance 
(TV) for single differences on different subjects is estimated by the sum of these two components: TV = (SS – 
RMS)/M + RMS. The resulting lower and upper limits of agreement will be estimated with 97.5% confidence 
mean(diff) ± 1.984*TV for a two-sided test. 
 
 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
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Monitoring in Pediatric Patients 
 
 
We want agreement to be the same or at least similar over the range of CO and CI measurements. Plots of the 
difference bias between device pairings (ClearSight vs Swan-Ganz, and FloTrac vs Swan-Ganz), for CO and CI 
measurements, on average of the two device measurements will be performed, with reference lines including 
zero, mean difference, and lower and upper limits of agreement. Two-sided 97.5% LOA will be calculated for 
bias between device pairings9. The statisticians will determine whether the standard deviation of the mean 
difference is constant or non-constant for each measure. The mean difference and standard deviation about the 
mean difference will be estimated for all measurements. The difference measures will be tested for 
heterogeneity using components of variance methods. The variance for single differences  between device pairs 
of measurements, on different subject, will be plotted. Also, mean difference will be plotted on the order in 
which observations are recorded for each subject.  
 
Visual check of the bias spread pattern and deviation using scatter plots of bias and/or percent error versus 
Fick principle reference mean CO, and scatter plot of bias and the percent error versus target device mean CO, 
with reference lines zero and limits of agreement  (ߜ͟ߜߜto the plot will be performed.  
 
8.2  Secondary Endpoint  
 
8.2.1 Percent Error calculated by CO as the secondary endpoint 
The secondary endpoint of the percent error between the matched pairs of CO measurements as 
determined by the Critchley and Critchley method will be tested as below using the one sample t-test.  
The hypothesis for PE is: 
 
H0: PE > 30% 
,ϭ͗ W ч ϯϬй 
 
 
8.3 Sensitivity Analysis 
 
8.3.1  Sensitivity analysis on study subject 
To determine the effectiveness of study subject on the analytical results, following sensitivity analysis will  
be conducted by artificially removing one or a few study subjects. The expected result is that no study  
subject or group of study subjects are influence subjects on the analytical result.   
 
8.3.2 Sensitivity analysis on reference device 
To determine the effectiveness of reference device on the test device in the analytical results, different 
reference devices will be applied in sensitivity analysis. The expected result is that the reference device 
performance is stable and consistency, which is not the influence factor for the analytical result. 
 
8.4 Exploratory Analyses 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
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Monitoring in Pediatric Patients 
 
 
The following exploratory analyses will be preformed 
x 
Comparison analysis of CI calculated for Bias as determined by Bland Altman method with 
confidence intervals.  
x 
Comparison analysis of CI as determined by the Critchley and Critchley method of percent error 
calculation with confidence intervals 
x 
Subgroup analysis of primary and secondary endpoint by age stratification 
x 
Subgroup analysis of primary and secondary endpoint by gender 
x 
Subgroup analysis of primary and secondary endpoint by race 
x 
Subgroup analysis of primary and secondary endpoint by site 
x 
Comparison of cardiac output from FloTrac, ClearSight and Swan-Ganz technologies to the Fick 
principle 
 
   8.4.1 Validation of Accuracy and Consistency 
Considering the variation of CO measurement from both device systems among patients, applying patient and 
patient age group as potential classification factors, the conclusion from 8.1.2 will be validated with bootstrap 
method through the 97.5% coverage intervals, which should be within the range from -ߜ to ߜ.  These analyses 
will be presented within clinical study report.  
 
   8.4.2 Variance component analysis 
 
With mixed effect model, the derived variable bias as the response, study site, surgery team, and subject as 
the random variable, estimate the variance component of each factor to trace the main source of variability, 
which will benefit to future variation control. This analysis will be present in the clinical study report. 
 
 
8.5 Interim analysis 
No interim analysis is planned for this study.  
 
8.6 Analysis of other hemodynamic parameters 

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Monitoring in Pediatric Patients 
 
 
 Below is a table of other hemodynamic parameters measures that will be collected in this study. 
Table 1. Measures by Device and Endpoint 
 
Device 
 
Parameters 
Swan 
Ganz  
FloTrac 
ClearSight 
ForeSight 
Endpoints 
Cardiac Output (CO) 
X 
X 
X 
 
Primary (Bland Altman), 
Secondary (Percent Error) 
Cardiac Index (CI) 
X 
X 
X 
 
None (exploratory analyses - 
descriptive stats) 
Central Venous Pressure 
(CVP) 
 
X 
 
 
None (exploratory analyses - 
descriptive stats) 
Diastolic Blood Pressure 
(DIA(ART)/DIA(PAP)) 
 
X 
 
 
None (exploratory analyses - 
descriptive stats) 
Dynamic Arterial 
Elastance (Ea(dyn)) 
 
X 
X 
 
None (exploratory analyses - 
descriptive stats) 
Intermittent cardiac index 
(iCI) 
X 
 
 
 
None (exploratory analyses - 
descriptive stats) 
Intermittent cardiac 
output (iCO) 
X 
 
 
 
None (exploratory analyses - 
descriptive stats) 
Intermittent systemic 
vascular resistance (iSVR) 
X 
 
 
 
None (exploratory analyses - 
descriptive stats) 
Intermittent systemic 
vascular resistance index 
(iSVRI) 
X 
 
 
 
None (exploratory analyses - 
descriptive stats) 
Mean Arterial Pressure 
(MAP) 
 
X 
X 
 
None (exploratory analyses - 
descriptive stats) 
Mean pulmonary artery 
blood pressure (MPAP) 
 
X 
 
 
None (exploratory analyses - 
descriptive stats) 
Noninvasive Arterial 
Diastolic Pressure 
(DIA(NI)) 
 
 
X 
 
None (exploratory analyses - 
descriptive stats) 
"Noninvasive arterial 
systolic blood pressure 
(SYS(NI))" 
 
 
X 
 
None (exploratory analyses - 
descriptive stats) 
Pulmonary artery diastolic 
blood pressure (DIA(PAP)) 
 
X 
 
 
None (exploratory analyses - 
descriptive stats) 
Pulmonary artery systolic 
blood (SYS(PAP)) 
 
X 
 
 
None (exploratory analyses - 
descriptive stats) 
Pulse Pressure Variation 
(PPV) 
 
X 
X 
 
None (exploratory analyses - 
descriptive stats) 
Pulse Rate (PR) 
X 
X 
X 
 
None (exploratory analyses - 
descriptive stats) 
Stroke volume (SV) 
X 
X 
X 
 
None (exploratory analyses - 
descriptive stats) 
Stroke volume index (SVI) 
X 
X 
X 
 
None (exploratory analyses - 

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Statistical Analysis Plan for A Prospective, Single-Arm, 
Nonrandomized, Observational Study of Cardiac Output 
Monitoring in Pediatric Patients 
 
 
Table 1. Measures by Device and Endpoint 
descriptive stats) 
Stroke Volume Variation 
(SVV) 
 
X 
X 
 
None (exploratory analyses - 
descriptive stats) 
Systemic arterial diastolic 
blood pressure (DIA (ART)) 
 
X 
 
 
None (exploratory analyses - 
descriptive stats) 
Systemic arterial systolic 
blood pressure (SYS(ART)) 
 
X 
 
 
None (exploratory analyses - 
descriptive stats) 
Systemic vascular 
resistance (SVR) 
 
X 
X 
 
None (exploratory analyses - 
descriptive stats) 
Systemic vascular 
resistance index (SVRI) 
 
X 
X 
 
None (exploratory analyses - 
descriptive stats) 
Systolic Pressure 
(SYS(ART)/SYS(PAP)) 
 
X 
 
 
None (exploratory analyses - 
descriptive stats) 
Systolic Slope (dP/dt) 
 
X 
X 
 
None (exploratory analyses - 
descriptive stats) 
StO2 - 1 (cerebral) 
 
 
 
X 
None (exploratory analyses - 
descriptive stats) 
StO2 - 2 (cerebral) 
 
 
 
X 
None (exploratory analyses - 
descriptive stats) 
 
 
9 
ANALYSIS OF SAFETY 
9.1 
Adverse Events 
 
The adverse events data will be summarized with frequency counts and percentages. The 
frequency distribution and percentage of adverse event related to a specific medical device will be 
presented. The primary safety endpoint will include summary of intraoperative and post-operative 
adverse events, discharge through 30 days followup, related or unrelated to the devices under 
study.  
 
9.2 
Deaths and Other Serious Adverse Events 
   
Death or other serious adverse events that occur during this study will be summarized with 
frequencies and percentages.  
 
 
10 CHANGES FROM PROTOCOL SPECIFIED ANALYSES 
  
There are no changes to the protocol specified analyses at this time. 
 
 

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Monitoring in Pediatric Patients 
 
 
12 
APPENDIX 
13 
LITERATURE SEARCH/REVIEW 
 
For the original FloTrac submission in 2004 and the publication (Nusmeier, van Der Hoeven, and 
Lemson, 2010), an abstract search was performed to compile relevant clinical data on the accuracy 
and acceptance criteria of various injectate and continuous cardiac output measurements (iCO, and 
CCO). PubMed was searched using the keywords “continuous” OR “Fick’ OR pulse contour" OR “TD”) 
AND "cardiac output" AND “precision”, to identify published literature that reported performance 
comparisons of cardiac output measurements. A total of 97 abstracts of published articles were found 
as a result of the search.  
 
Review of the abstracts showed that 42 of them were irrelevant. Of the 42 that were not taken into 
consideration, 17 reported on pre-clinical studies, 21 had insufficient statistics and 4 did not provide 
performance comparison of cardiac output. Hence, 55 abstracts were deemed relevant to this 
analysis. Ten out of 55 abstracts reported accuracy in terms of cardiac index. The remaining 45 
abstracts contained 75 pairs of Bland-Altman comparisons. Fourteen of the 75 Bland-Altman 
comparison pairs were reported as marginal or unacceptable, the remaining 61 pairs from 38 abstracts 
were reported as clinically acceptable [32-69].  
 
Figure 1 indicates a histogram of the bias reported in the 61 comparisons. The range of bias reported 
as clinically acceptable was [-0.79 …0.63]. However, from the histogram, it can be seen that only 
three of the reported values were outside +/- 0.6 l/min. Thus, the literature advocated outer limits of 
+/- 0.6 l/min for the bias of a Bland-Altman comparison of cardiac output values. 
 
Since then, several CO validation studies against pulmonary and transpulmonary thermodilution with 
the noninvasive technology have been performed. The analysis of 10 of these studies [70-79] showed 
a bias range of 0.0 to 0.6 L/min, with an average of 0.24 ± 0.19 L/min. Based on these data and after 
discussion with the Data Management and Bio-center of the National Center for Cardiovascular 

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Monitoring in Pediatric Patients 
 
 
Diseases (Professor Wei LI), the performance criterion was set at 0.5 L/min, i.e. bias is determined to 
be -0.5< bias < 0.5 l/min. This value is smaller in magnitude to the 0.8 l/min floor that the US FDA had 
previously considered for CO comparisons.  
 
14 PEER REVIEW REQUEST, PER SAP INSTRUCTION (DOC-0089205)  
 
Yes 
Name of Reviewer: 
No 
Reason Peer Review not Needed: 
;
 
 
܆