Evaluation of Fluid Volume in Patients With Sepsis and Refractory Hypotension
Phase: NA
Conditions: Sepsis, Hypotension
Sponsor: Cheetah Medical Inc.



Page 2 of 34 
 
Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
1. 
CONTENTS 
Investigator’s Statement and Signature .......................................................................................... 5 
2. 
LIST OF ABBREVIATIONS ................................................................................................. 6 
3. 
SYNOPSIS .............................................................................................................................. 7 
4. 
INTRODUCTION ................................................................................................................. 10 
4.1 
Background .................................................................................................................... 10 
5. 
STUDY JUSTIFICATION .................................................................................................... 10 
6. 
DEVICE ................................................................................................................................ 11 
6.1 
Device Description ......................................................................................................... 11 
6.2 
Device Accountability .................................................................................................... 11 
6.3 
Device Indication for Use .............................................................................................. 11 
6.4 
Device Procedure(s)/Training ........................................................................................ 12 
6.5 
Fluid Assessment-Passive Leg Raise (PLR) .................................................................. 12 
7. 
INVESTIGATIONAL DESIGN ........................................................................................... 12 
7.1 
Study Objective .............................................................................................................. 12 
7.2 
Study Design .................................................................................................................. 12 
7.3 
Study Endpoints ............................................................................................................. 13 
7.3.1 
Primary Endpoint ................................................................................................ 13 
7.3.2 
Secondary Endpoints ........................................................................................... 13 
7.4 
Study Duration ............................................................................................................... 13 
8. 
SUBJECT POPULATION AND SELECTION .................................................................... 14 
8.1 
Subject Population.......................................................................................................... 14 
8.2 
Inclusion Criteria ............................................................................................................ 15 
8.3 
Exclusion Criteria ........................................................................................................... 15 
8.4 
Subject Screening ........................................................................................................... 16 
8.5 
Informed Consent Procedures ........................................................................................ 16 
8.6 
Subject Randomization .................................................................................................. 17 
8.7 
Subject Discontinuation/Withdrawal Criteria ................................................................ 17 
8.7.1 
Subjects Lost to Follow-Up................................................................................. 17 
9. 
STUDY PROCEDURES ....................................................................................................... 17 
9.1 
Baseline Assessments ..................................................................................................... 17 
9.2 
Enrollment Procedure ..................................................................................................... 18 
9.3 
Data Collection Procedure ............................................................................................. 18 
9.3.1 
Hemodynamic Collection Methods ..................................................................... 18 

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
9.3.2 
Fluid Assessment................................................................................................. 18 
9.3.3 
Additional Data Collection.................................................................................. 19 
9.4 
Schedule of Assessments ............................................................................................... 19 
10. SAFETY/DEVICE ASSESSMENT...................................................................................... 20 
10.1 Adverse Events ............................................................................................................... 20 
10.1.1 
Device Related Adverse Event (AE) ................................................................... 20 
10.1.2 
Serious Adverse Events ....................................................................................... 20 
10.2 Reporting Procedures ..................................................................................................... 20 
10.2.1 
General Reporting Requirements ........................................................................ 20 
10.2.2 
Reporting Requirements of SAEs ....................................................................... 21 
10.2.3 
Sponsor Reporting ............................................................................................... 21 
11. STUDY MONITORING ....................................................................................................... 21 
11.1 Monitor Training ............................................................................................................ 21 
11.2 Site/Investigator Training ............................................................................................... 21 
11.2.1 
Protocol Training................................................................................................. 22 
11.2.2 
Device Training ................................................................................................... 22 
11.3 Site Monitoring .............................................................................................................. 22 
11.4 Regulatory Agency Inspection ....................................................................................... 22 
12. STATISTICAL CONSIDERATIONS .................................................................................. 22 
12.1 Sample Size Estimation .................................................................................................. 22 
12.2 Analysis Populations ...................................................................................................... 23 
12.2.1 
All Enrolled ......................................................................................................... 23 
12.2.2 
Intent-to-Treat (ITT) ........................................................................................... 23 
12.2.3 
Modified Intent-to-Treat (mITT) ........................................................................ 23 
12.3 Primary Endpoint Analysis ............................................................................................ 24 
12.4 Secondary and Exploratory Endpoints ........................................................................... 24 
12.5 Baseline Data Summary ................................................................................................. 25 
12.6 Subject Accountability and Missing Data ...................................................................... 25 
13. DATA HANDLING AND RECORD KEEPING ................................................................. 25 
13.1 Clinical Data Collection ................................................................................................. 26 
13.2 Data Reporting ............................................................................................................... 26 
13.3 Data Review ................................................................................................................... 26 
13.4 Investigator Records ....................................................................................................... 26 
13.5 Data Retention ................................................................................................................ 27 

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
13.6 Investigator Reports ....................................................................................................... 28 
14. QUALITY CONTROL AND ASSURANCE ....................................................................... 28 
14.1 Site and Investigator Selection ....................................................................................... 28 
14.2 Protocol Deviations ........................................................................................................ 28 
14.2.1 
Protocol Deviation Process ................................................................................. 29 
14.3 Corrective/Preventive Action ......................................................................................... 29 
14.4 Study Audit(s) ................................................................................................................ 29 
14.5 Study Registration .......................................................................................................... 29 
15. ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................. 30 
15.1 Statements of Compliance .............................................................................................. 30 
15.2 Institutional Review Board............................................................................................. 30 
15.3 Informed Consent Process .............................................................................................. 30 
15.4 Subject Confidentiality ................................................................................................... 31 
16. PROTOCOL AMENDMENTS ............................................................................................. 31 
17. TERMINATION OF STUDY OR STUDY SITE PARTICIPATION ................................. 31 
18. PUBLICATION POLICY ..................................................................................................... 32 
19. BIBLIOGRAPHY ................................................................................................................. 33 
Appendix A- Treatment Algorithm .............................................................................................. 34 
 
 
 

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
 
INVESTIGATOR’S STATEMENT AND SIGNATURE 
The signing of this protocol by the Principal Investigator signifies that the contents have been 
laid down in full agreement and that the study will be conducted according to this protocol, its 
amendments, the clinical trial agreement and the applicable regulatory requirements. 
 
 
 
Investigator approval: 
I have read this protocol and agree that it contains all the necessary information required to 
conduct the study, and I agree to conduct it as described. I understand that this study will not 
be initiated without appropriate Institutional Review Board (IRB) approval and that the 
administrative requirements of the governing body will be fully complied with.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Printed Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site Name 
 
Site # 
 

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
2. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AKI 
Acute kidney injury 
BP 
Blood pressure 
CPR 
CRF 
CV 
 
 
Cardiopulmonary resuscitation 
Case report form 
Curriculum vitae 
eCRF 
EDC 
FDA 
Electronic case report form 
Electronic data capture  
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICC 
ICF 
ICU 
Intraclass correlation 
Informed consent form 
Intensive Care Unit 
IRB 
Institutional Review Board 
ITT 
IV 
L/min 
mITT 
Intention to treat 
Intravenous  
Liter per minute 
Modified intent to treat 
PLR 
PPV 
RRT 
SAE 
SV 
SVI 
SVV 
TFC 
TPRI 
VET 
Passive leg raise 
Pulse Pressure Variation 
Renal replacement therapy 
Serious adverse event 
Stroke volume 
Stroke volume index 
Stroke volume variation 
Thoracic fluid content 
Total peripheral resistance index 
Ventricular ejection time 
 
 
 
 
 
 
 
 
 
 

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
3. 
SYNOPSIS 
Title: 
Evaluation of fluid volume in patients with sepsis and 
refractory hypotension 
Short Title: 
FRESH (Fluid Responsiveness Evaluation in Sepsis-
associated Hypotension) Fluid Trial 
 
Investigational Device: 
Noninvasive Starling™ SV  
Objective:  
To assess the mean difference in fluid balance and associated 
patient outcomes, based on a dynamic assessment of fluid 
responsiveness in septic patients with refractory hypotension in 
an ICU setting.  
Design: 
Multi-center randomized study comparing dynamic assessment 
of fluid responsiveness utilizing Starling SV compared to a 
control group. 
 
Subjects will be randomized in a 2:1 treatment to control group 
ratio to increase power for sub-analysis by patient population. 
 
Patients randomized to the Starling SV arm will have treatment 
guided by a dynamic assessment of fluid responsiveness 
(measured by a change in stroke volume index > +10%) as 
assessed by passive leg raise (PLR). 
 
Patients randomized to the control group will receive standard 
of care treatment. The use of dynamic fluid assessment (i.e. 
SVV, PPV, or SV change) to determine fluid responsiveness is 
prohibited. 
 
Primary Endpoint: 
Mean difference in fluid balance (L) at 72 hours or ICU 
discharge, whichever occurs first, between the two treatment 
groups  
Secondary Endpoints 
1. Length of ICU stay (days) until subject is medically 
ready for discharge 
2. Number of hours free from ventilator use  
3. Requirement for mechanical ventilation 
4. Number of hours free from vasopressor use  
5. Changes in serum creatinine levels from baseline 
6. Requirement for renal replacement therapy (RRT) 
7. Mean volume of fluid between the two treatment 
groups 
8. Incidence of Major Adverse Cardiac Event (MACE) 
9. Incidence of Adverse Events (AE) 
10. Number of ICU readmissions 
11. 30 day in-hospital mortality rate 
12. Discharge location 
13. Mean difference in fluid balance at ICU discharge 
 

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
Planned Enrollment: 
Approximately 210 subjects will be involved in the analysis 
population 
Population: 
Patients with sepsis who exhibit refractory hypotension (MAP 
< 65, or require treatment with vasopressors to maintain a MAP 
> 65) following initial  fluid resuscitation (1L of fluid). 
Follow-up Schedule: 
Hemodynamic data collection will occur for a 72 hour period 
starting at the time of study enrollment. Subject outcome data 
will be collected until the time of hospital discharge. 
Number of Sites: 
Between 7-15 clinical sites located in the US and 1-3 sites 
located in the UK 
Sub Analysis: 
Primary and secondary endpoints will also be evaluated by the 
following secondary analysis:  
• 
Patient disease state 
• 
Patients determined to be fluid responsive vs non-fluid 
responsive 
• 
AKI measures in patients determined to increase serum 
creatinine levels from baseline  
• 
Enrollment time frame 
Additional sub-analysis will be run as appropriate. 
Inclusion Criteria: 
1. Diagnosis of sepsis, as exhibited by 2 or more of the 
following SIRS criteria and a known or presumed infection 
at time of screening: 
o Temperature of > 38 C or < 36 C 
o Heart rate of > 90/min 
o Respiratory rate of > 20/min or PaCO2 < 32 mm 
Hg (4.3 kPA) 
o White blood cell count > 12000/mm3 or < 
4000/mm3 or >10% immature bands 
2. Refractory hypotension (either one single reading of MAP 
<65 exhibited during the evaluation period, or requiring 
treatment with vasopressors to maintain a MAP > 65) 
despite initial fluid resuscitation (1L of treatment fluid) 
3. Patient enrolled in study within 24 hours of arrival to the 
hospital 
4. Anticipated ICU admission. Patients may be maintained on 
another unit (such as within the ER or a step down unit) 
during the 72 hour monitoring period if the treatment 
algorithm is adhered to during this time period. 
5. Able to provide signed informed consent or consent can be 
obtained from the patient’s authorized representative 
 
Exclusion Criteria: 
1. Primary diagnosis of: acute cerebral vascular event, acute 
coronary syndrome, acute pulmonary edema, status 
asthmaticus, major cardiac arrhythmia, drug overdose, or 
injury from burn or trauma 
2. Known aortic insufficiency, or aortic abnormalities 

Page 9 of 34 
 
Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
3. Hemodynamic instability due to active hemorrhage (e.g. 
gastrointestinal bleeding / coagulopathy / trauma) 
4. Patient has received >3 liters of IV fluid prior to study 
randomization 
5. Requires immediate surgery 
6. Patient transferred to the ICU from another hospital unit 
7. Do not attempt resuscitation (DNAR or DNR) order 
8. Advanced directives restricting implementation of the 
resuscitation protocol 
9. Contraindication to blood transfusion 
10. Attending clinician deems aggressive resuscitation 
unsuitable 
11. Transferred from another in-hospital setting 
12. Not able to commence treatment protocol within 1 hour 
after randomization  
13. Known intraventricular heart defect, such as VSD or ASD 
14. Use of additional hemodynamic monitoring involving 
SVV, PPV, or SV change to determine fluid 
responsiveness 
15. Seizure in the last 24 hours 
16. Prisoner 
17. Pregnancy 
18. Age <18 
19. Known allergy to sensor material or gel 
20. Inability or contraindication to doing a passive leg raise 
with both extremities, such as inability to interrupt venous 
compression boots 
21. Patient has an epidural catheter in place 
22. Suspected intra-abdominal hypertension  
23. Inability to obtain IV access 
24. Diabetic ketoacidosis 
25. Hyper-osmolarity syndrome 
26. Patient treatment uncouples from the treatment algorithm 
27. Patient should be excluded based on the opinion of the 
Clinician/Investigator 
Statistical Design: 
Variables will be tabulated using descriptive statistics. 
Continuous variables will be presented as number, mean, and 
standard deviation with 95% confidence intervals, as well as 
medians and ranges. For categorical variables, relative 
frequencies and 95% confidence intervals will be provided. 
Any survival analyses performed will utilize the Kaplan-Meier 
method. 
 
All tests for continuous endpoints utilize a two-sided t-test for 
difference in two independent means at the overall 0.05 level of 
significance.  
 
 
The study will be conducted under a common protocol. To 
evaluate differences among investigational sites in the trial, 
summary tables by site will be presented and compared. 

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
Results from the sites will be pooled only if there are no 
statistical differences between the sites (95% confidence).  If 
variables are found to differ by investigational site, then the 
variable and/or study site may be identified for special 
consideration in subsequent analyses. 
 
 
Sponsor/ 
Manufacturer: 
Cheetah Medical, Inc 
1320 Centre Street 
Newton, MA 02459 
 
4. 
INTRODUCTION 
4.1 
Background 
Hemodynamic optimization of critically ill patients is a goal for clinicians in order to afford the 
patient the best possible outcomes.  Being able to precisely and rapidly determine patient fluid 
responsiveness provides the bedside physician and nursing staff the information needed to make 
critical decisions in regards to the patient’s fluid status and management of additional fluids and 
medications.  Patient management in the ICU is complex and multiple studies and meta-analyses 
have shown that clinicians struggle to diagnose which patients will benefit from fluid 
administration (i.e. the administration of intravenous fluids will increase cardiac output).1 The 
findings show that up to 50% of patients in the ICU will not benefit from fluid administration.2 
Studies have also shown that excessive fluid administration and fluid retention leads to poorer 
outcomes.3-5 Well-timed decision making with accurate information is critical and challenging 
particularly in the setting of a patient with sepsis.  
 
As fluid management and cardiac output determination are linked to better decision-making and 
improved outcomes in ICU, the use of a dynamic assessment of fluid responsiveness becomes a 
key tool for patient management. The Noninvasive Starling SV device, which is FDA cleared 
and CE marked, is currently in clinical use and can be used to provide a dynamic assessment of 
fluid responsiveness.  This study will show the clinical utility of initiating an assessment of 
patient fluid responsiveness prior to the administration of treatment fluid.  
5. 
STUDY JUSTIFICATION 
This study is designed to highlight the benefits of treatment guided by dynamic measures using 
the Starling SV within the population of patients diagnosed with sepsis and refractory 
hypotension.  To confirm this, treatment and outcome data will be compared between patients 
randomized to receive treatment guided by a dynamic assessment of fluid responsiveness, 
compared to the current standard of care treatment. 
 

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
6. 
DEVICE  
6.1 
Device Description 
Cheetah Medical’s Noninvasive Starling SV is a portable, non-invasive, cardiac output detector 
system. The Starling SV system measures the cardiac output by employing electrical 
bioreactance. Bioreactance is a measure of the electrical characteristics of a volume of tissue and 
fluid. In the case of cardiac output measurements, the relevant tissue includes the heart and the 
immediate surrounding volume of the thorax. The relevant fluid is blood. 
 
Cheetah Medical's Starling SV electrode is a double electrode sensor. Within each sensor, one 
electrode is used to transmit a high frequency sine wave into the body, while the 
resulting voltage is measured at the adjacent electrode. Four electrodes are 
placed at specific areas of the thorax, the impedance to the current flow calculated, and 
the electrical bioreactance waveform constructed.  This information is used to determine cardiac 
output.  The Starling SV device also measures and displays associated hemodynamic parameters 
based on calculations of measurements already incorporated into the Starling SV device.  These 
parameters are: Cardiac Index (CI), Ventricular Ejection Time (VET), Total Peripheral 
Resistance Index (TPRI), Stroke Volume Index (SVI), Stroke Volume Variation (SVV), Cardiac 
Power (CP), Cardiac Power Index (CPI) and Thoracic Fluid Content (TFC). Fluid responsiveness 
is indicated by a change in SV of > +10% in response to a fluid challenge.6 
6.2 
Device Accountability 
The Starling SV system (monitor and electrode disposables) will be supplied by Cheetah 
Medical to each investigational site.    
6.3 
Device Indication for Use 
The Starling SV with NIBP and SpO2 functionalities is a portable, hemodynamic monitoring 
non-invasive Cardiac Output monitoring device that monitors and displays a patient’s Cardiac 
Output (CO) in Ltr/Min with a Non Invasive Blood Pressure (NIBP) function that non-invasively 
measures and displays blood pressure (diastolic, systolic and mean arterial pressure) and heart 
rate and with a SpO2 function that non-invasively measures and displays blood oxygen 
saturation (SpO2).  The device displays associated hemodynamic parameters based on 
measurements or calculations of measurements already incorporated into the Starling SV.  These 
parameters are:  
• 
Cardiac Index (CI),  
• 
Stroke Volume (SV),  
• 
Stroke Volume Index (SVI),   
• 
Stroke Volume Variation (SVV),  
• 
Heart Rate (HR),  
• 
Ventricular Ejection Time (VET),  
• 
Total Peripheral Resistance (TPR),  
• 
Total Peripheral Resistance Index (TPRI),   
• 
Cardiac Power (CP),  
• 
Cardiac Power Index (CPI),   
• 
Blood Oxygenation (SPO2) 
• 
Oxygen Delivery Index (DO2I),  

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
• 
Electrical impedance of the chest cavity (Z0),  
• 
Thoracic Fluid Content (TFC),  
• 
Thoracic Fluid Content change from preset time period (TFCd) and  
• 
Thoracic Fluid Content from baseline (TFCd0).   
• 
Changes in SV, CO and other hemodynamic parameters which are derived by 
Bioreactance® as a result of posture 
 
The Starling SV with NIBP and SpO2 functionalities is intended for use within hospitals and 
other healthcare facilities (e.g., outpatient clinics) that provide patient care). 
 
6.4 
Device Procedure(s)/Training 
All sites will receive device training on the Cheetah Starling SV system prior to study initiation.  
 
6.5 
Fluid Assessment-Passive Leg Raise (PLR) 
The passive leg raise (PLR) shall be followed according to the following guidelines: 
• Select PLR Test from main menu on Starling SV system 
• With patient in semi-recumbent position (30-45°), obtain three minutes of monitoring for 
average baseline SVI 
• With patient legs raised to 45 degree angle, obtain three minutes of monitoring for peak 
SVI value 
• Fluid responsiveness is indicated by a Δ SVI ≥ +10% 
 
7. 
INVESTIGATIONAL DESIGN 
7.1 
Study Objective 
The objective of this study is to assess the mean difference in fluid balance at 72 hours or ICU 
discharge, whichever occurs first, and associated patient outcomes, based on a dynamic assessment 
of fluid responsiveness in septic patients with refractory hypotension in an ICU setting.  
7.2 
Study Design 
This study is a prospective, multi-center, randomized trial comparing the mean difference in 
fluid balance and associated patient outcomes between a treatment guided by a dynamic 
assessment of fluid responsiveness and a standard of care control group not using dynamic fluid 
assessment.   Between seven and fifteen sites will be used to enroll 210 subjects with the 
diagnosis of sepsis and refractory hypotension and in whom the Starling SV system can be 
attached. Subjects will be randomized in a 2:1 treatment to control group ratio. In the treatment 
group, a dynamic assessment of fluid responsiveness will be performed at every clinical decision 
point to treat hypoperfusion or impending hypoperfusion for the first 72 hours of study 
enrollment. Examples of a clinical decision point include a MAP of < 65, SBP < 90 or blood 
pressure that is rapidly trending lower,  low urine output, or any other clinical indication to 
administer/alter fluid bolus or pressors. Additionally, an assessment of fluid responsiveness will 
be performed every 12 hours if no clinical assessments have taken place during this time period. 

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
Fluid responsiveness will be assessed using a passive leg raise (PLR) to guide corresponding 
treatment (Appendix A).  Continuous data will be collected from the Starling SV system during 
the entire treatment period. In the control group, no required therapeutic protocol will be used for 
patient treatment, and is determined per the discretion of the physician and hospital standards. 
The use of dynamic fluid assessment (i.e. SVV, PPV, or SV change) to determine fluid responsiveness 
within the control group is prohibited. 
7.3 
Study Endpoints 
7.3.1 Primary Endpoint 
The primary endpoint is an evaluation of the difference (L) between the two treatment groups 
mean fluid balance at 72 hours or ICU discharge, whichever occurs first. The following 
hypothesis will be tested: 
 
Ha: μc - μT ≠ 0 
 
where μt and μc is the average fluid balance  in the Starling SV and control groups, respectively. 
  
7.3.2 Secondary Endpoints 
Secondary endpoints to be evaluated: 
 
1. Length of ICU stay (days) until subject is medically ready for discharge 
2. Number of hours free from ventilator use  
3. Requirement for mechanical ventilation 
4.  
5. Number of hours free from vasopressor use  
6. Changes in serum creatinine levels from baseline 
7. Requirement for renal replacement therapy (RRT) 
8. Mean volume of fluid between the two treatment groups 
9. Incidence of Major Adverse Cardiac Event (MACE) 
10. Incidence of Adverse Events (AE) 
11. Number of ICU readmissions 
12. 30 day in-hospital Mortality rate 
13. Discharge location 
14. Mean difference in fluid balance at ICU discharge 
 
 
7.4 
Study Duration 
Estimated Study Start:  
 
Q3 2016 
Estimated Enrollment Completion:  
Q2 2018 
Estimated Final Report: 
 
Q3 2018 
 
 

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
8. 
SUBJECT POPULATION AND SELECTION 
8.1 
Subject Population 
Adult subjects with the diagnosis of sepsis and refractory hypotension will be considered as a 
candidate for the study.   A maximum of 210 subjects enrolled and in the analysis population will 
be included in the study.  Subjects will be considered to be enrolled when they or their 
designated representative sign the informed consent form (ICF). 
 
Subjects who are enrolled will be assigned a subject ID.  Subjects that sign the ICF, but are 
found ineligible will be considered screen failures and will be exited from the study at that time.  
Enrolled subjects who meet study eligibility will be included in the analysis populations and are 
further described in Section 12. 
 
The diagnosis of sepsis is defined as a known or presumed infection and the presence of 2 or 
more SIRS criteria as detailed in Section 8.2. Refractory hypotension is defined as the presence 
of hypotension following initial resuscitation with 1L of fluid.  After obtaining ICF and 
confirming that the inclusion and exclusion criteria are met, the Cheetah sensors will be placed 
and connected to the Starling SV monitor.  Useable readings will be confirmed prior to initiating 
the study data collection period. 
 
A diagram outlining the overall subject enrollment plan is shown below: 
 
 
 
 
 
 
Figure 1: Subject Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF Signed 
(Subject is enrolled & 
Subject ID is assigned) 
Screen Failure 
• Subject is found ineligible after 
signing the ICF. 
• Reason for screen failure will 
be documented. 
• Subject will exit the study at 
the time they are found 
ineligible. 
 
Intent-to-Treat (ITT) 
• This population consists of all 
subjects that sign informed 
consent, meet study eligibility 
and are randomized to the 
treatment or control arm of the 
study. 
• The study is considered initiated 
in the subject following 
randomization to the treatment 
or control arm 

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
 
8.2 
Inclusion Criteria 
Subjects must meet the following inclusion criteria: 
 
1. Diagnosis of sepsis, as exhibited by 2 or more of the following SIRS criteria and a known 
or presumed infection at the time of screening: 
o Temperature of > 38 C or < 36 C 
o Heart rate of > 90/min 
o Respiratory rate of > 20/min or PaCO2 < 32 mm Hg (4.3 kPA) 
o White blood cell count > 12000/mm3 or < 4000/mm3 or >10% immature bands 
2. Refractory hypotension (either one single reading of MAP <65 exhibited during the 
evaluation period, or requiring treatment with vasopressors to maintain a MAP > 65) 
despite initial fluid resuscitation (1L of treatment fluid) 
3. Patient enrolled in study within 24 hours of arrival to the hospital 
4. Anticipated ICU admission. Patients may be maintained on another unit (such as within 
the ER or a step down unit) during the 72 hour monitoring period if the treatment 
algorithm is adhered to during this time period. 
5. Able to provide signed informed consent or consent can be obtained from the patient’s 
authorized representative 
  
8.3 
Exclusion Criteria 
Subjects must not have any of the following exclusion criteria:  
 
1. Primary diagnosis of: acute cerebral vascular event, acute coronary syndrome, acute 
pulmonary edema, status asthmaticus, major cardiac arrhythmia, drug overdose, or injury 
from burn or trauma 
2.  Known aortic insufficiency, or aortic abnormalities 
3.  Hemodynamic instability due to active hemorrhage, (e.g. gastrointestinal 
bleeding/coagulopathy/trauma) 
4. Patient has received >3 liters of IV fluid prior to study randomization 
5. Requires immediate surgery 
6. Patient transferred to the ICU from another hospital unit 
7. Do not attempt resuscitation (DNAR or DNR) order 
8. Advanced directives restricting implementation of the resuscitation protocol 
9. Contraindication to blood transfusion 
10. Attending clinician deems aggressive resuscitation unsuitable 
11. Transferred from another in-hospital setting 
12. Not able to commence treatment protocol within 1 hour after randomization  
13. Known intraventricular heart defect, such as VSD or ASD 
14. Use of additional hemodynamic monitoring involving SVV, PPV or SV changes to 
determine fluid responsiveness 
15. Seizure in the last 24 hours 
16. Prisoner 
17. Pregnancy 

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Cheetah Medical –Evaluation of fluid volume in patients with sepsis and refractory hypotension 
Clinical Protocol  
 
 
Rev. H 
 
18. Age <18 
19. Known allergy to sensor material or gel 
20. Inability or contraindication to doing a passive leg raise with both extremities, such as 
inability to interrupt venous compression boots 
21. Patient has an epidural catheter in place 
22. Suspected intra-abdominal hypertension  
23. Inability to obtain IV access 
24. Diabetic ketoacidosis 
25. Hyper-osmolarity syndrome 
26. Patient treatment uncouples from the treatment algorithm 
 
27. Patient should be excluded based on the opinion of the Clinician/Investigator 
 
 
8.4 
 Subject Screening 
All subjects diagnosed with sepsis and refractory hypotension will be considered potential 
candidates.  All subjects screened for the study will be captured on the site’s Screening Log.  The 
log will capture the subject’s gender, age, date of screening and the reason(s) for study exclusion. 
8.5 
Informed Consent Procedures 
Written informed consent on the approved IRB informed consent form must be obtained for all 
subjects who are potential study candidates before any study specific tests or procedures are 
performed.  Due to the high likelihood of the subject’s critical clinical state and therefore the 
possibility of their inability to provide informed written consent, the subject’s designated 
representative will be acceptable to provide written informed consent. 
 
The general process for obtaining informed consent shall: 
• Ensure that the principal investigator or his/her authorized designee conducts the 
informed consent process; 
• Include all aspects of the clinical investigation that are relevant to the subject's decision 
to participate throughout the clinical investigation; 
• Avoid any coercion or undue improper influence on, or inducement of, the subject to 
participate; 
• Not waive or appear to waive the subject's legal rights; 
• Use native non-technical language that is understandable to the subject; 
• Provide ample time for the subject, or designee, to read and understand the informed 
consent form and to consider participation in the clinical investigation; 
• Include personally dated signatures of the subject and the principal investigator or an 
authorized designee responsible for conducting the informed consent process; 
• Provide the subject, or designee, with a copy of the signed and dated informed consent 
form and any other written information required per Site’s Institutional Policy (i.e. 
additional HIPAA language).  
 

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8.6 
Subject Randomization 
Subjects will be randomized to either the treatment or control arm of the study once the decision 
has been made to admit the patient to the ICU. Any patients that are enrolled but are not admitted 
to the ICU, or who receive > 3L of treatment fluid prior to randomization will be considered a 
screen failure and will be exited from the study at this time. 
 
 
Subjects will be randomized in a 2:1 treatment to control ratio to increase power for sub-analysis 
by patient population. Additionally, subject randomization will be stratified to ensure even 
randomization between the three time windows of enrollment (0-6 hours, 6-12 hours, 12-24 
hours) 
 
8.7 
Subject Discontinuation/Withdrawal Criteria 
Once the subject has been enrolled in the study, she/he may withdraw her/his consent to 
participate in the study at any time without prejudice.  Participation in this clinical investigation 
is entirely voluntary.  Likewise, there may be a reason identified by the Investigator that deems 
the subject no longer suitable for the study.  In either case, the Investigator will contact Cheetah 
Medical to discuss the circumstances for discontinuation/withdrawal.  Discontinuation or 
withdrawal may occur for any of the reasons listed below (this list is not all inclusive).   
 
1. Subject is uncooperative with compliance of required study tests and/or medical 
management  
2. Investigator determines that subject has developed a condition in which continued 
participation in the study is considered potentially harmful to the subject 
3. Subject withdraws their consent 
4. Adverse event which is considered intolerable by the patient, their LAR of the Principal 
Investigator  
5. Subject has a significant protocol violation 
6. Subject incorrectly enrolled in the study 
7. Cheetah Medical terminates the study 
 
8.7.1 Subjects Lost to Follow-Up 
Subjects may be considered lost to follow-up for the following reasons: 
• During data analysis, data indicates there is unacceptable bias in the measurements 
• Data collection is interrupted prior to  72 hour data collection period of ICU stay 
• Severe agitation and/or cardiopulmonary resuscitations resulted in poor quality data 
9. 
STUDY PROCEDURES 
9.1 
Baseline Assessments 
After written informed consent is obtained, baseline assessments will be made to further 
determine the subject’s eligibility for the study.  Data collected will include: 
• Demographics 
• Age 
• Medical history 

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• SOFA assessment 
• Physical exam, limited 
• Hemoglobin and blood gas (per chart review, if available) 
• Serum creatinine level 
• Lactate level (per chart review, if available) 
• Urine sample (to be frozen for possible future testing) 
• Optional plasma serum collection (two, 5ml samples to be frozen for possible future 
testing) 
• Current medications 
9.2 
Enrollment Procedure 
Assuming the subject meets all study eligibility criteria, the investigator, or designees, will place 
the Cheetah device (Starling SV) on the subject. The device will be evaluated for obtaining the 
optimum expected hemodynamic readings before the study is begun according to the Starling SV 
Instructions for Use (IFU).  This is done to confirm that data collected from the monitoring 
devices will be evaluable.   It is recommended that approximately 15-20 minutes are allowed for 
the device to autocalibrate and achieve a stable baseline prior to beginning any measurements at 
the initiation of the study. 
 
If the Starling SV does not provide the expected hemodynamic recordings, it will be adjusted or 
replaced as needed until it provides the expected recordings.  If it is determined that the device 
will not provide the expected recording, then the subject will be withdrawn from the study.  
9.3 
Data Collection Procedure 
When the Starling SV is determined to be providing the expected waveforms and recordings, the 
study device data collection period will begin.  Recorded information will be collected and 
stored by the device. After the data collection period has ended the data will be downloaded and 
used for analysis. 
 
9.3.1 Hemodynamic Collection Methods 
 
Starling SV: Following the Instructions for Use, the Starling SV device will be 
connected to the subject by placing four of the system’s sensors on the subject’s chest: 
left and right mid-clavicle and left and right mid-last ribs.  The device will undergo 1 
minute of autocalibration after which measurements will begin to be obtained.  Data from 
the device is available as a visible read-out on the monitor screen and stored internally. 
At the conclusion of the data collection period, the data will be downloaded and provided 
to the sponsor or designee.   
 
9.3.2 Fluid Assessment 
A fluid assessment will be initiated at the following time points: 
• Baseline (at study enrollment) 
• At every clinical decision point for the first 72 hours of study enrollment. Examples of a 
clinical decision point include the decision to give additional fluid volume, or  escalate 
vasopressors.  

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resolution, and assessment of both the seriousness and the relationship to the investigational 
device.   
 
The following criteria must also be adhered to by the Investigator: 
• Completion of separate device related Adverse Event forms to document each event 
• The forms must be signed by the Investigator, and 
• Supplying to the Sponsor (or designee), upon Sponsor’s request, with any additional 
information related to the safety reporting of a particular event 
 
10.2.2 Reporting Requirements of SAEs 
All serious adverse events must be reported by the investigator by submitting the Adverse Event 
eCRF within 24 hours of learning of the adverse event.     
 
The Investigator shall: 
a) Report to the IRB serious adverse events per the institutional requirements for timing and 
amount of support information, 
b) Supply the Sponsor (or designee), upon Sponsor’s request, with any additional 
information related to the safety reporting of a particular event. 
 
10.2.3 Sponsor Reporting 
All adverse events will be reported to the applicable regulatory authority as required per 
applicable regulatory authority. 
 
Cheetah Medical, or their designee is responsible for the classification and reporting of adverse 
events and applicable regulatory requirements.  
 
11. 
STUDY MONITORING 
The study will be monitored according to Cheetah Medical’s monitoring procedures. A study 
specific monitoring plan will be developed to ensure protocol compliance and applicable 
regulatory requirements.  
 
Clinical monitors will be designated by Cheetah Medical. Monitors will verify subject data and 
ensure compliance with GCP, clinical protocol and other study requirements to be utilized for the 
study.  
11.1 Monitor Training 
All Cheetah Medical designated monitors will be trained appropriately to monitor study progress 
including but not limited to the protocol and CRFs. 
11.2 Site/Investigator Training 
Cheetah Medical will be responsible for providing training to the investigator and appropriate 
clinical site personnel.    
 

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11.2.1 Protocol Training 
Training on study protocol requirements will be provided for the entire study team at the 
initiation of the study.  It is ultimately the responsibility of the Investigator to ensure all clinical 
site personnel participating in this study are adequately trained. 
 
To ensure uniform data collection and protocol compliance, Cheetah Medical and/or designee 
will perform study initiation visits to review the clinical protocol, techniques for the 
identification of eligible subjects, instructions on in-hospital data collection, and methods for 
soliciting data from alternative sources. 
 
11.2.2 Device Training 
This procedure may only be performed by qualified investigators, familiar with the Cheetah 
Medical system. Training on the Starling SV system will be performed and documented for the 
site Investigator who is responsible for using the device, by the study Sponsor, Cheetah Medical.  
11.3 Site Monitoring 
The Sponsor or designee may conduct periodic compliance assessments at various study sites.  
The Sponsor or designee may request access to all study records including source documentation 
for inspection and photocopying during a compliance assessment.  The Investigator and research 
coordinator must be available to respond to reasonable requests and queries made during the 
compliance assessment process. 
11.4 Regulatory Agency Inspection 
In the event that an investigator is contacted by a regulatory agency regarding this study, the 
investigator will notify the Sponsor or its designee immediately.  The investigator and research 
coordinator must be available to respond to reasonable requests and queries made during the 
inspection process.  The investigator must provide the Sponsor or designee with copies of all 
correspondence that may affect review of the current trial.  The Sponsor may provide needed 
assistance in responding to regulatory audits. 
 
 
12. 
STATISTICAL CONSIDERATIONS  
 
12.1  Sample Size Estimation 
Subjects will be randomly assigned in a 2:1 ratio to treatment with Starling SV or to treatment 
with standard of care. The primary effectiveness endpoint for this study is the difference between 
the two treatment groups in mean fluid balance at ICU discharge. 
 
Minimum enrollment (Nmin) in the study will be set at 120 subjects (80 Starling SV and 40 
control) to power at 80% for possible demonstration of superiority for the secondary endpoint of 
creatinine levels as a measurement of change from baseline. The secondary endpoint for change 
in creatinine levels at 120 evaluable subjects displays 80% power at a two-sided alpha level of 

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Rev. H 
 
0.05 to demonstrate superiority under an assumption of a treatment effect of -1.4 mg/dL with a 
standard deviation of 2.5 mg/dL. 
 
Under an assumption of a treatment effect of -2 L with a standard deviation of 3 L, the sample 
size of 120 evaluable subjects provides 92.7% power in a test of superiority for the primary 
effectiveness endpoint. 
 
The trial will incorporate a sample size re-estimation (SSR) at the time of the interim look based 
on promise for superiority in the key secondary endpoint. Methods for the SSR have been 
described in detail in previous literature. The maximum enrollment being considered for this trial 
is 210 total enrolled (Nmax = 1.75 times Nmin). 
 
An interim analysis incorporating a SSR will take place when 120 subjects have been enrolled 
and completed endpoint evaluations. The interim analysis will be performed by an independent 
statistician. It is assumed that the acute endpoint assessments will be fully informed at the time 
of the interim analysis.  
 
At this point, the primary study endpoint will be tested as final, and will not incorporate an alpha 
spend.  
The conditional power to claim superiority (CPsup) on the key secondary endpoint for change in 
creatinine levels will be computed. The conditional power (CPsup) will be calculated based on the 
interim results of the key secondary endpoint, with the specific interest of demonstrating 
superiority. CPsup is defined as the approach that quantifies the statistical power to yield an 
answer different from that seen at the interim analysis. The data will be partitioned into three 
zones based on CPsup unfavorable zone (CPsup<50%), promising zone (50%≤CPsup<80%), and 
favorable zone (CPsup≥80%).  
 
12.2 Analysis Populations 
 
12.2.1 All Enrolled 
Any subject who has signed informed consent will be included in the all enrolled population.  
Should a subject be considered a screen failure, the reason for failure will be documented, and 
the subject will be exited from the study.  Adverse events will be reported for all enrolled 
subjects through the time of study exit. 
 
12.2.2 Intent-to-Treat (ITT) 
The intent-to-treat population (ITT) will consist of any subjects that have signed the ICF, meet 
study eligibility criteria, and are randomized to the treatment or control arm of the study.  
 
12.2.3 Modified Intent-to-Treat (mITT) 
Subjects will be included in the Modified Intent-to-Treat group if they sign the ICF, meet study 
eligibility criteria, are randomized, and in the treatment group receive monitoring for the first 72 
hours of study enrollment or until ICU discharge, whichever occurs first. The mITT population 
represents the Primary and Secondary Analysis population for this study. 
 

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12.2.4 Per-Protocol (PP) 
Subjects will be included in the Per-protocol group if they sign the ICF, are randomized and have 
the assigned procedure completed, meet critical study eligibility criteria and have no major protocol 
deviations (defined in the Statistical Analysis Plan), and, in the treatment group, receive 
monitoring for the first 72 hours of study enrollment. The PP population represents a subgroup 
analysis population for this study. 
 
 
12.3 Primary Endpoint Analysis 
The primary endpoint is an evaluation of the difference between the two treatment groups in 
mean fluid balance (L) at 72 hours or ICU discharge, whichever occurs first. The following 
hypothesis will be tested: 
 
Ho: μc - μT = 0 
Ha: μc - μT ≠ 0 
 
where μt and μc is the average fluid balance  in the Starling SV and control groups, respectively. 
Statistical summaries will include means, medians, and standard deviation, as well as 95% 
confidence intervals. A t-test for superiority at a significance level of 0.025 will be performed to 
test the hypothesis that μt is significantly less than μc. If it can be established that the difference 
is greater than 0 points (i.e. μC > μT), superiority will also be claimed. 
 
12.4 Secondary and Exploratory Endpoints 
Secondary objectives that have been pre-specified to be included in the formal statistical analysis 
will be tested in sequential fashion using the Holms step-down procedure for type-I error rate 
correction if and only if the primary objective passes according to the criteria outlined above. At 
the conclusion of the trial, the key secondary endpoints will be ordered sequentially from most 
significant to least significant. The endpoints will then be tested in order at adjusted levels of 
significance (i.e. E1: 0.05/k, E2: 0.05/k-1; E3: 0.05/k-2, where k=number of specified 
endpoints). Once an endpoint fails, all following endpoints will not be tested. Following is a list 
of key secondary endpoints: 
 
Following is a list of key secondary endpoints for formal testing: 
 
• Length of ICU stay (days) until subject is medically ready for discharge 
• Number of days free from ventilator use (30 day period) 
• Requirement for mechanical ventilation 
• Number of days free from vasopressor use  
• Changes in serum creatinine levels from baseline 
• Requirement for renal replacement therapy (RRT) 
 
Additional secondary endpoint have also been identified for testing, but will not be included in 
the formal statistical testing procedures for key secondary endpoints: 
 
• Incidence of Adverse Events (AE) 

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• Number of ICU readmissions 
• Mortality rate 
• Mean volume of treatment fluid 
• Incidence of Major Adverse Cardiac Event (MACE) 
• Discharge location 
• Mean difference in fluid balance at ICU discharge 
 
 
Additional sub-analyses have been planned for the primary and key secondary endpoints. 
Primary and secondary endpoints will also be evaluated by the following subgroup analysis:  
• Patient disease state 
• Patients determined to be fluid responsive vs non-fluid responsive 
• AKI measures in patients determined to increase serum creatinine levels from baseline vs 
decrease serum creatinine levels from baseline 
• Enrollment time frame 
 
12.5 Baseline Data Summary  
Baseline data including subject demographics, clinical history, risk factors, and pre-procedure 
patient characteristics will be summarized using descriptive statistics (e.g., mean, median, 
standard deviation, 25th percentile, 75th percentile, minimum and maximum) for continuous 
variables and frequency tables or percentages for categorical variables. 
 
12.6 Subject Accountability and Missing Data 
Subjects enrolled in this study are followed for a short time period, and missing data in this study 
is expected to occur at a low rate.  All efforts will be used to prevent missing data.  These efforts 
include, but are not limited to, complete site training and regular monitoring to help to minimize 
missing data. 
 
Subjects without the minimum amount of monitoring [i.e. throughout first 72 hours of study 
enrollment,] and measurements specified in the protocol will be considered as missing in the 
final analysis.  The impact of missing data on the study will be evaluated via sensitivity analyses 
if more than 5% of subjects do not have evaluable data for the primary outcome.  In the final 
report, the number and proportion of subjects eligible for and compliant with each analysis 
population will be presented. 
13. 
DATA HANDLING AND RECORD KEEPING 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with regulatory and institutional requirements for the protection of confidentiality of 
subjects.  As part of participating in a manufacturer-sponsored study, each site will permit 
authorized representatives of the Sponsor(s), the Sponsor’s designee, and regulatory agencies to 
examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits, and evaluation of the study safety and progress. 
 
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 trial. 

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13.1 Clinical Data Collection 
Electronic Case Report Forms (eCRFs) will be used to collect all subject data during the course 
of the study and will be entered into an electronic database. eCRFs must be fully completed for 
each subject and signed by the Investigator when complete. 
 
Good Clinical Practice Guidelines require that Investigators maintain information in the study 
subject’s medical records that corroborate data collected on the eCRFs.  In order to comply with 
these regulatory requirements, the following information should be maintained: 
 
• Medical history/physical condition of the study subject before involvement in the study 
sufficient to verify protocol entry criteria. 
• Dated and signed notes on the day of entry into the study including the study investigator, 
study name, subject number assigned and a statement that consent was obtained. 
• Dated and signed notes from each study subject visit with reference to the eCRFs for 
further information, if appropriate (for specific results of procedures and exams). 
• Information related to adverse events. 
• Study subject’s condition upon completion of or withdrawal from the study. 
• Discharge summaries/procedure reports. 
13.2 Data Reporting 
All site Investigators or designated individuals shall be responsible for recording all study data 
on the eCRFs.  The Investigator is required to electronically sign the eCRFs to verify that he/she 
has reviewed and agrees with the recorded data. All protocol deviations shall be documented and 
a justification for any missed assessments shall be provided on the Protocol Deviation eCRF. 
 
Completed eCRFs will be verified by the monitor at the investigational sites or by remote 
monitoring as at regular intervals throughout the study, as outlined in the Monitoring Plan.  The 
Investigator will allow the monitor and/or representative of the Sponsor, and any regulatory body 
to review and inspect the study files, subject eCRFs, subject medical records and other related 
study documents as required. 
 
13.3 Data Review 
eCRFs will be reviewed for completeness and clarity.  Missing or unclear data will be 
investigated by the monitor and will be retrieved, clarified and entered by study personnel as 
necessary throughout the study.  Cheetah Medical, or designee, may request additional 
documentation from the Investigator such as physician notes or physician written summaries 
when adverse events are observed and reported.  Documentation provided will also be used for 
the adjudication of specified adverse events by the Independent Safety Physician. 
 
Development of the data collection system for the study will be performed by Cheetah Medical, 
or designee.  Cheetah Medical, or designee will also be responsible for the quality control of the 
database and confirming the overall integrity of the data. 
13.4 Investigator Records 

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Rev. H 
 
Investigators will maintain complete, accurate and current study records.  The following records 
must be maintained in designated study files: 
 
• Clinical protocol and all amendments 
• Signed Clinical Trial Research Agreement 
• Institutional Review Board (IRB) Approval Letter(s)  
• IRB approved informed consent(s) (including any revisions)  
• CV for all Investigators, signed and dated 
• Investigator(s) medical license  
• Financial Disclosure Form for all Investigators 
• Correspondence relating to this study 
• Correspondence with the IRB 
• IRB membership list and/or assurance number  
• Delegation of Authority log 
• Device Instructions for Use 
• Printed copy of blank set of CRFs  
• Subject Log 
• Site Visit Log (e.g. for Monitor sign-in) 
• Site Training records 
• Investigational Device Accountability Logs   
• Reports (includes Adverse Event reports and final reports from Investigator and 
Sponsor) 
• Copy of all IRB approved subject-related materials and/or study advertising materials 
 
The following records must be maintained for each subject enrolled in the study: 
• Signed subject consent forms 
• Copy of final completed CRFs  
• Record of any adverse events with supporting documentation 
• Reports, progress notes, physician and/or nursing notes, and subject office files 
• Records pertaining to subject deaths throughout the course of the study  
 
13.5 Data Retention 
Study documents should be retained for a minimum of 5 years.  These documents should be 
retained for a longer period, however, if required by local regulations.  No records will be 
destroyed without the written consent of the Sponsor, if applicable.  It is the responsibility of the 
Sponsor to inform the Investigator when these documents no longer need to be retained. 
 
 

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Rev. H 
 
emergency circumstances, deviations from the protocol to protect the rights, safety and well-
being of human subjects may proceed without prior approval of the Sponsor and the IRB. 
 
A protocol deviation is a failure to comply with the requirements specified within this clinical 
study protocol.  Examples of protocol deviations may include enrollment of a study subject who 
does not meet all of the inclusion/exclusion criteria specified in the protocol and missed study 
visits without documentation.  Each investigator shall conduct this clinical study in accordance 
with this clinical study protocol, regulatory body regulations, Good Clinical Practices. 
 
All deviations are reviewed and assessed for their impact on subject safety by the Sponsor or 
designee.  The PI and study staff is responsible for knowing and adhering to their IRB reporting 
requirements. 
 
The protocol deviations for this protocol consist of, but not limited to the following: 
• Failure to obtain subject’s informed consent prior to any study-related activities; 
• Subject did not meet the inclusion and/or exclusion criteria and were enrolled; 
• Failure to conduct protocol required clinical test or assessment; 
• Failure to complete protocol required assessments within the required time frame 
• Failure to report serious adverse events according to protocol requirements. 
 
In the event of any deviation from the protocol, the Investigator will be notified of the site’s non-
compliance.  Corrective actions will be required, if necessary.  Continued protocol deviations 
despite re-education of the study site personnel or persistent protocol deviation may result in 
termination of the site’s study participation.  Subjects enrolled at these sites will continue to be 
followed per the clinical protocol. 
 
14.2.1 Protocol Deviation Process 
Investigators must report protocol deviations to the Sponsor within 5 working days of 
investigational site knowledge of the deviation by entering data into the eCRF.  Any protocol 
deviations that affect the rights, safety or well-being of the subject or the scientific integrity of 
the clinical investigation, including those which occur under emergency circumstances must be 
reported within 24 hours to the Sponsor and IRB, if required by the IRB, or national regulations. 
14.3 Corrective/Preventive Action 
Deviations from clinical protocol requirements will be reviewed and evaluated on an ongoing 
basis and, as necessary, appropriate corrective actions will be put into place to bring a site into 
compliance. 
14.4 Study Audit(s) 
Audits may be performed as deemed necessary by Cheetah Medical, in a manner consistent with 
applicable procedure. 
14.5 Study Registration 
A description of this trial will be available on www.clinicaltrials.gov, the U.S. approved clinical 
trial registry site.  

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Rev. H 
 
 
15. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
15.1 Statements of Compliance 
This study will be performed in accordance with Good Clinical Practice Guidelines, the Code of 
Federal Regulations Title 21 CFR Parts 50, 54, and 56. 
 
The clinical investigation shall not begin until the required approval/favorable opinion from the 
Institutional Review Board (IRB) has been obtained including approval of the Informed Consent 
Form to be used with subjects. 
 
Any additional requirements imposed by the IRB shall be followed. 
15.2 Institutional Review Board  
Each participating institution must provide for the review and approval of this protocol and the 
associated informed consent documents by an appropriate Institutional Review Board (IRB) 
prior to subject enrollment.  Any amendments to the protocol or changes to the informed consent 
document must also be approved before they are placed into use.  The Investigator should notify 
the IRB of deviations from the protocol and SAEs occurring at the site in accordance with local 
procedures.  The Investigator is responsible for continued study related communication with the 
IRB, including submission of study report and SAE notifications as per local regulatory 
requirements. 
15.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation.  Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects (and their families, as 
applicable).  Consent forms describing in detail the study interventions/ products, study 
procedures, and risks are given to the subject and written documentation of informed consent is 
required prior to starting any study-specific tests or intervention /administering of study product.   
 
Consent forms will be approved by the IRB and the subject will be asked to read and review the 
document.  Upon reviewing the document, the site investigator or designated study personnel 
will explain the research study to the subject and answer any questions that may arise.  The 
subject (or their authorized legal representative) will sign the informed consent document prior 
to any procedures being done specifically for the study.  The subject should have the opportunity 
to discuss the study with their surrogates or think about it prior to agreeing to participate, unless 
study timeframes do not allow for such discussions.  The subjects may withdraw consent at any 
time throughout the course of the trial.  A copy of the informed consent document will be given 
to the subjects for their records.  The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
 
Modifications to the study informed consent must have approval from the Sponsor and the EC as 
required. 

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15.4 Subject Confidentiality 
Confidentiality of data shall be observed by all parties involved at all times throughout the 
clinical investigation. All data shall be secured against unauthorized access.  Sites will maintain 
subject privacy in accordance with local and national regulations and institutional requirements 
including all applicable provisions of the Health Insurance Portability and Accountability Act 
(HIPAA) and its current regulations. 
 
Subjects must be identified only by their assigned study number and initials on all CRFs and 
other records and documents submitted to the Sponsor, the monitor, and other authorized parties. 
The Investigator should maintain a Subject Identification List with complete identification 
information (name, address, contact number, informed consent version number) on each subject. 
Documents not required to be submitted to the Sponsor such as subject written informed consent 
form, should be maintained by the Investigator in strict confidence.  
 
The privacy of each subject and confidentiality of his/her information shall be preserved in 
reports and when publishing any data.  The principal investigator or institution shall provide 
direct access to source data during and after the clinical investigation for monitoring, audits, IRB 
review and regulatory authority inspections. As required, the principal investigator or institution 
shall obtain permission for direct access to source documents from the subject, hospital 
administration and national regulatory authorities before starting the clinical investigation. 
 
16. 
PROTOCOL AMENDMENTS 
The clinical protocol, eCRFs, ICF and other subject information, or other clinical investigation 
documents shall be amended as needed throughout the clinical investigation, and a justification 
statement shall be included with each amended section of a document.  Proposed amendments to 
the protocol shall be agreed upon between the Sponsor and Principal Investigator, or the 
Coordinating Investigator.  The amendments to the protocol and the subject's informed consent 
form shall be notified to, or approved by, the IRB as required.  For non-substantial changes [e.g. 
minor logistical or administrative changes, change of monitor(s), telephone numbers, renewal of 
insurance] not affecting the rights, safety and well-being of human subjects or not related to the 
clinical investigation objectives or endpoints, a simple notification to the IRB can be sufficient.  
The version number and date of amendments shall be documented. 
 
17. 
TERMINATION OF STUDY OR STUDY SITE PARTICIPATION 
The Sponsor may terminate the study at any time.  If the study is terminated prior to the 
completion of expected enrollment for any reason, all participating centers will be notified within 
five working days.  All subjects already enrolled will continue to be followed for the planned 
course of study described in this protocol.  The study shall be terminated following the last 
enrolled subject. 
 

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Rev. H 
 
The Sponsor reserves the right to terminate study site participation and remove appropriate study 
materials at any time.  Specific instances that may precipitate such termination include but are 
not limited to the following: 
• Failure to meet minimum subject enrollment requirements 
• Failure to comply with protocol specified procedures and documentation 
• Failure to comply with regulatory regulations 
• Failure to comply with Good Clinical Practice 
 
The site Investigator may also discontinue study participation with suitable written notice to the 
Sponsor. 
 
18. 
PUBLICATION POLICY 
Specifics of the publication policy will be outlined in the Clinical Trial Research Agreement. 
 
 
 

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Rev. H 
 
19. 
BIBLIOGRAPHY 
 
1. Marik P and Cavallazzi R. Does central venous pressure predict fluid responsiveness? An 
updated meta-analysis and a plea for some common sense. Crit Care Med 2013; 41: 
1774-1778. 
 
2. Michard F and Teboul JL. Predicting fluid responsiveness in ICU patients: a critical 
analysis of the evidence. Chest. 2002; 121:2000-2008. 
 
3. Kelm DJ, et al. Fluid overload in patients with severe sepsis and septic shock treated with 
early goal-directed therapy is associated with increased acute need for fluid-related 
medical interventions and hospital death. Shock 2015; 43:68-73. 
 
4. Boyd et al. Vasopressin in Septic Shock Trial (VASST). Critical Care Medicine 2011; 
39:259-265. 
 
5. Vincent et al. Sepsis in European ICU: Results of the SOAP study. British Journal of 
Anesthesia 2006; 113: 740-747. 
 
6. Monnet X, Teboul JL. Passive leg raising. Intensive Care Med 2008, 34: 659-63. 
 
 

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CONFIDENTIAL 
 
Rev. H 
 
APPENDIX A- TREATMENT ALGORITHM