Evaluation of Impacts of Continuous Non-Invasive Intra-Operative Hemoglobin and PVI Monitoring on Intra-Operative and Post-Surgical Clinical Outcomes
Conditions: Surgery
Sponsor: Masimo Corporation

 
 
 
 
Official Title: Evaluation of Impacts of 
Continuous Non-Invasive Intra-Operative 
Hemoglobin and RPVi Monitoring on Intra-
Operative and Post-Surgical Clinical Outcomes 
 
Date of Protocol: 21 February 2017 
 
NCT Number:   
NCT02986789   

CLINICAL INVESTIGATION PLAN 
BIGT0001 
Evaluation of Impacts of Continuous Non-Invasive Intra-Operative 
Hemoglobin and RPVi Monitoring on Intra-Operative and Post-Surgical 
Clinical Outcomes 
Version: 2.0 
 
CONFIDENTIAL AND PROPRIETARY   
© 2021 Masimo Corporation (Unpublished) 
All Rights Reserved 
Page 1 of 45 
 
Evaluation of Impacts of Continuous Non-Invasive Intra-Operative 
Hemoglobin and RPVi Monitoring on Intra-Operative and Post-Surgical 
Clinical Outcomes 
 
 
Sponsor: 
Masimo 
52 Discovery 
Irvine, California 92618 
 
 
Lead Principal Investigator: 
Michael A.E. Ramsay, MD, FRCA 
 
Principal Investigators: 
Richard L. Applegate II, MD 
Maxime Cannesson, MD, PhD 
Davinder Ramsingh, MD 
Christer Svensén, MD, PhD 
Klaus D. Torp, MD 
 
Study Devices: 
Masimo rainbow® SET Radical-7® pulse CO-oximeter with In Vivo SpHb 
and RPVi features 
  Masimo RootTM Patient Monitoring and Connectivity Platform 
Masimo rainbow® SET pulse CO-oximetry sensors and accessories 
 
Sponsor Protocol Number: 
BIGT0001 
 
 
ClinicalTrials.gov NCT#: 
02986789 
 
 
 
 
 
 
 
Principal Investigator 
 
 
 
Title 
 
 
Signature 
Date 
Sponsor 
 
Vikram Ramakanth 
Title 
 
Director, Clinical Research 
Signature 
Date 

Evaluation of Impacts of Continuous Non-Invasive Intra-operative Hemoglobin and RPVi 
Monitoring on Intra-operative and Post-Surgical Clinical Outcomes  
BIGT0001 version 2 
 
CONFIDENTIAL AND PROPRIETARY   
© 2021 Masimo Corporation (Unpublished) 
All Rights Reserved 
 
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1 
INTRODUCTION 
This document is a clinical investigation plan (CIP) for a clinical research study sponsored by Masimo 
Corporation. The study will be conducted in compliance with all stipulations of this plan, the conditions of IRB 
approval, ISO-14155 and International Conference on Harmonization Good Clinical Practice guidelines ICH E6 
GCP. 
1.1 
Background and Rationale 
Acute and chronic anemia are associated with increased perioperative morbidity and mortality [1-3] Preoperative 
anemia is reported in many patients scheduled for surgery, with a greater prevalence in older and hospitalized 
patients.[4] However, transfusion of red blood cells is also associated with morbidity and mortality.[2,5] Evidence 
based transfusion guidelines are promoted to decrease unnecessary transfusion.[6,7]  
Blood management programs are designed to improve patient outcome through preoperative anemia treatment, 
use of agents that improve hemostasis or clot stability, employing alternatives to transfusion of banked red blood 
cells, and making individual patient-specific transfusion decisions.[8,9] Despite these programs transfusions are 
sometimes administered to patients when hemoglobin (Hb) has not decreased to a specified minimum acceptable 
range (inappropriate transfusion) or is continued after this has increased above the specified target range 
(excessive transfusion).[10-15] Shander and colleagues estimated that up to two-thirds of transfusions given to 
surgical patients considered inappropriate in one study.[16]  
Red blood cell transfusion is a specific treatment for perioperative anemia or surgical blood loss that is 
administered when clinicians judge the benefit to outweigh associated risks [8, 11, 17]. Transfusion decision-
making is guided by Hb measurements which are often invasive and intermittent, as well as observed bleeding in 
the setting of hemodynamic instability. Intermittent Hb measurement can be by blood sample analysis using 
clinical laboratory hematology analyzers (tHb). In patients undergoing procedures in which blood loss is likely, or 
ongoing blood loss is not obvious, intermittent Hb measurement can lag the clinical situation. This lag can be 
increased by long test turn-around time. A real-time and continuous monitor of Hb concentration could provide 
clinically useful information during surgery in which blood loss is likely or cannot be easily detected. Intravenous 
fluid is very important to improve hemodynamics of perioperative and critically ill patients. Before fluid infusion, 
evaluating volume status by monitoring some objective indicators to predict fluid responsiveness can ensure the 
fluid therapy reasonable and effective, avoiding excessive fluid infusion. Assessment of fluid responsiveness, 
described as the ability of the circulation to increase cardiac output in response to volume expansion, is essential 
to guide fluid therapy and optimize preload. 
Multi-wavelength pulse co-oximetry is an advanced design pulse oximeter that reports oxygen saturation (SpO2) 
and uses multiple light wavelengths to additionally determine carboxyhemoglobin, methemoglobin, total 
hemoglobin (SpHb) in addition to Pleth Variability Index (PVi). Continuous trend monitoring of hemoglobin 
could be more useful than absolute values to clinicians caring for patients who are at risk for blood loss if changes 
in SpHb accurately reflect tHb changes. To date, this hypothesis has not been formally tested. 
Dynamic indicators relying on cardiopulmonary interactions in mechanically ventilated patients, such as pulse 
pressure variation (PPV), systolic pressure variation, and stroke volume variation (SVV), consistently have been 
shown to be more accurate than static indicators in predicting fluid or preload responsiveness [18–22]. More 
recently, interest has focused on the availability of pleth variability index (PVi), which is a dynamic variable that 
automatically and continuously measures the respiratory variations in the pulse oximeter waveform amplitude 
[23]. 

Evaluation of Impacts of Continuous Non-Invasive Intra-operative Hemoglobin and RPVi 
Monitoring on Intra-operative and Post-Surgical Clinical Outcomes  
BIGT0001 version 2 
 
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PVi has also been suggested to be an effective dynamic indicator of fluid responsiveness and is used in many 
institutions. Recently, Masimo has created a new parameter called RPVi, which is the next generation of the 
currently available PVi parameter. RPVi is a multi-wavelength version of PVi powered by rainbow® technology. 
Compared to PVi, RPVi may provide enhanced specificity to changes in fluid volume, a reduction in variability 
under certain conditions, and fewer post-dropout spikes. Different from other invasive dynamic indices, PVi 
provides clinicians with a numerical value noninvasively, automatically, and continuously [24, 25, 26]. Similar to 
PVi, RPVi is calculated on the basis of perfusion index (PI). The PI value is generated by pulse oximetry and the 
scale of absorption of red and infrared light. Division of pulsatile fraction (AC, caused by blood flow) and non-
pulsatile fraction (DC, effected by skin and other tissues) of the red and infrared light is summarized by the 
following formula: 
                 PI = (AC/DC) x 100(%).  
RPVi reflects measurements of ventilation induced respiratory changes in PI over a constant period of time and is 
calculated as follows: 
                RPVi = [(PImax - PImin)/PImax] x 100(%) [27]. 
Additionally, the combination of RPVi and SpHb as part of a widely used Pulse CO-Oximeter provides a great 
opportunity to continuously optimize for both fluids and blood products provided together instead of 
independently. This may provide the means for mitigating anemia due to fluid overload, thereby providing the 
benefits of reduced transfusion in addition to the benefits of optimal fluid managements like Length of Stay 
(LOS) in the hospital etc. [28]. Hospitals may be able to benefit from quantifiable economic savings and enhanced 
safety standards. Clinicians may be able to benefit from a real-time feedback for total hemoglobin and fluid 
information. Patients may be able to benefit from the potential reduction of risk associated with excessive blood 
transfusions.  
2 
STUDY DEVICE 
2.1 
Study Devices 
 
Masimo rainbow® SET Radical-7® pulse CO-oximeter monitoring device (Radical-7®) with rainbow® 
parameters, including total hemoglobin concentration (SpHb) with In Vivo adjustment, and pleth 
variability index (RPVi).  
 
Masimo RootTM patient monitoring and connectivity platform.  
 
Masimo rainbow® pulse CO-oximetry sensors and accessories. 
The Masimo devices are designed as an integrated system to provide real-time, continuous monitoring of subjects 
during the study. The Masimo rainbow® pulse CO-oximetry sensor is placed onto the subject during data 
collection. The sensor uses a multi-wavelength light-emitting diode (LED) to pass light through the subject’s 
fingertip to the detector on the other side of the fingertip. Signal data are obtained by passing various visible and 
infrared lights through a capillary bed and measuring changes in light absorption during blood pulsatile cycles. 
The detector receives the light, converts it into an electronic signal and sends it to the Masimo Radical-7 pulse 
CO-oximeter monitoring device for calculation.  
Once the Masimo Radical-7 device receives the signal from the sensor, it utilizes proprietary algorithms to 
calculate various parameters that reflect the subject’s physical state. These parameters include functional oxygen 
saturation of arterial hemoglobin (SpO2), pulse rate, perfusion index (PI), carboxyhemoglobin saturation (SpCO), 
methemoglobin saturation (SpMet), total hemoglobin concentration (SpHb), respiratory rate (RRa), pleth 

Evaluation of Impacts of Continuous Non-Invasive Intra-operative Hemoglobin and RPVi 
Monitoring on Intra-operative and Post-Surgical Clinical Outcomes  
BIGT0001 version 2 
 
CONFIDENTIAL AND PROPRIETARY   
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All Rights Reserved 
 
Page 5 of 45 
 
 
variability index (PVi), and/or RPVi. SpHb with In Vivo adjustment and RPVi are investigational features 
currently not cleared by the FDA.  
The Masimo Radical-7 docks to the Masimo Root Patient Monitoring and Connectivity Platform. The Masimo 
Root acts as a display monitor and charging station for the Masimo Radical-7 Pulse CO-Oximeter.  
The study devices are FDA-cleared Masimo devices that have been modified to include features not cleared by 
the FDA, rendering the devices as investigational devices.  Refer to Table 1 for a summary of study devices. 
2.1.1 
Description of Investigational Features  
2.1.1.1 SpHb with In Vivo Adjustment  
In certain situations, there could be individual differences between the SpHb value and a laboratory hemoglobin 
measurement.  These discrepancies may be due to sensor placement, anatomical variability, and/or measurement 
methodology of the lab device.  The In Vivo Adjustment feature lets clinicians manually adjust the device’s SpHb 
reading to match that of a corresponding laboratory reference. This feature is CE marked in the European Union.  
2.1.1.2 RPVi  
RPVi is a noninvasive and continuous measurement of the dynamic changes in perfusion index (PI) that occur 
during one or more respiratory cycles. RPVi is designed to show changes that reflect physiologic factors such as 
vascular tone, circulating blood volume, and intrathoracic pressure excursions. RPVi is a multi-wavelength 
version of the currently available Pleth Variability Index (PVi). RPVi is designed to provide enhanced specificity 
to changes in fluid volume compared to PVi.  The RPVi feature is CE marked in the European Union.   
Similar to PVi, RPVi is calculated on the basis of perfusion index (PI). The PI value is generated by pulse 
oximetry and the scale of absorption of red and infrared light. Division of pulsatile fraction (AC, caused by blood 
flow) and non-pulsatile fraction (DC, effected by skin and other tissues) of the red and infrared light is 
summarized by the following formula:  
                 PI = (AC/DC) x 100(%).  
RPVi reflects measurements of ventilation induced respiratory changes in PI over a constant period of time and is 
calculated as follows: 
                RPVi = [(PImax - PImin)/PImax] x 100(%) [27]. 
2.1.2 
Intended use of the Investigational Devices  
The investigational devices are intended to be used for monitoring in accordance with K110028 (Radical-7), 
K142394 (Root), and K081659 (rainbow SET sensors). The cleared devices have been modified to include the 
following non-cleared software measurements/functions for the IDE study. These measurements/functions are: 
 
Noninvasive total hemoglobin (SpHb with In Vivo adjustment), and  
 
Pleth variability index (RPVi) FDA-cleared indications.   
The Root with Radical 7 Pulse CO-Oximeter and accessories are indicated for the continuous non-invasive 
monitoring of functional oxygen saturation of arterial hemoglobin (SpO2), pulse rate, carboxyhemoglobin 
saturation (SpCO), methemoglobin saturation (SpMet), total hemoglobin concentration (SpHb), and/or respiratory 
rate (RRa). The Root with Radical 7 Pulse CO-Oximeter and accessories are indicated for use with adult, 

Evaluation of Impacts of Continuous Non-Invasive Intra-operative Hemoglobin and RPVi 
Monitoring on Intra-operative and Post-Surgical Clinical Outcomes  
BIGT0001 version 2 
 
CONFIDENTIAL AND PROPRIETARY   
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All Rights Reserved 
 
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pediatric, and neonatal patients during both no motion and motion conditions, and for patients who are well or 
poorly perfused in hospitals, hospital-type facilities, mobile, and home environments.  
 
Table 1.Summary of Study Devices 
Device  
Is the Cleared Device 
Modified? 
How is the Device 
modified? 
Does modification change 
the basic safety* of 
Device? 
Masimo Root Patient 
Monitoring and 
Connectivity Platform 
Yes 
Software changes to add 
RPVi and In Vivo SpHb 
to the Root display. 
No (no hardware changes) 
Masimo Radical-7 Pulse 
CO-Oximeter Device 
Yes 
Software on the tech 
board changes to add 
RPVi and In Vivo SpHb. 
No (no hardware changes) 
Masimo Rainbow Pulse 
CO-Oximetry Sensors (R1-
25) 
Yes 
Config file changes to add 
RPVi and In Vivo SpHb. 
No (no hardware changes) 
* Basic safety definition: electrical, mechanical and fire in accordance with IEC 60601-1. 
 
2.2 
Device Accountability 
2.2.1 
Device Records 
The sponsor will keep records to document the physical location of all investigational devices from shipment of the 
investigational devices to the clinical sites until return or disposal.  
The principal investigator or a designated site staff shall keep records documenting the receipt, use, return and 
disposal of the investigational devices using the Device Accountability Log provided by the sponsor.  
2.2.2 
Receipt of Study Device 
Upon receipt of the study devices, an inventory must be performed and the device accountability log filled out and 
signed by the person accepting the shipment.  It is important that the designated study staff counts and verifies 
that the shipment contains all the items noted in the shipment inventory.  Any damaged or unusable study devices 
in a given shipment will be documented in the study files.  The investigator must notify the study sponsor of any 
damaged or unusable study devices that were supplied to the investigator’s site. 
2.2.3 
Use of Study Device 
Use of devices and sensors will be documented on case report forms for each subject. 
2.2.4 
Return or Destruction of Study Device 
At the completion of the study, there will be a final reconciliation of study devices and sensors shipped, 
devices/sensors used, and devices/sensors remaining.  This reconciliation will be logged on the device 
accountability log.  Any discrepancies noted will be investigated, resolved, and documented prior to return or 
destruction of unused study devices.  Devices destroyed on site will only be upon written instruction from the 
sponsor and will be documented in the study files. 
3 
STUDY DESIGN AND OBJECTIVES 
3.1 
Overview of the Study Design  

Evaluation of Impacts of Continuous Non-Invasive Intra-operative Hemoglobin and RPVi 
Monitoring on Intra-operative and Post-Surgical Clinical Outcomes  
BIGT0001 version 2 
 
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This is a sequential, stepped-wedge, controlled, multi-center study with a total enrollment of approximately 2304 
subjects across all participating sites (See Figure 1). There will be six clinical sites participating in this study. One 
interim analysis and one final analysis will be performed.  
All control group subjects at each participating clinical site will be enrolled prior to the enrollment of the 
intervention group subjects. The control group for each site will consist of 75% retrospective cases and 25% 
prospective cases.  
The retrospective control group will involve the collection of historical medical records from patients who had 
undergone similar surgeries as the prospective control and intervention groups. Subjects for the retrospective 
control group will be selected at random from a list of eligible patients. Refer to Section 5.1.2 Subject Selection 
Methods for details on selection of the retrospective control subjects.  
The prospective control group will be treated as per standard of care. The prospective control group subjects will 
be given the study device in order to collect In Vivo SpHb and RPVi data during the surgery for post-study 
analysis; the recorded In Vivo SpHb and RPVi measurements will not be viewable to the investigators, rendering 
them blinded to In Vivo SpHb and RPVi data during the surgery.   
The prospective intervention group will be treated as per standard of care with the addition of non-invasive In 
Vivo SpHb and RPVi monitoring via the study device as per the procedure stated in the Study Procedure section 
in this CIP.  
Subjects for both prospective control group and intervention group will be enrolled on a convenience sampling 
basis from hospital patients who are already scheduled for surgery. Refer to Section 5.1.2 Subject Selection 
Methods for details on selection of the prospective subjects.  
Patients’ characteristic data such as demographics, skin tone, ASA status, surgery type, etc. will be recorded as 
part of the study Case Report Form (CRF) and analyzed for comparability between control and intervention 
groups. 
3.2 
Rationale for the Study Design  
The stepped-wedge design will minimize potential treatment contamination between control and intervention 
participants, by completing the enrollment of the control group before enrollment of the intervention group. The 
stepped-wedge design is being employed to mitigate for any potential temporal variability in patient population 
and variability in institutional standard of care procedures.  

Evaluation of Impacts of Continuous Non-Invasive Intra-operative Hemoglobin and RPVi 
Monitoring on Intra-operative and Post-Surgical Clinical Outcomes  
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3.3 
Minimization of Potential Bias 
Investigator’s behavior may be biased due to the Hawthorne/Observer effect. There is the possibility that by 
simply participating in the study, the investigator may change his/her behavior in terms of blood transfusions 
because he/she is aware of the study objectives.  
By using retrospective controls which establish a historical baseline through chart review and by comparing the 
blood transfusion patterns/behaviors of the investigators in the prospective control group cases against the 
retrospective control group cases, possible alteration of behavior by the study investigators from past blood 
transfusion practice patterns, if any, can be identified and addressed during data analysis.  
3.4 
Hypothesis 
The addition of real-time, continuous, noninvasive, intra-operative SpHb with In Vivo adjustment and RPVi 
monitoring via study devices to current hospital standard of care parameters will lead to reduction of total volume 
of blood transfusions during major surgical procedures. Reduction in total blood transfusion will in turn lead to 
reduction of complications related to blood transfusions thus shortening length of stay (LOS) for patients and 
improving clinical outcomes. The real-time, continuous In Vivo SpHb and RPVi data will help shorten the time 
between detection of patients’ changing hemoglobin and fluid status and subsequent clinical decisions for 
transfusion and infusion. 
3.5 
Study Objectives 
 
Figure 1. Overview of study design as a stepped wedge implementation. Control phase consist of 75% retrospective and 
25% prospective cases. Intervention phase each consist of 100% prospective cases. Note: the length of the Control and 
Intervention phases may be different from site to site depending on enrollment rate.  
Intervention start
Intervention Phase
Control Phase
Intervention Phase
Control Phase
Intervention Phase
Control Phase
Intervention Phase
Control Phase
Intervention Phase
Control Phase
Site 1
Site 2
Site 3
Site 4
Site 5
Intervention Phase
Control Phase
Site 6

Evaluation of Impacts of Continuous Non-Invasive Intra-operative Hemoglobin and RPVi 
Monitoring on Intra-operative and Post-Surgical Clinical Outcomes  
BIGT0001 version 2 
 
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3.5.1 
Primary 
To determine whether the addition of SpHb with In Vivo adjustment and RPVi monitoring using the study device 
will reduce overall allogenic transfusion, where reduction is defined as the decrease in volume of transfusion of 
the intervention group relative to control group, intra-operatively.  
3.5.2 
Secondary 
Secondary objectives are to determine whether application of the study device will: 
 
Reduce overall allogenic transfusion, where reduction is defined as the decrease in number of units of 
blood transfused to the intervention group relative to control group, intra-operatively 
 
Reduce incidence of patients with any allogenic transfusions, both intra-operatively and post-operatively.  
 
Reduce excessive allogenic transfusions. Excessive transfusions are defined by the number of extra units 
of blood administered after the patient’s hemoglobin is above a predetermined acceptable value of 
hemoglobin concentration specific to the patient (e.g. predetermined acceptable value for a specific 
patient may be 10 g/dL) when resuscitating a patient from an anemic state.  
 
Reduce the percentage or proportion of patients with incidence of the above mentioned excessive 
transfusion. 
 
Optimize/minimize infusion of IV Fluids 
 
Reduce length of hospital stay (LOS) after surgery. LOS is defined as the number of nights spent in the 
hospital after the day of surgery.  
 
Reduce post-operative complications. Post-operative complications include: Acute Kidney Injury (AKI), 
Deep Vein Thrombosis (DVT), Myocardial Infarction (MI), Pneumonia (PE), Sepsis, Stroke, Surgical 
Site Infection (SSI), and Urinary Tract Infection (UTI) as defined by the National Surgical Quality 
Improvement Program (NSQIP).  
 
Improve clinical outcomes, including Length of Stay (LOS), unplanned post-operative mechanical 
ventilation, 30 day morbidity, 30 day mortality, ICU transfer rate, post-operative transfusion related 
complications (e.g. re bleeding, coronary syndrome, sepsis, transfusion related infections, etc.), etc.  
 
Determine if utilizing SpHb will provide early warning of critical drops in hemoglobin due to under 
transfusion or late transfusions 
 
Correlate SpHb value approaching pre-determined transfusion thresholds with lab hemoglobin 
concentration (tHb) value approaching pre-determined transfusion thresholds (i.e. investigate the value of 
SpHb as a screening or early warning tool to indicate a need for blood draw when A-lines are not 
available).  
 
Examine economic impact in terms of cost savings due to fewer transfusions, fewer post-operative 
complications, shorter length of stay, reduced ICU time, etc.  
3.6 
Study Outcome Measures 
3.6.1 
Primary 
Volume (mL) of allogenic red blood cells (RBC) transfused intra-operatively.  

Evaluation of Impacts of Continuous Non-Invasive Intra-operative Hemoglobin and RPVi 
Monitoring on Intra-operative and Post-Surgical Clinical Outcomes  
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3.6.2 
Secondary 
 
Total number of units of blood transfused intra-operatively. 
 
Total number of units of blood transfused post-operatively. 
 
Volume (mL) of allogenic RBC transfused post-operatively.  
 
Number of patients with incidence of allogenic transfusion intra-operatively. 
 
Number of patients with incidence of allogenic transfusion post-operatively.  
 
Volume (mL) of excessive transfusions (See excessive transfusion definition in Secondary Outcome 
section above).  
 
Number of patients with incidence of excessive transfusions  
 
Volume (mL) of IV fluids infused  
 
Length of stay (LOS) in the hospital after surgery  
 
Risk-adjusted length of stay in the hospital after surgery  
 
Length of ICU stay (number of nights stayed in the ICU after surgery)  
 
Number of ICU transfers after surgery 
 
Number of various anemias 
 
Number of unplanned intubations for more than 6 hours after surgery  
 
Length of time between detection of critical Hemoglobin value by SpHb device and standard blood draw 
 
Number of early warning of critical drops in hemoglobin due to under-transfusion or late transfusions as 
defined below:  
The time interval between when the In vivo SpHb device identified a critical hemoglobin value compared 
with when it was recognized by a blood draw obtained in the operating room. For the purpose of this 
study, critical hemoglobin value is defined as either of: 
a) Significant drop in hemoglobin (> 12 g/dL) as defined by a drop of 2 g/dL from a previous 
hemoglobin value measured in the operating room above 12 g/dL; or 
b) Significant drop in hemoglobin (< 12 g/dL) as defined by a drop of 2 g/dL from a previous 
hemoglobin value measured in the operating room below 12 g/dL; or 
c) Significant surgical anemia as defined by hemoglobin dropping below 8 g/dL (9 g/dL in patients 
with ischemic type comorbidities such as ischemic heart disease or cerebral vascular disease) any 
time in the operating room; or 
d) Critical anemia as defined by hemoglobin dropping below 6 g/dL regardless of ischemic 
comorbidities such as ischemic heart disease or cerebral vascular disease) any time in the operating 
room.  
 
Sensitivity and Specificity for In Vivo SpHb as compared to tHb.  

Evaluation of Impacts of Continuous Non-Invasive Intra-operative Hemoglobin and RPVi 
Monitoring on Intra-operative and Post-Surgical Clinical Outcomes  
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 
Number of 30 day readmission (hospital readmission within 30 days after surgery) 
 
Number of 30 day mortality 
 
Number of post-operative transfusion related complications 
 
Number of the following complications based on NSQIP definitions:  
o Acute Kidney injury (AKI) 
o Deep Vein Thrombosis (DVT) 
o Myocardial Infarction (MI) 
o Stroke 
o Pneumonia 
o Pulmonary embolism (PE) 
o Urinary tract infection (UTI) 
o Surgical site infection (SSI)  
o Sepsis 
o Anemia 
o Illeus
3.7 
Study Safety Endpoint  
All investigational devices in the study are non-invasive and present minimal risks to the subjects. Safety 
data, including the number of occurrences of Adverse Events, Serious Adverse Events, and Unanticipated 
Adverse Device Effects for each study group will be collected during the study. The safety data will be 
periodically evaluated by the Sponsor and the Data Safety Monitoring Board to ensure subject safety. At 
the end of the study, all safety data will be analyzed to determine whether or not there was a significant 
difference between the occurrences of Adverse Events seen between the intervention group and the 
control group.  
4 
CLINICAL TEST SITES AND KEY PERSONNEL 
There are six clinical sites participating in this study: Sites may start enrollment in any order, except for 
Baylor University Medical Center, which shall be the first site to enroll. 
 
Table 2. List of Participating Clinical Sites and Principal Investigators.  
Site 
Number 
Site Name 
Address 
Principal Investigator 
1 
Baylor University Medical 
Center 
Department of 
Anesthesiology and Pain 
Management 
Webb Roberts Hospital 
3500 Gaston Avenue 
Dallas, TX 75246 
Michael A. E. Ramsay, 
MD, FRCA 
2 
Ronald Reagan UCLA 
Medical Center 
Department of 
Anesthesiology & 
Perioperative Medicine  
757 Westwood Plaza 
Los Angeles, CA 90095 
Maxime Cannesson, MD, 
PhD 

Evaluation of Impacts of Continuous Non-Invasive Intra-operative Hemoglobin and RPVi 
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Site 
Number 
Site Name 
Address 
Principal Investigator 
3 
Karolinska University 
Hospital 
Anestesi och intensivvård 
Södersjukhuset 
S-118 83  
Stockholm, Sweden 
Christer Svensén, MD, PhD 
4 
UC Davis Medical Center 
Anesthesiology and Pain 
Medicine 
4150 V Street, 
PSSB Suite 1200 
Sacramento, CA 95817 
Richard L. Applegate II, 
MD 
5 
Mayo Clinic Jacksonville 
Department of 
Anesthesiology 
4500 San Pablo Road 
Jacksonville, FL 32224 
Klaus D. Torp, MD 
6 
Loma Linda University 
Medical Center 
Department of 
Anesthesiology 
11234 Anderson St.  
Loma Linda, CA 92354 
Davinder Ramsingh, MD 
5 
SUBJECT SELECTION AND WITHDRAWAL 
5.1 
Number of Subjects 
Approximately 2304 adult subjects undergoing major surgical procedures associated with possibility of 
significant blood loss will be enrolled into this study. Approximately 384 subjects will be enrolled at each 
participating clinical site with 256 subjects enrolled in the control group and 128 enrolled in the 
intervention group.  
5.1.1 
Study Groups: 
 
Control group: the control group will be subdivided into two types of cases: (1) up to 75% of the 
control group (N=192) would be retrospective chart review cases, and (2) a minimum of 25% of 
the control group (N=64) would be prospective data collection. The actual enrolled number for 
retrospective control or prospective control may differ from site to site. Retrospective control 
subject data will be collected by reviewing historical patient and reporting required information in 
study case report forms (CRFs). Prospective control subjects will be treated per the institution’s 
standard of care (SOC) procedures with the addition of the study devices.  Data collection of In 
Vivo SpHb and RPVi information would occur, but clinicians will be unable to view the In Vivo 
SpHb and RPVi information. Intra and post-operative clinical data will be collected and 
documented on the CRF.  
 
Intervention group (N=128 per site): After the control group is completed, patients will be 
enrolled into the intervention group. In addition to standard of care, anesthesiologists/anesthesia 
providers will also be using In Vivo SpHb and RPVi monitoring information as a guide to trigger 
laboratory blood draws. Results obtained from the standard of care blood draws will trigger 

Evaluation of Impacts of Continuous Non-Invasive Intra-operative Hemoglobin and RPVi 
Monitoring on Intra-operative and Post-Surgical Clinical Outcomes  
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standard of care blood transfusion and fluid infusion decisions. While the use of dynamic fluid 
responsiveness is used frequently for volume measurements, blood transfusions will not be based 
just on In Vivo SpHb and RPVi values alone. Final blood transfusion and fluid infusion decisions 
will still be made by the investigator based on confirmatory laboratory blood draws.  
5.1.2 
Subject Selection Methods:  
 
For the retrospective control group, the study biostatistician will receive a list of patients whose 
surgeries were overseen by study anesthesiologists. Only the patients’ medical record number 
(MRN) will be provided. Patients from this list will be selected randomly for screening and 
enrollment. The selected patients will be screened based on study eligibility criteria, and those 
who meet eligibility criteria will be enrolled to the retrospective control group. Ineligible patients 
will be replaced by randomly selecting additional patients from the list.  
 
Prospective control and prospective intervention groups will be selected based on a convenience 
sampling from eligible patients that have scheduled surgery at the clinical site based on a 
screening review of their medical records. Patients will be enrolled into the control group until the 
required number of control subjects have been met, after which time the intervention group 
enrollment shall commence. 
5.2 
Inclusion Criteria 
 
Adult patients undergoing major surgeries associated with possibility of significant blood loss (e.g. 
such that blood is cross-matched and available before the start of the case as per hospital routine 
practice) under general anesthesia.  
 
At least one finger available and accessible for performing non-invasive hemoglobin monitoring.  
5.3 
Exclusion Criteria 
 
Patient has skin abnormalities affecting the digits such as psoriasis, eczema, angioma, scar tissue, 
burn, fungal infection, substantial skin breakdown, nail polish or acrylic nails that would prevent 
the proper fit and application of the sensors 
 
Procedures performed using robotics surgery 
 
Any patients with a known hemoglobinopathy 
 
Any patients undergoing Cardio-Pulmonary Bypass (CPB) 
 
Any patients who cannot be transfused or has refused consent for a blood transfusion 
 
Patients being treated by any artificial oxygen carriers within 30 days of hospital stay 
 
Patients being managed outside of an operating room in the participating centers, or in operating 
room with conditions not conducive to perform and complete the study procedures (including use 
of the hemoglobin monitoring device)    
 
Patients younger than 18 years old 
 
Patients who are pregnant  
 
Patients with cardiac arrhythmia 
 
Patients with tidal volume setting < 6ml/kg 
 
Patients with PEEP >= 10cm H2O 
 
Patients undergoing cardiac and/or any open chest procedures 

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 
Emergency patients due to the foreseeable difficulty in consenting 
 
Patients deemed not suitable for study at the discretion of the Principal Investigator 
 
5.4 
Study Timelines 
Enrollment period for the study is set to be 6-12 months with possible extension depending on individual 
site’s enrollment progress. 
 
Following the stepped wedge design, Site 1 will start control phase enrollment. After all prospective 
control group subjects have been enrolled, Site 1 will commence enrollment in the intervention phase. All 
subsequent sites will start their respective intervention phase approximately 6 weeks after the intervention 
phase start time of the previous site. Therefore, after approximately 24 weeks or 6 months, all sites should 
be participating in the intervention group. The entire clinical investigation is anticipated to last 
approximately 12 to 24 months to complete depending on participating sites’ enrollment progress.  
5.5 
Subject Recruitment and Screening 
For the retrospective control group, the study biostatistician will receive a list of patients whose surgeries 
were overseen by study anesthesiologists. Only the patients’ medical record number (MRN) will be 
provided. Patients from this list will be selected randomly for screening and enrollment. The selected 
patients will be screened based on study eligibility criteria, and those who meet eligibility criteria will be 
enrolled to the retrospective control group. Ineligible patients will be replaced by randomly selecting 
additional patients from the list.   
 
 
Figure 2. Study Timelines: at intervention start, the first site will begin prospective use of in vivo SpHb and PVI.  
Subsequent sites will start their respective Intervention Phase 6 weeks after the start of Intervention Phase of the previous 
site. Note: length of the Control and Intervention Phases may be different from site to site. 
Intervention start
Intervention Phase
Control Phase
Intervention Phase
Control Phase
Intervention Phase
Control Phase
Intervention Phase
Control Phase
Intervention Phase
Control Phase
Site 1
Site 2
Site 3
Site 4
Site 5
Intervention Phase
Control Phase
Site 6
6 
wks

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Prospective control and prospective intervention groups will be selected based on a convenience sampling 
from eligible patients that have scheduled surgery at the clinical site based on a screening review of their 
medical records. Patients will be enrolled into the control group until the required number of control 
subjects have been met, after which time the intervention group enrollment shall commence. The site staff 
will clearly inform the patient regarding which group (control or intervention) the patient will be enrolled 
into.  
All subjects will have their medical history reviewed at the time of screening, after informed consent has 
been obtained, by either the PI or study staff who are delegated for this task. Subjects will be evaluated 
based on the inclusion and exclusion criteria to determine eligibility to be enrolled into the study. If the 
subject meets all eligibility criteria, the subject will be enrolled in the study.  Enrollment into the either 
the control group or the intervention group will depend on the phase of the study the site is conducting. 
Subjects will be informed prior to enrollment as to which group he/she will be enrolled into. The group 
that the subject is being enrolled into will be clearly indicated on the ICF.  
Information regarding the subject’s demographic (including, but not limited to age, weight, race, 
ethnicity, comorbidities, medications, etc.), preexisting allergies, skin abnormalities, and other preexisting 
diseases/conditions that may be relevant to the study will be recorded within the CRF.  
5.5.1 
HIPAA Waiver 
The pre-screening of patients will require the investigators and designated study staff to access personal 
health information to identify prospective subjects without HIPAA authorization prior to obtaining 
written informed consent for the study. Informed consent and HIPAA authorization will be obtained 
during recruitment and screening procedures as described in previous sections of this clinical 
investigational plan; however, pre-screening process would require a waiver of HIPAA authorization, as 
the research study could not be practicably carried out without this implied waiver of consent. The 
participants’ rights and welfare will not be adversely affected by this HIPAA waiver. Patients’ protected 
health information (PHI) will not be inappropriately reused or disclosed to any other person or entity. To 
further safeguard all protected health information, the data collected during the study will not be labeled 
with any personal identifying information. The data will not be stored with any protected health 
information identifiers.  
5.6 
Informed Consent 
The retrospective control group of this study meets the requirements for waiver of consent, as defined in 
FDA guidance document titled: “IRB Waiver or Alteration of Informed Consent for Clinical 
Investigations Involving No More Than Minimal Risk to Human Subjects; Guidance for Sponsors, 
Investigators, and Institutional Review Boards”, released July 2017.  As approved by the IRB, 
documentation of informed consent will not be required for the retrospective control group involving only 
medical chart review and collection of de-identified historical information. 
A written informed consent will be required for the prospective groups in the study. All items of the 
Informed Consent will be explained in a way that is easily understandable for the patient. The patient will 
be given adequate time to read through the Informed Consent, and they will be given adequate time and 
privacy to consider the decision of whether or not to sign the Informed Consent Form. Once all of the 
patient’s questions have been answered and the Informed Consent Form signed, the patient will be 

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enrolled as a study subject, at which time the subject will be assigned a unique study identification 
number.  
5.7 
Withdrawal of Subjects 
Informed consent discussions will explicitly include emphasis that neither patient enrollment nor patient 
withdrawal from the study will result in any alterations to the standard clinical care that he/she will 
receive.  Subjects may elect to withdraw from the study at any time.  
In order to obtain the required number of subjects at each clinical site, if a subject withdraws or is 
withdrawn from the study, the site staff should make arrangements to enroll an additional subject as a 
replacement. See Section 7.7 Handling Missing Data in Statistical Analysis for details regarding how data 
from withdrawn subjects will be handled when analyzing study outcome measures.  
6 
STUDY PROCEDURES 
6.1 
Control Group 
6.1.1 
Retrospective Control Group 
Approximately 75% of the control group will be retrospective data collected from the site’s medical 
records. The retrospective data will be collected by designated site personnel only and reported to the 
sponsor via CRFs.  
6.1.2 
Prospective Control Group  
Approximately 25% of the control group will be prospective data collection from subjects undergoing 
surgery. Prospective subjects enrolled in the control arm will be treated per individual clinical site’s 
standard of care (SOC) procedures during and after surgery. The amount of blood transfused, amount of 
fluid infused, along with other study outcome measures and physiological parameters will be reported on 
the CRF. In Vivo SpHb and RPVi data will be automatically recorded in the study devices or through a 
data collection laptop. The display on the study devices will be blacked out so that anesthesiologists will 
be blinded to the In Vivo SpHb and RPVi monitoring throughout the surgical procedure. All blood 
transfusion and fluid infusion decisions will be made by clinician’s judgment and per SOC procedures. 
Subjects will receive a phone call from the clinical site staff for a 30-day post-op follow-up on the 
subject’s conditions. 
6.2 
Intervention Group 
Prospective subjects will be enrolled in the intervention group after the control group enrollment phase 
has been completed. Intervention group subjects will be treated per individual clinical site’s SOC 
procedures during and after surgery. In addition, these subjects will also be monitored with SpHb with In 
Vivo adjustment and RPVi monitoring devices to trigger confirmatory laboratory blood draws, which will 
then be used to guide standard of care blood transfusion and fluid infusion decisions. The investigator will 
make a determination of the threshold for blood transfusion on a case-by-case basis depending on 
individualized patient clinical conditions. This threshold value will be determined prior to the start of the 
surgical procedure and it will be recorded in the CRF. Dynamic fluid responsiveness parameters such as 
RPVi are already in use by many providers to guide fluid infusion decisions, but unlike RPVi, most 
dynamic fluid responsiveness parameters are often obtained by invasive means, along with other 
hemodynamic parameters. The procedure for monitoring with In Vivo SpHb and RPVi is illustrated in the 

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Flow Diagram (Figure 3). The amount of blood transfused, amount of fluid infused, the time of blood 
draw, the value of tHb, along with other study outcome measures and physiological parameters will be 
reported on the CRF. In Vivo SpHb and RPVi data will be automatically recorded and stored in data files. 
All blood transfusion and fluid infusion decisions will be made by clinician’s judgment with additional 
supplemental information provided by In-Vivo SpHb and RPVi parameters. Subjects will receive a phone 
call from the clinical site staff for a 30-day post-op follow-up on the subject’s condition.  
In Vivo SpHb and RPVi readings that signal a change in the patient’s status shall be confirmed with a 
confirmatory blood draw, as shown in the Intervention Group Study Procedures Flow Diagram (Figure 3).  
At all times, anesthesiologists shall use their clinical judgment and standard of care tools to make blood 
transfusion and fluid infusion decisions.  
6.3 
Intervention Group Study Procedures Flow Diagram  

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Monitor
SpHb + RPVi 
Trending
SpHb <
pre-determined 
lower trigger
Yes
RPVi > pre-
determined 
upper trigger
RPVi < pre-
determined 
lower trigger
Is BP within 
10% of 
normal?
Yes
No
Yes
Other vitals 
indicate 
hypovolemia?
No
Blood Draw
Blood Draw
No
pRBC transfusion 
per clinician’s 
judgment and SOC
fluid infusion per 
clinician’s 
judgment and 
SOC
Clinician’s 
judgment and 
SOC
Yes
Yes
No
No
SpHb >
pre-determined 
upper trigger
Yes
Blood Draw
pRBC transfusion 
per clinician’s 
judgment and 
SOC
No
Blood Draw
fluid infusion per 
clinician’s 
judgment and 
SOC
SpHb >
pre-determined 
upper trigger
Yes
Blood Draw
pRBC transfusion 
per clinician’s 
judgment and 
SOC
No
 
 
Figure 3. For intervention group only. Monitor displayed In Vivo SpHb and RPVi values are to be used to 
prompt for blood draws. Patient care and decisions for transfusions and/or infusions will be conducted per 
clinician’s judgment and institution’s standard of care procedures.  
 

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6.4 
SpHb In Vivo Adjustment and RPVi  
6.4.1 
In Vivo SpHb:  
The SpHb In Vivo Adjustment feature allow clinicians to manually adjust the SpHb parameter to match 
that of a corresponding laboratory reference for continuous trending. In order to utilize the In Vivo 
Adjustment feature of SpHb, the device requires the user to enable this feature and input an offset value. 
The offset value is the difference between a laboratory tHb value from analyzing a blood sample and the 
displayed SpHb value when the blood sample was drawn. After the offset value has been entered, the 
device will incorporate the offset as it compute SpHb values. An In Vivo Adjustment should be 
performed during the initial stages of the subject’s procedure, when the SpHb value is below 12 g/dL and 
a blood draw for tHb is conducted.  
6.4.2 
RPVi:  
Since RPVi is a newer development with limited market use thus far, information from the more 
established and widely used PVi parameter is included to serve as reference.  
Most dynamic variables assessing fluid responsiveness, such as stroke volume variation (SVV) and pulse 
pressure variation (PPV), are invasive, technically challenging or require additional catheters [26], thus 
the potential usefulness of PVi and RPVi as a non-invasive tool to predict fluid responsiveness in 
mechanically ventilated patients is readily apparent. Therefore, the current investigation seeks to evaluate 
the utility for RPVi to predict fluid responsiveness in the surgical setting when used by anesthesiologists 
along with other standard of care tools.  
The Intervention Group Study Procedures Flow Diagram in Figure 3 specifies a pre-determined RPVi 
upper trigger and a pre-determined RPVi lower trigger. These trigger values have been studied and 
empirically derived from previous studies for PVi and may help investigators determine the fluid 
responsiveness of a particular subject. For PVi, the upper trigger is 14% and the lower trigger is 9.5% [26, 
27]. 
It is worth noting that PVi, as any other dynamic indicator, may not be reliable in spontaneously breathing 
patients [27, 32]; therefore, the current investigation will enroll general anesthesia patients who by 
standard practice will be mechanically ventilated during surgery.  Furthermore, PVi depends on 
vasomotor tone, so any use of vasopressors or vasodilators will affect the value of PVi [26, 33-35]. 
6.5 
Laboratory Evaluation 
Throughout the study procedure, venous or arterial blood draws will be taken at the anesthesiologist’s 
discretion either as confirmatory blood draws based on the triggers from the Masimo monitor or based on 
standard of care clinical judgment in support of blood transfusion or fluid infusion decisions. Each blood 
draw will be approximately 2 mL and the total amount of blood drawn per subject will not exceed 50 mL 
for this research study. Blood samples will be analyzed by the local laboratory with a co-oximeter or an 
arterial blood gas (ABG) machine. Data on any hemoglobin measurements and/or ABG performed during 
the surgery will be recorded on the CRF.   
6.6 
Follow-Up Procedures 
For each subject, this study consists of only one visit which occurs on the day of surgery. The only 
follow-up being performed is a phone follow-up 30 days after the day of surgery. Subjects will receive a 

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phone call from the research staff to check on subjects’ condition and gather information as required in 
the Case Report Form. This follow-up provides information for secondary outcome measures only.  
6.7 
Schedule of Activities  
Table 3. Study activities and relative time for each subject. 
Schedule 
Study Activities 
Day 0 – 1 
Screening 
Day 1 
Informed Consent 
Day 1 
Enrollment, Study Data Collection 
Day 30 - 40 
Subject Follow-Up Phone Call, Case Report Form 
Completion 
7 
SAMPLE SIZE AND STATISTICAL CONSIDERATIONS 
7.1 
Power Analysis and Sample Size Determination 
The sample size calculation is based on the primary endpoint. The sample size is first estimated assuming 
each subject in each site is statistically independent (Estimated Sample Size).  The sample size is then 
adjusted for the Intra-class Correlation (ICC) to account for dependencies among Subjects within a 
particular site (Adjusted Sample Size).  
Since data on subjects at each site prior to this study can be used for the null hypothesis distribution, 
unequal sample sizes could be utilized (2 controls to one intervention case). This will reduce the number 
of required intervention (alternate hypothesis) subjects required.  
The Estimated Sample Size is determined by simulating many combinations of Subjects using bootstrap 
sampling with replacement. The null hypothesis cohort data were simulated from the data in Table 4.  
Alternate hypothesis data were created by reducing the observed number of transfusions by 
approximately 21.7%.  Data were fit to a Zero Inflated Negative Binomial model. Estimated power to 
detect the 21.7% drop was estimated at each iteration.  
7.2 
Prior Study Data  
Table 4 contains the transfusion data used as input for the sample size determination and power analysis.  
The data were collected from UCLA blood bank; therefore, categorical groupings were only available in 
units of liters of fluid.  Assuming a typical unit of blood is approximately 250 mL, an estimate of the units 
of whole blood administered was calculated for each column in Table 4. 
Table 4. Percentage of patients receiving RBC transfusions categorized by the type of surgery. 
 
 
Percent of Patients Receiving RBC Transfusions  
Total Volume Received[L] 
Type of Surgery 
Number 
of cases 
per 
year 
<1L 
1-2L 
2-3L 
3-4L 
4-5L 
>=5L 

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Cesarean Section 
31 
93.9% 
6.1% 
Colorectal Resection 
904 
97.9% 
1.4% 
0.2% 
0.2% 
0.2% 
Excision, Lysis 
Peritoneal Adhesions 
68 
97.1% 
1.4% 
1.4% 
Exploratory Laparotomy 
189 
94.5% 
3.5% 
0.5% 
1.5% 
Nephrectomy, Partial Or 
Complete 
638 
97.3% 
1.8% 
0.5% 
0.2% 
0.3% 
Other Or Gastrointestinal 
Therapeutic Procedures 
500 
96.7% 
2.4% 
0.2% 
0.3% 
0.2% 
0.3% 
Liver Transplant 
377 
45.3% 
8.2% 
7.4% 
6.8% 
6.7% 
25.6% 
Procedures On Spleen 
46 
75.4% 
13.1% 
6.6% 
1.6% 
1.6% 
1.6% 
7.3 
Generation of Alternate Hypothesis Distribution 
Figure 4 shows the mapping of the original transfusion count in the control distribution to the transfusion 
count in the intervention distribution. Patients with 0,1, or 2 transfusion units were not changed. 
This reduced the mean transfusion rate from 2.81 units per subject to 2.18 units per subject. 

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7.4 
Adjusting For Intra-class Correlation  
Assuming that the intra class correlation (ICC = ) is 0.001, the estimated sample size from the 
simulation is adjusted for the design effect (DE) to account for correlation within each Site. 
Adjusted Sample Size = Estimated Sample Size x DE 
Where DE = 1 + (m – 1) and m equal to the average estimated sample size per site. 
7.5 
Sample Size Results  
A sample of 1536 subjects will be enrolled in the control group and a convenience sample of 768 subjects 
will be enrolled into the intervention group for this study to achieve more than 80% power to detect a 
reduction in mean transfusion rate of at least 22% with a one-sided significance level of 0.05. Refer to 
Section 5.5 Subject Recruitment and Screening for details regarding subject enrollment methods for each 
study group.  
Table 5. Sample Size Results 
 
Figure 4. Mapping of the original transfusion count in the control distribution to the transfusion count in the 
intervention distribution.   
 

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Inputs 
Number of Sampling Iterations 
2000 
 
Reduction Factor for Alternate hypothesis 
0.8 
 
Ratio of Control to Intervention Group 
Sample Size 
2:1 
 
alpha- one sided 
0.05 
 
beta  
0.2 
 
Power 
0.8 
 
Outputs 
Control Group Mean Transfusion Rate (units 
per Subject)  
2.81 
 
Intervention Group Mean Transfusion Rate 
(units per Subject)  
2.18 
 
Reduction in Transfusion Rate 
22% 
 
Sample Size 
Estimated Adjusted 
Control Group Estimated Sample Size 
1176 
1536 
Intervention Group Estimated Sample Size 
588 
768 
The Control group will consist of a combination of retrospective (up to 75%) and prospective (a 
minimum of 25%) patients. Based on the adjusted sample size estimations, approximately up to 1152 
subjects of the control group will be retrospective, and a minimum of 384 subjects of the control group 
will be prospective.  
The following graph shows the relationship between the adjusted sample size for six clinical sites and the 
power. 

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Figure 5. Graph of Power vs. Total Number of Subjects (Adjusted to Design Effect, Raho = 0.001). 
7.6 
Data Analysis 
7.6.1 Interim Analysis 
One interim data analysis and a final analysis will be performed; the interim analysis will be performed 
after collecting data on 281 subjects in the intervention group and 562 subjects in the control group.  
7.6.2 Statistical Analysis  
Data from the intervention group will be compared to the control group for statistically significant 
changes. For those outcome measures that result in statistically significant differences between the 
intervention and control, study investigators will evaluate the numerical values of the differences for 
clinical significance. Any study outcome measures determined to be clinically significant are considered 
successful. All outcome measures will be reported for each site individually and for all sites pooled. Note, 
exact numerical values for clinical significance are not able to be pre-determined for all outcome 
measures, as the clinical setting and subject population targeted by this investigation are novel and are 
difficult to predict.  
7.6.2.1 Summary Statistics and Baseline comparisons: 
Descriptive statistics will be estimated for each group. Continuous variables will be described by their 
means, medians, standard deviations, and interquartile ranges.  Categorical variables will be described by 
their frequencies and percentages. Demographics and baseline clinical measurements will be compared 
 

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between the groups using ANOVA to compare the means of the continuous variables and Fisher’s exact 
test / Pearson’s chi-squared test (2) to compare the rates of the categorical variables. 
7.6.2.2 Study Outcomes Statistical Analysis: 
Having measurements collected within clusters (clinical site) creates correlated observations. These 
correlations invalidate the independence assumption in commonly used univariate and multivariate 
statistical techniques such as t-tests and multiple linear regression.  Generalized Linear mixed models 
(GLMMs) are a flexible class of models that account for correlated observations and thus are a commonly 
used method for cluster data analysis. This class of model does not require the normality assumption.  
Generalized linear mixed models will be used for outcomes following a distribution from the exponential 
family other than normal. 
GLMMs will be used to assess the effect of the intervention on continuous and discrete dependent 
variables.  GLMMs differing with respect to their fixed effects, random effects, and residual covariance 
matrix will be examined.  GLMM generally take the form of Equation 1 for baseline observations.  
Equation 1.  Generalized Linear mixed model assessing intervention effect for a given outcome: 
 
ij
p
k
k
k
j
x
ervention










2
1
0
0
int
*
)
(
     (1) 
The outcome,
ijy  is the value of a response variable for the ith individual of the jth cluster (clinical site). 
The betas represent fixed effects for the intercept (
0
), intervention coefficient (
1
), as well as 
coefficients (
2
, …,
p
) for other variables to be included in the model (e.g. demographic and clinical 
variables).   The gamma coefficient (
j
0

) represents a cluster-specific random intercept.  It is assumed 
that 
j
0

 has a normal distribution with a mean of zero and a variance of
2
0


.   
Type III tests will be used to test the null hypothesis that a specific fixed effect equals zero (
0
:
0

k
H

).  Wald z-tests will be used to test for a significant random intercept (
0
:
2
0
0 


H
).  Residual and 
influence diagnostics will be assessed for all models.   
Sequential boundary tolerances will be estimated using Lan & DeMets alpha spending function approach. 
Statistical analysis will be performed using SAS 9.4 (SAS Institute, Cary, NC)  
 
Table 6. Aims, Outcome Measures and Associated Analysis Planned for those Aims.  
Aims/Objectives 
Outcome Measures 
Planned Statistical Analysis 
Reduce overall allogenic 
transfusion - Volume 
Volume of allogenic RBC 
transfused: Intra operatively 
Binomial-Gamma hurdle model. 
We will include intervention 
group, demographic and clinical 
data in the model as progresses. 
  
Volume of allogenic RBC 
transfused: Post operatively 

ijy

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Aims/Objectives 
Outcome Measures 
Planned Statistical Analysis 
 
Total Volume of allogenic RBC 
transfused: Intra and Post 
Clinical Site will be the random 
effect 
Reduce overall allogenic 
transfusion - Units 
Number of transfusion units per 
Subjects: Intra operatively 
Generalized linear mixed model 
with Zero inflated Negative 
Binomial (ZINB) distribution. We 
will include intervention group, 
demographic and clinical data in 
the model as progresses. Clinical 
Site will be the random effect 
 
Number of transfusion units per 
Subjects: Post operatively 
  
Total number of transfusion units 
per Subjects: Intra + Post 
Reduce percentage or 
proportion of transfused 
patients   
Number of patients with transfusion 
Fisher Exact test Control vs 
Intervention  
Generalized linear mixed model, 
with logit link 
Reduce percentage or 
proportion of patients with 
incidence of above 
mentioned excessive 
transfusion.  
Percent(ratio) of patients getting too 
much: Intra and Post Operatively 
(Total) 
Fisher Exact test Control vs 
Intervention  
Generalized linear mixed model, 
with logit link 
  
Number of patients with incidence 
of allogenic transfusion: Intra 
operatively  
 
  
Number of patients with incidence 
of allogenic transfusion: Post 
operatively  
 
Optimize/minimize 
infusion of IV Fluids 
Volume of IV fluids infused 
Generalized linear mixed Model. 
Assuming Normal distribution 
Reduce length of hospital 
stay (LOS) after surgery 
Length of stay (LOS) in hospital 
after surgery (number of nights or 
number of hours as appropriate)  
  
Risk-adjusted length of stay  
  
Length of stay ICU stay  
Reduce post-operative 
complications 
Number of ICU transfers after 
surgery 
Fisher Exact test Control vs 
Intervention 
  
Number of various anemias 

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Aims/Objectives 
Outcome Measures 
Planned Statistical Analysis 
  
Number of unplanned intubations 
for more than 6 hours after surgery 
Generalized linear mixed model 
logit link 
  
Number of hospital readmission 
within 30 days after surgery 
  
Number of 30 day mortality 
  
Number of post-operative 
transfusion related complications. 
  
Number of specific complications 
based on the NSQIP definitions (see 
list in protocol):  
   Acute Kidney injury (AKI),  
   Deep Vein Thrombosis (DVT),  
   Myocardial Infarction (MI),  
   Stroke, Pneumonia,  
   Pulmonary embolism (PE),  
   Urinary tract infection (UTI),  
   Surgical site infection (SSI),  
   Sepsis, Anemia,  
   Illeus 
Descriptive Statistics frequency 
and Percentages 
Fisher Exact test Control vs 
Intervention (for the overall 
complication Yes/no) 
Generalized linear mixed model, 
with logit link 
Impending Required 
Transfusions Time 
Time interval (minutes) between 
SpHb and tHb low hemoglobin 
warning. 
Generalized linear mixed model 
with Normal distribution 
Applicable only to patients with 
critical values 
  
incidence percentage for early 
warning of critical drops in 
hemoglobin due to under-
transfusion or late transfusion as 
defined below:  
   Starting tHb>12, Drop 2 g/dL 
   Starting tHb<12, Drop 2 g/dL 
   Surgical Anemia; tHb<8 
   Critical anemia; tHb<6 
Fisher Exact test Control vs 
Intervention (for the overall 
complication Yes/no) 
Generalized linear mixed model, 
with logit link 
Utility of SpHb+RPVi 
Sensitivity and Specificity for SpHb 
as compare to tHb 
Sensitivity and Specificity and 
Receiver operating characteristic 
(ROC) 

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Aims/Objectives 
Outcome Measures 
Planned Statistical Analysis 
Total Cost Savings 
Length of Stay 
Number of transfusion units 
ICU Time 
Post Op Complication Rate 
Cost saving analysis 
 
7.7 
Handling Missing Data in Statistical Analysis 
Missing data is a potential problem with any study. All efforts will be made to have a complete and valid 
data set; however, if the situation occurs, where certain data are missing for a particular subject, the 
following rules shall be followed:  
 
If volume (mL) of allogenic RBC transfused and total number of units of blood transfused are 
both missing for a particular subject, and there is indication for blood transfusion, then the subject 
with the missing data will be excluded from the relevant analysis. If only one value is missing and 
the other is valid, then estimation for the missing value will be derived from the valid value.  
 
Missing other outcomes: subjects with missing outcomes data will be excluded from the relevant 
analysis.  
 
Missing Covariates: imputations will be used to account for missing covariates; imputation is the 
substitution of estimate for a missing data point.  
7.8 
Interim Analysis decisions 
The interim analysis will be performed after collecting data on 281 subjects in the intervention group and 
562 subjects in the control group. 
The Lan-DeMets bounds using O’Brien-Fleming spending function was utilized to calculate the spending 
alpha. The Overall alpha is 0.05 and One-Sided Bounds 
Table 7. Adjusted Alpha and Boundary Results 
Analysis 
Time 
Upper Boundary 
Adjusted Alpha 
Cumulative Alpha 
Interim 
0.5 
2.5380 
0.0056 
0.0056 
Final 
1 
1.6621 
0.0444 
0.0500 
Interim Analysis results will be presented to the principal investigators, the sponsor, and the DSMB for 
evaluation and decision-making. 
7.9 
Early Stopping Rules  
 
Upon review of occurrence of unanticipated adverse device effects and/or other harmful events as 
a direct result of the clinical investigational procedures, principal investigators, sponsor, and 
DSMB may decide to terminate the study to safeguard subject safety.  
 
If the results of the interim analysis show a statistically significant result relating to the outcome 
measures, then the principal investigators, sponsor, and DSMB may decide to terminate the study.  

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8 
SAFETY AND ADVERSE EVENTS 
8.1 
Definitions 
The definitions for adverse event, adverse device effect, serious adverse event, serious adverse device 
effect, and unanticipated adverse device effect are provided below (ISO 14155:2011, 21 CFR 812.3(s)). 
 
Adverse Event (AE): an adverse event is any untoward medical occurrence in a subject which 
need not be related to the device under investigation. 
 
Adverse Device Effect (ADE): an adverse device effect is any untoward or unintended response 
to a medical device which may result from insufficiencies in the instructions for use or 
deployment of the device, or from use error.  
 
Serious Adverse Event (SAE): a serious adverse event is an adverse event that results in death, 
inpatient hospitalization, severe or permanent disability, a life threatening illness or injury, fetal 
distress, fetal death, a congenital abnormality, a birth defect, or medical or surgical intervention to 
prevent permanent impairment to body or structure. 
 
Serious Adverse Device Effect (SADE): a serious adverse device effect is an adverse device 
effect that results in death, inpatient hospitalization, severe or permanent disability or is life 
threatening. 
 
Unanticipated Adverse Device Effect (UADE): any serious adverse effect on health or safety or 
any life threatening problem or death cause by or associated with, a device, if the effect, problem, 
or death was not previously identified in nature, severity or degree of incidence in the 
investigational plan, or application (including a supplementary plan or application) or any other 
unanticipated serious problem associated with a device that related to the rights, safety or welfare 
of subjects.  Refer to the Device Risk Analysis and Risk Assessment section for details on 
anticipated adverse device effects.  
8.2 
Anticipated Adverse Events:  
 
Mild allergic reaction to sensor material and adhesives.  
 
Low risk of thermal burn from sensor LEDs.  
 
Low risk of pressure damage if sensors are applied too tightly.  
AEs related to surgical procedures are not listed in this CIP.  
8.3 
Recording and Assessment of Adverse Effects 
All adverse events, regardless of treatment group and suspected causal relationship to the investigational 
device, will be recorded in the sponsor-provided Adverse Event Log at each site. For all adverse events, 
sufficient information will be pursued and/or obtained so as to permit 1) an adequate determination of the 
outcome of the event (i.e., whether the event should be classified as a serious adverse event) and, 2) an 
assessment of the casual relationship between the adverse event and the investigational device.  
 
Adverse event findings associated with the investigational device will be followed until the event (or its 
sequelae) resolves or stabilizes at a level acceptable to the Principal Investigator.  

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8.3.1 
Causality and severity assessment 
The Principal Investigators of each participating clinical site will promptly review adverse events to 
determine 1) if there is a reasonable possibility that the adverse event was caused by the investigational 
device and 2) if the adverse event meets the criteria for a serious adverse event.  
 
If the Principal Investigator’s final determination of causality is “unknown and of questionable 
relationship to the investigational device,” the adverse event will be classified as “Related” with the use 
of the investigational device for reporting purposes. If the Principal Investigator’s final determination of 
causality is “unknown but not related to the investigational device,” this determination and the rationale 
for the determination will be documented in the respective subject’s sponsor-provided adverse event 
report form.  
8.4 
Adverse Event Reporting 
8.4.1 
Investigator reporting of adverse events to the sponsor 
 
The investigator must document all adverse events, whether related or unrelated to the study 
device(s) and/or unanticipated or anticipated in the Adverse Event section of the CRF, and in an 
Adverse Event Log, which is to be kept in the clinical site’s regulatory binder.  
 
All study device related adverse events and serious adverse events, both anticipated and 
unanticipated, must be recorded in detail in the sponsor-provided adverse event report form.  
 
The investigator shall submit to the sponsor a report of any Unanticipated Adverse Device Effect 
(UADE) as soon as possible, but in no event later than 10 working days after the investigator first 
learns of the effect. 
8.4.2 
Investigator reporting of adverse events to the responsible IRB 
 
The investigator shall submit to the reviewing IRB a report of any UADE as soon as possible, but 
in no event later than 10 days after the investigator first learns of the effect. These reports shall be 
submitted according to the local IRB’s requirements.  
8.4.3 
Sponsor reporting of adverse device effects to the FDA 
 
The Sponsor shall report the results of any evaluation of an observed or volunteered adverse 
event that is determined to be an UADE. The sponsor shall report the results to FDA, all 
reviewing IRBs, and investigators as soon as possible, but no later than 10 working days after the 
sponsor first receives notice of the effect. 
 
If the results of the Sponsor’s follow-up evaluation show that an adverse event that was initially 
determined to not constitute an unanticipated adverse device effect does, in fact, meet the 
requirements for reporting, the Sponsor will submit a report of the results of the evaluation to 
FDA, reviewing IRBs, and investigators as soon as possible, but in no event later than 10 working 
days, after the determination was made.  
 
At regular intervals, and at least yearly, the Sponsor shall submit progress reports to all reviewing 
IRBs and to FDA.  
8.5 
Additional Reporting Requirements for EU sites 

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 
The following events are considered reportable events in accordance with Annex 7, section 2.3.5 
and Annex X, section 2.3.5 of the Medical Device Directive 90/385/EEC and 93/42/EEC, 
respectively:  
o Any SAE,  
o Any Investigational Medical Device Deficiency that might have led to a SAE if (a) suitable 
action had not been taken or (b) intervention had not been made or (c) if circumstances had 
been less fortunate,  
o New findings/updates in relation to already reported events.  
 
All reportable events must be reported by the sponsor or the sponsor’s authorized representative 
to the National Competent Authorities (NCAs) where the clinical investigation has commenced at 
the same time.  
 
The sponsor or the sponsor’s authorized representative must report to the NCAs according to the 
following timelines:  
o For a SAE which indicates an imminent risk of death, serious injury, or serious illness and 
that requires prompt remedial action for other patients/subjects, users or other persons or a 
new finding to it, the sponsor or authorized representative must report to the NCAs 
immediately, but not later than 2 calendar days after awareness by sponsor of a new 
reportable event or of new information in relation with an already reported event.  
o For any other reportable events or a new finding/update to it, the sponsor or authorized 
representative must report to the NCAs immediately, but not later than 7 calendar days 
following the date of awareness by the sponsor.  
 
The clinical site must report the reportable events to the sponsor in a timely manner, but not later 
than within 3 calendar days after the occurrence of the event. The Principal Investigator of a 
particular clinical site may delegate the task of reporting to a site staff, but has ultimate 
responsibility in this matter.  
 
When providing SAE reports to the NCAs, the sponsor or the sponsor’s authorized 
representatives will use the standardized SAE reporting form provided by the European 
Commission website.  
 
For Karolinska Institutet clinical site, a copy of the completed SAE reporting forms should be 
sent to the Swedish Medical Product Agency via email to meddev.central@mpa.se.  
8.6 
Withdrawal of subjects due to Adverse Device Effect 
In the event that an Unanticipated Adverse Device Effect occurs, the Principal Investigator may 
immediately remove the investigational device from the subject and withdraw the subject from the study. 
The PI will then need to follow any AE reporting guidelines as stated in the CIP.   
8.7 
Deviations from the study protocol 
Deviations from the protocol must receive both Sponsor and the investigator’s IRB approval before they 
are initiated, except for deviations to protect the rights, safety, and well-being of human subjects in an 
emergency. Any protocol deviations initiated without Sponsor and the investigator’s IRB approval that 
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must be reported to the Sponsor and to the investigator’s IRB as soon as a possible, but no later than 5 
working days of the protocol deviation. 
All deviations from the protocol will be recorded in a protocol deviation form provided by the sponsor, 
and will be promptly reported to the sponsor by the clinical site. All protocol deviation forms require 
signature and date from the Principal Investigator before being send to the sponsor. Upon receipt of the 
protocol deviation form, the sponsor will make an assessment of the protocol deviation and resolve it in a 
timely manner. The sponsor will determine the necessary resolution to the protocol deviation and record 
the resolution in the protocol deviation form.  
Corrective and preventive actions and principal investigator disqualification from the study will be 
determined by the sponsor on a case by case basis as the deviations occur. The sponsor will assess the 
nature and impact of the deviation in order to take appropriate actions to correct and prevent 
reoccurrences of the same deviation. The sponsor will assess the frequency and severity of the deviation 
in order to make a determination for possible PI disqualification from the study.  
8.8 
Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the investigator’s reviewing IRB 
as soon as possible, but no later than 5 working days of the IRB notification of withdrawal of approval. 
8.9 
Suspension or Termination of Clinical Site 
The sponsor can suspend or prematurely terminate any PI’s and site’s participation in the study, 
particularly if sponsor finds serious non-compliance by the PI or site, and if such non-compliance was not 
resolved in a timely manner. The sponsor will document the decision to suspend or terminate the 
investigation in writing. A suspended study site cannot enroll new subjects.  
If the sponsor determines that any study site’s compliance to be inadequate at any point during the study, 
and sponsor move to suspend or terminate the study site, the sponsor will provide notification in writing 
to that site’s principal investigator. The study site is eligible for reinstatement upon correction of any 
findings and any open action items prior to the suspension, and provides a written guarantee that the same 
non-compliance will not reoccur in the future. Site can only resume patient enrollment upon receiving 
written notification of reinstatement from the sponsor.  
If for any GCP and Regulatory non-compliance reasons the study site is prematurely terminated by the 
sponsor, then the study site is not eligible for reinstatement under the same Clinical Investigational 
Plan/Study Protocol.  
8.10 
Termination of Clinical Investigation due to UADE 
The clinical investigation may be terminated if sponsor determines that an unanticipated adverse device 
effect presents an unreasonable risk to the subjects. Termination shall occur no later than 5 working days 
after the sponsor makes this determination, and no later than 15 working days after the sponsor first 
received notice of the effect. Sponsor shall follow the appropriate reporting guidelines described in earlier 
section.  
Additional European Commission (EC) requirements:  
The manufacturer or his authorized representative shall notify the competent authorities of the Member 
States concerned of the end of the clinical investigation, with a justification in case of early termination. 

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In the case of early termination of the clinical investigation on safety grounds this notification shall be 
communicated to all Member States and the European Commission (refer to MDD 93/42/EEC Article 
15.7).  
In the context of this clinical investigation, the sponsor or the sponsor’s authorized representative shall 
notify the Swedish MPA via written report regarding the end of the clinical investigation and/or early 
termination as the case may be.  
9 
DATA MANAGEMENT 
Study documentation and communication during the study will be centrally managed by the 
Sponsor.  Essential study documents must be version-controlled and reviewed by the Sponsor prior to use 
at individual sites. 
All case report forms and device data files collected will be transmitted securely to the Sponsor via secure 
file transfer protocol.  
9.1 
Provisions to Protect the Privacy Interests of Subjects 
Potential study candidates will be identified following a review of the surgical schedule. Patient 
recruitment and informed consent will be obtained when there is sufficient time for a complete discussion 
between the investigator and the patient. Recruitment will be by direct discussion between the prospective 
candidates and the study investigators and/or designated study staff prior to their scheduled surgical 
procedure.  The investigators and/or designated study staff will provide the consent form in person and 
give the prospective subject sufficient time to review the consent form and discuss the study with friends 
and family.  
9.2 
Data Management and Confidentiality 
All documents associated with this protocol will be kept in the locked offices or on password protected 
computers.  All data will be de-identified before any statistical analysis. Only de-identified data will be 
shared with Masimo for research purposes stated in this clinical investigation plan.  Data collected by data 
capture software and data entered in case report form will be transferred to Masimo via a secure, 
password protected server that only study staff and Masimo study team members will have access to.  
Blood specimens, if any are required per current clinical investigation plan, will be handled according to 
standard procedures for biological materials.  Sponsors and investigators must maintain the required 
records for a period of two years after the date the investigation is completed or terminated or the records 
are no longer required to support a regulatory submission, whichever date is later. 
9.3 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, recorded data from automated instruments, and 
copies or transcriptions certified after verification as being accurate and complete.  
The site is responsible to ensure to remove all PHI from source documents before releasing to the 
sponsor. 
9.4 
Screening and Enrollment Logs 

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A subject screening and enrollment log will be provided to study site by sponsor, and maintained by study 
site. The screening and enrollment log will document, at a minimum, information such as the number of 
subjects approached for informed consent, the date of consent, subject eligibility, subject enrollment 
status, subject withdraw (if applicable) and reason(s) for withdrawal. Screening and enrollment log will 
not contain identifiable information relating to the subjects; subjects will only be identified by a unique 
subject ID number.  
9.5 
Case Report Forms and Data Acquisition  
The sponsor shall provide a Case Report Form (CRF) to the Site (See sample CRF in Appendix A1). The 
site shall capture study data in the CRFs for each subject enrolled.  
In Vivo SpHb and RPVi parameters will be captured automatically via data collection software.  
The CRF shall capture the following information, if available:  
 
Patient demographics (e.g. age, gender, ethnicity, height, weight, BMI, ASA status) 
 
Surgical profile 
 
Patient history (co-morbidities) 
 
Complete anesthesia records (all notes with clinical observations, e.g. bronchial spasms, lung 
crackles)  
 
Relevant pre-op, intra-op, and post-operative information from EMR records for determination of 
post-operative outcome measures.  
 
Pre-determined lower and upper triggers for SpHb and RPVi 
 
Reasons for blood transfusion and IV fluid infusion 
 
Intraoperative and post-operative packed red blood cell transfusion (pRBC) volumes 
 
Number of pRBC units transfused both intraoperatively and post-operatively.  
 
Intraoperative and post-operative IV fluid infusion volumes.  
 
Hemodynamic reference parameters such as Cardiac Output (CO), Stroke Volume Variance 
(SVV), Systemic Vascular Resistance (SVR), Mean Arterial Pressure (MAP), Central Venous 
Pressure, etc. 
 
Estimated and observed blood loss 
 
Urine output 
 
Fluid volume in/out information 
 
Lab hemoglobin values 
 
Complete blood gas and labs (include artCO2, Bilirubin, if available)  
 
Vital signs: PR, BP, RR, Temp, EtCO2 
 
Postoperative unplanned intubation events 
 
Length of stay (LOS) 
 
Length of stay in the ICU 
 
NSQIP (National Surgical Quality Improvement Program) complications  
 
Measurements from pulmonary artery catheter (PAC).  
9.5.1 
The CRFs will be reviewed and signed by principal investigator. This also applies to those 
subjects who fail to complete the study. If a subject withdraws from the study, it is recommended 
that the reason(s) be noted on the CRF. Case report forms are to be completed on an ongoing 

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basis. CRF entries and corrections will only be performed by study staffs that are authorized by 
the investigator. Entries and corrections to the CRF will be made following Good Documentation 
Practices.  
9.5.2 
The CRF will include the following information, including but not limited to: inclusion / 
exclusion criteria, whether patient consent obtained before start of study, demographic 
information, type and name of surgery, sensor placement, amount of blood transfused, amount of 
fluid infused, reason for transfusion and/or infusion, amount of blood drawn, timing of blood 
draws, other event timing, etc.  
9.5.3 
CRF entries will be checked by Sponsor personnel after receipt and any errors or inconsistencies 
will be queried to the site on an ongoing basis. Query resolution will be assessed and confirmed 
by study monitor during site visit. 
9.6 
Data Transfer and Storage 
9.6.1 
Device data will be captured through data capture software provided by the Sponsor (e.g. Pulse-
Ox Automated Data Collection software on a laptop) or within the study devices directly. Device 
data along with the CRF will be uploaded to sponsor via secure transfer methods.  
9.6.2 
Site will upload device data and CRFs on a weekly basis. Site will provide summary details on 
the data and CRFs being uploaded to Sponsor.  Details may include: how many cases collected 
during the week prior to data transfer, how many files are being transferred in the current 
iteration, etc.  
9.6.3 
Only authorized sponsor personnel will have access to the uploaded data on the secure file 
transfer portal, and will move it to a secure and backed-up drive at Masimo after receiving the 
upload from study site.  
9.6.4 
Device data and CRFs will be checked for completeness. If there are inconsistent or missing data 
points, a data query list will be generated and submitted to the site for corrections. Once all 
queries have been resolved, Masimo engineers are notified that data is ready for analysis. To 
ensure data integrity, Masimo engineers will only have read access to the location where data is 
being securely stored.  
9.7 
Data Entry Procedures  
In the case that paper CRFs are used for the study, study data will be entered into a database by the 
appropriate Sponsor personnel. Study data for a particular subject will be entered and verified by two 
different individuals in order to ensure data quality (i.e. the first data entry person enters the initial data, 
and a different data entry person will verify the first person’s work).  
9.8 
Data Processing and Analysis  
Recorded continuous In Vivo SpHb and RPVi trend data will be processed and analyzed to help evaluate 
secondary outcome measures. These recorded data for each subject will be used to plot trends for In Vivo 
SpHb and RPVi, which in turn will be analyzed to compare blood transfusion and fluid infusion patterns 
in both the control phase and intervention phase. For example, trend plots can be used to help evaluate 
whether SpHb can provide an early warning of critical drops in hemoglobin due to under-transfusion or 
late transfusion.  

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9.9 
Record Retention 
Study data will be retained by each Clinical Site for the necessary period of time as required by the 
institution’s regulations.  Sponsors and investigators must maintain the required records for a period of 
two years after the date the investigation is completed or terminated or the records are no longer required 
to support a regulatory submission, whichever date is later. The Institution’s own retention policies and 
regulations may apply in addition to the minimal requirement, but no less than 2 years following study 
closure.  
10 
MONITORING PLAN 
10.1 
As the sponsor of this clinical investigation, Masimo Corporation is required by 21 CFR Part 812 
of the Food and Drug Administration regulations to monitor and oversee the progress of the 
investigation.  The monitor(s) assigned by Masimo Corporation to this task will be employee(s) 
from the Clinical Research department who are trained on departmental SOPs and have adequate 
experience in conducting monitoring visits. Masimo Clinical Research Associates (CRAs) will be 
responsible for conducting study monitoring activities for this study.  
10.2 
In accordance with good clinical practices guidelines, the following monitoring visits shall be 
conducted at each clinical site to ensure overall regulatory compliance of the study:  
 
An initiation visit, prior to any subject enrollment to confirm site readiness, and to document 
training on the study protocol and procedures, and use of equipment.  
 
At least one interim monitoring visit during early enrollment for each the control phase and the 
intervention phase, preferably when site enrollment has reached 10% of subjects for each phase. 
 
Interim monitoring visits should occur approximately every 90 days.  Depending on the outcome 
of these visits, Sponsor may conduct additional monitoring visits.  
 
A final close out visit after the last patient had completed the study.  
10.3 
Prior to the initiation of the clinical investigation at the site, the monitor will conduct a site 
initiation visit at each clinical site to ensure that the investigator: 
 
Understands the investigational status of the test article and the requirements for this 
accountability. · Understands the nature of the protocol or investigational plan.  
 
Understands the requirements for an adequate and well-controlled study.  
 
Understands and accepts his or her obligations to obtain informed consent in accordance with 21 
CFR Part 50. The monitor should review a specimen of each consent document to be used by the 
investigator to assure that reasonably foreseeable risks are adequately explained.  
 
Understands and accepts his or her obligation to obtain IRB review and approval of a clinical 
investigation before the investigation may be initiated and to ensure continuing review of the 
study by the IRB in accordance with 21 CFR Part 56, and to keep the sponsor informed of such 
IRB approval and subsequent IRB actions concerning the study.  
 
Has access to an adequate number of suitable subjects to conduct the investigation. 
 
Has adequate facilities for conducting the clinical investigation.  
 
Has sufficient time from other obligations to carry out the responsibilities to which the 
investigator is committed by applicable regulations 

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10.4 
Study monitor(s) should visit the investigator at each site frequently enough to assure that: 
 
The facilities used by the investigator continue to be acceptable for purposes of the study.  
 
The study protocol or investigational plan is being followed.  
 
Changes to the protocol have been approved by the IRB and/or reported to the sponsor and the 
IRB.  
 
Accurate, complete, and current records are being maintained.  
 
Accurate, complete, and timely reports are being made to the sponsor and IRB.  
 
The investigator is carrying out the agreed-upon activities and has not delegated them to other 
previously unspecified staff. 
10.5 
Study monitor(s) will initiate contact and set up on-site visits with the investigator. Study 
monitor(s) will be allowed, on request, access to all source documents needed to verify the entries 
in the CRFs and to all other GCP-related documents (IRB approvals, IRB correspondences, and 
ICFs) provided that subject confidentiality is maintained in agreement with HIPAA regulations. 
10.6 
It will be the monitor's responsibility to inspect the CRFs at regular intervals throughout the 
study, to verify the adherence to the CIP and the completeness, consistency and accuracy of the 
data being entered on them.  
10.7 
During each visit, the monitor will also verify presence of informed consent, adherence to the 
inclusion/exclusion criteria, and documentation of SAEs/SADEs and protocol 
deviations/violations, and check CRF against source documentation. During each visit, the 
monitor should compare a representative number of subject records and other supporting 
documents with the CRFs to determine that: 
 
The information recorded in the investigator’s report is complete, accurate, and legible.  
 
Subjects failing to complete the study and the reason for each failure are noted in the reports. 
 
Informed consent has been documented in accordance with 21 CFR Parts 50 and 56. 
10.8 
After each visit, the monitor will provide a monitoring report to the investigator within 4 weeks 
of visit completion. The monitoring report will detail findings and open action items observed 
during the visit. Each report should include the following information: the date of the visit, the 
name of the individual who conducted the visit, the name and address of the investigator visited, 
and a statement of findings, conclusions, and any actions taken to correct deficiencies noted 
during the visit. It is the responsibility of the Principal Investigator and Study Coordinator(s) to 
respond to the findings of the monitoring report, and complete any open action items as soon as 
possible but no later than 60 days of receiving the monitoring report. Any open action items not 
completed within the time allowed may be sufficient grounds for study site suspension or 
termination; it will be up to the sponsor to determine whether any incomplete action items are 
sufficient grounds for suspension or termination. See Section 13 for details on suspension and 
termination.  
10.9 
Depending on the quality of the data and/or changes to factors affecting patient safety, additional 
monitoring visits may be necessary at the sponsor’s discretion. 

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11 
DATA SAFETY MONITORING BOARD (DSMB) MONITORING AND REPORTING 
PROCEDURES  
11.1 
DSMB Responsibilities 
DSMB responsibilities are outlined by the DSMB Charter, which include but are not limited to the 
following:  
 
Evaluate the progress of the clinical investigation; 
 
Review study performance and safety information; 
 
Protect the safety of the study participants; 
 
Make recommendations to the Sponsor regarding the continuation, termination or other 
modifications to the clinical investigation;  
 
Ensure the confidentiality of the study data and results of monitoring. 
11.2 
Sponsor Responsibilities 
Sponsor responsibilities are outlined by the DSMB Charter, which include but are not limited to the 
following:  
 
Assure the proper conduct of the study; 
 
Assure collection of accurate and timely data; 
 
Compile and report Serious Adverse Events (SAEs), Serious Adverse Device Effects (SADEs), 
and Unanticipated Adverse Device Effects (UADEs) to the DSMB; 
 
Report safety concern(s) to the DSMB; 
 
Prepare summary reports of relevant data for the DSMB, if requested; 
 
Communicate with regulatory authorities, IRB/EC, and investigators, in a manner that maintains 
integrity of the data, as necessary.  
11.3 
Frequency of Data and Safety Monitoring by DSMB 
Meetings of the DSMB will be held at least every 90 days, or at the request of the DSMB Chairperson. 
Meetings can be held telephonically, or in person, or a combination of the two methods.  
11.4 
Content of Data and Safety Monitoring Report  
Interim reports to the DSMB shall be prepared by the Sponsor and the Study Biostatistician. Interim 
reports to the DSMB shall be provided approximately every 90 days after the date of the first official 
DSMB meeting. The final format of the reports, tables, and listings are to be determined by the Data and 
Safety Monitoring Board. Data and Safety Monitoring Reports may include, but are not limited, to the 
following contents:  
 
Overall study status (e.g. screening, enrollment, and withdraw status)  
 
Participant descriptive information (e.g. demographic)  
 
Safety information (e.g. Adverse Events, Serious Adverse Events, UADEs)  

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 
Study quality (e.g. Protocol Deviations, missing variables on CRFs)  
11.5 
DSMB Membership and Affiliation 
The DSMB for the current clinical investigation will consist of 3 voting members. Members will have 
expertise related to the therapeutic discipline specific to the panel’s purpose. DSMB voting members will 
be from interdisciplinary specialists appropriate to the trial and may include physicians, medical ethicists, 
biostatisticians, or other specialists as indicated. The members may be recommended by representatives 
of the Sponsor but will not be affiliated and will be independent of the research under consideration and 
the investigational product.  
11.6 
Conflict of Interest for DSMB 
Board members should strive to remain free of conflicts of interest after appointment to the DSMB panel 
and for the duration of their service. Each DSMB member will sign a non-conflict of interest statement in 
regard to this clinical investigation.  
11.7 
Protection of Confidentiality  
Study data will be presented to the DSMB in a manner that would preserve the confidentiality of the 
study participants.  
All materials, discussions and proceedings of the DSMB are confidential. DSMB members and other 
participants in DSMB meetings are expected to maintain confidentiality of the study participants, trial 
data, and the results of the monitoring.  
12 
BENEFIT / RISK ANALYSIS 
The target patient population for the current investigation is adult patients undergoing major surgical 
procedures associated with the possibility of significant blood loss. A Benefit and Risk Analysis has been 
performed by the Sponsor, and the Sponsor has concluded that the anticipated benefits outweigh the 
potential risks in the current investigation/study. Benefits from the use of the information provided by the 
study devices have the potential to improve the patient’s clinical outcomes, while the risks are minimal 
and are mitigated by study procedures that require for blood draws to confirm device information. Cross 
reference IDE application Appendix A4, Benefit and Risk Analysis for the BIGT0001 Clinical 
Investigation for details.  
13 
ADMINISTRATIVE ASPECTS 
13.1 
Confidentiality 
All data collected will be kept confidential and de-identified. It can only be accessed by site staff assigned 
to the study and authorized sponsor personnel. All data collected will be used for research purposes only.  
13.2 
Publication of study results 
The principal investigators of this study plan to publish the study data and results in a peer-reviewed 
journal when the study is completed.  
The specific terms and conditions under which the principal investigators may publish the study will be 
documented in the mutual agreements set between Sponsor and Institutions of the principal investigators; 
the agreements will be separate documents apart from the CIP.  

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13.3 
Protocol Amendments 
Any deviations from the clinical investigational plan/study protocol will require Sponsor and IRB 
approval and will be documented by way of an amendment. Before submitting protocol amendment to the 
IRB, the protocol amendment must be agreed upon and signed by the principal investigator and the 
sponsor. The protocol amendment will be submitted to clinical site IRB for approval. At a minimum, a 
clean version of the new protocol amendment will be kept on file by the clinical site and the sponsor, but 
it is recommended to keep both a clean copy and a redline copy of the protocol amendment. Protocol 
amendments will need to be version controlled. Clinical site PI and sponsor will retain the IRB approval 
letter as confirmation that the protocol amendment was approved.  
Changes to the investigational plan/protocol amendments will also need to be reported to the FDA via a 
supplemental IDE application (21 CFR 812.35(a)), with the exception of the following situations:  
A. Changes effected for emergency use.  
This exception applies in the case of a deviation from the investigational plan to protect the life or 
physical well-being of a subject in an emergency. Such deviation shall be reported to the FDA 
within 5-working days after the sponsor learns of it (812.150(a)(4)).  
 
B. Changes effected with notice to FDA within 5 days.  
The following changes to the protocol do not require prior approval from the FDA, and may be 
reported in a 5-day notice to the FDA after the changes have been made, if the changes do not 
affect:  
1. The validity of the data or information resulting from the completion of an approved 
protocol, or the relationship of likely patient risk to benefit relied up on to approve the 
protocol;  
2. The scientific soundness of the investigational plan; or  
3. The rights, safety, or welfare of the human subjects involved in the investigation.  
These changes will need to be supported by credible information. Credible information is defined 
as the sponsor’s documentation supporting the conclusion that a change does not have a 
significant impact on the study design or planned statistical analysis, and that the changes does 
not affect the rights, safety, or welfare of the subjects. Documentation shall include information 
such as peer reviewed published literature, the recommendation of the clinical investigator(s), 
and/or the data gathered during the clinical trial or marketing. The sponsor is responsible for 
initially determining if the changes meet the statutory criteria described in 21 CFR 812.35(a)(3).  
C. Changes submitted in annual report 
These are minor investigational plan changes to the purpose of the study, risk analysis, 
monitoring procedures, labeling, informed consent materials, and IRB information that do not 
affect the validity of data/information; patient risk to benefit relationship; scientific soundness of 
the plan; or rights, safety or welfare of the subjects (21 CFR 812.35(a)(4)).  
In addition, the following site specific requirements will apply for protocol amendments for Karolinska 
Institute: any amendments to the protocol and informed consent form shall be submitted to the Swedish 
Medical Product Agency (MPA) for approval prior to implementation.  

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14 
AGREEMENT BETWEEN INVESTIGATORS AND SPONSOR REGARDING 
RESPONSIBILITIES FOR GOOD CLINICAL PRACTICE 
International Conference of Harmonization (ICH) E6 Good Clinical Practice guidance is an international 
ethical and scientific quality standard for designing, conducting, recording, and reporting trials that 
involve the participation of human subjects. 
It specifies general requirements intended to: 
 
Protect the rights, safety and well-being of human subjects, 
 
Ensure the scientific conduct of the clinical investigation and the credibility of the clinical 
investigation results, 
 
Assist sponsors, monitors, investigators, ethics committees, regulatory authorities and other 
bodies involved in the conformity assessment of medical devices. 
The Principal Investigators of the clinical investigation shall: 
 
Obtain and maintain IRB approval of the study. 
 
Ensure all subjects are consented prior to enrollment, per FDA Code of Federal Regulations titled 
21 CFR 50. 
 
Ensure only appropriately trained personnel will be involved in clinical investigation. 
 
Maintain study records mentioned in the CIP. 
 
Maintain logs for study team delegation, site visit/monitoring, equipment disposition, study team 
training, subject recruitment and enrollment. 
 
Evaluate all adverse events and adverse device effects and determining whether the study is safe 
to continue. 
 
Allow the sponsor to conduct periodic monitoring of study activities to ensure GCP compliance. 
 
Not promote device prior to clearance by FDA for commercial distribution, except for academic 
purposes and scientific presentations. 
The Sponsor shall ensure existence and record of all necessary compliance documents, and will conduct 
monitoring visits to ensure appropriate conduct of the study.  
Furthermore, the Sponsor and the Principal Investigator shall agree to the following:  
 
To conduct the clinical investigation outlined in this CIP in accordance with the ethical principles 
that have their origin in the Declaration of Helsinki.  
 
To conduct this clinical investigation in compliance with all stipulations of this plan, the 
conditions of IRB/EC approval, ISO-14155 and International Conference on Harmonization 
Good Clinical Practice guidelines ICH E6 GCP.  
 
To not begin the clinical investigation until the required approval/favorable opinion from the 
IRB/EC or regulatory authority have been obtained, if appropriate.  
 
To follow any additional requirements imposed by the IRB/EC or regulatory authority, if 
appropriate.  
 
To provide adequate insurance to the study subjects, if appropriate.  

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The Sponsor shall ensure that all study investigators have signed the Investigator Agreement provided by 
the Sponsor prior to participating in this study (Cross reference IDE application Appendix A5 for a 
sample copy of the Investigator Agreement).  
15 
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26.  Zimmermann M, Feibicke T, Keyl C, Prasser C, Moritz S, Graf BM, Wiesenack C. Accuracy of 
stroke volume variation compared with pleth variability index to predict fluid responsiveness in 
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31. Lan K and Zucker D. Sequential monitoring of clinical trials: the role of information and brownian 
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33. Feissel M, Kalakhy R, Banwarth P, Badie J, Pavon A, Faller JP, Quenot JP: Plethysmographic 
variation index predicts fluid responsiveness in ventilated patients in the early phase of septic shock 
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34. Loupec T, Nanadoumgar H, Frasca D, Petitpas F, Laksiri L, Baudouin D, Debaene B, Dahyot-Fizelier 
C, Mimoz O: Pleth variability index predicts fluid responsiveness in critically ill patients. Crit Care 
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47-52 
 
 
 
 
 
16 
APPENDICES 
16.1 
Appendix A1 – Case Report Form sample 
 
 
 
 
 
 

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17 
DOCUMENT REVISION HISTORY 
Version Number 
Version Date 
Summary of Revisions Made:  
1.0  
July 11, 2016 
Original version  
2.0  
Sept 20, 2017 
Removed the optional SedLine device from the study. 
Changed all references of PVi to RPVi.  
Restructured to meet requirements for IDE application.