The Influence of Age on EEG Signals and Consciousness During Anesthesia (TIARA)
Phase: NA
Conditions: Anesthesia
Sponsor: Medtronic - MITG



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APPROVALS
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DOCUMENT/RECORD 
 
 
This document/record is electronically controlled; printed copies are considered uncontrolled. 
System of Record: Regulatory Affairs Domain 
 
Document Name
RAD Version
Title
Clinical Study Manager (CSM)
Clinical Leadership
Medical Writer
12/15/2022 16:47:41
8.0
Document Approver
12/13/2022 21:49:00
Deshpande, Monika
15Nov2022 Version 5.1
Therapy SME
Stuart, Ami
12/14/2022 11:06:14
Schoen, Shirley
12/13/2022 20:40:27
Pant, Dhruba
Stuart, Ami
Biostatistician
Clinical Quality/Compliance
12/13/2022 20:40:29
Stuart, Ami
12/13/2022 23:00:58
Shih, Alex [MN043]
Stuart, Ami
12/13/2022 20:40:28
12/13/2022 20:40:28
Safety
12/15/2022 22:11:16
Klochak, Anna
Monitor
CIP TIARA

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Clinical Investigation Plan
Clinical Investigation Plan/Study Title The influence of age on EEG signals and 
consciousness during anesthesia (TIARA)  
Clinical Investigation Plan Identifier
MDT18067TIARA
Study Product Name
Bispectral (BIS™) index complete monitoring 
system 
Sponsor/Local Sponsor
Sponsor
Medtronic
Medical Surgical Portfolio
Patient Monitoring Operating Unit
6135 Gunbarrel Avenue, 
Boulder, Colorado, 80301 
USA 
Local Sponsor
EU Legal Representative
Medtronic Bakken Research Center
Endepolsdomein 5
6229 GW Maastricht The Netherlands
Document Version
5.1
Version Date
12DEC2022
Confidentiality Statement
The information contained in this document is confidential and the proprietary property of
Medtronic. Any distribution, copying, or disclosure without the prior written authorization of
Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that it is
confidential and that it may not be further disclosed by them.

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1.
Investigator Statement
Study product Name
Bispectral (BIS™) index complete monitoring system 
(BIS™Monitoring System; The 4 Channel BISx™; BISTM
bilateral sensor)
Sponsor
Sponsor
Medtronic Medical Surgical Portfolio
Patient Monitoring Operating Unit
6135 Gunbarrel Avenue, 
Boulder, Colorado, 80301 
USA 
Local Sponsor
EU Legal Representative
Medtronic Bakken Research Center
Endepolsdomein 5
6229 GW Maastricht The Netherlands
Clinical Investigation Plan Identifier
MDT18067TIARA
Version Number/Date Version 5.1, 12DEC2022
I have read the protocol, including all appendices, and I agree that it contains all necessary details for 
me and my staff to conduct this study as described. I will conduct this study as outlined herein and will 
make a reasonable effort to complete the study within the time designated.
I agree to comply with Good Clinical Practice principles outlined in ISO 14155, and other applicable 
regulatory guidelines under which the study is being conducted. I agree to ensure that the confidential 
information contained in this document will not be used for any purpose other than the evaluation and 
conduct of the clinical investigation without the prior written consent of Medtronic.
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Medtronic. I will discuss this material with them to ensure that they are fully 
informed about the products and the study.
Investigator’s Signature:
Investigator’s Name:
Institution:
Date:

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Table of Contents
1.
Investigator Statement...................................................................................................... 2
Table of Contents ...................................................................................................................... 3
2.
Glossary.............................................................................................................................. 7
3.
Synopsis ........................................................................................................................... 10
4.
Introduction ..................................................................................................................... 13
4.1
Background ...........................................................................................................................13
4.2
Purpose.................................................................................................................................14
5.
Objectives and/or Endpoints ........................................................................................... 14
5.1
Objectives .............................................................................................................................14
5.1.1
Primary Objective(s)............................................................................................................14
5.1.2
Primary Endpoint ................................................................................................................14
5.1.3
Secondary Objective(s) .......................................................................................................14
5.1.4
Secondary Endpoint............................................................................................................14
6.
Study Design .................................................................................................................... 15
6.1
Duration................................................................................................................................15
6.2
Rationale...............................................................................................................................15
7.
Product Description.......................................................................................................... 16
7.1
General .................................................................................................................................16
7.2
Manufacturer .........................................................................................................................16
7.3
Packaging..............................................................................................................................16
7.4
Intended Population...............................................................................................................17
7.5
Equipment.............................................................................................................................17
7.5.1
BIS™ Complete Monitoring System ....................................................................................17
7.5.2
BISx4™.................................................................................................................................18
7.5.3
Patient Interface Cable .......................................................................................................19
7.5.4
BIS™Bilateral Sensor...........................................................................................................19
7.5.5
Bispectral Index™(BIS)........................................................................................................20
7.5.6
Nellcor™Pulse Oximetry System ........................................................................................21
7.6
Product Use...........................................................................................................................22

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7.7
Product Training Materials ......................................................................................................22
7.8
Product Receipt and Tracking .................................................................................................22
7.9
Product Accountability............................................................................................................23
7.10 Product Storage.....................................................................................................................23
7.11 Product Return ......................................................................................................................23
8.
Study Site Requirements ................................................................................................. 24
8.1
Investigator/Investigation Site Selection..................................................................................24
8.2
Study Site Activation ..............................................................................................................24
8.3
Role of the Sponsor Representatives .......................................................................................25
9.
Selection of Subjects........................................................................................................ 25
9.1
Study Population....................................................................................................................25
9.2
Subject Enrollment.................................................................................................................26
9.3
Inclusion Criteria....................................................................................................................26
9.4
Exclusion Criteria ...................................................................................................................26
10.
Study Procedures.......................................................................................................... 27
10.1 Schedule of Events & Data Collection ......................................................................................27
10.2 Subject Screening ..................................................................................................................28
10.3 Subject Consent.....................................................................................................................28
10.4 Enrollment.............................................................................................................................29
10.5 Baseline ................................................................................................................................29
10.5.1
Demographic and Medical History......................................................................................29
10.5.2
Vital Signs............................................................................................................................30
10.5.3
Physiological & Cognitive Assessments ..............................................................................30
10.5.4
Blood Samples.....................................................................................................................31
10.6 Surgery .................................................................................................................................32
10.6.1
Pregnancy Screening...........................................................................................................32
10.6.2
Sensor Application ..............................................................................................................33
10.6.3
Induction Period..................................................................................................................33
10.6.4
Maintenance & Recovery....................................................................................................33
10.6.5
Data Collection....................................................................................................................34

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10.7 Assessment of Safety .............................................................................................................34
10.8 Recording Data......................................................................................................................34
10.9 Deviation Handling.................................................................................................................35
10.10
Subject Exit, Withdrawal or Discontinuation......................................................................36
10.11
Study Exit From Study ....................................................................................................37
10.11.1
Study Completed.............................................................................................................37
10.11.2
Subject Chooses to Exit (i.e. Revokes Consent) ..............................................................38
10.11.3
Investigator Withdraws Subject......................................................................................38
11.
Risks and Benefits ........................................................................................................ 38
11.1 Potential Risks .......................................................................................................................38
11.1.1
BIS™ Sensor Risks................................................................................................................38
11.1.2
BIS™Complete Monitoring System Risks ...........................................................................39
11.1.3
Nellcor™Oximetry Sensor Risks..........................................................................................39
11.1.4
Surgery ................................................................................................................................40
11.1.5
General Anesthetics............................................................................................................40
11.2 Potential Benefits...................................................................................................................40
11.3 Risk-Benefit Rationale ............................................................................................................41
12.
Adverse Events and Device Deficiencies ...................................................................... 41
12.1 Adverse Events ......................................................................................................................42
12.1.1
Foreseeable AE or SAE ........................................................................................................42
12.2 Device Deficiency...................................................................................................................42
12.3 Definitions/Classifications .......................................................................................................42
12.3.1
Adverse Event and Device Deficiency Reporting Requirements ........................................45
12.4 Reporting of Adverse Events...................................................................................................47
12.5 Product Complaint Reporting ..................................................................................................47
13.
Data Review Committees ............................................................................................. 48
14.
Statistical Design and Methods .................................................................................... 48
14.1 Sample Size Justification.........................................................................................................48
15.
Ethics ............................................................................................................................ 49
15.1 Statement(s) of Compliance....................................................................................................49

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16.
Study Administration.................................................................................................... 50
16.1 Monitoring.............................................................................................................................50
16.1.1
Monitoring Visits.................................................................................................................50
16.2 Data Management..................................................................................................................51
16.3 Direct Access to Source Data/Documents ................................................................................52
16.4 Confidentiality........................................................................................................................52
16.5 Liability/Warranty/Insurance Information ................................................................................52
16.5.1
Insurance.............................................................................................................................52
16.6 CIP Amendments ...................................................................................................................53
16.7 Record Retention ...................................................................................................................53
16.8 Publication and Use of Information .........................................................................................53
16.9 Suspension or Early Termination.............................................................................................54
17.
References.................................................................................................................... 56
18.
Appendices ................................................................................................................... 57
18.1 Appendix A - Modified Observer's Assessment of Alertness/Sedation scale (MOAA/S) .................57
18.2 Appendix B – Mini Mental State Examination (MMSE) ...............................................................58
18.3 Appendix C – Mini Nutritional Assessment (MNA®-SF) .............................................................59
18.4 Appendix D – Edmonton Frail Scale (EFS)................................................................................60
19.
Version History ............................................................................................................. 62

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2.
Glossary
Acronym
Definition
ADE
Adverse Device Effect
Adverse event related to the use of an investigational medical device. (ISO 14155)
AE
Adverse Event 
Untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including abnormal 
laboratory findings) in subjects, users or other persons, whether or not related to the investigational medical
device and whether anticipated or unanticipated. (ISO 14155)
A-Line
Arterial catheterization 
A catheter inserted into the artery that allows measurement of Mean Arterial Pressure (MAP) and sampling of 
arterial blood gas samples.
ASA
American Society of Anesthesiology
BIS
Bispectral Index™
This monitoring technology uses processed EEG signals to measure sedation depth based on the level of 
consciousness. 
Ce
Effective Site Concentration
CE
"Conformité Européenne" (French for European Conformity)
CE marking is a certification indication in the European Economic Area that the device or product being sold 
meets the expected health, safety and environmental standards.
CIP
Clinical Investigation Plan (“Protocol”)
Official document that states the rationale, objectives, design, conduct, monitoring, etc. of the clinical 
investigation.  
CO2
Carbon Dioxide
Levels can be monitored with a capnograph, a device that measures the concentration of carbon dioxide from 
each inspired and expired breath. Gases are collected with a non-invasive side stream from the inhaled and 
exhaled gases of the subject. Capnograph outputs numeric values and waveforms of the fractioned concentration 
of CO2 of each breath.
CRF
Case Report Form
Forms where the clinical data are collected. eCRF is the electronic version.
CTA
Clinical Trial Agreement
A formal legal contract executed by both the sponsor (Medtronic) and participating Institution which outlines 
study expectations, including compensation.
CV
Curriculum Vitae
Written record of an individual’s education, qualifications and work history.
DD
Device Deficiency
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or performance. 
(ISO 14155)
EC
Ethics Committee
Responsible for ensuring that research is carried out in a safe and ethical manner in accordance with all local and 
international law. 
ECG
Electrocardiogram 
A diagnostic tool that measures and records the electrical activity of the heart.
eCRF
Electronic Case Report Form

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Acronym
Definition
ED
Effective dose
The minimum dose or concentration of a drug that produces the intended biological response. 
EDC
Electronic Data Capture
Electronic systems where the data are collected through the eCRF (Oracle Clinical). May also be referred to as 
RDC (Remote Data Capture).
EEG
Electroencephalogram
A record of the brain activity.
EFS
Edmonton Frail Scale
Assessment measuring domains of frailty.
ET
End-tidal concentration
This is a clinical indicator for predicting the emergence from inhalation anesthetics. 
EMG
Electromyogram 
EMR
Electronic Medical Record
Digital version of a patient’s medical record within a single facility.
EtCO2
End-tidal Carbon Dioxide 
The value of exhaled carbon dioxide displayed by the capnograph device. 
EtO2
Fraction of inspired oxygen
FiO2
End expiratory oxygen
GCP
Good Clinical Practice
An international quality standard for conducting clinical trials. 
GDP
Good Documentation Practice
Guidelines or standards by which documents are created and maintained.  
HC
Helsinki Committee
Responsible for ensuring that research is carried out in a safe and ethical manner in accordance with all local and 
international law.
ICF
Informed Consent Form
An informational document that serves as a voluntary agreement to participate in research. 
IFU
Instructions for Use
IRB
Institutional Review Board
An administrative body created to protect the rights and welfare of human research subjects. 
ISF
Investigator Site File
Structured regulatory binder(s) supplied by the sponsor for study record maintenance. 
LMA
Laryngeal mask airway
Medical device that keeps a patient’s airway open during anesthesia.  
LOC
Level of consciousness
This is a measurement of a person’s responsiveness to stimuli or arousability.
MAC
Minimum alveolar concentration
The concentration of the vapor in the alveoli of the lungs that is needed to prevent movement or motor response 
of patients in response to surgical stimulus, including pain. 
MMSE
Mini Mental State Examination
This is a standardized assessment for measuring cognitive function.

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Acronym
Definition
MNA®-SF
Mini Nutritional Assessment
This is a standardized assessment for identifying malnutrition in elderly persons.
MOAA/S
Modified Observer’s Assessment of Alertness/Sedation Scale
A six-point sedation scale to assess sedation levels.  
NMBA
neuro-muscular blocking agents
PI
Principal Investigator
The person responsible for overseeing the study and assuring study completion in compliance with applicable 
regulations.
PIC
Patient Interface Cable
This sensor cable connects the BISx4 to the BIS Sensor. 
RDC
Remote Data Capture
The collection of scientific data for clinical trials, often referred to as electronic data capture (EDC). 
SAE
Serious Adverse Event
Adverse event that led to death, serious deterioration in the health of the subject…fetal distress, fetal death or a 
congenital abnormality or birth defect including physical or mental impairment.  (ISO 14155)
SpO2
Peripheral capillary oxygen saturation
A non-invasive spectroscopic estimate of arterial oxygen saturation measured transcutaneously by a pulse 
oximeter
SOP
Standard Operating Procedures
Instructions compiled by an organization to assist in carrying out complex routine operations, aiming to achieve 
efficiency and quality output. 
TCI
Target-controlled infusion
This technique of infusing IV drugs to achieve a user-defined predicted drug concentration.
TMF
Trial Master File
The collection of all essential documents which allows the conduct of a trial to be traced and evaluated. 
TIVA
Total Intravenous Anesthesia
A technique of general anesthesia in which agents are given exclusively intravenously without the use of 
inhalation agents.  

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3.
Synopsis
Title
The influence of age on EEG signals and consciousness during anesthesia 
(TIARA)  
Product Name
Bispectral (BIS™) index complete monitoring system
Sponsor 
Medtronic 
Medical Surgical Portfolio
Patient Monitoring Operating Unit
6135 Gunbarrel Avenue, 
Boulder, Colorado, 80301 
USA 
Local Sponsor
EU Legal Representative
Medtronic Bakken Research Center
Endepolsdomein 5
6229 GW Maastricht The Netherlands
Indication under investigation 
The BIS™ system will be used on-label as approved in the respective study 
site country to monitor and non-invasively measure and interpret brain wave 
activity directly related to the effects of anesthetic agents.  
Investigation Purpose
To evaluate the relationships between BIS parameters, age, and depth of 
anesthesia in patients undergoing surgery under general anesthesia. In 
particular, to improve the BIS™ Index performance in the elderly population. 
Product Status
All Medtronic products used in this study are commercially available in the
study site’s country and will be used within the specifications of the product 
labeling.  
Primary Objective
To evaluate the relationships between BIS™parameters, age, and depth of 
anesthesia in patients undergoing surgery under general anesthesia. 
Secondary Objective
To investigate BIS™parameters, depth of anesthesia and physical and 
cognitive states in these patient populations.  
Study Design
Multicenter, non-invasive, interventional, data collection study to improve 
the current BIS™algorithm.  Eligible consented subjects 18 years or older will 
be given pre-surgical assessments. Subjects will have the BIS™sensors 
applied to their forehead during the duration of the surgery.  
Sample Size
It is planned to enroll up to 100 subjects from 2 centers.  It is anticipated that 
approximately 35% of enrolled patients will be between ages 18-64 years 
old, and approximately 65% of patients will be above the age of 65 years.

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Inclusion/Exclusion Criteria
Inclusion Criteria
A potential subject may be included for participation in the study if the 
subject has/is:
1.
≥18 years of age
2.
ASA physical status I-III
3.
Able and willing to participate in the study and sign the informed 
consent form 
4.
Will undergo non-ambulatory elective surgery under general 
anesthesia
5.
Has an expected surgery time > 1 hours
Exclusion Criteria
A potential subject will be excluded from participating in the study if the 
subject has/is:
1.
Pregnant 
2.
Unwilling to undergo EEG measurement
3.
Undergone brain surgery procedure or had a cerebrovascular 
accident or severe head trauma in the last 10 years
4.
Alcohol or illicit drug use, which prevents normal functioning in 
society or has led to organ toxicity. Chronic use of opioids, narcotics, 
or analgesics, which may limit a subject's responsiveness to 
analgesic dosages.
5.
Known or suspected electroencephalograph abnormality (e.g., 
epilepsy or scarring)
6.
Presence of a major psychiatric condition such as Bipolar disorder/ 
schizophrenia/ Alzheimer's disease/ dementia/ Parkinson's disease 
/major depression
7.
Severe visual or auditory disorder
8.
Cannot understand or is unwilling to perform the study 
assessments, according to the investigator's judgment
Study Procedures and 
Assessments
Subjects will be considered enrolled at the time they sign the informed 
consent.  Basic demographic and Medical History data will be collected at the 
baseline visit, and subjects will be given three assessments:

Mini Mental State Examination (MMSE)

Mini Nutritional Assessment (MNA®-SF)

The Edmonton Frail Scale (EFS)
During the surgical procedure, the BIS™sensors will be placed on the 
subject’s forehead before any anesthetics are given, and data will be 
collected throughout the duration of the surgery.  The subject will also be 
fitted with Nellcor™pulse oximetry sensors.  

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Prior to induction subjects will be assessed using the Modified Observer’s 
Assessment of Alertness/Sedation Scale (MOAA/S). 
A slower induction of anesthesia will be achieved by setting a lower initial 
target propofol dose and making an incremental increase in the targeted 
dose. This is a conservative approach which maintains consistency across all 
study subjects and will ensure safety of the elderly patients included in the 
study, which should also closely align with standard institutional practices.  
The propofol will be administered using target-controlled infusion (TCI) 
pump, and the initial targeted effective site concentration (Ce) will be half of 
the effective site propofol concentration based on drug Instructions for Use 
(IFU) and on the subject’s body mass used for induction. The TCI will 
calculate the initial bolus and infusion rate required to rapidly achieve and 
maintain this drug level based on propofol's population pharmacokinetics 
using the Schnider Model. At this step, the depth of anesthesia will be 
assessed using MOAA/S after an equilibrium time of approximately 5 
minutes (from the start of propofol infusion.) After this initial step, the target 
effect site concentration is subsequently adjusted in an attempt to maintain 
the desired level of sedation and three-quarters of the Ce will be 
administered.  This second step will also require depth of anesthesia 
assessment using MOAA/S after an equilibrium time of approximately 5 
minutes.  Lastly, the final/full Ce of the propofol will be administered, and 
the MOAA/S will be assessed after another equilibrium time of 5 minutes is 
reached.  The specified induction period will last approximately 15 minutes 
in order to record and monitor the BIS values, EEG readings, and MOAA/S 
scores across the anesthetic agent introduction into the subject.  After these 
steps, anesthesia will be delivered and maintained per institutional guidance.
During the anesthesia maintenance phase, anesthesia medications will 
continue according to standard practice without any other intervention. 
The depth of anesthesia will be assessed at the beginning of the 
maintenance period to confirm a MOAA/S of 0 has been achieved. 
The administration of anesthetic drugs, neuro-muscular blocking agents 
(NMBA), NMBA reversal drugs, anti-nausea drugs, and drugs that reduce 
pain will be recorded on the electronic Case Report Form (eCRF)
(administration time and dosage).
BIS values and EEG data will be recorded with a USB storage device 
connected to the BIS complete monitor. Blood pressure, EtCO2, SpO2, pulse 
rate, respiration rate, end-tidal anesthetic gas, FiO2%, EtO2%, and 
temperature will be gathered from the hospital computerized database and 
the Nellcor system, digital records, labeled with patient ID, will be provided 
to Medtronic. The BIS data file labeled with patient ID will be provided to 
Medtronic.

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Only adverse events related to the BIS™and Nellcor™systems will be 
reported.  
Statistics
Descriptive statistics will be used to summarize study outcomes.  Subjects 
with valid recorded data from the study device (EEG signals) and a 
completed eCRF will be included in the data analysis.
Up to 100 subjects are planned to enroll, with 65% subjects over the age of 
65 years. The sample size is not powered to detect a statistically significant 
difference as this study is a feasibility study.
The relationships between BIS™ parameters, age, physical and cognitive 
state, and depth of anesthesia in patients undergoing surgery under general 
anesthesia will be assessed. Pearson’s correlation or Spearman’s rank 
correlation will be calculated as appropriate. Continuous variables will be 
evaluated using analysis of variance or nonlinear Emax model, and categorical 
variables will be evaluated using the chi-square or Fisher’s exact test, as well 
as multivariate logistic regression with age as an explanatory factor.  A P-
value of less than 0.05 is considered statistically significant unless otherwise 
specified.    
An early data review will be performed for the first 40 enrolled subjects to 
ensure data validity and no safety concern. Sample size re-estimation may be 
performed to ensure sufficient data to be collected to meet the study 
objectives.
4.
Introduction
4.1
Background
Brain function monitoring with Bispectral Index™ (BIS™) technology during surgical procedures gives 
anesthesia providers the ability to directly monitor the anesthetic effect on the patient’s brain and 
optimize the anesthetic dosing for the individual. 
The BIS™technology converts raw EEG data acquired from the frontal cortex into a single number 
between 0 (isoelectric EEG) and 100 (fully awake). Given the numerous changes that occur in brain 
anatomy and physiology with typical aging, it is reasonable to assume that the EEG patterns of elderly 
patients and young patients under general anesthesia differ.
In general, elderly patients are more sensitive to anesthetic agents. Less medication is usually required to 
achieve a desired clinical effect, and drug effect is often prolonged[1]. We might thus hypothesize that the 
BIS™technology should be age adjusted under the assumption that the anesthetic state is also dependent 
on the patient's physical, mental, and cognitive state.

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4.2
Purpose
To evaluate the relationships between BIS™parameters, age, and depth of anesthesia in patients 
undergoing surgery under general anesthesia. In particular, to improve the BIS™ Index performance in the 
elderly population. 
5.
Objectives and/or Endpoints
5.1
Objectives
This study is evaluating the BIS™system’s response under specified and standard clinical practices for 
patients undergoing elective surgery under general anesthesia.  
5.1.1 Primary Objective(s)
To evalute the relationships between BIS™parameters, age, and depth of anesthesia in patients 
undergoing surgery under general anesthesia. 
5.1.2 Primary Endpoint
All data gathered by the BIS™system during general anesthesia, including:

EEG waveforms

Electromyogram (EMG)

BIS Number

Total Power

Anesthesia records
5.1.3 Secondary Objective(s)
To investigate BIS™parameters, depth of anesthesia and physical and cognitive states in the study subject 
population.  
5.1.4 Secondary Endpoint
Assessments of the subject’s demographics, age and blood panel as well as the physical and cognitive 
state using:

Mini Mental State Examination (MMSE)

Mini Nutritional Assessment (MNA®-SF)

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
Edmonton Frail Scale (EFS)
6.
Study Design
This is a multicenter, non-invasive, interventional data collection study to improve the current BIS™
algorithm. Subjects undergoing a standard of care, elective non-ambulatory surgery under general 
anesthesia will be recruited. Eligible patients 18 years and older, will be informed of the study and invited 
to participate. Each eligible and consented subject will undergo the study assessments and procedures.  
The BIS™sensors will be applied to the patient’s forehead before anesthesia is administered. The BIS™
data will be collected throughout the surgery. The data recorded during the surgery will be provided to 
Medtronic.
It is planned to enroll up to 100 subjects from 2 centers.  It is anticipated that approximately 35% of 
enrolled patients will be between ages 18-64 years old, and approximately 65% of patients will be above 
the age of 65 years. In addition to basic demographic data collection, three assessments, the Mini Mental 
State Examination (MMSE), the Mini Nutritional Assessment (MNA®-SF), and the Edmonton Frail Scale
(EFS) will be administered to each subject prior to surgery.  
Study sites that enroll faster than others will be allowed to do so in order to maintain an adequate 
enrollment rate.  
6.1
Duration
Enrollment begins at patient consent and lasts through the duration of the surgery. This may span one 
day or multiple days depending on site-preference and consent timing. No additional follow-up visits will 
be required after the surgery is complete. 
The trial is expected to last approximately 2 years after subject enrollment begins.  
6.2
Rationale
The BIS™technology converts raw EEG data acquired from the frontal cortex into a single number 
between 0 (isoelectric EEG) and 100 (fully awake). Given the numerous changes that occur in brain 
anatomy and physiology with typical aging, it is reasonable to assume that the EEG patterns of elderly 
patients and young patients under general anesthesia differ. Medtronic is continuously improving its 
monitoring devices to improve performance and widen the range of capabilities. To assess an algorithm, 
more robust clinical data is required to ensure the optimal functionality of the system.  All data collected 
will be stored and may be used for future research and development.  

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7.
Product Description
7.1
General 
The BIS™Complete Monitoring System is a user-configurable patient monitoring system designed to 
monitor the hypnotic state of the brain based on the acquisition and processing of EEG signals. The BIS™
complete system processes raw EEG signals to produce a single number, called the BIS™index, which 
correlates with the patient's level of hypnosis. The bilateral sensor placed on the patient’s head collects 
EEG signals and transmits them to the BISx4™unit.  The BISx4™unit filters and digitizes the signal, analyzes 
it for the artifact, and processes it using digital signal processing techniques to derive processed EEG 
parameters such as the BIS index, and finally sends the processed data to the monitor for display. The
purpose of processing the EEG waveform data is to extract characteristic features from the complex signal 
that the BIS algorithm can utilize to ultimately derive the BIS™Index.
The Nellcor™ Pulse Oximetry System continuously records Sp02 measurements through one or more 
sensors.  The Nellcor™ Adult SpO2 Sensor, is indicated for single patient use when continuous noninvasive 
arterial oxygen saturation and pulse rate monitoring is needed.  
7.2
Manufacturer
BIS™ and Nellcor™are manufactured by Covidien LP, an indirect wholly owned subsidiary of Medtronic 
plc. with an address at Mansfield, MA USA.
7.3
Packaging
The BIS™ Complete Monitoring System will be provided by the sponsor at no charge and will be used as a 
study product.  The Nellcor™ Pulse Oximetry System may also be provided to study sites at no charge and 
used as a study product as needed.
Conformité Européenne, or European Conformity (CE) marked devices will be used within intended use 
as described in the approved Instructions for Use (IFU) for which CE mark has been obtained.
All equipment associated with the clinical study will be identified with visible markings stating, “For clinical 
trial use only.” Labeling of devices will be provided in accordance with local language requirements.  
The consumables (BIS™ bilateral sensor and Nellcor™ adult sensor) are for single patient use, and each 
consumable is packaged individually.  

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7.4
Intended Population
The BIS™ EEG complete monitor system is intended for use under the direct supervision of a licensed 
healthcare practitioner or by personnel trained in its proper use. The system, and all its associated 
parameters, is intended for use on adult and pediatric patients within a hospital or medical facility 
providing patient care to monitor the state of the brain by data acquisition of EEG signals. The BIS™ index, 
one of the Complete Monitor output parameters, may be used as an aid in monitoring the effects of 
certain anesthetic agents; and its usage with certain anesthetic agents may be associated with a reduction 
in primary anesthetic use and a reduction in emergence and recovery time. Use of the BIS™ index for 
monitoring to help guide anesthetic administration may be associated with the reduction of incidence of 
awareness with recall in adults during general anesthesia and sedation.
In this study, the intended population is adults undergoing standard of care, elective non-ambulatory 
surgery with general anesthesia.
7.5
Equipment
The following equipment will be made available at each study site to support study activities.
7.5.1 BIS™ Complete Monitoring System 
The BIS™Complete Monitor is an easy to use microprocessor-based EEG monitor. The BIS™Complete 
Monitor reports a BIS value by acquiring up to two channels of EEG from sensors attached to the patient’s 
forehead and performing the computations necessary to produce the BIS™ Index. The BIS™ Index is then 
numerically displayed for the clinician’s use. The BIS™Complete Monitoring System consists of the 
following components as shown below in Figure 1:

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
BIS™Complete Monitor

BISx4™(BISx4 will be used in this study)

Patient Interface Cable (PIC) 

BIS™Bilateral Sensor

Detachable Power Cord
Figure 1: The BIS™Complete Monitoring System. 1 - Monitor Interface Cable; 2 - BIS™ Monitor; 3- BIS™ bilateral sensor will be 
used; 4- Patient Interface Cable (PIC); 5- BISx4™ (LoC 4 Channel)
7.5.2 BISx4™
The BISx4™receives, filters, digitizes and processes patient EEG signals. It is located close to the patient's 
head, where the EEG signal is less subject to interference from other medical equipment. The BISx4™is 
shown in Figure 2. Its long flexible Monitor Interface Cable connects to the front of the monitor. The 
Patient Interface Cable (PIC) connects the BIS sensor to the BISx4™. The attachment clip on the BISx4™is 
used to secure it in a convenient location near the patient's head. The BISx4™Module is a variant of the 
BISx™Module, and it processes up to four channels of EEG data. In this study, BISx4™Module will be used 
with Bilateral Sensor.

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Figure 2: BISx4™- 1- Monitor Interface Cable connects to Monitor; 2- Patient Interface Cable connects to BIS sensor; 3-
BISx4™ (BIS LoC 4 Channel)
7.5.3 Patient Interface Cable
The Patient Interface Cable (PIC) connects the BISx4™to the BIS™Sensor, refer to Figure 2 above. 
7.5.4 BIS™Bilateral Sensor
The sensor is the single-use component of the BIS™Monitoring System and should be replaced after each 
use. BIS™Bilateral Sensors are designed with a 6 electrode pre-gelled EEG electrode array that is applied 
directly to the patient’s forehead to transmit EEG signals to the BISx4™Module as shown below in Figure 
3. When the System is connected to a BISx4™module and a BIS™ Bilateral Sensor, the monitor displays 
four channels of EEG.
Figure 3: BIS™Bilateral Sensor

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7.5.5 Bispectral Index™(BIS)
Bispectral Index™(BIS) monitoring systems allow anesthesia professionals the ability to access processed 
EEG information as a measure of the effect of certain anesthetics during the care of patients they select 
to monitor. The clinical impact of BIS™monitoring has been demonstrated in a variety of randomized 
controlled trials that reveal the potential for BIS monitoring to facilitate improvements – including patient 
safety – in anesthesia care[2].
The BIS™Index is a number between 0 and 100 scaled to correlate important clinical endpoints, such as 
moderate sedation or deep anesthesia, and EEG states during the administration of anesthetic agents (see
Figure 4). BIS™values near 100 represent an “awake” clinical state while 0 denotes the maximal EEG effect 
possible (i.e., an isoelectric EEG). A BIS™value of 60 has a high sensitivity for identifying drug-induced 
unconsciousness. However, in some settings and with some combinations of sedatives and analgesics, 
unconscious individuals may have BIS™values >60.
Figure 4: BIS™Index Scale
Consideration of BIS™ information may be useful in various clinical situations that develop during 
anesthesia care, such as intra-operative awareness and too deep anesthesia. Ideally, BIS™ information 
can be integrated with other available monitoring information and patient assessment. As defined in the 

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A Pocket Guide for Clinicians of the BIS™, several clinical situations can influence the accuracy of the BIS™
value as an indicator of anesthetic hypnotic effect. Four key areas include the influence of muscle tone 
(EMG) from the forehead muscles; electrical and mechanical artifacts from medical devices; abnormal 
EEG states; and certain anesthetic agents and adjuvants – which can all lead to elevated BIS™values. 
Serious clinical conditions – which may require a prompt response – have been associated with the sudden 
appearance of low BIS™values. BIS™responses are similar when most, but not all, anesthetic agents are 
administered in increasing amounts. Specifically, BIS™responses to typical hypnotic agents (midazolam, 
Propofol, thiopental, isoflurane) were similar[3,4]. However, halothane has been found to have higher BIS™
values at an equipotent minimum alveolar concentration dose[5]. Further, BIS responses to ketamine 
administration are atypical[6.7]. In addition, BIS™responses to administration of analgesic agents –
including opioid analgesics and nitrous oxide –depend on the level of concomitant stimulation.
A significant correlation between BIS™ Index values and reduction in whole brain metabolic activity due 
to increasing anesthetic effect was measured using positron emission tomography[8]. Thus, factors other 
than drug administration that can influence brain metabolism (e.g., alterations in temperature or 
physiologic homeostasis) may also produce changes in the BIS™ Index.
7.5.6 Nellcor™Pulse Oximetry System
The Nellcor™ bedside respiratory patient monitoring system provides continuous Sp02 recording through 
one or more sensors.  The market-approved system, sensors and cables or other monitor may be provided 
by the sponsor to the study site.  A laptop may also be provided to stream and record the Sp02 data if 
needed.  
The Nellcor™ Adult SpO2 Sensor, is indicated for single patient use when continuous noninvasive arterial 
oxygen saturation and pulse rate monitoring are required for patients weighing more than 30 kg.  One or 
more sensors may be used, and can be applied to a small finger, thumb, or big toe.  
Figure 5: Nellcor Adult Sp02 Sensor

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7.6
Product Use
A member of the Medtronic team will set up the BIS™system at each participating research site upon site 
initiation and will ensure all equipment is fully functional. Specific instructions for the Site Investigator(s) 
and staff on system set up, use sensor application, and data transfer will be provided before subject 
enrollment.
7.7
Product Training Materials
All investigators and study staff members will be trained by the sponsor. The training will be performed 
prior to site activation and the recruitment of the first subject. Investigators or staff members are not 
permitted to perform any activity in the study before training is completed and correctly documented. 
Training will include at least the following topics: 

Study procedures

Informed consent procedures and documentation

Adverse Events (AEs), Safety Events, Device Deficiencies (DDs) and the reporting procedures of 
these events

Good Clinical Practice (GCP)

Study device management

Case Report Form (CRF) completion

Overview of the physical and cognitive assessment procedures 

Overview of ISO14155
It is the responsibility of the Principal Investigator (PI) at each participating site to ensure any staff 
performing tasks related to the clinical trial (e.g., Study Coordinators, Study Nurses, Sub-Investigators, 
etc.) have been appropriately trained, their training documented and included on the Delegation of 
Authority Log.
7.8
Product Receipt and Tracking
The investigator or designee will maintain records of all devices or products provided by Medtronic free 
of charge to the study site. 
Due to potential device variations across the regions in which the study will be conducted, all device 
components for both the BIS™ and Nellcor™ systems, including models and versions will be specified 
according to product accountability records.

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7.9
Product Accountability
Product accountability will be documented by the PI or an authorized designee, using the sponsor shipping 
records, the Product Accountability Log, and also entry into the Device Accountability eCRF.  The PI or an 
authorized designee shall keep source records documenting the receipt, use, return, and disposal of the 
study devices, which shall include (but is not limited to):

Date of receipt, and name of person who received the shipment

Identification of each study device (e.g. model number/part number, serial number/lot number, 
firmware/software number, etc.),

Expiration date, if applicable,

Subject ID association (applicable for Sensors only)

Return or disposal date, including reason and name of person who disposed or returned device
The monitor is responsible to verify that the product is stored and maintained as described in Sections 
7.9-7.11 and to verify the product accountability using the Device Accountability eCRF.
All products used in this study are market released in the geographies they are used. Additional device 
traceability may be required per local laws and regulations. If there are additional local requirements 
beyond what is collected by Medtronic on the eCRF, this is the Investigator’s responsibility and should be 
recorded in the subject’s medical records, but will not be collected by Medtronic (e.g., identification code 
linked to names and contact information, log of all subjects enrolled in the  study, batch number, etc.). 
7.10 Product Storage
The study equipment will be stored in a locked room, ideally in the Anesthesiology and Recovery Room 
department, whenever possible. The PI or his or her delegate is responsible for the appropriate storage 
of the product according to the study protocol and the device operator's manual.  The study equipment 
should be easily identifiable and stored in a dry room at ambient temperature. Only the study staff 
delegated to use the equipment by the PI and trained by the sponsor should have access to the study 
equipment.
7.11 Product Return
All the study products will be returned to the sponsor at the end of the study. The product return will be 
documented in the Trial Master File (TMF) and Investigator Site File (ISF). All used single-patient 
consumables shall be destroyed, and the sponsor will provide further instructions to do so. All unused 
consumables will be returned to the sponsor. 

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8.
Study Site Requirements
8.1
Investigator/Investigation Site Selection
All investigators managing the subject’s anesthesia during surgery must be qualified and experienced 
practitioners.  The physicians be experienced and/or trained in the handling of the BIS™and Nellcor™
systems.
The role of the PI is to implement and manage the day-to-day conduct of the clinical investigation as well 
as ensure data integrity and the rights, safety and well-being of the subjects involved in the clinical 
investigation.
The PI shall:

Be qualified by education, training, and experience to assume responsibility for the proper 
conduct of the clinical investigation

Be experienced in the field of application and training in the use of BIS

Disclose potential conflicts of interest, including financial, that interfere with the conduct of the 
clinical investigation or interpretation of results

Be able to demonstrate that the proposed investigational study site:
o
Has the required number of eligible subjects needed within the recruitment period
o
Has one or more qualified investigators, a qualified investigational study site team and 
adequate facilities for the foreseen duration of the clinical investigation
Study site personnel training will be completed and documented prior to participation in this study.
8.2
Study Site Activation
During the activation process (prior to subject enrollment), Medtronic will train study site personnel on 
the clinical investigation plan, on relevant standards and regulations, informed consent, and on data 
collection and reporting tools. If new members join the study site team, they will receive training on the 
applicable study requirements relevant to their role before contributing to the study.
Prior to performing study related activities, all regulatory requirements as well as financing agreements
shall be fulfilled, including, but not limited to the following: 

Institutional Review Board/ Ethics or Helsinki Committee (IRB/EC/HC) approval (and voting list, as 
required by local law) of the current version of the Clinical Investigation Plan (CIP) and Informed 
Consent Form (ICF). 

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
Regulatory Authority approval or notification (as required per local law) 

Fully executed Clinical Trial Agreement (CTA)

Financial disclosure

Curriculum Vitae (CV) of investigators and key members of the investigation study site team (as 
required). The signature on the CV must be dated within 3 years prior to the date of activation of 
the study site.  

Documentation of delegated tasks

Documentation of study training

Additional requirements imposed by local regulations, the IRB/EC/HC and Regulatory Authority
shall be followed, if appropriate. 
In addition, all participating study site staff must be trained on the current version of the CIP as well as on 
the applicable study requirements depending on their role and must be delegated by the principal 
investigator to perform study related activities.  
Medtronic will provide each study site with documentation of study site/investigator readiness; this letter 
must be received prior to performing study related activities.
8.3
Role of the Sponsor Representatives
Sponsor representatives may provide support at the study site as required for the study under supervision 
of the Principal Investigator, including:

Provide study training relevant and pertinent to the involvement of personnel conducting study 
activities and investigator responsibilities

Technical support at the Surgery Visit under the supervision of a study investigator, but no data 
entry, shall be performed by Medtronic personnel or their representatives at study sites

Monitoring and auditing activities 
9.
Selection of Subjects
9.1
Study Population
Potential subjects will include patients scheduled for a standard of care, elective non-ambulatory surgery 
under general anesthesia who meet all the inclusion and none of the exclusion criteria as specified in 
Sections 9.3 and 9.4.

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9.2
Subject Enrollment
Subjects are eligible for enrollment into the study only after all inclusion and exclusion criteria have been 
reviewed and verified by the PI or a delegated study staff member.  Study enrollment is accomplished by 
signing the Informed Consent Form (ICF) and documenting the entire informed consent process.  Subjects 
who sign informed consent, but later are discovered to not meet and inclusion or exclusion criteria, will 
be withdrawn from the study.  
9.3
Inclusion Criteria
A potential subject may be included for participation in the study if the subject has/is:
1.
≥18 years of age
2.
ASA physical status I-III
3.
Able and willing to participate in the study and sign the informed consent form 
4.
Will undergo non-ambulatory elective surgery under general anesthesia.
5.
Has an expected surgery time > 1 hours
9.4
Exclusion Criteria
A potential subject will be excluded from participating in the study if the subject has/is:
1.
Pregnant 
2.
Unwilling to undergo EEG measurement
3.
Undergone brain surgery procedure or had a cerebrovascular accident or severe head trauma in 
the last 10 years. 
4.
Alcohol or illicit drug use, which prevents normal functioning in society or has led to organ toxicity. 
Chronic use of opioids, narcotics, or analgesics, which may limit a subject's responsiveness to 
analgesic dosages.
5.
Known or suspected electroencephalograph abnormality (e.g., epilepsy or scarring).
6.
Presence of a major psychiatric condition such as Bipolar disorder/ schizophrenia/ Alzheimer's 
disease/ dementia / Parkinson's disease /major depression.
7.
Severe visual or auditory disorder.
8.
Cannot understand or is unwilling to perform the study assessments, according to the 
investigator's judgment.

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10. Study Procedures
Study Procedures will take place during the Baseline and Surgery phase of the study, which may be split 
into two separate days, or combined into one.  A Schedule of Events table is located in Section 10.1 below, 
with additional details following.  
10.1 Schedule of Events & Data Collection
Table 1. Schedule of Events & Data Collection Requirements
Data
Baseline
Surgery
Informed Consent Process and Documentation
X
Inclusion/Exclusion criteria evaluation
X
Demographic & Medical history 
X
Mini Mental State Examination (MMSE)
X
Mini Nutritional Assessment (MNA-SF®)
X
Edmonton Frail Scale
X
Blood sample - levels of albumin, total protein, hemoglobin, total 
cholesterol
X
Pregnancy screening (See section 10.6.1)
X
BIS™ sensor and Nellcor™ sensor application 
X
BIS™ data collection
X
Patient vital signs (blood pressure, EtCO2, SpO2, pulse rate, FiO2%, EtO2%, 
respiration rate and temperature) 
X
DOA according to the Modified OAA/S Responsive Scale
X
Drug administration during the surgery - Anesthetic drugs, drugs that 
induced or reduced paralysis, anti-nausea drugs, drugs that reduce pain 
(drug, dosage and time)
X
X
Adverse Events as described in Section 12 
X
Protocol Deviations
X
Reason for Premature Study Termination (including patient death)
X
X

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10.2 Subject Screening
Patients will be identified as potential study candidates at the pre-surgical evaluation when being 
considered for surgery. 
The investigator will ensure that the patient can be enrolled in the study according to the 
inclusion/exclusion criteria, including the ability to sign the informed consent form.  The delegated study 
team member performing the consent process will be responsible for all documentation of the informed 
consent process. 
The investigator will register the subject in the enrollment log with their name, ID number, and unique 
study code. The study code assigned after the enrollment process will be used for all data identification. 
The identifying details of the subject will be written only in the enrollment log and the ICF and will not be 
transmitted to the sponsor or any other unauthorized person or entity.
10.3 Subject Consent
Informed consent initiates enrollment, and therefore must be obtained before any study-specific 
procedures are initiated. Only the PI or authorized designee may conduct the informed consent process, 
and this should be done only after all inclusion and exclusion criteria have been verified.  The ICF used 
must be the most recent form that was approved by the sponsor and the Institutional Review Board/ 
Ethics or Helsinki Committee (IRB/EC/HC) and implemented to the site through proper training.  The ICF 
must be current on the date signature.  The ICF should be in a language that is clear to the subject.  The 
subject must have ample time and opportunity to read and understand the informed consent form, to 
inquire about the details of the study, and to decide whether or not to participate in the clinical study. All 
questions about the study should be answered to the satisfaction of the subject.  The original ICF, as well 
as all corresponding documentation, must be placed in the subject’s original source file.  A copy of the ICF 
should be given to the subject.
In the event the subject cannot read and/or write, the informed consent process shall be obtained through 
a supervised oral process.  An independent and impartial witness must be present during this process.  All 
ICF and any other information must be read aloud to the prospective subject, and when possible, the 
subject shall personally sign and date the ICF.  The witness signs and personally dates the ICF attesting 
that the information was accurately explained and that informed consent was freely given.  
Consistent with the DoH, vulnerable adults (i.e. those subjects mentally incapable of giving consent) are 
excluded from this protocol.  Any subjects with mental incompetence (e.g. Alzheimer’s, dementia, 
psychiatric disorders, developmental disorders) should be assessed for vulnerable status. If the ICF is 
signed by an individual other than the subject, the monitor may discuss whether the Investigator believes 
the subject meets the definition of a vulnerable adult.  This protocol defines vulnerable adult as those 

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subjects mentally incapable of giving consent, in the Investigator’s opinion.  The Investigator should 
consider the definition of vulnerable adult per ISO 14155, which defines vulnerable adults as: “individuals 
who are unable to fully understand all aspects of the investigation that are relevant to the decision to 
participate, or who could be manipulated or unduly influenced as a result of a compromised position, 
expectation of benefits or fear of a retaliatory response. For example, this could include Individuals with 
loss of autonomy due to immaturity or through mental disability, persons in nursing homes, children, 
impoverished persons, subjects in emergency situations, ethnic minority groups, homeless persons, 
nomads, refugees, and those incapable of giving informed consent. Other vulnerable subjects could 
include, for example, members of a group with a hierarchical structure such as university students, 
subordinate hospital and laboratory personnel, employees of the sponsor, members of the armed forces, 
and persons kept in detention.
Legally authorized/designated representatives or guardians will not be permitted to execute the informed 
consent for this study.  
Participation in this study is voluntary. The subject may elect not to be a part of the study or to leave the 
study at any time, for any reason. If the subject elects not to be a part of the study or to leave the study, 
this will not result in any penalty, and the subject will not lose any benefit to which the subject is entitled. 
This will not affect the routine treatment the subject receives, their relationship with the hospital, the 
clinic, or their doctors.
10.4 Enrollment
A subject is considered enrolled when the informed consent process has been finalized. The date the 
subject signed the ICF (and Data Protection Authorization, as required by local law) must be documented 
in the subject’s medical records. A log of all subjects enrolled in the study should be maintained, as this 
study following ISO 14155 standards. Enrollment can be a stand-alone visit or can occur on the same day 
as the baseline.  
10.5 Baseline
The baseline study procedures can be a stand-alone visit, or can be performed on the same day prior to 
the start of the surgery.  
The following subsections outline the required procedures and data collection.  
10.5.1
Demographic and Medical History
Demographic details (i.e., gender, weight, height, age, skin pigmentation), and medical history including 
primary and secondary diagnosis will be transcribed into the eCRF.  

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There are no medication/therapy restrictions in the study unless they are investigational and may 
confound the study results, in which case, prior approval would be needed from Medtronic.  All 
prescription and over-the-counter medications taken within 14 days prior to screening will be collected 
and transcribed into the eCRF.  The name of the medication, dose, and frequency and start and stop dates 
will be recorded.  
If the baseline procedures occur on a separate date from the surgery visit, the subject should identify to 
the study team, the name and contact information of an individual that can be contacted in case the 
subject cannot be reached for any reason.  This individual may be asked how the study subject may be 
reached, and about the subject’s health status.
Subjects who are completing the baseline and surgery requirements on the same day will not be required 
to provide a contact person as there is no follow-up period beyond surgery.
10.5.2
Vital Signs
Baseline vital signs will be collected and transcribed into the eCRF.  All baseline vitals should be collected 
prior to any surgery or induction procedures and will include the following:

Systolic Blood Pressure

Diastolic Blood Pressure

Mean Blood Pressure

Sp02

Heart Rate

Respiratory Rate
10.5.3
Physiological & Cognitive Assessments
Three assessments, the Mini Mental State Examination (MMSE), the and the Mini Nutritional Assessment 
(MNA®-SF), and the Edmonton Frail Scale (EFS) will be administered to evaluate the subject’s cognitive 
function. The test will be administered at the baseline visit or prior to surgery. 
10.5.3.1
Mini Mental State Examination (MMSE)
The MMSE is widely used for a measure of cognitive function[9]. The MMSE consists of a variety of 
questions, has a maximum score of 30 points, and ordinarily can be administered in 5-10 minutes. The 
questions are grouped into seven categories, each rationally representing a different cognitive domain or 
function: Orientation to time (5 points); Orientation to place (5 points); Registration of three words (3 
points); Attention and Calculation (5 points); Recall of three words (3 points); Language (8 points) and 

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Visual Construction (1 point). The total score will be recorded on the eCRFs.  A sample copy is located in 
Appendix B. 
10.5.3.2
Mini Nutritional Assessment – Short Form (MNA®-SF)
The MNA®-SF provides a simple and quick method of identifying elderly persons who are at risk for 
malnutrition, or who are already malnourished.[10] It identifies the risk of malnutrition before severe 
changes in weight or serum protein levels occur. The MNA®-SF was developed by Nestlé and leading 
international geriatricians and remains one of the few validated screening tools for the elderly. It has been 
well validated in international studies in a variety of settings. The scoring provides a maximum subtotal of 
14 points, and it takes 5-10 minutes to administer. The score between 12-14 points is considered normal 
nutritional status; 8-11 points indicate the patient is at risk of malnutrition, and 0-7 points are 
malnourished. The total score will be recorded on the eCRFs.  See Appendix C for a sample copy of the 
scale.  
10.5.3.3
Edmonton Frail Scale (EFS)
Frailty is a medical syndrome with multiple causes and contributors that is characterized by diminished 
strength, endurance, and reduced physiologic function that increases an individual's vulnerability for 
developing increased dependency. The Edmonton Frail Scale assesses nine domains of frailty including a 
cognition evaluation (i.e. hand-draw a face clock), functional performance (i.e. timed get up & go test), 
general health status, functional independence, social support, medication usage, nutrition, mood, and 
continence.[11] It can be administered in 5-10 minutes and is scored from 0 to 17.  A higher score indicates 
a higher degree of frailty, scores 10+ in the severe range.  The total test score will be recorded on the 
eCRFs.  A sample copy of the scale can be found in Appendix D. 
10.5.4
Blood Samples
Blood sample collection can be completed after informed consent has been obtained.  The blood sample 
can be collected at Baseline, before surgery, or at the start of the surgery visit.  If the blood sample is 
taken after the patient has been sedated and anesthesia induction begins, the blood sample should be 
taken from the opposite arm from which the intravenous therapy infusion of propofol was administered.  
The blood sample should be taken as soon as possible, but is required to be taken before intubation or 
the first surgical incision is made (whichever comes first).  

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Blood samples to assess the levels of the following will be collected and documented in the eCRF:

Albumin (gm/dL)

Hemoglobin (gm/dL)

Total cholesterol (mg/dL)

Total protein (gm/dL)
10.6 Surgery
The following sub-sections outline the required procedures and data collection during the surgery.  
10.6.1
Pregnancy Screening
Due to the potential risk the surgery and anesthesia administration might pose, pregnant women should 
not take part in this study.  It is expected that female subjects of child-bearing potential (i.e. not post-
menopausal or surgically sterile) will be screened for pregnancy according to standard institutional 
policies before the surgery visit.  If standard screening is not in place, then a urine or blood pregnancy test 
must be administered, and results confirmed as close to the time the surgery begins as possible to confirm 
they are not pregnant.  
If the Baseline and Surgery visits take place on separate days, female subjects must agree to not become 
pregnancy during the study by using a medically acceptable method of birth control.  If a subject does 
become pregnancy, there may be risks to the subject or to their unborn child that are not yet known.  
Subjects must notify the study doctor immediately if they think they are pregnant or if they become 
pregnant during the study.  If in the Investigator’s opinion enough time has passed between the test and 
the time of surgery, the subject may be required to undergo another pregnancy test.
Site personnel are responsible for the following:

Documenting all available information regarding the pregnancy in the source documents and 
notifying Medtronic study personnel

Notifying the IRB per the study site’s requirements
Exiting the subject from the study and completing the appropriate eCRF(s) according to Section 10.10.1.

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10.6.2
Sensor Application
Prior to any anesthesia administration and following preparation of the skin of the subject's forehead, a 
bilateral BIS™sensor will be applied. The BIS™data collection will start with sensor application and 
continue throughout the entire duration of the surgery. 
One or more Nellcor™sensors may also be applied at this time to collect pulse oximetry data.  The 
sensor(s) should be placed on a finger on the opposite arm in which the intravenous therapy line is located
or can also be placed on a big toe.  The precise location of each sensor will be captured in the eCRF.  
10.6.3
Induction Period
During the induction procedure, subjects will be pre-medicated per institutional guidance. All pre-
medications, doses, and times of administration will be recorded in the eCRFs. 
Prior to induction, subjects will be assessed using the Modified Observer’s Assessment of 
Alertness/Sedation Scale (MOAA/S) which can be referenced in Appendix A. 
A slower induction of anesthesia will be achieved by setting a lower initial target propofol dose and making 
an incremental increase in the targeted dose. This is a conservative approach which maintains consistency 
across all study subjects and will ensure safety of the elderly patients included in the study, which should 
also closely align with standard institutional practices. The propofol will be administered using target-
controlled infusion (TCI) pump, and the initial targeted effective site concentration (Ce) will be half of the 
effective site propofol concentration dosage based on drug Instructions for Use (IFU) based on the 
subject’s body mass used for induction. The TCI will calculate the initial bolus and infusion rate required 
to rapidly achieve and maintain this drug level based on propofol's population pharmacokinetics using the 
Schnider Model. At this step, the depth of anesthesia will be assessed using MOAA/S after an equilibrium 
time of approximately 5 minutes (from the start of propofol infusion.) After this initial step, the target 
effect site concentration is subsequently adjusted in an attempt to maintain the desired level of sedation 
and three-quarters of the Ce will be administered.  This second step will also require depth of anesthesia 
assessment using MOAA/S after an equilibrium time of approximately 5 minutes.  Lastly, the final/full Ce
dose of the propofol will be administered, and the MOAA/S will be assessed after another equilibrium 
time of 5 minutes is reached.  The specified induction period will last approximately 15 minutes in order 
to record and monitor the BIS values, EEG readings, and MOAA/S scores across the anesthetic agent 
introduction into the subject.  
10.6.4
Maintenance & Recovery
After the specified induction period, anesthesia will continue according to standard practice/institutional 
guidance.

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At the beginning of induction, the depth of anesthesia will be assessed to ensure a MOAA/S of 0 has been 
obtained.
In addition, the time of the following assessments will be collected during the surgery:

Start of induction of anesthesia

Intubation

Surgical Incision

Skin Closure

End of The Surgery

Extubation

Immediately Prior To BIS™Sensor Removal
10.6.5
Data Collection
The start time of any drug infusion, target effect-site concentrations, infusion rate, the start time of the 
assessment including BIS value prior to MOAA/S assessment, and MOAA/S assessment will be recorded 
in the eCRFs. Any adjustments to the infusion rate and time of adjustment will be recorded, and any 
changes to subject management during the procedure will be noted on the eCRFs. 
The MOAA/S score, time of and main procedural event will be recorded on the eCRFs. 
The anesthetic drugs, muscular blocking agents (NMBA), NMBA reversal drugs, anti-nausea drugs, and 
drugs that reduce pain the drug, dosage, and time will be recorded on the eCRF.
Blood pressure, EtCO2, SpO2, pulse rate, respiration rate, end-tidal anesthetic gas, FiO2%, EtO2%, and 
temperature will be gathered from the hospital computerized database, and digital records will be 
provided to Medtronic. BIS values and EEG data will be recorded with a USB storage device connected to 
the BIS™complete monitor.  The BIS data file labeled with patient ID will be provided to Medtronic.
10.7 Assessment of Safety
Subjects will be assessed from enrollment through the end of the study for all safety events related to the 
BIS™and Nellcor™devices as well as any device deficiencies. Events will be reported to Medtronic and 
the IRB/EC/HC according to Section 11. 
10.8 Recording Data
Data entered must be traceable to source documents. Source documentation is defined as the first time 
data appear, and may include original documents, data, and records (e.g., hospital records, clinical and 
office charts, procedure reports, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 

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pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, device data and records kept at the pharmacy, at the 
laboratories and at medico-technical departments involved in the study).
Electronic data will be downloaded from the BISTM device and the hospital computerized system.  
Evaluation of data quality of the recorded data will be performed after the first 3 or 5 valid subjects and 
for at least every 10 subjects afterward. 
This study will be utilizing a Remote Data Capture (RDC) system to collect study required Case Report Form 
(CRF) information. Electronic CRFs (eCRFs) will be provided by the sponsor and required data will be 
recorded from source documents and entered into the study database via the eCRFs by the appropriately 
delegated site personnel, in accordance with applicable regulations. 
The PI or appropriately delegated individuals are responsible for entering data for the study on the eCRFs. 
The PI is required to approve all data on eCRFs via electronic signature.
In general, eCRFs (or paper copies) may not serve as source documents.Source documentation for data 
elements not routinely captured in medical records may vary from study site to study site; the study site 
may use source document worksheets if identified as source documents.
The investigator must ensure the availability of source documents from which the information on the 
eCRFs was derived. The type and location of source documents should be documented. Where printouts 
of electronic medical records, are provided as source documents, or where copies of source documents 
are retained as source documents, those should be certified. Certification must contain:
1.
The signature of the individual making the copy, 
2.
the date the copy was made, and 
3.
a statement attesting to the accuracy and completeness of the copy. 
The source documents must be made available for monitoring or auditing by Medtronic’s representative 
or representatives of the competent authorities and other applicable regulatory agencies.
10.9 Deviation Handling
A study deviation is defined as an event within a study that did not occur according to the CIP or the CTA.
Prior approval by Medtronic is expected in situations where the investigator anticipates, contemplates, 
or makes a conscious decision to deviate. Prior approval is not required when a deviation is necessary to 
protect the safety, rights or well-being of a subject in an emergency or in unforeseen situations beyond 

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the investigator’s control (e.g. subject failure to attend scheduled follow-up visits, inadvertent loss of data 
due to computer malfunction, inability to perform required procedures due to subject illness).
All study deviations must be reported on the CRF regardless of whether medically justifiable, pre-
approved by Medtronic, an inadvertent occurrence, or taken to protect the subject in an emergency. 
Multiple deviations of the same type at the same visit may be reported on one case report form.
In the event the deviation involves a failure to obtain a subject’s consent, or is made to protect the life or 
physical well-being of a subject in an emergency, the deviation must be reported to the EC as well as 
Medtronic within five (5) working days. Reporting of all other study deviations should comply with EC 
policies and/or local laws and must be reported to Medtronic as soon as possible upon the study site 
becoming aware of the deviation. Reporting of deviations must comply with IRB/EC/HC policies, local laws, 
and/or Regulatory Authority requirements.  
Medtronic is responsible for analyzing deviations, assessing their significance, and identifying any 
additional corrective and/or preventive actions (e.g. amend the CIP, conduct additional training, 
terminate the investigation). Repetitive or serious investigator compliance issues may result in initiation 
of a corrective action plan with the investigator and study site, and in some cases, may necessitate 
suspending enrollment until the problem is resolved or ultimately terminating the investigator's 
participation in the study. Medtronic will provide study site-specific reports to investigators summarizing 
information on deviations that occurred at the investigational study site on a periodic basis. 
In case of major deviation from the protocol or missing data, the data manager may consider excluding 
the subject from the study.  If so, the data will not be used, and if needed, a new subject will be recruited 
into the study. 
Examples of study deviations include but are not limited to:

Failure to obtain proper Informed Consent

Failure to collect required study data (e.g. MOAA/S Scores, patient assessments, BIS raw signals)

Inclusion/exclusion criteria not met

Missing required anesthesia administration documentation
10.10
Subject Exit, Withdrawal or Discontinuation
It is the subject’s right to withdraw from  the  study  at  any  time  and  for  any  reason  without  sanction,  
penalty or loss of benefits to which the subject is otherwise entitled, and without jeopardizing their future 
medical  care.  The investigator may withdraw the subject at  any  time  to  protect  the  health,  safety,  
or welfare of the subject. Every effort should be made to collect the status of any ongoing adverse events,

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at a minimum. All subjects will be encouraged to remain in the study through the follow-up phone call.  If 
the  subject  discontinues  participating  in  the  study  prior  to  completing  the  study  requirements,  the  
reason for withdrawal will be recorded in the subject’s study records and eCRF. If withdrawal  from  the  
study  is  due  to  problems  related  to  the  investigational  device  safety  or  performance, the investigator 
shall ask for the subject’s permission to follow his/her status outside the clinical study. 
10.11
Study Exit From Study
A study exit eCRF is required for all subjects. Prior to exiting a subject from the study, it is recommended 
to follow the subject until all ongoing system related AEs are resolved or unresolved with no further 
actions planned.  Following exit, subjects will continue to receive standard medical care.  Upon exiting 
from the study, no further study data will be collected, or study visits will occur for the subject. All data 
available through the time of the subject’s exit may still be used for analysis. 
Subjects are urged to remain in the study as long as possible but may be exited from the study for any of 
the following situations:

Study completed

Subject death

Subject did not meet inclusion/exclusion criteria 

Subject did not provide consent

Subject chooses to withdraw for any reason (e.g., consent withdrawal, relocation to another 
geographic location) 

Investigator deems withdrawal necessary (e.g., medically justified, inclusion/exclusion criteria not 
met, failure of subject to maintain adequate study compliance) 
The following information is required to be collected at study exit:

Date of Study Exit

Subject’s status upon Exit

Any applicable AE or death information
10.11.1
Study Completed
At the completion of the surgery, subjects will be exited from the study. There are no further follow-up 
visits required for this study.  

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10.11.2
Subject Chooses to Exit (i.e. Revokes Consent)
A subject can withdraw from the study at any time. If the subject wishes to exit from the study (i.e. the 
subject revokes consent), the study site is required to document the reason for exit on the Exit CRF. In 
addition, study sites shall follow the regulations set forth by the governing EC.
10.11.3
Investigator Withdraws Subject
No subjects should be withdrawn by investigators unless compelling medical justification is present or 
surgical procedure is cancelled. It is recommended investigators discuss any withdrawals with the study 
team prior to withdrawing subjects.
11. Risks and Benefits
11.1 Potential Risks
Both the BIS™ monitor system and Nellcor™system is cleared in the United States, CE marked, AMAR 
approved in Israel, and used routinely in clinical care to monitor patients.  In the routine clinical procedure, 
the anesthetist uses unilateral sensor, and in some surgeries the BISTM is part of the monitoring system. 
For the study, the BISTM will be used as a standalone monitor with the bilateral sensor. During the surgery, 
the BISTM value will be calculated from the left side, as in the routine clinical procedure. The BISTM device 
that will be used as study product will be stored outside the operating room after the study procedure. 
The monitor is being used in accordance with the intended use that has been cleared by regulatory 
authorities worldwide. 
Risks to participation are primarily physical. There are no social, economic, legal, long-term psychological, 
or other risks that have been identified. Risks under this protocol relate to both study devices and study 
procedures.  The risks from the device(s) are in keeping with the definition of non-significant risk devices.  
Further, the devices in this study are non-invasive, and the clinical protocol design is minimal risk to the 
subject. No treatment or treatment decisions will be made during the course of this study. Following is a 
list detailing potential risks from study devices and the clinical protocol.  
11.1.1
BIS™Sensor Risks
The BIS™Sensor is applied directly to the patient’s skin to enable recordings of electrophysiological (such 
as EEG) signals. The sensor will be used as per Instructions for Use (IFU). The sensors used in this study 
may expose subjects to the following risks: 

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
Minor discomfort, allergic reaction, or skin irritation (such as redness, itching) at the sensor 
application site is probable but is usually self-limited within hours. 

Pressure points/ injury in application areas are possible but anticipated to be rare due to the short 
duration of the study. Care in the application and removal of the sensors is advised. Skin reactions 
will be observed during and after the study procedures. 

Electric shock is very rare, and the product design and testing ensure insulation and ground fault 
detection. 

Burn to the skin (due to a small amount of heat generated) is a rare unanticipated risk, and not 
likely due to the short duration of the study. 
For a full list of Sensor Warnings and Cautions, refer to the country-specific IFU.
11.1.2
BIS™Complete Monitoring System Risks
BIS™Complete Monitoring System will be used per IFU. More information on warnings and cautions 
should be referenced in the country-specific IFU.  
11.1.3
Nellcor™Oximetry Sensor Risks
Pulse and Tissue Oximetry Sensor placement involves positioning pulse and tissue oximetry sensors on 
the subject per the IFUs. 
The sensors may be warm to the touch. Under normal operating conditions (no fault conditions), the 
sensors are not expected to overheat. If the sensors are too warm, they will be removed immediately. 
The sensors exert a minimal amount of pressure. Sensors may leave minor impressions at the sensor 
application site, which should fade and resolve within the day. They should not cause discomfort. If the 
sensors are too uncomfortable, they will be removed.  
Adhesive sensors may cause some irritations to the skin in some subjects. Typical skin irritations present 
with redness of the skin, and in some cases of sensitivity, an allergic reaction can occur. Removal of the 
sensor may cause pulling of the skin or hair, and this can be felt as pain. The risk in the use of oximetry 
sensors is believed to be minimal.
A heating pad or hot water bottles may be used on the hands to improve circulation. The subject may 
experience some mild discomfort if the water is too warm. To minimize the discomfort, the subject will 
be asked if the heating is too warm, it will be turned on the lowest level possible for comfort, removed or 
additional separation will be used between the heater and the site for comfort.

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11.1.4
Surgery
Data from peer-reviews indicates that 14.4% of the surgical patients had at least one AE or SAE[12]. The 
patient may suffer from AEs or SAEs that are related to the standard clinical procedures or the hospital 
environment and not to the study.  Patients should be given the applicable consent forms to understand 
the risks of the surgery and environment to which they will be exposed.
11.1.5
General Anesthetics
Along with the protocol-specified propofol induction period, general anesthesia maintenance will resume 
per institutional practice as is needed for the surgical procedure. 
There are some risks associated with general anesthetics, which should be explained to the patient and 
covered in the standard surgery clinical consent form.  All subjects will be monitored by health care 
professionals closely for the effects. The most common side effects of general anesthesia include sore 
throat due to the breathing tube, nausea, vomiting, dizziness, bruising, or soreness from the intravenous 
therapy drip, shivering and feeling cold, and difficulty passing urine. These may occur despite the best 
efforts to avoid them. 
Also, when placing a breathing tube, there is a small risk that the anesthesia provider can damage the 
subject’s teeth. This risk increases if the subject has loose teeth or other dental problems. With any 
medication given, the subject could have an allergic reaction. Although rare, unexpected severe 
complications with anesthesia can occur and include, but not limited to, the remote possibility of 
infection, bleeding, drug reactions, blood clots, loss of sensation, loss of limb function, paralysis, stroke, 
brain damage, heart attack or death. The delegated anesthesiologist will be present during the procedure 
to minimize all risks related to anesthesia.
11.2 Potential Benefits
There are no expected direct medical benefits to the subjects who participate in this study. There is, 
however, the potential for benefiting future subjects should this study enable the development of 
improved medical monitoring devices.

T h e i nfl u e n c e of a g e o n E E G si g n al s a n d 
c o n s ci o u s n e s s d uri n g a n e st h e si a ( T I A R A ) Cli ni c al 
I n v e sti g ati o n Pl a n
F or m
V ersi o n 5 . 1
P a g e 4 1 of 6 5
T his d o c u m e nt is el e ctr o ni c all y c o ntr oll e d M e dtr o ni c B u si n e s s R e stri ct e d    0 5 6- F 2 7 5, v B Cli ni c al I n v esti g ati o n Pl a n T e m pl at e
1 1. 3 Ri s k -B e n efit R ati o n al e
M e dtr o nic h as d et er mi n e d t h at t his is a st u d y of a “ n o n -si g nific a nt ris k d evic e” d u e t o t h e n at ur e of t h e 
d e vic es b ei n g t est e d . Utilizi n g t h e F D A crit eri a1, 2 list e d b el o w t o disti n g uis h b et w e e n si g nific a nt a n d n o n-
si g nific a nt ris k d evic es, M e dtr o nic h as d et er mi n e d t h at: 

T h e i nv esti g ati o n al d e vic e is n ot i nt e n d e d as a n i m pl a nt a n d d o es n ot pr es e nt a p ot e nti al f or 
s eri o us ris k t o t h e h e alt h, s af et y, or w elf ar e of a s u bj ect; 

T h e i n v esti g ati o n al d e vic e is n ot p ur p ort e d or r e pr es e nt e d t o b e f or us e s u p p orti n g or s ust ai ni n g 
h u m a n lif e a n d d o es n ot pr es e nt a p ot e nti al f or s eri o us ris k t o t h e h e alt h, s af et y, or w elf ar e of a 
s u bj ect; 

T h e i nv esti g ati o n al d evic e is n ot f or a us e of s u bst a nti al i m p ort a nc e i n di a g n osi n g, c uri n g, 
miti g ati n g, or tr e ati n g dis e as e, or ot h er wis e pr ev e nti n g i m p air m e nt of h u m a n h e alt h, a n d d o es 
n ot pr es e nt a p ot e nti al f or s eri o us ris k t o t h e h e alt h, s af et y, or w elf ar e of a s u bj ect; a n d

T h e i nv esti g ati o n al d e vic e d o es n ot ot h er wis e pr es e nt a p ot e nti al f or s eri o us risk t o t h e h e alt h, 
s af et y, or w elf ar e of a s u bj ect. 
T h e p ot e nti al ris ks of t h es e d evic es h av e b e e n ass ess e d a n d ar e n ot gr e at er t h a n t h os e of c urr e ntly 
a p pr o v e d a n d m ar k et e d d e vic es of t h e s a m e t y p e ( e. g., p uls e a n d tiss u e oxi m et ers, Et C O 2 m o nit ors, n o n -
i n v asi v e bl o o d pr ess ur e m o nit ors, E C G or r es pir ati o n m o nit ors). S oci et y m a y b e n efit fr o m m or e acc ur at e 
a n est h esi a m o nit ors.
M e dtr o nic r e q u ests t h at t h e r e vi e wi n g I R B/ E C/ H C i n dic at esits a gr e e m e nt wit h t his d et er mi n ati o n of n o n -
si g nific a nt ris k d evic e i n its l ett er of a p pr ov al f or t his st u d y. 
1 2.
A d v er s e E v e nt s a n d D e vi c e D efi ci e n ci e s
F or t h e p ur p os es of t h e cli nic al st u d y, a dv ers e ev e nts will b e c at e g oriz e d acc or di n g t o t h e l at est v ersi o n 
of I S O 1 4 1 5 5.  W h er e t h e d efi niti o n i n dic at es “ d e vic e”, it r ef ers t o BI S ™a n d N ellc or ™d evic e s us e d i n t h e 
st u d y.  S e e T a bl e 3 b el o w f or A dv ers e Ev e nt ( A E) a n d D evic e D efici e nc y ( D D) D efi niti o ns.  
                                                          
1 2 1 C F R 8 1 2. 2 ( b)( 1)(ii) a n d 2 1 C F R 8 1 2. 3( m)
2 I nf or m ati o n S h e et G ui d a nc e F or I R B / E C , Cli nic al I n v esti g at ors, a n d S p o ns or. Si g nific a nt Ris k a n d N o n-si g nific a nt Ris k M e dic al D e vic e St u di es /  
J a n u ar y 2 0 0 6 / U M C 1 2 6 4 1 8

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12.1 Adverse Events
AE definitions are provided in Table 3.  Events related to the surgical procedure including anesthesia 
administration will not be collected as they related to standard of care practices.  AEs will only be collected 
as they are related to the BIS™ and Nellcor™ devices as well as any device deficiencies as these are 
commercially released products.  All reportable AE information will therefore only be collected beginning 
at the time of the BIS™and Nellcor™sensor placement at the start of surgery and ending when the BIS™
and Nellcor™sensors are removed.  
12.1.1
Foreseeable AE or SAE
Any foreseeable events are discussed in Section 11.1 Potential Risks. 
12.2 Device Deficiency
The DD definition is provided in Table 3 below. DD information will be collected throughout the study and 
reported to Medtronic. Note that DD that result in an AE to the subject should be captured as an AE only.
12.3 Definitions/Classifications
Where the definition indicates “device”, it refers to BIS™and/or Nellcor™devices used in the study.

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Table 3: Adverse Event and Device Deficiency Definitions (ISO 14155)
Adverse Event (AE)
Untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) 
in subjects, users or other persons, whether or not related to the 
investigational medical device and whether anticipated or 
unanticipated
NOTE 1: This definition includes events related to the 
investigational medical device or the comparator.
NOTE 2: This definition includes events related to the procedures 
involved.
NOTE 3: For users or other persons, this definition is restricted to 
events related to investigational medical devices.
Adverse Device Effect (ADE)
AE related to the use of an investigational medical device
NOTE 1: This definition includes AEs resulting from insufficient or 
inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the 
investigational medical device.
NOTE 2: This definition includes any event resulting from an 
error use or from intentional misuse of the investigational 
medical device. 
NOTE 3: this includes ‘comparator’ if the comparator is a medical 
device. 
Device Deficiency (DD)
Inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, usability, safety or performance. 
NOTE 1: DD include malfunctions, use errors and inadequacy in 
the information supplied by the manufacturer including labeling. 
NOTE2: This definition includes device deficiencies related to the 
investigational medical device or the comparator. 

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Seriousness
Serious Adverse Event (SAE)
AE that led to any of the following
a) death,
b) serious deterioration in the health of the subject, users or 
other persons as defined by one or more of the following: 
1) a life-threatening illness or injury, or
2) a permanent impairment of a body structure or a 
body function, including chronic disease, or
3) in-patient or prolonged hospitalization, or
4) medical or surgical intervention to prevent life-
threatening illness or injury or permanent impairment 
to a body structure or a body function,
c) fetal distress, fetal death or a congenital abnormality or 
birth defect including physical or mental impairment
NOTE 1: Planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP, without serious deterioration in 
health, is not considered an SAE.
Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event.
Unanticipated Serious Adverse Device
Effect (USADE)
A SADE which by its nature, incidence, severity or outcome
has notbeen identified in the current version of the risk
analysis report.
Note: Anticipated Serious Adverse Device Effect (ASADE) is 
an effectwhich by its nature, incidence, severity or outcome 
has been identified in the risk analysis report.
Serious Health Threat
A signal from any adverse event or device deficiency that 
indicates an imminent risk of death or a serious deterioration 
in the health in subjects, users or other persons, and that 
requires prompt remedial action for other subjects, users or 
other persons.
Note: This would include events that are of significant and 
unexpected nature such that they become alarming as a 
potential serious health hazard or possibility of multiple 
deaths occurring at short intervals.

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12.3.1
Adverse Event and Device Deficiency Reporting Requirements
AE and DD information will be collected throughout the study from the BIS sensor application until end of 
the surgery. A list of anticipated adverse events and risks that are expected in nature is included in Section 
11. 
Adverse Event assessment for the purposes of this study will cease after the procedure. All AEs considered 
at least possibly related to the study devices will be followed until resolved, stabilized, and/or returned to 
baseline.
Medtronic will immediately conduct an evaluation of reported events. Table 4 shows event reporting 
requirements. At a minimum, the following information will be recorded:

A description of the event

The date of event onset

The relatedness of the event to the device

Actions are taken as a result of the event

The outcome of the event
Table 4: Reporting Requirements for Events
Serious Adverse Device Effects (SADE), including Unanticipated Adverse Device Effect (UADE):
Investigator submits to:
Medtronic
Within 24 hours after the investigator first learns of the event.
Regulatory Authority
As per local reporting requirements. 
IRB
Submit to IRB per local reporting requirement.
Sponsor submits to:
Regulatory Authorities 
Reporting timeframe as per local requirement.
IRB
Submit to IRB per local reporting requirement.
Serious Adverse Events (SAE)
Investigator submits to:
Medtronic
Within 24 hours after the investigator first learns of the event.
Regulatory Authority
As per local reporting requirements. 
IRB 
Submit to IRB per local reporting requirement.
Sponsor submits to:

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Regulatory Authorities 
Reporting timeframe as per local requirement.
IRB 
Submit to IRB per local reporting requirement.
Adverse Device Effects (ADE)
Investigator submits to:
Medtronic
Within 24 hours after the investigator first learns of the event.
Sponsor submits to:
Regulatory Authority
As per local reporting requirements. 
IRB 
Submit to IRB per local reporting requirement.
Sponsor submits to:
Regulatory Authorities
Reporting timeframe as per local requirement
IRB 
Submit to IRB per local reporting requirement.
All other AEs
Investigator submits to:
Medtronic
Submit as soon as possible, but no later than within 10 working days after 
the investigator first learns of the event.
Regulatory Authority
As per local reporting. 
IRB 
Submit to IRB per local reporting requirement.
Device Deficiency with SADE potential
Investigator submits to:
Medtronic
No later than 48 hours after the investigator first learns of the event.
Regulatory Authorities
As per local reporting requirements.
IRB 
As per local reporting requirement.
Sponsor submits to:
Regulatory Authorities
As per local reporting requirements.
IRB 
As per local reporting requirement.
All other Device Deficiencies
Investigator submits to
Medtronic
No later than 48 hours after the investigator first learns of the event.
Regulatory Authorities
As per local reporting requirements.
IRB 
As per local reporting requirement.

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Sponsor submits to:
Regulatory Authorities
As per local reporting requirements.
IRB 
As per local reporting requirement.
12.4 Reporting of Adverse Events
Principal Investigators must report applicable events and product deficiencies to Medtronic and where 
appropriate an EC or Regulatory Authority.
Study Contact Information:
Clinical Affairs
Medical Affairs
Ami Stuart, PhD
Senior Clinical Research Specialist/Clinical Study 
Manager/Medtronic
6135 Gunbarrel Avenue
Boulder, CO 80301
(801) 793 - 4800
Ami.stuart@medtronic.com
Sam Ajizian, MD
Chief Medical Officer-Patient Monitoring
Medtronic
350 Cedar Trail
Winston-Salem, NC 27104
Phone: (336) 749-8557
Sam.ajizian@medtronic.com
12.5 Product Complaint Reporting
It is the responsibility of the investigator to report all product complaint(s) associated with a medical 
device distributed by Medtronic, regardless whether they are related to intended use, misuse or abuse of 
the product. Reporting must be done immediately and via the regular channels for market-released 
products. The reporting of product complaints by the clinical team must be done according to the local 
Standard Operating Procedures. Medtronic will notify the Regulatory Authorities as applicable for the
following incidents immediately upon learning of them and is not limited to AEs and DDs only:

Any malfunction or deterioration in the characteristics and/or performance of a device, as well as 
any inadequacy in the labeling or instructions for use which led or might have led to the death or 
serious deterioration in the state of health of a patient, user, or other person.

Any technical or medical reason resulting in withdrawal of a device from the market by the 
manufacturer.

Any serious deterioration in the state of health, including:

Life-threatening illness or injury

Permanent impairment of a body function or permanent damage to a body structure

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
A condition necessitating medical or surgical intervention to prevent permanent impairment of a 
body function or permanent damage to a body structure
13. Data Review Committees
No Data Monitoring Committee, Clinical Events Committee or other external committee will be 
nominated for this study as the study includes no significant interventions (i.e. blood draw only) intended 
to sustain life or reduce risk of a major adverse health outcome.
14. Statistical Design and Methods
This is a preliminary study aimed at collecting data from enrolled subjects for algorithm development and 
improvement. Subjects with valid recorded data from the study device (EEG signals) and a completed eCRF 
will be considered as valid subjects and will be included in the primary analysis.
A statistical analysis plan with detailed statistical procedures and methods will be finalized prior to data 
analysis. Any changes in statistical methods will be detailed in the Clinical Study Report. 
14.1 Sample Size Justification
Up to 100 subjects will be enrolled in the study, with 65% subjects over the age of 65 years. The sample 
size estimate was not based on hypothesis testing. The primary objective is to evaluate the age impact on 
the relationship between the BIS score and the depth of anesthesia.  The sample size is not powered to detect 
a statistically significant difference as this study is a feasibility study.Statistical Methods
Descriptive statistics will be used to summarize study outcomes. Subjects with valid recorded data from 
the study device (EEG signals) and a completed eCRF will be included in the primary analysis.
The relationships between BIS parameters, age, physical and cognitive state, and depth of anesthesia in 
patients undergoing surgery under general anesthesia will be assessed. Pearson’s correlation or 
Spearman’s rank correlation will be calculated as appropriate. Continuous variables will be evaluated 
using analysis of variance (ANOVA) or nonlinear Emax model, and categorical variables will be evaluated 
using the chi-square or Fisher’s exact test, as well as multivariate logistic regression with age as an 
explanatory factor.  A P-value of less than 0.05 is considered statistically significant unless otherwise 
specified.    

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An early data review will be performed for the first 40 enrolled subjects to ensure data validity and no 
safety concern. Sample size re-estimation may be performed to ensure sufficient data to be collected to 
meet the study objectives. 
For safety assessments, AEs will be summarized using frequency counts and percentages. Descriptive 
summary will be provided by severity and relationship as needed. 
15. Ethics
15.1 Statement(s) of Compliance
The MDT18067TIARA study will be conducted in full conformity with this study protocol, with its ethical 
principles having origin in the Declaration of Helsinki.  TIARA was designed to reflect the GCP principles 
outlined in the latest version of ISO 14155 and other international clinical requirements outlined below. 
These include the protection of the rights, safety and well-being of human subjects, controls to ensure 
the scientific conduct and credibility of the clinical investigation and the definition of responsibilities of 
the sponsor and investigators. In accordance with ISO 14155, the sponsor shall avoid improper influence 
on, or inducement of, the subject, monitor, any investigator(s) or other parties participating in, or 
contributing to, the clinical investigation. All investigators shall avoid improper influence on or 
inducement of the subject, sponsor, monitor, other investigator(s) or other parties participating in or 
contributing to the clinical investigation. AE and DD handling in the TIARA study is ISO 14155 compliant 
for all participating geographies.  As the ISO 14155 AE collection requirements are focused on pre-market 
release studies, AEs will only be collected as they are related to the BIS™and Nellcor™devices as well as 
any device deficiencies as these are post-market or commercially released products.  USADE assessment 
is not applicable for this reason.  Events related to the surgical procedure including anesthesia 
administration will not be collected as they related to standard of care practices.
Ultimately, all study sites in all geographies will follow and comply with:

The CTA

The procedures described within this CIP

Local IRB/EC/HC Requirements
No study procedures at the site will be performed until the governing IRB/EC/HC provides approval.  Any 
action that is taken by the local IRB/EC/HC with respect to this study will be forwarded to the sponsor as 
soon as possible.  

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In addition to the regulatory requirements outlined above, the study will be conducted according to 
federal, national and local laws, regulations, standards, and requirements of the countries/geographies 
where the study is being conducted. These include but are not limited to: 

In Europe the study will be conducted in compliance with the DoH version 2013. 
The study will be publicly registered in the US prior to any enrolments in accordance with ISO 14155 on 
http://clinicaltrials.gov. In addition, the study may be registered in local regulatory databases where 
required by local law including the Israel Ministry of Health website for clinical trials at 
https://my.health.gov.il/MyPortal/CliniTrials/Pages/Editor.aspx. For the Netherlands, it is expected that 
the study may be listed at www.rijksoverheid.nl/mensenonderzoek.  Requirements for each region will 
be confirmed once sites are selected.
Approval of the CIP and CIP amendments is required from the following groups prior to any study 
procedures at a study site:

Medtronic

Principal Investigators (where required by local law/regulations)

Geography-specific regulatory authorities (if regulatory approval is required)

An independent medical IRB/EC/HC
16. Study Administration
16.1 Monitoring
It is the responsibility of Medtronic to ensure proper monitoring of this study.  Trained Medtronic 
personnel or delegates appointed by Medtronic may perform study monitoring at the study site or 
remotely in order to ensure that the study is conducted in accordance with the CIP, the CTA, and the 
applicable regulatory and local requirements. Medtronic, or delegates, must therefore be allowed access 
to the subjects’ case histories (i.e. clinic and hospital records, and other source data/documentation) upon 
request as per the ICF, Research Authorization (where applicable) and CTA.  The PI should also be available 
during monitoring visits, as detailed in the monitoring plan, to review together with the monitor the visit 
outcomes and general study progress.  
16.1.1
Monitoring Visits
Frequency of monitoring visits may be based upon subject enrollment, study compliance, number of 
adverse events, number of deviations, observations from previous monitoring visits and any suspected 

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inconsistency in data that requires investigation. Regulatory documents will be reviewed at each study 
site. Monitoring for the study, site initiation visits, interim monitoring visits, and closeout visits, will be 
done in accordance to the study-specific monitoring plan.
Monitoring visits may be conducted periodically to assess study site progress, the investigator’s adherence 
to the CIP, regulatory compliance including but not limited to IRB/EC/HC approval and review of the study, 
maintenance of records and reports, and review of source documents against subject CRFs in accordance 
to the study-specific monitoring plan. Monitors review study site regulatory and study compliance by 
identifying observations of non-compliance and communicating those observations along with 
recommendations for preventative/corrective actions to study site personnel.  Monitors may work with 
study personnel to determine appropriate corrective action recommendations and to identify trends 
within the study or at a particular study site.
16.2 Data Management
Data will be collected using an electronic data management system for studies.  CRF data will be stored in 
a secure, password-protected database which will be backed up nightly.  Data will be reviewed using 
programmed and manual data checks.  Data queries will be made available to study sites for resolution.  
Study management reports may be generated to monitor data quality and study progress.  At the end of 
the study, the data will be frozen and will be retained indefinitely by Medtronic.
All records and other information about subjects participating in this study will be treated as confidential. 
Data will be transferred and processed by Medtronic or a third party designated by 
Procedures in the CIP require source documentation. Source documentation will be maintained at the 
study site. Source documents, which may include worksheets, forms, subject medical records, 
programmer printouts, and interrogation files, must be created and maintained by the investigational 
study site team. 
The investigator will clearly mark clinical records to indicate that the subject is enrolled in this clinical 
investigation. 
The data reported on the CRFs shall be derived from source documents and be consistent with these 
source documents, and any discrepancies shall be explained in writing. 
Device data s will be uploaded to secure servers.  Save-to-disk data collected at the site will be sent to 
Medtronic. Upon receipt, device data will be maintained and retrieved for analysis and reporting.

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16.3 Direct Access to Source Data/Documents
Medtronic may conduct audits at participating study sites. The purpose of an audit is to verify the 
performance of the monitoring process and the study conduct, independently of the personnel directly 
involved in the study. Regulatory Authorities may also perform inspections at participating study sites. 
The investigator and/or institution shall permit Medtronic, governing IRB/EC/HCs and Regulatory 
Authorities direct access to source data and documents during monitoring, audits and regulatory 
inspections.
16.4 Confidentiality
All information and data sent to parties involved in study conduct concerning subjects or their 
participation in this study will be considered confidential. Study sites will assign a unique subject ID to 
each subject. Records of the subject and subject ID relationship will be maintained by the study site. The 
subject ID number is to be recorded on all study documents to link them to the subject’s medical records 
at the study site.  Confidentiality of data will be observed by all parties involved at all times throughout 
the clinical investigation. All data shall be secured against unauthorized access. The privacy of each subject 
and confidentiality of his/her information shall be preserved in reports and when publishing any data to 
maintain confidentiality, the subject’s name or any other protected health information should not be 
recorded on any study document other than the ICF. This scenario will be covered in the ICF. In the event 
a subject’s name is included for any reason, it will be blinded as applicable. In the event of inability to 
blind the identification (e.g., digital media), it will be handled in a confidential manner by the authorized 
personnel.  Data relating to the study might be made available to third parties (for example in case of an 
audit performed by the Regulatory Authority), provided the data are treated as confidential and that the 
subject’s privacy is guaranteed. No identifiable subject information will be published.
16.5 Liability/Warranty/Insurance Information
Medtronic maintains appropriate clinical study liability insurance coverage as required under applicable 
laws and regulations and will comply with applicable law and custom concerning specific insurance 
coverage. A Clinical Trial Insurance statement/certificate will be provided to the IRB/EC/HC in the 
submission. 
16.5.1
Insurance 
Medtronic Bakken Research Site B.V. is a wholly owned subsidiary of Medtronic, which as the parent 
company of such entity maintains appropriate clinical study liability insurance coverage as required under 
applicable laws and regulations and will comply with applicable local law and custom concerning specific 

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insurance coverage. If required, a Clinical Trial insurance statement/certificate will be provided to the 
IRB/EC/HC.
16.6 CIP Amendments
Any revisions or amendments to the CIP or ICF document, along with a statement of justification for the 
changes, will be submitted to all affected Regulatory Authorities and governing IRB/EC/HCs, according to 
applicable regulations. All amendments to the CIP shall be agreed upon between Medtronic and the 
principal investigator(s), or the coordinating investigator. Approval by regulatory agencies and IRB/EC/HCs 
(where applicable) must be obtained prior to implementing a CIP revision at the study site.
16.7 Record Retention
Study-related documents including all study-related Source Documents, CRFs, ICFs, ISFs, Final study 
reports, etc. should be maintained for a minimum of 2 years after the completion or termination of the 
study or until the records are no longer required to support a marketing application (or longer in 
compliance to local requirements). The retention period may be longer if required by Medtronic or local 
or global regulatory requirements. Prior to the destruction of the study related data, the investigator must 
notify the sponsor. The PI will ensure that essential study documents are not destroyed until written 
permission has been obtained from Medtronic.
An investigator may withdraw from the responsibility to maintain records for the period required, as 
indicated in the paragraph above and transfer custody of the records to any other person who will accept
responsibility. An investigator must notify the Sponsor prior records are being transferred. 
16.8 Publication and Use of Information
Publications from the MDT18067TIARA study will be handled according to Standard Operating Procedures 
and as indicated in the CTA.  The investigator will not publish any data from the study without the 
sponsor’s permission. 
The sponsor may publish the results from the influence of age on EEG signals and consciousness during 
anesthesia (TIARA) study in a timely manner as data becomes available. These publication activities may 
include abstracts, presentations/posters to scientific meetings, and manuscripts. Investigators who 
gathered data for this study (i.e., enrolled subjects and complied with the protocol) may be asked to write 
or contribute to the writing of abstracts and manuscripts based on the results of this study. Investigators 
who meet the study-specific criteria above will be considered for abstract/manuscript authorship if they 
meet the International Committee of Medical Journal Editors, Ethical Considerations in the Conduct and 
Reporting of Research criteria. 

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The sponsor will register the study at the U.S. National Institutes of Health clinical trials website 
(https://clinicaltrials.gov/), and may register as required, according to local regulations in Israel’s Ministry 
of Health website for clinical trials (https://my.health.gov.il/MyPortal/CliniTrials/Pages/Editor.aspx) as 
well as the Netherlands’ webpage (www.rijksoverheid.nl/mensenonderzoe). 
16.9 Suspension or Early Termination
The Sponsor reserves the right to discontinue the study at any stage, with written notice to all 
investigators, all reviewing IRB/EC/HCs. Similarly, investigators may withdraw from the study at any time, 
subject to providing written notification to the Sponsor 30 days prior to the date they intend to withdraw. 
The Sponsor and investigators will be bound by their obligation to complete the follow-up of subjects 
already participating in the study. If the study is terminated or suspended, no additional enrollment will 
be allowed unless otherwise informed by the sponsor. The current subjects will be followed according to 
the protocol, and information obtained during subject follow-up shall be reported to the Sponsor on the 
appropriate eCRF.
If the study is terminated prematurely or suspended by the sponsor, the sponsor will promptly inform the 
investigators and regulatory authorities (if required) of the termination and the reason(s). The IRB/EC/HC
will also be promptly informed and provided with the reason(s) for termination or suspension by the 
sponsor or by the investigator. The investigator will promptly inform the subjects and assure appropriate 
therapy and follow-up for the subject, as needed.
If the investigator (or IRB/EC/HC) terminates or suspends the investigation without the prior agreement 
of the sponsor, the investigator will promptly inform the sponsor, the institution (if required), and the 
IRB/EC/HC and provide a detailed written explanation of the termination or suspension. The sponsor will 
inform the regulatory authorities (if required.)
Medtronic reserves the right to discontinue the study at any time for administrative or other reasons. 
Written notice of study termination will be submitted to the investigator in advance of such termination. 
Possible reasons for considering study suspension or termination of the study for all centers include but 
are not limited to:

Failure to obtain initial IRB/EC/HC approval or annual renewal of the study

Consistent non-compliance to the CIP (e.g., failure to adhere to inclusion/exclusion criteria, failure 
to follow subjects per scheduled follow-ups, failure to implement required corrective and 
preventive actions, etc.)

Lack of enrollment

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
Noncompliance to regulations and the terms of the CTA (e.g., failure to submit data in a timely 
manner, failure to follow-up on data queries and monitoring findings in a timely manner, etc.)

IRB/EC/HC suspension of the center

Fraud or fraudulent misconduct (as defined by local law and regulations)

Investigator request (e.g., no longer able to support the study)

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17. References
1.
Kanonidou, Z. and G. Karystianou, Anesthesia for the elderly. Hippokratia, 2007. 11(4): p. 175-
7.
2.
Punjasawadwong, Y., A. Phongchiewboon, and N. Bunchungmongkol, Bispectral index for 
improving anaesthetic delivery and postoperative recovery. Cochrane Database Syst Rev, 
2014(6): p. CD003843.
3.
Glass, P.S., et al., Bispectral analysis measures sedation and memory effects of propofol, 
midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology, 1997. 86(4): p. 
836-47.
4.
Flaishon, R., et al., Recovery of consciousness after thiopental or propofol. Bispectral index 
and isolated forearm technique. Anesthesiology, 1997. 86(3): p. 613-9.
5.
Schwab HS, S.M., Eger EI, Kindler CH, Filipovic M.  , Sevoflurane decreases bispectral index 
values more than does halothane at equal MAC multiples. . Anesth Analg., 2004. 99: p. 1723-
1727.
6.
Hans P, D.P., Brichant JF, Bonhomme V, Comparative effects of ketamine on Bispectral Index 
and spectral entropy of the electroencephalogram under sevoflurane anaesthesia. Br J 
Anaesth, 2005. 94: p. 336-340.
7.
Sengupta, S., et al., Effect of ketamine on bispectral index during propofol--fentanyl 
anesthesia: a randomized controlled study. Middle East J Anaesthesiol, 2011. 21(3): p. 391-5.
8.
Alkire, M.T., Quantitative EEG correlations with brain glucose metabolic rate during 
anesthesia in volunteers. Anesthesiology, 1998. 89(2): p. 323-33.
9.
Werner, P., et al., Examining the reliability and validity of the Hebrew version of the Mini 
Mental State Examination. Aging (Milano), 1999. 11(5): p. 329-34.
10.
Vellas, B., et al., Overview of the MNA--Its history and challenges. J Nutr Health Aging, 2006. 
10(6): p. 456-63; discussion 463-5.
11. 
Perna, S. et al., Performance of Edmonton Frail Scale on frailty assessment: its association 
with multi-dimensional geriatric conditions assessed with specific screening tools.  BMC 
Geriatrics, 2017. doi: 10.1186/s12877-016-0382-3. url: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209899/
12. 
Anderson, O., et al., Surgical adverse events: a systematic review. Am J Surg, 2013. 206(2): p. 
253-62.

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18. Appendices
18.1 Appendix A - Modified Observer's Assessment of 
Alertness/Sedation scale (MOAA/S)
The Observer Assessment of Alertness/Sedation (OAA/S) Scale [51]
Response 
Score
Responds readily to name spoken in normal tone
5
Responds lethargically to name spoken in normal tone
4
Responds only after name is called loudly, repeatedly, or both
3
Responds only after mild prodding or shaking
2
Responds only after painful trapezius squeeze
1
Does not respond to painful trapezius squeeze
0

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18.2 Appendix B – Mini Mental State Examination (MMSE)

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18.3 Appendix C – Mini Nutritional Assessment (MNA®-SF) 

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18.4 Appendix D – Edmonton Frail Scale (EFS)

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19. Version History
Version
Summary of changes
Justification of 
changes
Potential 
impact of the 
change on 
performance, 
effectiveness, 
or safety or 
other 
endpoints
Identification 
of the 
affected 
study 
documents
Author(s)/Title
1.0
Not Applicable, New 
Document
N/A
N/A
N/A
Maegan J. 
Johnson, Clinical 
Research 
Specialist
2.0
Administrative Updates:
Correcting/adding
expected baseline vitals
collection 
Formatting and text 
consistency updates
Baseline vitals 
was a planned 
collection point 
and was 
inadvertently left 
off
Improve visual 
structure of 
document
N/A
N/A – The 
planned 
baseline 
vitals 
collection 
was already 
reflected in 
the eCRFs
Maegan J. 
Johnson, Clinical 
Research 
Specialist
3.0
Administrative Update:
Removed Nellcor system 
and sensor model 
specification
To ensure models 
used are licensed 
and consistent 
across all study 
site countries
N/A
N/A – This 
change does 
not affect the 
CIP synopsis 
or other 
documents
Maegan J. 
Johnson, Clinical 
Research 
Specialist

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4.0
Added additional 
product information 
regarding Nellcor, as 
well as possibility of 
using more than one 
sensor 
Removed Nellcor 
measurements as 
primary endpoint
Provided more detail 
regarding product 
accountability per ISO 
14155 standards
Added additional ISO 
14155 language for 
subject consenting
Added collection of 
contact person
information if baseline 
and surgery procedures 
occur separately
Added pregnancy 
screening details for 
surgery procedure
Clarified AE collection 
details per ISO 14155
More product 
details provided 
for usage 
specifications
Nellcor may not 
be able to be used 
at all sites, 
therefore was 
removed as 
endpoint to not 
affect other data 
analysis
As product 
models and 
shipping methods 
may vary across 
the various 
regions, 
additional details 
were provided on 
how to maintain 
oversight
Additional 
information for 
ISO compliance
Additional 
information for 
ISO compliance
Defined process 
on how this 
exclusion criteria 
can be verified if 
the process is not 
part of the 
institution’s 
standard of care
N/A

Study 
ICF(s)
Maegan J. 
Johnson, Clinical 
Research 
Specialist

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Updated various 
regional registration 
websites
Updated Edmonton Frail 
Scale assessment 
template in appendix
Formatting and text 
consistency updates
Additional 
information for 
ISO compliance
Including more 
specifics on 
regional 
registration
Updated to 
version obtained 
by assessment 
license holder
Improve visual 
structure of 
document
5.0

Subject Number 
updated to 100 from 
200

Site number reduced 
from approximately 5 
to 2

Safety Contact 
information changed to 
Stephanie Monza from 
Julia Katilius

MOAA/S assessment 
changed from every 20 
minutes to once at the 
beginning of 
maintenance and at the 
end of emergence

Inclusion criteria 
decrease from 2 to 1.5 
hours for surgery 
length
Business request
Business request
Julia Katilius no 
longer with OU
MOAA/S 
assessment is not
appropriate while 
subject is in 
maintenance

1.5 hours is 
adequate for 
collection of 
subject data and 
will improve 
study 
recruitment
N/A
N/A
Stephanie 
Monza, Senior 
Clinical Research 
Specialist

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5.1

Safety Contact 
information changed to 
Ami Stuart from 
Stephanie Monza 

Primary objective
updated

Sample size 
determination sections 
updated

Stephanie 
Monza no longer 
with OU

The primary 
objective was 
updated from 
“to determine” 
to “to evaluate” 
as this is a 
feasibility study.

The sample size 
was based on 
the idea that this 
protocol was 
written as a 
validation study 
when the study 
was planned by 
the business to 
be a feasibility 
study.
Ami Stuart, 
Senior Clinical 
Research 
Specialist