EEG-based Depth of Anesthesia-monitoring During General Anesthesia - Effects on Time to Wake-up and Post-operative Cognition
Phase: NA
Conditions: Postoperative Complications, Delayed Emergence From Anesthesia, Cognitive Dysfunction
Sponsor: Oslo University Hospital

 
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Title Page 
Protocol Title: EEG-based depth of anesthesia monitoring – effects on wake-up times and 
cognition. 
Protocol Number: 32173 ver. 2.0 
Principal Investigator: Dr Med Luis Romundstad 
Collaborator: Anders Aasheim PhD Fellowship 
Sponsor Name: Oslo University Hospital, Akuttklinikken v Øyvind Skraastad 
Regulatory Agency Identifier Number(s) 
REK 32173 
 
Approval Date: 14.11.2019 
 
 

 
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Sponsor Signatory: 
 
 
 
 
 
[Name] 
[Title] 
 
Date 
 
 
 
 
 
 
 
 
Medical Monitor  
Luis Romundstad 
luirom@ous-hf.no  
Mob +47 994 26 414 
 
 
 
 

 
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Table of Contents 
Title Page ........................................................................................................................................1 
Table of Contents ...........................................................................................................................3 
1. 
Protocol Summary ..........................................................................................................5 
1.1. 
Synopsis ............................................................................................................................5 
1.2. 
Schedule of Activities (SoA) ............................................................................................7 
2. 
Introduction .....................................................................................................................8 
2.1. 
Study Rationale .................................................................................................................8 
2.2. 
Background .......................................................................................................................8 
2.3. 
Benefit/Risk Assessment ..................................................................................................9 
3. 
Objectives and Endpoints ............................................................................................10 
4. 
Study Design ..................................................................................................................11 
4.1. 
Overall Design ................................................................................................................11 
4.2. 
Scientific Rationale for Study Design ............................................................................11 
4.2.1. 
Participant Input into Design ..........................................................................................11 
4.3.1 
End of Study Definition ..................................................................................................11 
5. 
Study Population ...........................................................................................................12 
5.1. 
Inclusion Criteria ............................................................................................................12 
5.2. 
Exclusion Criteria ...........................................................................................................12 
6. 
Study Intervention ........................................................................................................13 
6.1. 
Study Intervention(s) Administered................................................................................13 
6.1.1. 
Medical Devices..............................................................................................................13 
6.2. 
Measures to Minimize Bias: Randomization and Blinding ............................................13 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................14 
7.1. 
Discontinuation of Study Intervention ............................................................................14 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................14 
7.3. 
Lost to Follow up ............................................................................................................14 
8. 
Study Assessments and Procedures.............................................................................15 
8.1. 
Safety Assessments .........................................................................................................15 
8.1.1. 
Physical Examinations ....................................................................................................15 
8.2. 
Adverse Events and Serious Adverse Events .................................................................15 
8.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................15 
8.2.2. 
Follow-up of AEs and SAEs ...........................................................................................15 
8.2.3. 
Regulatory Reporting Requirements for SAEs ...............................................................16 
9. 
Statistical Considerations .............................................................................................17 
9.1. 
Statistical Hypotheses .....................................................................................................17 
9.2. 
Sample Size Determination ............................................................................................17 
9.3. 
Populations for Analyses ................................................................................................17 

 
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9.4. 
Statistical Analyses .........................................................................................................17 
9.4.1. 
General considerations ....................................................................................................17 
9.4.2. 
Primary endpoint(s) ........................................................................................................17 
9.4.3. 
Secondary endpoint(s) ....................................................................................................18 
9.4.4. 
Other safety Analyse(s)...................................................................................................18 
10. 
Supporting Documentation and Operational Considerations ..................................19 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................19 
10.1.1. Regulatory and Ethical Considerations ...........................................................................19 
10.1.2. Financial Disclosure........................................................................................................19 
10.1.3. Informed Consent Process ..............................................................................................19 
10.1.4. Data Protection................................................................................................................20 
10.1.5. Committees Structure......................................................................................................20 
10.1.6. Dissemination of Clinical Study Data.............................................................................20 
10.1.7. Data Quality Assurance ..................................................................................................20 
10.1.8. Source Documents ..........................................................................................................21 
10.1.9. Study and Site Start and Closure ....................................................................................22 
10.1.10. Publication Policy ...........................................................................................................22 
10.2. 
Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................23 
10.2.1. Definition of AE .............................................................................................................23 
10.2.2. Recording and Follow-Up of AE ....................................................................................23 
10.3. 
Appendix 3: Protocol Amendment History ....................................................................25 
11. 
References ......................................................................................................................26 
 

 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: EEG-based depth of anesthesia monitoring – effects on wake-up times and 
cognition. 
Short Title:  
Rationale:  
Depth of anesthesia-monitoring (DoA-mon) based on EEG changes demands knowledge about 
the effects of the different anesthetic medications on EEG waveforms. We want to investigate 
the use of the raw-EEG waveform in addition to indexes (BIS) and EEG spectrogram analyses 
for depth of anesthesia monitoring. We hypothesize that with the use of this monitoring, we will 
be able to better individualize the dosage of anesthetic drugs, and that this will reduce the total 
consumption of anesthetic medication, thus reducing time to wake-up after surgery. Some studies 
have indicated that too deep anesthesia, confirmed by "burst-suppression" or isoelectric-EEG, is 
associated with increased postoperative cognitive dysfunction (POCD). We will therefore assess 
the patients with the Cambridge Neuropsychological Test Automated Battery (CANTAB) 
cognitive function assessment tool. 
 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
 Use of DoA-mon reduces anesthetic 
dosage and wake-up times 
 Total amount of propofol (mg/kg/hr) 
administered 
 Time to wake-up after halt of anesthetic 
administration 
Secondary 
 
 Use of DoA-mon reduces POCD 
 Cognitive functioning 
 
 
 
Overall Design 
 

 
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Disclosure Statement: This is an interventional study. The study has two arms, and is single 
blinded for the participant, and assessment masked for the investigator. It is blinded for the post-
operative care providers. 
Number of Participants:100 
Approximately 200 patients will be screened to achieve enrolled to study intervention and 100 
evaluable participants for an estimated total of 50 evaluable participants per intervention group. 
 
Intervention Groups and Duration:  
Perioperatively guiding depth of anesthesia by EEG-based monitoring, assessed preoperatively 1 day 
before surgery, and at 3 hours, and at 24 hours after surgery. 
 
Data Monitoring :  
Yes, by clinical trial units monitor Jacob Jacobsen. 
 
 

 
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1.2. 
Schedule of Activities (SoA) 
 
Procedure 
Screening  
(up to 14 days 
before Day 1) 
Intervention Period  
Days/Hours 
–1 
1 
directly 
prior to 
surgery  
1 / 3 hrs 
after 
surgery 
2 / 24 hrs 
after 
surgery 
Comments 
Informed consent 
X 
X 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
physical examination  
X 
 
 
 
 
Standard 
preoperative/anesthetic 
assessment 
Height and weight 
 
X 
 
 
 
 
Medical history  
X 
 
 
 
 
 
Vital signs 
 
X 
X 
X 
 
 
Pain and sedation  level 
assessment 
 
X 
X 
X 
X 
VAS scale/RASS sedation 
score 
Randomization 
 
 
X 
 
 
 
Study intervention 
 
 
X 
 
 
 
CANTAB cognitive assessment 
X 
 
 
X 
X 
 
AE review 
 
 
 
X 
X 
 
 
 

 
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2. 
Introduction 
Depth of anesthesia-monitoring based on EEG changes demands knowledge concerning the effects of 
the different anesthetic medications on EEG waveforms. We want to investigate the use of the raw-EEG 
waveform in addition to indices (BIS) and EEG spectrogram analyses for depth of anesthesia monitoring. 
We hypothesize that with the use of this monitoring, we will be able to better individualize the dosage of 
anesthetic drugs, and that this will reduce the total consumption of anesthetic medication, thus reducing 
time to wake-up after surgery. Some studies have indicated that too deep anesthesia, confirmed by 
"burst-suppression" or isoelectric-EEG, is associated with increased postoperative cognitive dysfunction 
(POCD). We will therefore assess the patients with the Cambridge Neuropsychological Test Automated 
Battery (CANTAB) cognitive function assessment tool. 
2.1. 
Study Rationale 
To investigate options to individualize anesthetic dosage based on the EEG-responses to 
hypnotic drugs during general anesthesia. This to potentially reduce total amount of anesthetic 
drugs administered, and henceforth possibly reduce postoperative cognitive dysfunction after 
surgery and anesthesia. 
 
2.2. 
Background 
It has been over 80 years since Gibbs et al (1) showed how the electroencephalogram (EEG) 
systematically changed in concurrence with increasing doses of hypnotic drugs such as 
penthobarbital and Ether. The study concluded that  “Electroencephalography may therefore be 
of value in controlling depth of anesthesia and sedation”. In spite of a solid documentation of the 
systematic connection between dosing of anesthetic drugs, EEG-patterns and level of 
sedation/anesthesia (2-8), EEG-based DoA has not become a part of standard of care in 
anesthetic management. There is abundant evidence of how different anesthetic drugs leads to 
characteristic fluctuations in human brain electrical activity, relating to depth of anesthesia, 
anesthetic drug of choice, and age (7,8,9-15). These anesthetic induced fluctuations are readily 
visible as changes in the patients EEG.  
Anesthetic drugs are usually administered in pharmacological models based on a population 
taking into account their age, weight and height. However, there is a significant difference in 
how patients respond to these models. In adults there is evidence that the doses needed to 
achieve consciousness varies with a factor of 2 above and below suggested doses (20). In under-
dosing of anesthetics there is a risk of peroperative awareness (21,22). On the other hand there is 
also evidence that overdosing of anesthetics has harmful effects; children receiving more than 
4% Sevoflurane can demonstrate epileptiform activity (23,24), and adults overdosing into “burst 
suppression” during anesthesia has a higher risk of postoperative delirium (POD) and increased 
occurrence of postoperative cognitive dysfunction (POCD) (25,26). 
Bispectral Index (BIS) is an algorithm developed by Aspect Medical Systems in 1994, which is 
based on weighted sums of EEG subparameters to present an index from 0 to 100 for depth of 
anesthesia, where 100 is wide awake, and 0 is an isoelectric EEG. The BIS target for a deep 

 
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enough anesthesia is set to be between 40 and 60. The BIS number is often in concurrence with 
other clinical observations related to anesthetic depth, however there is also an experience of 
divergence. BIS and other EEG-based indices are programmed from adult cohorts, and cannot be 
directly trusted in children, or the elderly (29,30). There is also an incapability in these 
preprogrammed indices (BIS and other) to integrate how specific anesthetic drugs affect the EEG, 
and thenceforth the BIS value. An example of this is how the drug Ketamine induces a specific 
gamma-frequency in the EEG, which the BIS-index translate as a lighter anesthesia, even though 
the drug is administered “on top of” an already deep level of anesthesia. 
2.3. 
Benefit/Risk Assessment 
The benefit for the participants in this study is an increased attention from the anesthetic staff, 
and that the monitoring of levels of anesthesia will be standardized and thorough regardless of 
which study-group you wind up in. The risk of awareness during surgery is what we always 
achieve to avoid, and the risk of this is low in both study-arms. We will screen for this after 
surgery; all patients will be interviewed to assess their experience of the procedure, what they 
remember and overall satisfaction with our treatment. 
Both arms of the study represents ways of delivering general anesthesia in surgery today. The 
incindence of awareness in North America and Europe is 1 to 2 cases/1000 (45-50). A 2019 
meta-analysis of randomized trials compared BIS-EEG guidance of anesthetic depth to reduce 
the risk of awareness from 9 to 3 pr 1000 (51). So there is a small possibility that the intervention 
reduces the risk for awareness for the participants in this study. 

 
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3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
 Use of DoA-mon reduces anesthetic 
dosage and wake-up times 
 Total amount of propofol (mg/kg/hr) 
administered 
 Time to wake-up after stop of 
anesthetic administration 
Secondary 
 
 Use of DoA-mon reduces POCD 
 Cognitive functioning 
 
 
 
 
 
 
 
 

 
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4. 
Study Design 
This is a randomized controlled blinded study, with two groups; intervention and control. 
4.1. 
Overall Design 
Both groups will receive standard of care in total intravenous anesthesia (TIVA), with 
onitoring of clinical signs relating to level of anesthesia and to the satisfaction of the surgeon. In 
the intervention group, the anesthesia providers will guide the dosage of hypnotics based on a 
BIS-index of 45-60 perioperative, also avoiding burst-suppression (visually 
detected)/suppression-ratio (SR) of 0, and EEG-frequency alpha (peak alpha) of 10-12 hz. 
All patients will have a recording of their perioperative EEG. All patients will be assessed pre 
and postoperatively using the Cambridge Neuropsychological  Automated Test Battery 
(CANTAB) to assess how they are affected , testing for executive cognitive functioning. The 
participants use an IPAD to self-assess, so the assessor is blinded. 
4.2. 
Scientific Rationale for Study Design 
 
4.2.1. Participant Input into Design 
We seek to include patient representation, not in study design, but in the design/text of the 
participant information leaflet. 
 
4.3.1 End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last assessment on day 2 of surgery. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
 

 
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5. 
Study Population 
Patients coming to Oslo University hospital Rikshospitalet, for planned elective spinal surgery. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
. 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 18 to 65 years of age inclusive, at the time of signing the informed 
consent. 
Sex 
2.  Male and/or female 
Informed Consent 
3. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
4.  Psychiatric disorders 
5.  Pregnancy 
6.  Breast feeding 
7.  Using antiepileptic drugs. 
8.  Central neurological disease 
9.  Unable to complete baseline CANTAB-test. 

 
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6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. 
Study Intervention(s) Administered 
EEG-based DoA-mon, Bilateral BIS from Medtronic, to help guide dosage of anesthetic 
medication perioperatively. 
 
6.1.1. 
Medical Devices 
1. The manufactured medical device provided for use in this study is the Bilateral BIS by 
Medtronic. Electrodes are purchased by the hospital, and the medical device company is 
not a part of this study. 
6.2. 
Measures to Minimize Bias: Randomization and Blinding 
 
Included patients 
randomized blindly 
On the day of surgery, the participants are randomized by an outside party to 
intervention or control group. The patient is blinded to allocated group. All patients 
are connected to EEG-BIS before sleep, and EEG-device is covered up (for 
control-group) after they are asleep. Cover is removed before wake-up. Anesthesia 
providers are masked from assessing outcome.  Investigator is masked from 
assessing cognitive function through patient “self-assessing” using IPAD software. 
 
 

 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated. 
 
 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
  
 
A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
 
If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 
 
If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 
  
7.3. 
Lost to Follow up 
  
A participant will be considered lost to follow-up if he or she is discharged prior to 24 postop 
assessment, or unable to be approached for assessment at local hospital due to transfer from Oslo 
University Hospital. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study. 
 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  

 
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8. 
Study Assessments and Procedures 
  
 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 
8.1. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.1.1. 
Physical Examinations 
 
Assessment of pain levels 
 
Assessment of experience during and after anesthesia 
 
Cognitive assessments using CANTAB IPAD software 
8.2. 
Adverse Events(AE) and Serious Adverse Events(SAE) 
There will be a collection of data on adverse events; movement during surgery, serious 
hypotension during anesthesia (MAP<60) or  awareness with recall after surgery, and other 
events that is related to the anesthetic administration. We will not collect data on events related 
to the surgery. 
  
8.2.1. 
Time Period and Frequency for Collecting AE and SAE Information 
Data on adverse events will be collected directly after surgery, and on the 2 postoperative visits. 
8.2.2. 
Follow-up of AEs and SAEs 
All SAEs, and AEs of special interest will be followed up until resolution, or the event is 
otherwise explained, or the participant is lost to follow-up. 

 
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8.2.3. 
Regulatory Reporting Requirements for SAEs 
 
The only unexpected and Seriuos Adverse Event in our planned study, will be the 
occurrence of awareness with recall after surgery.  
 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study intervention under clinical investigation are met. 
 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 

 
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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
We anticipate that wake-up happens at mean 15 min, standard deviation 5 min (41-44) in the 
control group. We hypothesize that there will be an improvement of 20% (3 min) in the 
intervention group. 
9.2. 
Sample Size Determination 
We hypothesize that the intervention will reduce amount of propofol administered by up to 20%, 
also that wake-up may be reduced from 15 min, SD 5 min – to 20 min SD 3 min. With an 
improvement of 20%, 80% power and a significance level of 0.05, the study will require 88 
patients in total, calculated in a two-sample t-test. To add for margin of error/loss we will include 
50 patients in each group, summing at 100 patients in total. Due to a difference in plasma levels 
of anesthetic drugs in men and women, we will do gender stratification when randomizing, to 
ensure an equal number of sexes in both groups. 
9.3. 
Populations for Analyses 
The following populations are defined: 
Population 
Description 
Enrolled  
All participants who sign the ICF 
Randomly Assigned to 
Study Intervention 
50-50 
Evaluable 
All  
 
9.4. 
Statistical Analyses 
 
The statistical analysis plan will be finalized prior to database lock, and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. 
9.4.1. General considerations 
 
9.4.2. 
Primary endpoint(s) 
Medication usage; total amount of propofol used (mg/kg/hr) from start to end of anesthesia. 

 
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TCI effect site target at start, and each 10 min interval during anesthesia. 
9.4.3. 
 Secondary endpoint(s) 
Time to wake-up; from halt of anesthetic drugs to 
 
extubation (sec)  
 Verbal respons (sec) 
 Motoric response (show right index finger)(sec) 
Medication usage of remifentanil micg/kg/min 
Medication usage of inotropes (phenylephrine, norepinephrine) 
Cognitive function, assessed with 4 trials in the CANTAB IPAD-tool, preoperative function 
compared with 3hrs after wake-up, and preoperative compared with 24 hrs after wake-up. 
 
9.4.4. 
Other safety Analyse(s) 
Adverse events 
 

 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
 
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
 
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
 
The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
This study is financed in total by the investigator/sponsors hospital; either through the 
investigators PhD-fellowship program, or equipment purchased by the anesthetic department of 
said hospital. 
10.1.3. 
Informed Consent Process 
  
 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 
 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 

 
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50, local regulations, ICH guidelines, Health Insurance Portability and Accountability 
Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF. 
 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
10.1.4. 
Data Protection 
  
 
Participants will be assigned a unique identifier by the sponsor.  
 
The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for their 
data to be used as described in the informed consent  
 
Third party software providers (Cambridge Cognition), will store data from the 
CANTAB cognitive assessment tests as without name or information which would 
make the participant identifiable. These results will be stored on extra safe servers 
belonging to Cambridge Cognition in the UK, accessed only by principal investigator 
and PhD-fellow in the study-group. The handling of this data is covered in the DAP 
agreement between sponsor, and Cambridge Cognition. 
 
10.1.5. 
Committees Structure 
Leiv Arne Rosseland, co-supervisor, and responsible for randomization. He will not 
be in contact with participants in this study. 
Luis Romundstad, Principal Investigator, supervisor, and Medical monitor. 
Anders Aasheim, PhD-fellow, responsible for conducting inclusion of patients in 
cooperation with PI, managing day-to day operations of participants, collection of 
study-data. 
10.1.6. 
Dissemination of Clinical Study Data 
10.1.7. 
Data Quality Assurance 
  

 
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 
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 
The investigator must permit study-related monitoring, and provide direct access to 
source data documents. 
 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.  
 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
 
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 5 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to 
the sponsor. 
  
10.1.8. 
Source Documents 
  
 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 

 
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 
Definition of what constitutes source data can be found in the SoA data list. 
  
10.1.9. 
Study and Site Start and Closure 
  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is 15 of February 2020, and will be the study start date. 
  
  
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
 
Inadequate recruitment of participants by the investigator 
 
Discontinuation of further study intervention development 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the subject and 
should assure appropriate subject therapy and/or follow-up 
  
10.1.10. 
Publication Policy 
  
 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 

 
32173 ver 2.0 
 
 
23 
 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating investigator will be designated by mutual agreement. 
 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
  
10.2. 
Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
  
10.2.1. 
Definition of AE 
AE Definition 
 An AE is any untoward occurrence in a patient or clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention. We will only collect AE’s from events related to the anestetic 
administration, not from events related to the surgery. 
 
 
10.2.2. 
Recording and Follow-Up of AE  
AE  
 When an AE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 The investigator will then record all relevant AE information in the CRF. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records in lieu of completion of the AE CRF page. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 

 
32173 ver 2.0 
 
 
24 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 The investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
 For each AE, the investigator must document in the medical notes that he/she has 
reviewed the AE and has provided an assessment of causality. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs  
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or 
causality of the AE as fully as possible.  
 New or updated information will be recorded in the originally completed CRF. 
 
 
 
 

 
32173 ver 2.0 
 
 
25 
10.3. 
Appendix 3: Protocol Amendment History 
  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [32173 ver 2.0]: (02.01.20) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
This is an amendment of the original protocol sent to, and approved by REK-Helse Sør-Øst, due 
to a request by the clinical trial unit (CTU) of Oslo University Hospital, in order to make a more 
precise protocol. This amendment will be sent forwarded to REK after CTU has looked it over. 
Section # and Name 
Description of Change 
Brief Rationale 
32173 ver 2.0 
Specification of details 
 
 
 
 
 
 
 
  
 

 
32173 ver 2.0 
 
 
26 
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