A Randomized Controlled Trial Comparing Blood Glucose Control Intraoperative Between Insulin Drip vs. Insulin Boluses
Phase: NA
Conditions: Hypoglycemia (Diabetic)
Sponsor: King Faisal Specialist Hospital & Research Center

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Document Title: 
------------ 
 
(IRB Study # 2023-45) 
 
Document No. 
(IRB Study # 2023-45) 
Version 
Version # 2 
 
Page 1 of 10 
 
Title Page 
Protocol Cover page 
Title: 
 
A Randomized Controlled Trial Comparing Blood Glucose Control Intraoperative 
Between Insulin Drip vs. Insulin Boluses  
(IRB Study # 2023-45) 
 IRB Approved Study 
Version Date:  
Dated 10 Oct 2024 
Version: 
Version # 2 
Sponsor: 
King Faisal Specialist Hospital & Research Centre-Jeddah 
 
 
 
 
 
 
 
 
 

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Table of Contents 
PROTOCOL COVER PAGE .................................................................................................................. 1 
2.0 PROTOCOL SYNOPSIS ................................................................................................................. 5 
SPONSOR ............................................................................................................................................................... 5 
FUNDING ORGANIZATION ..................................................................................................................................... 5 
NUMBER OF SITES.................................................................................................................................................. 5 
RATIONALE ............................................................................................................................................................ 5 
STUDY DESIGN ....................................................................................................................................................... 5 
PRIMARY OBJECTIVE: ............................................................................................................................................. 5 
SECONDARY OBJECTIVES ....................................................................................................................................... 5 
NUMBER OF SUBJECTS: .......................................................................................................................................... 6 
SUBJECT SELECTION CRITERIA: ............................................................................................................................... 6 
TEST PRODUCT, DOSE, AND ROUTE OF ADMINISTRATION: .................................................................................... 6 
CONTROL PRODUCT, DOSE AND ROUTE OF ADMINISTRATION: ............................................................................. 6 
DURATION OF SUBJECT PARTICIPATION AND DURATION OF STUDY:..................................................................... 6 
CONCOMMITANT MEDICATIONS ........................................................................................................................... 6 
3.0 MAIN PROTOCOL ....................................................................................................................... 7 
BACKGROUND ....................................................................................................................................................... 7 
Methodology ......................................................................................................................................................... 7 
Statistical analysis: ................................................................................................................................................ 7 
4. SUBJECT SELECTION ..................................................................................................................... 8 
4.1. Study Population: ............................................................................................................................................ 8 
4.2. Inclusion Criteria: ............................................................................................................................................ 8 

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4.3. Exclusion Criteria: ........................................................................................................................................... 8 
4.4. Treatment ....................................................................................................................................................... 8 
4.4.1 Material: ........................................................................................................................................................... 9 
4.4.2 Preparation: ...................................................................................................................................................... 9 
4.5. Supply of Study Drug at the Site ...................................................................................................................... 9 
4.6. Storage: .......................................................................................................................................................... 9 
5. 
STUDY PROCEDURE ................................................................................................................... 9 
5.1. Study schedule ................................................................................................................................................ 9 
6. SAFETY ASSESMENTS ................................................................................................................. 10 
6.1. Adverse Effects/Events (AEs) ........................................................................................................................ 10 
6.1.1 Adverse event reporting period .................................................................................................................. 10 
6.1.2 Adverse Event Reporting ............................................................................................................................. 10 
6.2. 
Serious Adverse Experiences (SAE) .......................................................................................................... 11 
6.2.1 Serious Adverse Experience Reporting: .......................................................................................................... 11 
7. STATISTICAL ANALYSIS: .............................................................................................................. 11 
7.1 Sample size .................................................................................................................................................... 11 
7.2 Definition of study population ....................................................................................................................... 11 
7.3 Overall statistical and analytical plan ............................................................................................................. 11 
8. DATA COLLECTION, HANDLING AND RECORD KEEPING .............................................................. 12 
8.1 Case Report Form ........................................................................................................................................... 12 
8.2 Source Data .................................................................................................................................................... 12 
8.3 Protocol Deviations ........................................................................................................................................ 13 
9. ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS .................................................... 13 
9.1. 
Investigator Responsibilities .................................................................................................................... 13 

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10. REFERENCES: ............................................................................................................................ 16 
 
 
 

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2.0 Protocol Synopsis 
TITLE:  
A Randomized Controlled Trial Comparing Blood Glucose Control Intraoperative Between 
Insulin Drip vs. Insulin Boluses 
SPONSOR 
No sponsor for this study  
FUNDING ORGANIZATION  
King Faisal Specialist Hospital & Research Center-Jeddah  
NUMBER OF SITES  
Only (King Faisal Specialist Hospital & Research Center-Jeddah) 
RATIONALE: 
This randomized controlled trial will provide valuable information on the optimal method for 
achieving blood glucose control intraoperatively. The results of this study may help improve 
patient outcomes and reduce the incidence of postoperative complications. 
STUDY DESIGN:  
Randomized Controlled Trial 
PRIMARY OBJECTIVE:  
Is to compare blood glucose control intraoperatively between patients who receive insulin drip 
and patients who receive insulin boluses during adult cardiac surgery. 
SECONDARY OBJECTIVES:  
Is to evaluate the incidence of hypoglycemic events and the need for insulin adjustments during 
surgery. 
PRIMARY OUTCOME:  
rate of severe hypoglycemia 
 
SECONDARY OUTCOME: 
-duration of ICU stay 
-lactate clearance 

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-wound infection day 7; and day 30 (clinic follow-up) 
NUMBER OF SUBJECTS:  
If you assume that 6% of the participants receiving boluses will acquire a wound infection and 1% 
of the participants receiving insulin drip will acquire an infection, you will need to enroll the 
following number of participants in your study to detect this difference: 
Assuming a two-sided test and an alpha = 0.05, to have power = 80% to detect the difference, you 
need to enroll 192 participants per group for a total of 384 participants. 
SUBJECT SELECTION CRITERIA: 
Inclusion Criteria: 
 
All adult patients (above 18 y of age undergoing Cardiac surgery with preoperative blood glucose 
level (80 -180 mg/dL) 
 
Patient with History of diabetes and those taking antidiabietic medications. 
 
Exclusion Criteria: 
 
Patients with known allergy or insulin intolerance. 
 
Patients with severe hepatic Dysfunction. 
 
Patient with History of hypoglycemic events in the past 6 month prior to surgery. 
 
TEST PRODUCT, DOSE, AND ROUTE OF ADMINISTRATION: 
Insulin drip will be administered at a starting rate of 2 units/hour and titrated to maintain blood 
glucose levels between 80-180 mg/dL. 
CONTROL PRODUCT, DOSE AND ROUTE OF ADMINISTRATION: 
Insulin boluses will be administered every 30 minutes to maintain blood glucose levels between 
80-180 mg/dL. 
DURATION OF SUBJECT PARTICIPATION AND DURATION OF STUDY: 
Data will be collected 24 hours before the surgery, then patients will be followed up immediately, 
one week after, one month, 6 months and one year. Overall study duration is estimated to be 4 
years. 
CONCOMMITANT MEDICATIONS.   
No concomitant medications 
EFFICACY EVALUATIONS.  
SAFETY EVALUATIONS.  

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Since both methods of insulin delivery are already in use and FDA approved there is no safety 
concerns at the time being. However, an interim analysis will be carried out throughout the hospital 
stay and in each visit in the first postoperative year. 
PLANNED INTERIM ANALYSES.  
An interim analysis will be carried out throughout the hospital stay and in each visit in the first 
postoperative year.  
STATISTICS. Analysis plan:  
Using relative risk for statistical analysis and log rank. A P value of less than 0.05 will be 
considered statistically significant. Statistical analyses will be carried out using the SPSS or SAS. 
 
Rationale for Number of Subjects:  
Sample size calculated basis of a two-sided test and an alpha = 0.05, to have power = 80%. The 
results will be presented as mean (SD), median (interquartile (range), or proportion. 
3.0 Main Protocol 
BACKGROUND 
General Overview:  
Hyperglycemia during surgery has been linked to increased risk of postoperative complications, 
including wound infections, delayed wound healing, and cardiovascular events. Maintaining 
blood glucose within a target range during surgery has been shown to reduce the incidence of 
these complications. Two methods commonly used for maintaining blood glucose control 
intraoperatively are insulin drip and insulin boluses. However, the optimal method for achieving 
blood glucose control remains unclear. Therefore, we propose a randomized controlled trial to 
compare blood glucose control intraoperative between two groups using insulin drip in one 
group and insulin boluses in the other group. 
 Methodology 
  Inclusion criteria: 
 
All adult  Diabetic patients  ( Both type I & Type II) undergoing Cardiac surgery with preoperative 
blood glucose level (80 -180 mg/dL) 
 
Patient with History of diabetes and those taking antidiabetic medications. 
 
Exclusion criteria: 
 
Patients with known allergy or insulin intolerance. 
 
Patients with severe hepatic Dysfunction. 

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 
Patient with History of hypoglycemic events in the past 6 month prior to surgery. 
 
Randomization: 
Simple randomization will be used for randomization. The participants will be randomized into 
two groups based on methods of insulin delivery.  
 Group A: Insulin drip will be administered at a starting rate of 2 units/hour and titrated to 
maintain blood glucose levels between 80-180 mg/dL. 
 Group B: Insulin boluses will be administered every 30 minutes to maintain blood 
glucose levels between 80-180 mg/dL. 
 
Insulin boluses will be considered as a control group. 
Statistical analysis: 
The results will be presented as mean (SD), median (interquartile (range), or proportion. Using 
relative risk for statistical analysis and log rank. A P value of less than 0.05 will be considered 
statistically significant. Statistical analyses will be carried out using the SPSS or SAS. 
4. SUBJECT SELECTION 
4.1. Study Population: 
All adult patients (above 18 y of age undergoing Elective Cardiac surgery with preoperative blood 
glucose level (80 -180 mg/dL) 
 
4.2. Inclusion Criteria: 
 All adult patients (above 18 y of age undergoing Elective Cardiac surgery with 
preoperative blood glucose level (80 -180 mg/dL) 
 Patient with History of Both Type I & Type II diabetes and those taking antidiabetic 
medications. 
4.3. Exclusion Criteria: 
Patients with known allergy or insulin intolerance. 
Patients with severe hepatic Dysfunction. 
Patient with History of hypoglycemic events in the past 6 month prior to surgery. 
4.4. Treatment 
 Group A: Insulin drip will be administered at a starting rate of 2 units/hour and titrated to 
maintain blood glucose levels between 80-180 mg/dL. 
 Group B: Insulin boluses will be administered every 30 minutes to maintain blood 
glucose levels between 80-180 mg/dL. 
 

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4.4.1 Material:   
Insulin infusion 
4.4.2 Preparation:  
The medication will be prepared by the pharmacy  
 
4.5. Supply of Study Drug at the Site 
Insulin delivery are already in use and FDA approved there is no safety concerns at the time being  
 
4.6. Storage: The hospital pharmacy  
5. 
STUDY PROCEDURE 
5.1. Study schedule 
All adult patients (above 18 y of age undergoing Cardiac surgery with preoperative blood glucose 
level (80 -180 mg/dL) Patient with History of diabetes and those taking antidiabetic medications. 
On admission, all patient will stop all preoperative anti diabetic medications and will be converted 
to Insulin short acting sliding scale as per protocol according to insulin requirement preoperatively. 
Patient requiring < 40 unites/ day will receive Low dose Insulin sliding scale, Patient requiring 40-
80 unites/ day will receive Medium dose Insulin sliding scale and Patient requiring >80 unites/ day 
will receive High dose Insulin sliding scale. (Appendix 1) 
 
5.1.1 Schedule of events 
All demographic data, diagnosis, procedure (insulin delivery), surgery and hospital course details 
 
Age, Sex, DM, HTN, NYHA class, HbA1C, 
Pre op FBS, 
Intraop lactate,Postop lactate, 
wound scale, BMI, BSA, Preop insulin, CKD, Pre antibiotic, Intraop antibiotic and length of stay 
will be collected from the day of admission to the day of discharge. 
Data will be collected 24 hours before the surgery, then patients will be followed up 
immediately, one week after, one month, 6 months and one year. 
Blood sugar level will be monitored hourly in the first postoperative day and every 4-6 hours 
during hospital stay. 

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6. SAFETY ASSESMENTS   
Blood sugar level 
6.1. Adverse Effects/Events (AEs) 
Table 3.  AE Relationship to Study Drug 
 
6.1.1 Adverse event reporting period 
The period for recording AEs in the CRF begins when signs the ICF and ends at the end of study 
visit. 
6.1.2 Adverse Event Reporting 
Both serious and non-serous AEs are to be reported on the AE page of the CRF as specified in 
the CRF data entry guidelines. 
 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by 
stopping or reducing the dosage of the drug; and that is not explained by any 
other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration 
of the drug; that follows a known or expected response pattern to the 
suspected drug; that is confirmed by stopping or reducing the dosage of the 
drug; and that is unlikely to be explained by the known characteristics of the 
subject’s clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration 
of the drug; that follows a known or expected response pattern to that 
suspected drug; but that could readily have been produced by a number of 
other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the 
study drug. 
 
 
The only foreseen adverse may be of the mouthwash giving a bitter taste. 

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6.2. 
Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
1. 
Death 
2. 
A Life-Threatening Adverse Experience 
3. 
Inpatient Hospitalization or Prolongation of Existing Hospitalization 
4. 
A Persistent or Significant Disability/Incapacity 
5. 
A Congenital Anomaly/Birth Defect  
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed.  
6.2.1 Serious Adverse Experience Reporting:  
1. Designee investigator(s) will document all SAEs that occur (whether or not related to study 
drug) per UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed. 
2. In accordance with the standard operating procedures and policies of the KFSHRC’s 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC), the investigators will 
report SAEs to the IRB/IEC.   
7. STATISTICAL ANALYSIS: 
7.1 Sample size 
This study will include a total of 384 adult patients randomly assigned to each arm (192 per arm).  
7.2 Definition of study population 
All adult patients (above 18 y of age undergoing Cardiac surgery with preoperative blood glucose 
level (80 -180 mg/dL) Patient with History of diabetes and those taking antidiabetic medications. 
 
 
7.3 Overall statistical and analytical plan 
This study will include a total of 384 adult patients randomly assigned to each arm (192 per arm). 
Sample size calculated basis of a two-sided test and an alpha = 0.05, to have power = 80%. The 
results will be presented as mean (SD), median (interquartile (range), or proportion. Using relative 
risk for statistical analysis and log rank. A P value of less than 0.05 will be considered statistically 
significant. Statistical analyses will be carried out using the SPSS or SAS. 

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8. DATA COLLECTION, HANDLING AND RECORD KEEPING 
8.1 Case Report Form 
All demographic data, diagnosis, procedure (insulin delivery), surgery and hospital course details 
Age, Sex, DM, HTN, NYHA class, HbA1C, Pre op FBS, 
Intraoperative  lactate, Postop lactate, 
wound scale, BMI, BSA, Preoperative insulin, CKD, Pre antibiotic, Intraoperative Intraop 
antibiotic and length of stay will be collected from the day of admission to the day of discharge. 
 
8.2 Source Data 
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, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, subject 
files, and records kept at the pharmacy, at the laboratories). Information in source documents 
(i.e., medical history/physical condition) dated prior to the Patient Information and Informed 
Consent Form signature date may be used to verify patient eligibility criteria. 
Clinical records must be marked to indicate a subject has been enrolled into the clinical study. 
The Investigator must ensure the availability of source documents from which the information on 
the CRFs was derived. Where printouts of electronic medical records are provided as source 
documents, or where copies of source documents are retained as source documents, they should 
be signed and dated by a member of the investigational site team indicating they are a true 
reproduction of the original source document. 
Clinical Investigation Plan 
The source documents must be made available for monitoring or auditing.Copies of source 
documents will be requested to support event adjudication. 
Data will be collected through ICIS power chart and will be entered into a secured database. A 
data management plan will be created before data collection begins and will describe all functions, 
processes, and specifications for data collection, cleaning and validation. Concurrent manual data 
review will be performed based on parameters dictated by the plan. High quality standards will be 
maintained, and processes and procedures utilized to repeatedly ensure that the data as clean and 
accurate as possible when presented for analysis. 

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8.3 Protocol Deviations 
A study deviation is an event where the investigator or site personnel did not conduct the clinical 
study according to the Clinical Investigational Plan. The investigator is not allowed to deviate 
from the above-mentioned documents except with prior approval and under emergency 
circumstances. All deviations shall be documented and explained, regardless the reason for the 
deviation.  
In this study where all patients receive standard hospital care, reporting of deviations is only 
required in case informed consent cannot be obtained before data entry. No further data should 
be entered until the issue has been resolved. Failure to obtain consent from the patient to release 
personal information might ultimately result in removing the patient from the study.  
The investigator is obliged to comply with Ethical Committee procedures and/or local laws for 
reporting deviations.  
9. ADMINISTRATIVE, ETHICAL, REGULATORY 
CONSIDERATIONS 
9.1. 
Investigator Responsibilities 
Informed consent is defined as a legally effective documented confirmation of a subject’s or their 
legally authorized/designated representative’s voluntary agreement to participate in a particular 
study after information has been given and explained to the subject on all aspects of the study 
that are relevant to the subject’s decision to participate. 
Here and throughout the document, “EC/IRB” is the term that will be used collectively in 
reference to an Institutional Review Board (IRB), Ethics Committee (EC). 
It is the responsibility of the investigator to confirm the approval requirements of the hospital 
and local regulations for this observational study with his/her EC/IRB prior to start of the study. 
As a minimum, it is strongly recommended notifying the local Ethics Committee about the 
conduct of this study. 
Patients’ confidentiality will be maintained, removing any identifying informations from the data 
set by the data controller before further usage and analysis. The data of both variables and their 
values were coded into Alpha-numeric format for concealment with few designated persons 
having the coding key. 
The study will be conducted according to the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. It will also follow 
the International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines 
Patient engagement and withdrawals:  

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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. A participant will be considered lost to follow-up if he or she repeatedly 
fails to return for scheduled visits and is unable to be contacted by the study site. 
Regulatory and Ethical Considerations: 
•This study will be conducted in accordance with the protocol and the following: 
• 
Consensus ethical principles derived from international guidelines, including 
the Declaration of Helsinki and Council for International 
• 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
• 
Applicable ICH GCP Guidelines 
• 
Applicable laws and regulations 
•The Investigator must submit the protocol, protocol amendments (if applicable), ICF, 
and other relevant documents to an IRB/IEC and the IRB/IEC must review and approve them 
before the study is initiated. 
•Any protocol amendments (i.e., changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary to 
eliminate an immediate hazard to study participants. When applicable, amendments will be 
submitted to the appropriate Health Authorities. 
•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 per the IRB’s/IEC’s requirements, policies, and procedures. 
o Notifying the IRB/IEC of SAEs or other significant safety findings, as required by IRB/IEC 
procedures 
o Providing oversight of the study conduct at the site and adherence to requirements of ICH 
guidelines, the IRB/IEC, for clinical studies (if applicable), and all other applicable local 
regulations 
Publication: 
•The results of this study may be published or presented at scientific meetings. If this is 
Foreseen. 

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•The investigator will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice. 
•Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
Data Quality Assurance: 
•All participant study data will be recorded on printed or electronic CRFs or transmitted to 
the designee electronically (e.g., laboratory data). The Investigator is responsible for verifying 
that data entries are complete, accurate, legible, and timely by physically or electronically 
signing the CRF.  
•The Investigator must maintain accurate documentation (source data) that supports the 
information in the CRF. 
•The Investigator must permit study-related monitoring, quality assurance audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to the study file and source 
data. 
•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. 
•Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion, unless local regulations, 
institutional policies. No records may be destroyed during the retention period without the 
Sponsor’s written approval.  
Protocol adherence and amendments: 
Adherence to the study design requirements, including those specified in the SoA, is essential and 
required for study conduct. 
 
Informed Consent Form: 
If full Informed Consent is requested by local laws or by the EC/IRB, a signed “Patient Informed 
Consent” (PIC) document should be obtained. In this case, a patient informed consent form will 
be given to each patient, which includes all aspects of the clinical study that are relevant to the 
subject’s decision to participate throughout the clinical study. 

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The informed consent form will be translated into the appropriate language of each country in 
which the study will be conducted. 
Each patient and Principal Investigator or authorized delegated designee obtaining informed 
consent must personally sign and date, in the appropriate local language a “Patient Informed 
Consent Form”. 
The physician must keep the original informed consent form signed by the patient (a signed copy 
is given to the patient). For subjects that are unable to read or write, the informed consent shall 
be obtained through a supervised oral process. The independent witness shall be present 
throughout the entire process. The informed consent form and any other information shall be 
read aloud and explained to the subject, and whenever possible, either shall sign and personally 
date the informed consent form. The witness also signs and personally dates the informed 
consent form attesting that the information was accurately explained and that informed consent 
was freely given. 
Where a patient has initially verbally consented or a patient’s legally acceptable representative has 
consented on behalf of the patient, written consent should be sought from the patient as soon as, 
in the investigator’s opinion, the patient is capable of understanding the process and capable of 
signing the consent form. 
10. REFERENCES: 
1. Hovorka R, Kremen J, Blaha J, Matias M, Anderlova K, Bosanska L, Roubicek T, 
Wilinska ME, Chassin LJ, Svacina S, Haluzik M. Blood glucose control by a model 
predictive control algorithm with variable sampling rate versus a routine glucose 
management protocol in cardiac surgery patients: a randomized controlled trial. J Clin 
Endocrinol Metab. 2007 Aug;92(8):2960-4. doi: 10.1210/jc.2007-0434. Epub 2007 Jun 5. 
PMID: 17550955. 
2. Rao RH, Perreiah PL, Cunningham CA. Monitoring the Impact of Aggressive Glycemic 
Intervention during Critical Care after Cardiac Surgery with a Glycemic Expert System 
for Nurse-Implemented Euglycemia: The MAGIC GENIE Project. J Diabetes Sci 
Technol. 2021 Mar;15(2):251-264. doi: 10.1177/1932296821995568. PMID: 33650454; 
PMCID: PMC8256075. 
 
3. Blaha J, Kopecky P, Matias M, Hovorka R, Kunstyr J, Kotulak T, Lips M, Rubes D, 
Stritesky M, Lindner J, Semrad M, Haluzik M.Comparison of three protocols for tight 
glycemic control in cardiac surgery patients. Diabetes Care. 2009 May;32(5):757-61. doi: 
10.2337/dc08-1851. Epub 2009 Feb 5. 
 
4. Cordingley JJ, Vlasselaers D, Dormand NC, Wouters PJ, Squire SD, Chassin LJ, 
Wilinska ME, Morgan CJ, Hovorka R, Van den Berghe G.Intensive insulin therapy: 

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enhanced Model Predictive Control algorithm versus standard care. Intensive Care Med. 
2009 Jan;35(1):123-8. doi: 10.1007/s00134-008-1236-z. Epub 2008 Jul 26. 
 
5. Roubícek T, Kremen J, Bláha J, Matias M, Kopecký P, Rulísek J, Anderlová K, 
Bosanská L, Mráz M, Chassin LJ, Hovorka R, Svacina S, Haluzík M. [Pilot study to 
evaluate blood glucose control by a model predictive control algorithm with variable 
sampling rate vs. routine glucose management protocol in peri- and postoperative period 
in cardiac surgery patients]Cas Lek Cesk. 2007;146(11):868-73. 
 
6. Vogt AP, Bally L. Perioperative glucose management: Current status and future 
directions. Best Pract Res Clin Anaesthesiol. 2020 Jun;34(2):213-224. doi: 
10.1016/j.bpa.2020.04.015. Epub 2020 May 11. PMID: 32711830. 
7. Ferrari LR. New insulin analogues and insulin delivery devices for the perioperative 
management of diabetic patients. Curr Opin Anaesthesiol. 2008 Jun;21(3):401-5. doi: 
10.1097/ACO.0b013e3282faa2f0. PMID: 18458562. 
8. Corney SM, Dukatz T, Rosenblatt S, Harrison B, Murray R, Sakharova A, 
Balasubramaniam M. Comparison of insulin pump therapy (continuous subcutaneous 
insulin infusion) to alternative methods for perioperative glycemic management in 
patients with planned postoperative admissions. J Diabetes Sci Technol. 2012 Sep 
1;6(5):1003-15. doi: 10.1177/193229681200600503. PMID: 23063025; PMCID: 
PMC3570833. 
9. Kuntschen FR, Galletti PM, Hahn C, Arnulf JJ, Isetta C, Dor V. Alterations of insulin 
and glucose metabolism during cardiopulmonary bypass under normothermia. J Thorac 
Cardiovasc Surg. 1985 Jan;89(1):97-106. PMID: 3880848. 
10. Schmeltz, L.R., DeSantis, A.J., Thiyagarajan, V., et al. (2007) Reduction of Surgical 
Mortality and Morbidity in Diabetic Patients Undergoing Cardiac Surgery with a 
Combined Intravenous and Subcutaneous Insulin Glucose Management Strategy. 
Diabetes Care, 30, 823-82 
11. Furnary, A.P., Wu, Y. and Bookin, S.O. (2004) Effect of Hyperglycemia and Continuous 
Intravenous Insulin Infusion on Outcomes of Cardiac Surgical Procedures: The Portland 
Diabetic Project. Endocrine Practice, 10, 21-33. http://dx.doi.org/10.4158/EP.10.S2.2 
12. Van den Berghe, G., Wouters, P.J., Bouillon, R., et al. (2003) Outcome Benefit of 
Intensive Insulin Therapy in the Critically Ill: Insulin Dose versus Glycemic Control. 
Critical Care Medicine, 31, 359-366. 
http://dx.doi.org/10.1097/01.CCM.0000045568.12881.10 
13. Van Den Berghe, G., Wilmer, A., Milants, I., et al. (2006) Intensive Insulin Therapy in 
Mixed Medical/Surgical. Heal, 55, 3151-3159. http://dx.doi.org/10.2337/db06-0855 
 
 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and the following: 

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 
Consensus ethical principles derived from international guidelines, including the Declaration of Helsinki and 
Council for International 
 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
 
Applicable ICH GCP Guidelines 
 
Applicable laws and regulations 
The Investigator must submit the protocol, protocol amendments (if applicable), ICF, 
and other relevant documents to an IRB/IEC and the IRB/IEC must review and approve them before the study is 
initiated. 
Any protocol amendments (i.e., changes to the protocol) will be documented in writing 
and require IRB/IEC approval before implementation of changes, except for changes 
necessary to eliminate an immediate hazard to study participants. When applicable, 
amendments will be submitted to the appropriate Health Authorities. 
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 per the IRB’s/IEC’s requirements, policies, and procedures. 
o Notifying the IRB/IEC of SAEs or other significant safety findings, as required by 
IRB/IEC procedures 
o Providing oversight of the study conduct at the site and adherence to requirements of ICH guidelines, the IRB/IEC, 
for clinical studies (if applicable), and all other applicable local regulations 
 
Publication 
The results of this study may be published or presented at scientific meetings. If this is 
Foreseen. 
The investigator will comply with the requirements for publication of study results. Per 
standard editorial and ethical practice. 
Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
Data Quality Assurance 
All participant study data will be recorded on printed or electronic CRFs or transmitted to 
the designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are complete, accurate, legible, and timely by 
physically or electronically signing the CRF.  
The Investigator must maintain accurate documentation (source data) that supports the 
information in the CRF. 
The Investigator must permit study-related monitoring, quality assurance audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to the study file and 
source data. 
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. 
Records and documents, including signed ICFs, pertaining to the conduct of this study 

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must be retained by the Investigator for 15 years after study completion, unless local 
regulations, institutional policies. No records may be destroyed during the retention period without the Sponsor’s 
written approval.