The Effect of Low-dose Empagliflozin on Glucose Control in Adult Patients With Type 1 Diabetes on a Closed-loop Insulin System: a Randomized Cross-over Controlled Trial
Phase: PHASE1
Conditions: Type 1 Diabetes
Sponsor: McGill University

Protocol #: 2021 – 6542 
Version: 15 
Date: 2021-05-17 
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Clinical Study Protocol 
 
Title: The effect of low-dose empagliflozin on glucose control in adult patients with type 1 
diabetes on a closed-loop insulin system: a randomized cross-over controlled trial. 
 
Protocol #: 2021 – 6542  
 
Principal Investigator: 
Dr. Michael TSOUKAS, M.D.  
Assistant Professor 
Division of Endocrinology 
Royal Victoria Hospital 
1001, boul. Decarie  
Montreal, QC, H4A 3J1 
 
Co-Investigator 
Dr. Melissa-Rosina PASQUA, M.D.  
Resident in Endocrinology & Metabolism  
McGill University 
3775, rue University 
 
Dr. Ahmad HAIDAR, Ph.D.  
Assistant professor  
Department of Biomedical Engineering  
McGill University  
3775, rue University 
 
Funding: self-funded  
 
Sponsor: Dr. Michael Tsoukas 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
1 
Background and Rationale ............................................................................................. 6 
1.1 
Summary of our team’s prior closed-loop system studies in adults with type 1 diabetes ... 7 
1.2 
Summary of prior studies using SGLT2i in adults with type 1 diabetes ............................. 8 
1.3 
Summary of our prior studies using both closed-loop system and SGLT2i in adults with 
type 1 diabetes ................................................................................................................................. 8 
2 
Objective, Design, and Hypotheses .................................................................................. 9 
2.1 
Objective ............................................................................................................................. 9 
2.2 
Study Design ....................................................................................................................... 9 
2.3 
Hypotheses ........................................................................................................................ 10 
3 
Study Population ........................................................................................................... 10 
3.1 
Criteria ............................................................................................................................. 10 
3.1.1 
Inclusion Criteria ................................................................................................................................. 10 
3.1.2 
Exclusion Criteria ............................................................................................................................... 11 
3.1.3 
Discontinuation Criteria ...................................................................................................................... 12 
3.2 
Study Withdrawal ............................................................................................................. 12 
3.3 
Recruitment and Study Centres ....................................................................................... 12 
4 
Study Drugs and Materials ............................................................................................ 13 
4.1 
Study Drugs ...................................................................................................................... 13 
4.2 
Study Devices and Materials ............................................................................................. 13 
4.3 
McGill Artificial Pancreas (MAP) System ........................................................................ 14 
5 
Trial Design ................................................................................................................... 14 
5.1 
Phases of treatment therapy ............................................................................................. 14 
5.2 
Questionnaires .................................................................................................................. 14 
5.3 
Randomization .................................................................................................................. 15 
5.4 
Blinding ............................................................................................................................. 15 
5.5 
Visit Schedule .................................................................................................................... 15 
6 
Study Procedures ........................................................................................................... 16 
6.1 
Initial study visit ............................................................................................................... 16 
6.2 
Training of study materials ............................................................................................... 17 
6.3 
Closed-loop run-in period ................................................................................................. 18 
6.3.1 
Alternative Path: For Patients Already on Closed-Loop Therapy ....................................................... 18 
6.4 
Interventions ..................................................................................................................... 18 
6.4.1 
General Procedures for All Interventions (14 days) ............................................................................ 18 
6.4.2 
Point-of-care ketone measurement during interventions ..................................................................... 19 

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6.5 
Wash-out period ............................................................................................................... 19 
6.6 
End of study visit .............................................................................................................. 19 
6.6.1 
Interview ............................................................................................................................................. 20 
7 
Risk and Risk Mitigation ............................................................................................... 20 
7.1 
Empagliflozin dose rationale ............................................................................................. 20 
7.2 
Medical and Safety Monitoring ........................................................................................ 20 
7.2.1 
Monitoring .......................................................................................................................................... 21 
7.2.2 
Concomitant and prohibited medications ............................................................................................ 21 
7.3 
Risks Associated with the Study ....................................................................................... 21 
7.3.1 
Empagliflozin ...................................................................................................................................... 21 
7.3.2 
Blood sampling ................................................................................................................................... 22 
7.3.3 
Glucose sensors and insulin infusion sets ........................................................................................... 22 
7.3.4 
Hypoglycemia ..................................................................................................................................... 22 
7.3.5 
Hyperglycemia (and associated conditions) ........................................................................................ 22 
7.3.6 
Genito-urinary and soft tissue infections ............................................................................................. 24 
7.3.7 
Dehydration ......................................................................................................................................... 24 
7.3.8 
Risks related to the MAP system ........................................................................................................ 24 
7.4 
Pregnancy ......................................................................................................................... 25 
8 
Statistical Analysis ......................................................................................................... 25 
8.1 
Study Endpoints ................................................................................................................ 26 
8.1.1 
Primary endpoints ............................................................................................................................... 26 
8.1.2 
Secondary endpoints ........................................................................................................................... 26 
8.1.3 
Safety endpoints .................................................................................................................................. 26 
8.2 
Sample Size and Power Calculations ................................................................................ 27 
8.2.1 
Level of significance ........................................................................................................................... 27 
8.2.2 
Statistical analysis ............................................................................................................................... 27 
9 
Ethical and Legal consideration .................................................................................... 27 
9.1 
Good clinical practice ....................................................................................................... 27 
9.2 
Delegation of investigator’s duties .................................................................................... 27 
9.3 
Participant’s Informed Consent ....................................................................................... 28 
9.4 
Confidentiality .................................................................................................................. 28 
9.5 
Approval of the clinical study protocol and amendments ................................................. 28 
9.6 
Record retention ............................................................................................................... 28 
10 
Data Safety and Monitoring Board ............................................................................ 28 
 
Roles and Responsibilities ..................................................................................................... 28 
10.1 ................................................................................................................................................ 28 
 
Membership .......................................................................................................................... 28 
10.2 ................................................................................................................................................ 28 
 
Conflict of Interest ................................................................................................................ 29 

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10.3 ................................................................................................................................................ 29 
 
Meetings ................................................................................................................................ 29 
10.4 ................................................................................................................................................ 29 
10.4.1 
Meeting Format .............................................................................................................................. 29 
 
Decisions ................................................................................................................................................. 29 
10.4.2 ................................................................................................................................................................. 29 
 
Study Reports ........................................................................................................................................... 30 
10.4.3 ................................................................................................................................................................. 30 
10.5 
Reports from the DSMB ................................................................................................... 30 
11 
Adverse events ............................................................................................................ 30 
11.1 
Adverse events .................................................................................................................. 30 
11.2 
Classification of specific adverse events ............................................................................ 31 
11.2.1 
Hypoglycemia and hyperglycemia ................................................................................................. 31 
11.2.2 
Ketoacidosis ................................................................................................................................... 31 
11.2.3 
Local skin reactions ........................................................................................................................ 32 
11.2.4 
Infection and soft tissue ischemia ................................................................................................... 32 
11.2.5 
Dehydration .................................................................................................................................... 33 
11.2.6 
Phlebotomy .................................................................................................................................... 33 
11.2.7 
Closed-loop system device failure .................................................................................................. 33 
11.3 
Severity (intensity) and causality of adverse events .......................................................... 33 
11.4 
Reporting serious adverse events ...................................................................................... 34 
11.4.1 
Responsibilities of the principal investigator ................................................................................. 34 
11.4.2 
Definition of a Serious Adverse Event (SAE) ................................................................................ 34 
12 
References ................................................................................................................. 35 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Version Tracker/Revision History  
# 
Date 
Author 
 
Description 
REB 
ITA 
NOL 
Submission 
date 
Response date 
Submission date 
Response date 
Submission date 
Response date 
7 
2020-
04-28 
Melissa-
Rosina 
Pasqua 
Initial submission draft (different 
versions = internal edits).   
N/A 
2020-05-01 
2020-06-11 
(Response) 
N/A 
8 
2020-
06-18 
Melissa-
Rosina 
Pasqua 
1) COVID19 precautions (option of 
remote visits). 
2) Daily ketones during interventions 
(vs selected days) 
N/A 
N/A 
2020-06-19 
2020-07-21 
(Approval) 
9 
2020-
07-21 
Melissa-
Rosina 
Pasqua 
1) Site change from RI MUHC to 
Clinique Médicale Hygea 
2) Inclusion of Dexcom G6 
2020-07-21 
2020-08-05 
(Approval) 
N/A 
2020-07-21 
2020-07-21 
(Acknowledged) 
10 
2020-
08-18 
Melissa-
Rosina 
Pasqua 
1) Emergency kit given to all 
participants (as per REB request) 
2) Dr Pasqua listed as co-investigator 
from co-PI 
3) Self-funding declared 
2020-08-18 
2020-08-24 
(Approval) 
2020-08-23 
2020-09-20 
(Response) 
2020-11-02 
(Approval) 
2020-08-25 
2020-08-25 
(Acknowledged) 
11 
2020-
9-29 
Melissa-
Rosina 
Pasqua 
Timing of last HbA1c used for 
inclusion criteria extended to 12 
months.  This change was retracted. 
2020-09-29 
2020-10-01 
(Approval) 
2020-10-01  
(Submission 
cancelled) 
2020-09-30 
2020-09-30 
(Acknowledged) 
10.1 
2020-
10-08 
Melissa-
Rosina 
Pasqua 
Identical to version 10, used only to 
retract version 11 from REB 
2020-10-08 
2020-10-14 
(Approval) 
N/A 
N/A 
12 
2020-
12-14 
Melissa-
Rosina 
Pasqua 
1) Timing of HbA1c used for inclusion 
criteria extended to 6 months from 3 
months 
2) Creatinine for inclusion criteria 
specified as within 12 months 
3) Rewording of exclusion criteria 
referring to glucocorticoid use 
4) No prophylactic insulin reduction if 
hyperglycemic. 
N/A 
(Submission 
cancelled) 
N/A (Submission 
cancelled) 
2020-12-14 
2020-12-17 
(Response) 
13 
2020-
12-17 
Melissa-
Rosina 
Pasqua 
Clarification of protocol number as per 
request by Health Canada 
2020-12-17 
2021-01-6 
(Approval) 
2020-12-22 
2021-01-13 
(Acknowledged) 
2020-12-17 
2021-01-07 
(Approval) 
14 
2021-
03-01 
Melissa-
Rosina 
Pasqua 
Creation of Drug and Safety 
Monitoring Board 
2021-03-02 
2021-03-08 
(Approval) 
2021-03-11 
2021-03-12 
(Acknowledged) 
2021-03-11  
2021-03-11 
(Acknowledged) 
15 
2021-
05-10 
Melissa-
Rosina 
Pasqua 
1) Direct entry pathway for those 
already on closed-loop therapy  
2) Ongoing recruitment in between 
DSMB assessment 
To be 
submitted 
To be submitted 
To be submitted 
NB: versions 1 - 6 were edited internally 
Versions 7 and 8 were originally intended for the RI MUHC's REB.   
 

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1 
Background and Rationale 
 
Type 1 diabetes is a chronic medical condition that is caused by autoimmune destruction of the 
insulin-producing beta cells; though it only accounts for 10% of all cases of diabetes mellitus, it 
is marked by the need for lifetime insulin therapy as well as risk of ketoacidosis and micro- and 
macrovascular complications.(1)  Though many advances have allowed for new methods of 
glycemic monitoring, novel insulin formulations, and different methods of insulin 
administration, the gold standard for treatment remains intensive insulin therapy,(2) which has 
been linked to improved long-term outcomes in reduction of micro- and macrovascular 
complications.(3,4)  Limitations include risk of hypoglycemia and increased disease burden to 
mimic the many variables in glycemic control.(2,4)  Because of this, many patients with type 1 
diabetes do not meet glycemic levels reflecting a target HbA1c of < 7% recommended by 
Canadian diabetes guidelines.(2,5)  
 
The rise of diabetes technology has greatly mitigated the treatment of glycemic variability.  
Continuous subcutaneous insulin pump therapy (CSII) is now, like basal-bolus insulin therapy, 
considered standard of care for type 1 diabetes management,(2) though has been shown to 
improve both HbA1c and quality of life in comparison to multi-daily injections (MDI).(6)  This, 
combined with continuous glucose monitoring (CGM), allows patients with type 1 diabetes to 
finetune their insulin therapy to daily life.   
 
A step further is the combination of both technologies, i.e. closed-loop insulin system, also 
referred to as the “artificial pancreas” (AP).  A closed-loop insulin system refers to an insulin 
delivery system utilizing both CGM and CSII, where insulin delivery is modified based on 
glucose readings from CGM.  Multiple studies have shown the benefit of closed-loop insulin 
systems on glycemic control,(7–13) with thus far one system commercially available in Canada, 
i.e. the Medtronic 670G.(12)  The strength of closed-loop insulin delivery (as seen in the 
aforementioned studies) is nocturnal euglycemia, while post-prandial hyperglycemia remains a 
challenge given the need for accurate carbohydrate counting as well as decreased insulin 
absorption.   
 
Though optimization of diabetes technology is one way to mind this gap, novel medication 
therapies previously used for type 2 diabetes are also under investigation.  Sodium glucose-
linked cotransporter inhibitors (SGLT2i’s) are a relatively new medication which allows for 
increased urinary glucose excretion and, in doing so, euglycemia.  Their use is predominantly in 
type 2 diabetes, both for improved glucose control as well as concomitant renal and 
cardiovascular protection.(14–16)  Empagliflozin specifically was shown to reduce admission 
rates for heart failure, cardiovascular mortality, and all-cause mortality.(16)  
 
However, various studies have demonstrated improved glycemic control with SGLT2i use as 
adjunct to insulin therapy in the treatment of type 1 diabetes, though this is not yet standard of 
care.(17–19)  The use of both closed-loop insulin therapy in conjunction with SGLT2i therapy is 
thus a novel treatment for optimizing glycemic control in type 1 diabetes, in particular those who 
do not yet reach target time in range despite being on a closed-loop system. 
 

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1.1 
Summary of our team’s prior closed-loop system studies in adults with type 1 
diabetes 
Our research group focusses on innovative methods for closed-loop insulin therapy, including 
the impact of closed-loop insulin pump therapy itself (the algorithm created by our research 
group) as well as the use of dual hormone pump systems, such as the use of insulin in 
conjunction with pramlintide or glucagon.    
 
More than 12 studies with more than 200 participants have been performed by our research 
group thus far.(7–10,20,21)  These studies use the McGill Artificial Pancreas (MAP) system (see 
Section 4.3 for more details).  Our studies have demonstrated decreased hypoglycemia 
(particularly nocturnal) as well as increased time in range in single-hormone closed-loop insulin 
delivery compared to conventional insulin pump therapy, with further improvements with the use 
of dual-hormone artificial pancreas with pramlintide or glucagon (see Figure 1).(9,11)  
Figure 1.  Taken from Haidar et al., 2016 in JCEM.  Glucose levels, percentage of nights in hypoglycemia (need for 
treatment indicated below) and percentage of nights in hyperglycemia in 28 participants with type 1 diabetes, using 
one of the three interventions: dual-hormone artificial pancreas (insulin and glucagon), single-hormone artificial 
pancreas (insulin), and conventional insulin pump therapy.  See the original article for further details.(9)        

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1.2 
Summary of prior studies using SGLT2i in adults with type 1 diabetes 
Various SGLT2i agents have been used to improve glycemic control in type 1 diabetes as 
adjunctive therapy with intensive insulin therapy.   
 
Dapagliflozin was one of the first SGLT2i’s to be studied in type 1 diabetes patients.(22)  More 
recently, in the DEPICT-2 trial, dapagliflozin 5 mg vs 10 mg vs placebo were tested in adults 
with type 1 diabetes in conjunction with either MDI or CSII; overall those on dapagliflozin had 
significantly reduced HbA1c, body weight, and total daily dose, with a 2 – 3% risk of DKA 
compared to 0% in placebo group.(18)  It is with this data that the National Institute for Care and 
Health Excellence accepted approval of dapagliflozin as adjunctive therapy in type 1 diabetes 
patients with a BMI > 27 kg/m2 not achieving glycemic target.(23)  
 
Sotagliflozin and empagliflozin have also been studied in type 1 diabetes with reduction in 
HbA1c and total daily dose of insulin without increased hypoglycemia.(24,25)  The EASE trials 
demonstrated that empagliflozin as low as 2.5 mg oral daily, a quarter of the starting dose for 
type 2 diabetes, was able to improve HbA1c, reduce body weight, improve blood pressure, and 
lower total daily dose; unique among the studies was that the 2.5 mg dose was equivalent in risk 
of DKA compared to placebo, while the higher doses at 10 and 25 mg had approximately triple 
the risk.(19,25) This dose produces an optimal balance in glycemic improvement without the 
increased risk of diabetic ketoacidosis.  It is with this basis that our study desires to further the 
knowledge concerning the benefit of SGLT2i’s in reducing glycemic variability in type 1 
diabetes patients.  
 
1.3 
Summary of our prior studies using both closed-loop system and SGLT2i in adults 
with type 1 diabetes 
Our research group has previously studied SGLT2i use in conjunction with a single-hormone 
artificial pancreas.(26)  The objectives of the prior study (with manuscript in process) aimed to 
assess alleviation from carbohydrate counting with the use of empagliflozin and single-hormone 
closed loop insulin system.  The treatment arms included (all with the closed-loop system but 
with or without empagliflozin 25 mg once daily): no carbohydrate counting, simple carbohydrate 
counting (i.e. meal announcement input into the pump), or full carbohydrate counting.  The study 
was not only safe but that the use of empagliflozin with meal announcement demonstrated meal 
glucose and time in range (TIR) of glucose readings between 3.9 and 10.0 mmol/L [i.e. mean 
glucose 8.5 mM + 1.4 mM, TIR 68% + 16%] that were non-inferior to the closed-loop system 
with full carbohydrate counting [i.e. mean glucose 8.5 mM + 1.5 mM, TIR 70% + 23%] (Figure 
2A).  Of all the arms, carbohydrate counting with empagliflozin had the lowest mean glucose 
and TIR [mean glucose 7.4 mM + 1.3 mM, TIR 84% + 11%] (Figure 2B).   
 
Though this project’s aim was to assess alleviation of carbohydrate counting, it managed to 
demonstrate an increase of time in range between 3.9 and 10 mmol/L with the use of 
empagliflozin and the artificial pancreas.  This was with the use of a large dose of empagliflozin, 
lower doses have been shown to benefit patients with type 1 diabetes without risk of 
DKA.(19,25)  Our study aims to not only focus on time in range, but whether the lowest doses of 
empagliflozin can result in glycemic improvements while on the artificial pancreas to achieve 
therapeutic effect without increased adverse effects.   
 

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A) 
 
B)
 
Figure 2.  Average serum glucose as measured by CGM over 24 hours in participants with type 1 diabetes using 
various arms with or without empagliflozin (25 mg) and carbohydrate counting.  A) CGM data for artificial pancreas 
with carbohydrate counting (red) or with simple meal announcement and empagliflozin (blue); empagliflozin with 
simple meal announcement was shown to be non-inferior to AP with carbohydrate counting (p < 0.05).  B) CGM 
data for empagliflozin (blue) on AP and carbohydrate counting results in more time in range than AP alone (p < 
0.002).  All data to be included in the manuscript in process.(26)  
2 
Objective, Design, and Hypotheses 
 
2.1 
Objective 
The objective of our study is to assess the effectiveness of low-dose empagliflozin (2.5 mg and 5 
mg) on glucose control in adult patients with type 1 diabetes on a closed-loop insulin pump 
system, who would not otherwise be within a time in range (TIR) of > 70% on the system.   
 
2.2 
Study Design  
This is a three-way, randomized, cross-over double-blinded trial to compare the baseline closed-
loop insulin pump system with placebo, empagliflozin 2.5 mg daily, and empagliflozin 5 mg 
daily (with a wash-out period of 7 – 21 days between each).  A run-in period of 14 days will be 
done to identify participants who have TIR < 70% despite being on the MAP closed-loop system 
who do not otherwise use closed-loop therapy for routine diabetes care (alternative inclusion 
includes those who obtain TIR < 70% on at-home closed-loop therapy in the last 14 days).   

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2.3 
Hypotheses  
The primary hypotheses of the study are the following: 
1) The use of empagliflozin 2.5 mg daily will increase time in range of 3.9 to 10.0 
mmol/L compared to placebo for those on the closed-loop system.  
2) The use of empagliflozin 5 mg daily will increase time in range 3.9 to 10.0 mmol/L  
compared to placebo for those on the closed-loop system.  
 
The secondary hypotheses of the study are the following: 
1) The use of empagliflozin 2.5 mg daily will do the following (compared to placebo): 
- 
Increase the percentage of time spent: 
o Between 3.9 and 7.8 mmol/L 
- 
Decrease the time spent: 
o Below 3.9, 3.3 and 2.8 mmol/L  
o Above 7.8, 10, 13.9, and 16.7 mmol/L  
- 
Proportion of participants having a TIR of 3.9 - 10.0 mmol/L of > 70% 
- 
Result in improved quality of life 
- 
Decrease average total daily dose 
- 
Result in no change in ketone level compared to placebo  
2) The use of empagliflozin 5 mg daily will do the following (compared to placebo): 
- 
 Increase the percentage of time spent: 
o Between 3.9 and 7.8 mmol/L 
o Between 3.9 and 10 mmol/L  
- 
Decrease the time spent: 
o Below 3.9, 3.3 and 2.8 mmol/L  
o Above 7.8, 10, 13.9, and 16.7 mmol/L  
- 
Proportion of participants having a TIR of 3.9 - 10.0 mmol/L of > 70% 
- 
Result in improved quality of life 
- 
Decreased average total daily dose of insulin 
- 
Result in no change in ketone level compared to placebo  
3 
Study Population 
3.1 
Criteria  
The trial will enroll 25 participants above 18 years old with type 1 diabetes who meet the below 
criteria (after the run-in period). 
 
3.1.1 Inclusion Criteria 
1) > 18 years of age 
2) A clinical diagnosis of type 1 diabetes for at least one year, as per their treating diabetes 
physician in agreement with the primary investigator’s clinical judgment (confirmatory 
C-peptide and antibodies will not be required) 
3) HbA1c between 7 and 10.5% (both extremes inclusive), performed within the last 6 
months prior to study inclusion 
4) Insulin pump use (of any modality) for minimum 3 months  
5) Agreement to the use of highly effective method of birth control in women of child-
bearing age and active avoidance of pregnancy during the trial.  Child-bearing potential 

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refers to participants of the female sex post-menarche and have not reached menopause 
or have a disclosed medical condition causing sterility (e.g. hysterectomy).  Post-
menopausal state refers to the absence of menses for 12 months without any alternative 
cause. 
6) Time in range (3.9 – 10.0 mmol/L) < 70% as per CGM readings of the last 10 days 
during a 2-week run-in period on the closed-loop insulin delivery system. 
Alternative inclusion: Time in range (3.9 to 10.0 mmol/L) < 70% as per CGM readings of the 
last 14 days from the participant's at-home closed-loop system (if time spent in closed loop is 
minimum 50%), downloaded within 7 days of the admission visit.   
 
3.1.2 Exclusion Criteria 
1) Current or < 2 week use of any anti-hyperglycemic agent other than insulin 
2) Current or < 1 month use of supraphysiological doses of oral glucocorticoids.  
3) Requirement for regular use of acetaminophen (which may decrease CGM fidelity) 
4) Planned or ongoing pregnancy 
5) Breastfeeding individuals 
6) Severe hypoglycemic episode within the last 3 months, defined as an event where glucose 
was < 4 mmol/L resulting in seizure, loss of consciousness, or need to present to the 
emergency department 
7) Severe diabetic ketoacidosis within the last 3 years (“severe” referring to need to present 
to medical attention and requirement of intravenous insulin) 
8) Active infection of any kind at the time of study enrollment, or any active foot ulcer 
9) Recurrent infections (i.e. more than 2 in 1 year) of the following: genital, urinary tract 
infections, soft tissue, joint, or bone  
10) Known severe peripheral vascular disease including the following: symptomatic 
claudication, loss of peripheral pulses, signs of peripheral arterial insufficiency as per 
initial clinical exam, previously documented insufficiency as per ankle or toe brachial 
index, prior amputations due to peripheral vascular disease 
11) Osteoporosis defined as prior fragility fracture, previously measured bone mineral 
density with T or Z score < -2.5, or need for anti-osteoporotic medications 
12) Glomerular filtration rate less than 30 mL/minutes/1.73 m2 as per CKD-EPI formula as 
measured by creatinine level taken within the last 12 months. 
13) Any serious medical or psychiatric illness likely to interfere with study participation as 
per the judgment of the investigator (e.g. cirrhosis, active cancer, decompensated 
schizophrenia) 
14) Prior adverse reaction to SGLT2i  
15) Inability to travel to the research center within 3 hours if needed during the study 
interventions 
16) Failure to comply to the study protocol and/or research group’s recommendations (e.g. 
change in pump parameters, ketone measurement) 
17) Inability or unwillingness to comply to safe diabetes management in the view of the study 
group (e.g. inappropriate treatment of hypoglycemia or lack thereof) 
18) Anticipation of a significant change in exercise regimen between initiation of the 
intervention blocks (i.e. starting or stopping an organized sport)  
19) Any demonstrate of difficulty in using the iMAP System following training, as per 
investigator’s judgment 

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20) Concern for safety of the participant, as per the clinical judgment of the primary 
investigator 
 
3.1.3 Discontinuation Criteria 
Participation in the study can be withdrawn prior to completion for the following reasons: 
1) Failure to comply with the study’s protocol and/or instructions given from the study team 
2) Pregnancy 
3) Withdrawal of consent to participate or desire to no longer take part in the study  
4) The required use of medications listed in the exclusion criteria  
5) Severe hypoglycemia 
6) Diabetic ketoacidosis  
7) Hospitalization or acute illness for any reason 
8) Decision by the study group to prematurely terminate the clinical trial 
 
3.2 
Study Withdrawal  
The participant of the clinical trial may cease participation at any time.  Their clinical data from 
the study prior to cessation will be collected nonetheless; decision to use the data will depend on 
its completeness and the opinion of the investigators.  It will be advisable that the participant 
complete the “End of Study” visit prior to exit, to ensure the participant’s safety, to screen for 
any problems within the study and its materials, and to assess for reason for discontinuation that 
may affect the study.  The study team will continue to follow the participant for an additional 
week to aid in transition from the closed loop system and off the medication (placebo vs 
empagliflozin) back to the participant’s usual regimen.     
 
3.3 
Recruitment and Study Centres 
The study will be conducted in Montreal, Quebec at the Clinique Médicale Hygea, affiliated with 
McGill University.  Enrolment will consist of 25 adult participants after the run-in period 
(therefore more may be required to attain this number).  Recruitment will predominantly take 
place among the clinic for adult type 1 diabetes care seen by specialists in Endocrinology & 
Metabolism at the Clinique Médicale Hygea, where patients will be approached by the study 
team and/or their endocrinologist.  However, affiliate members of the division of Endocrinology 
& Metabolism at McGill University may also invite patients to the study, after which they will 
be approached by the study team.  Prior participants of previous closed-loop studies performed 
by the research group will also be invited if they have previously written consent to be contacted 
for future studies.  
 
Of those participants interested in the study, the study team will describe in detail what the study 
entails, answer any questions the participants have, and record clinical details pertaining to 
inclusion and exclusion criteria, and obtain consent (via an official consent form) from the 
participants. 
 
 
  

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4 
Study Drugs and Materials 
4.1 
Study Drugs 
Empagliflozin 
Empagliflozin is an SGLT2 inhibitor that aids in glucose reduction 
through the urination of excess glucose in the context of 
hyperglycemia (see Section 1). The medication will be used once 
daily, at either 2.5 mg or 5 mg oral dose.   
Placebo 
A placebo pill (i.e. a pill that includes only buffer and no 
empagliflozin) that mimics the appearance of empagliflozin 
quarters to mitigate perceived changes due to “placebo effect”.  
The placebo will also be used to conceal the dose of empagliflozin. 
 
4.2 
Study Devices and Materials 
The following are the devices and materials that will be used by study participants: 
t:slim Tandem Diabetes 
Care insulin pump, and 
associated materials 
This is the choice of continuous subcutaneous insulin infusion 
(CSII) administering rapid-acting insulin, on which the closed-
loop system administers insulin.  The insulin pump is a small 
machine with a computer-driven piston administering insulin via a 
reservoir-tubing-catheter pathway, with which the catheter is 
inserted subcutaneously.  Each study participant will receive one 
pump, with the infusion sets and reservoirs as needed. 
Dexcom G5/G6 
Continuous Glucose 
Monitor (CGM) 
The device measures interstitial glucose continuously, on the basis 
of which the algorithm modifies insulin delivery.  The device itself 
is inserted subcutaneously onto the patient and the data transmitted 
via Bluetooth technology.   
FreeStyle Precision Neo 
meter with glucose and 
ketone test strips 
This will be the meter of choice for the study to measure capillary 
blood glucose and ketones.  This is required for Dexcom 
calibration, to detect measurement errors, and to measure ketones 
to assess for baseline ketone bodies while on SGLT2i and to rule 
out ketoacidosis in the event of illness and unexplained high 
glucose.  Participants will be asked to check ketones daily. 
 
In the event of Precision Neo malfunction, participants will be 
requested to use other means of ketone measurement available at 
home until the meter may be repaired or replaced as soon as 
possible.  Other options include other Abbott ketone meters (such 
as the Freestyle Libre reader) or urine ketone test strips.  Blood 
samples will be highly recommended over urine. 
Study Smartphone 
The main algorithm for the closed-loop system is set on this device 
via the iMAP application (see section 4.3).  The smartphone, 
pump, and sensor communicate via Bluetooth.  Each study 
participant is given one smartphone. 
Empagliflozin 
Empagliflozin 2.5 mg and 5 mg tablets will be used.  To ensure 
dose is concealed, tablets will be encapsulated to ensure the tablets 
appear identical.   
Placebo 
Participants’ encapsulated pills may placebo pills with identical 
appearance to the treatment medication. 

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Emergency kit 
The kit includes fasting acting glucose tablets, insulin syringes, 
and intranasal glucagon.  This will be given to all participants.   
 
4.3 
McGill Artificial Pancreas (MAP) System  
The McGill Artificial Pancreas (MAP) is an insulin delivery closed-loop system that uses an 
algorithm to modify continuous subcutaneous insulin administration based on continuous 
glucose monitoring, with communication through Bluetooth technology.  The system is 
comprised of the following: 
1) Glucose sensor (via the Dexcom G5 or G6) 
2) A mobile application, called iMAP, on a study smartphone 
3) An insulin pump, via the t:slim Tandem pump 
 
 
 
Figure 4.  Depiction of the McGill Artificial Pancreas. 
5 
Trial Design 
5.1 
Phases of treatment therapy  
This is an outpatient randomized cross-over trial to compare the following medications while on 
insulin closed-loop system (MAP):  
1) Placebo  
2) Empagliflozin 2.5 mg daily 
3) Empagliflozin 5 mg daily  
 
Treatment period: Each patient will use each of the pills for 2 weeks, with a washout period of 7 
– 21 days between each intervention.  The order of medication use will be randomized, though 
each participant will use each of the 3 interventions during the study.   
 
5.2 
Questionnaires 
Participants’ quality of life will be measured by the following questionnaires: 
- 
Type 1 Diabetes Distress Scale 

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- 
Hypoglycemic Fear Survey – II 
- 
INSPIRE questionnaire for adults 
- 
Study drug symptom questionnaire (to rule out symptoms at baseline)  
 
Participants will fill out the questionnaires at the admission visit, and after each intervention 
remotely (documents will be mailed to participant). All questionnaires will be collected at the 
End-of-Study Visit.   
 
5.3 
Randomization 
Randomization will be done by block-balanced randomization (block size 6) to randomize to 
whichever sequence of interventions.  This will be performed by a study member after inclusion 
into the study (i.e. after the run-in period). 
 
5.4 
Blinding  
This study will be double-blinded, so that both participants and investigators will not know the 
sequence of interventions for each participant.  The participants will be given encapsulated 
identical tablets of either placebo, empagliflozin 2.5 mg, or empagliflozin 5 mg.   
 
5.5 
Visit Schedule 
The overall time within the study for each participant upon inclusion will be 9 – 15 weeks.   
For any visit (i.e. initial visit, training visit, or end-of-study visit), if there are any concerns or 
issues preventing the patient from physically coming in to the hospital or clinic setting, the 
meeting can be done by teleconference.  If research material will be required during the 
teleconference, this will be securely mailed to the participant to be used during the visit, and then 
securely mailed back to the research group.  If laboratory investigations are required in this 
remote setting, they can be done using a bloodwork requisition at the closest laboratory centre to 
the patient. 
 
 
Figure 5.  Timeline of study interventions for each participant.  Each intervention will consist of 
either placebo, empagliflozin 2.5 mg daily, or empagliflozin 5 mg daily, depending on the 
patient’s randomized sequence of treatment.  This results in 6 different sequences (see Section 
6.4.1). 
Initial 
Visit
Intervention
#1
Washout
Intervention
#2
Washout
Intervention
#3
Washout
End of 
Study Visit
2 – 3 
hours
7 – 21 days
14 days
7 - 21 days
14 days
6 – 10 days
1– 2 hours
14 days
14 days
Inclusion if last 10 days after optimization
at days 2 – 4 demonstrate TIR < 70%
Run-In
7 – 21 
days
Training 
visit
Direct entry for
those < 70% in 
last 14 days on 
home closed-loop 
therapy 
4 day run in 

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6 
Study Procedures 
6.1 
Initial study visit  
The initial study visit with the participant will be conducted by one of the members of the study 
group, and will entail the following. 
 
General procedures 
- 
Explanation of the study and answering of questions 
- 
Assessment of inclusion and exclusion criteria 
- 
Signing of consent form  
Medical history 
- 
Complete past medical history, both of their type 1 diabetes 
and other medical conditions 
- 
Current diabetes care (frequency of glucose checks, recent 
difficulties in glycemic control, history of DKA, etc.) 
- 
Current diabetes regimen and doses, in particular the last 7 
days of insulin therapy  
- 
Social history and habits (work, education, exercise, smoking, 
etc.) 
- 
Other medications, over-the-counter medications, and 
supplements 
Physical examination 
- 
Blood pressure 
- 
Height and weight 
- 
Foot and peripheral vascular exam  
- 
Signs of lipo-hypertrophy in areas of insulin catheter sites 
Blood laboratory 
investigations  
5 mL of serum via intravenous catheter will be taken to assess 
HbA1c for glycemic control, creatinine to ensure appropriate renal 
function, and (if woman of child-bearing age) beta-HCG to rule 
out pregnancy.  Beta-hydroxybutyrate, bicarbonate, and basic 
electrolytes (sodium, potassium, and chloride) will be used as a 
baseline for level of ketosis and for possible risk of ketoacidosis 
during the study.  At the visit, finger-prick testing on the patient’s 
study meter will be done for glucose and ketone level (as 
measured on the meter) for a baseline. 
Questionnaires 
 Participants will be given time to fill out quality of life 
questionnaires (see section 5.2). 
Discussion of risks of 
empagliflozin 
Along with the discussion of risks and benefits of empagliflozin in 
the consent form, participants will be taught to identify the 
symptoms of urinary tract infections, fungal infections, 
dehydration, or any other acute illness or infection, and what to do 
in each scenario.  A prescription for clotrimazole 1% cream will be 
given to treat any topical fungal infection on an as-needed basis 
(this will be given if participant is accepted after the run-in study).  
The patient will be asked to seek medical attention for any other 
concerns of infection.  
Emergency kit 
An emergency kit (see Section 4.2) will be given if its contents are 
not already possessed by the participant.  The participant will be 
instructed to carry these items at all time.  A study wallet card 

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must be carried by the participant at all times, which will include 
the following: 
- 
Study title 
- 
Protocol number 
- 
Devices 
- 
Medication names 
- 
Physician contact information in the case of emergency 
 
Given the current pandemic and the delays in seeking laboratory investigations, there will be an 
option to use the laboratory investigations from the initial visit to be used as inclusion criteria if 
there have not been recent tests within the last 6 months.  If this is done, the MAP will not be 
started until results are back. 
 
6.2 
Training of study materials 
Another meeting on a separate day will potentially be held for the training of study materials.  If 
a participant lives far away enough that having both the initial clinic visit and the training visit be 
the same day, this will be offered.   
 
During the training visit, participants will receive the following devices: 
- 
T:slim Tandem insulin pump and required materials 
- 
Dexcom G5 or G6 sensors and transmitter 
- 
Study smartphone with pre-installed iMAP application 
- 
Freestyle Precision Neo meter with glucose and ketone strips 
 
Training on the use of t:slim Tandem insulin pump will be provided (if not already in use by the 
participant), as well as for the installation and use of Dexcom G5 or G6 transmitter and sensors 
and the iMAP system (all with accompanying user guides). 
- 
The member of the study group will insert patient’s current pump parameters into the new 
device and assist with the physical transition from usual to study pump. 
- 
Participants will be reminded to calibrate their Dexcom G5/G6 with the Freestyle Precision 
Neo meter and instructed when to check for ketones.  Additional training will be performed 
to ensure safe diabetes and glucose management. 
- 
Discussion on how to titrate insulin-to-carbohydrate ratios due to reduced insulin 
requirements on the pill will be provided.   
- 
Participants will be instructed that insulin-to-carbohydrate ratios should be reduced by 10% 
at the beginning of each intervention (unless told so as per clinician judgment due to 
hyperglycemia); the effect of this will be reassessed remotely with the research team. 
- 
The risks and possible side effects of empagliflozin will be discussed with the patient.  
Instructions on how to proceed in the case of nausea, illness, high levels of ketones, or any 
concern for DKA will be given. 
- 
Participants will be instructed to measure point-of-care ketones daily.  If ketone bodies rise 
above 0.6 mmol/L or symptoms of impending ketoacidosis are present, participants must 
follow study instructions for DKA. 
- 
If there are any concerns from the study team that the patient is not capable of following 
these instructions, the patient will not be included in the study. 
 

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6.3 
Closed-loop run-in period 
After the initial study visit and completion of training with transition to the MAP in the office, a 
run-in period of 14 days will take place.  On the first day of this run-in period, participants will 
be asked to activate “exercise mode” of the closed-loop system before driving any vehicle for 
more than 10 minutes to prevent hypoglycemia while driving.   
 
Participants are encouraged to contact the on-call staff (available 24/7 throughout the study) if 
technical issues or questions arise.  There is a remote follow-up with the study team 2 – 4 days 
after initiation of the run-in period, which is done via email, phone call or text message, or other 
communication.  This is to ensure the participant’s safety and comfort on the system. 
 
After the run-in period, CGM data will be analyzed for time in range.  If the time in range is less 
than 70% during the last 10 days, the participant will be included in the study.  Data will also be 
reviewed to optimize any insulin to carb ratios or parameters that need adjustments.  If the 
participant is not to be included in the study, the participant must return the study devices back to 
the research group. 
 
6.3.1 Alternative Path: For Patients Already on Closed-Loop Therapy  
The use of commercial forms of closed-loop therapy in routine diabetes care has become more 
prominent since the development of the original protocol.  The participant's experience with their 
own system may be more reflective of deficits in optimized control with closed-loop therapy, 
and still reflects the objective of the study.  Therefore, participants are able to bypass the full 
run-in assessment if they use a closed-loop insulin system (with use of closed-loop minimum 
50% of the time) and their time in target range (3.9 to 10 mmol/L) is less than 70% within the 
last 14 days, from data downloaded within 7 days of the admission visit.  This direct entry will 
only apply to participants after protocol approval. 
 
Note that there may be circumstances where an eligible participant owns a pump with capacity 
for closed-loop insulin delivery but does not use this function or does not have the information 
available; this may be due to lack of sensor use, personal choice, or failure to download data.  In 
this situation, the participant will undergo the 14-day run-in on the McGill Artificial Pancreas. 
 
For participants entering the study directly, there will be 4 days of a small run-in to familiarize 
the participant to the system and optimize settings via 1 remote visit on a day between Days 2 to 
4.  After this optimization, the participant will be able to start Intervention 1 directly. 
 
6.4 
Interventions 
After inclusion (whether after run-in or at the admission visit via direct entry), the participant 
will undergo randomization.  The study drugs will be sent to the individual before each 
intervention in the order of the sequence chosen by randomization.  For those undergoing direct 
entry, this will be given at the initial visit. 
 
6.4.1 General Procedures for All Interventions (14 days) 
For each intervention, the participant will switch from their usual diabetes regimen to the study 
insulin pump (MAP), which will require installation of the Dexcom G5/G6 sensor one day prior 
for calibration.  The closed-loop algorithm will be initiated in the morning of Day 1.  The 

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participant will be recommended to reduce mealtime boluses by 10% (i.e. carbohydrate ratios 
will be increased by 10%) prophylactically at the beginning of each intervention (unless told not 
to do so as per clinical judgment due to ongoing hyperglycemia) to avoid hypoglycemia from the 
study drug.  The participant will take the study drugs each morning from Days 1 to 14 of each 
intervention.   
 
A remote follow-up will be provided 2 – 4 days into each intervention (by similar means to the 
run-in period) to reassess safety, comfort, and to optimize insulin settings.  Remote follow-up 
can also be performed as needed throughout the rest of the intervention.  Because of the 
optimization the first 4 days, the last 10 days of CGM data will be used for analysis.   
 
After each intervention, participants will fill out the questionnaires (Section 5.2); these however 
may be completed during the following wash-out period. 
 
Note the above sequences are 6 possibilities: 
1) Placebo à Empagliflozin 2.5 mg à Empagliflozin 5 mg  
2) Placebo à Empagliflozin 5 mg à Empagliflozin 2.5 mg  
3) Empagliflozin 2.5 mg à Placebo à Empagliflozin 5 mg  
4) Empagliflozin 2.5 mg à Empagliflozin 5 mg à Placebo  
5) Empagliflozin 5 mg à Placebo à Empagliflozin 2.5 mg  
6) Empagliflozin 5 mg à Empagliflozin 2.5 mg à Placebo  
 
6.4.2 Point-of-care ketone measurement during interventions  
As there is a known increased risk of ketoacidosis in type 1 diabetes patients on SGLT2i, point-
of-care ketone testing will be performed at the clinic visit, and daily during each intervention.  
This is not only to document a baseline level of ketones (as empagliflozin may slightly elevate 
baseline ketones without acidosis, independent of sugar levels), but also to predict any 
development of early ketoacidosis.  Due to this unique form of ketosis, patients will be instructed 
on treatment in this specific context (i.e. bolus with carbohydrates).  Any concerns at any time 
may be answered remotely by a member of the study team.   
 
6.5 
Wash-out period  
The wash-out period between each intervention is 7 – 21 days.  This is to allow for excretion and 
metabolism of any study medication in each participant to ensure no following intervention is 
affected by the prior.  The half-life of empagliflozin is estimated at 12.4 hours (27), therefore by 
7 days, a sufficient amount of the drug will be cleared.  During the wash-out period, each patient 
will be able to return to their usual method of diabetes treatment outside of the study.  Remote 
contact by the study group will be performed at day 4 (+ 2 days) of the wash-out period to ensure 
safety with their diabetes care and other matters of health.   
 
6.6 
End of study visit  
An end of study visit will be conducted 6 to 10 days following completion of the final washout 
period.  This will take approximately 1 – 2 hours, and will entail a detailed interview (Section 
6.6.1), the return of quality-of-life questionnaires (Section 5.2), and the return of all study 
devices.  
 

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6.6.1 Interview  
Initial questions 
- 
Can you describe your experience concerning your diabetes 
care during the study?  
Questions concerning 
the closed-loop system 
- 
Can I ask you about your experience and feelings concerning 
being on a closed-loop system? 
o What did you like about this pump system? 
o What did you not like about this pump system? 
o What were your experiences with food and boluses on 
this system? 
o What were your experiences overnight with this 
system? 
o Would you replace your current regimen with this 
system? 
Questions concerning 
the use of 
empagliflozin 
- 
Can I ask you about your experience and feelings concerning 
the study drug? 
o Did you notice a difference in your overall diabetes care 
while taking the pill? 
o Is there anything you liked about taking the pill? 
o Is there anything you did not like about taking the pill? 
o What were your experiences with food and boluses 
while using the pill? 
o What were your experiences overnight with this 
system? 
o Did you notice differences between interventions? 
o Would you want to continue taking the pill? 
Final question 
- Is there anything else that you would like to tell us about your 
experience of these glucose management systems? 
7 
Risk and Risk Mitigation  
7.1 
Empagliflozin dose rationale  
The doses of empagliflozin used stem from the EASE trials previously performed in patients 
with type 1 diabetes.(19,25)  Though 10 and 25 mg of empagliflozin are the commercial doses 
for glycemic control in type 2 diabetes, these doses have demonstrated increased risk of diabetic 
ketoacidosis in those with type 1 diabetes.  Empagliflozin 2.5 mg once daily was used in the 
EASE-1 and EASE-3 trails with therapeutic benefit, with equivalent risk of DKA compared to 
placebo in EASE-3.(19,25)(19,25)  A dose of 5 mg adds an additional “low-dose” option to 
optimize euglycemia with little to no risk of ketoacidosis, which makes it a novel dose not seen 
previously in the literature but one that is used off-label by some endocrinologists.  
 
7.2 
Medical and Safety Monitoring 
During the study, an endocrinologist involved with the research study will be on call at all times 
in the need for immediate assistance for medical guidance in the case of acute illness.  For 
technical support, a study team member will be able to answer questions by participants at all 
times. 
 

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7.2.1 Monitoring 
As described previously, remote visits will be performed to screen for any difficulties by the 
participant.  To ensure no adverse events go unnoticed by the research team, adverse events 
(both passive and active surveillance through the questionnaires) and glucose outcomes will be 
verified by the study team after every 5 participants.  If a non-physician notices a pattern 
concerning adverse events, this will be brought up to one of the physicians in the study. 
 
7.2.2 Concomitant and prohibited medications 
7.2.2.1 Empagliflozin 
There are various medications that are discouraged and contraindicated to reduce the risk of 
adverse events in the use of empagliflozin (see Section 7.3.1): 
 
- 
Medications that increase risk of dehydration 
o Loop diuretics, thiazide diuretics, alpha-blockers (e.g. tamsulosin) 
o Interventions for above: continued hydration, possible need to assess renal or blood 
pressure measurements 
- 
Medications that increase risk of low blood pressure 
o Calcium channel blockers, loop and thiazide diuretics, ACE inhibitor, Angiotensin-
receptor blocker, Angiotensin-receptor neprilysin inhibitor (ARNI), Clonidine 
o Interventions for above: continued hydration, possible need to assess renal or blood 
pressure measurements 
- 
Medications that increase risk of hypoglycemia  
o Salicylates, fluoroquinolones, oral hypoglycemic agents (e.g. metformin), 
somatostatin analogues (e.g. octreotide), sulfonamide antibiotics, pramlintide 
o Intervention for above: fast-acting dextrose in the acute setting, decreased insulin 
doses in the chronic setting 
 
7.2.2.2 Continuous glucose monitoring  
- 
Acetaminophen may reduce fidelity of glucose monitoring.  Therefore, avoidance of regular 
acetaminophen is highly recommended and the need for regular use of the medication is an 
exclusion criteria.   
 
7.3 
Risks Associated with the Study  
7.3.1 Empagliflozin 
The mechanism of action of empagliflozin is inhibition of the sodium-glucose-linked 
cotransporter 2, which blocks reabsorption of glucose in the tubules of the kidney.  This creates a 
glucosuric and diuretic effect.  The following are known risks in order of likelihood:(27)  
- 
Common risks (>10%) 
o Reduced need for insulin (and in doing so, possibly hypoglycemia) 
- 
Less common risks (1 – 10%) 
o Increased urine output  
o Urinary tract infection 
o Genito-urinary fungal infection 
o Nausea 
o Dyslipidemia 
o Hypotension  

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- 
Rare risks (< 1%) 
o Ketoacidosis 
o Acute kidney injury  
o Hypersensitivity reaction, including urticaria, skin rash, angioedema  
o Dehydration 
o Necrotizing fasciitis 
o Severe urinary infection including: pyelonephritis, urosepsis 
- 
Reported associations with SGLT2is 
o Canagliflozin was associated with increased risk of amputation in the CANVAS 
trial;(14) however no other study using SGLT2 inhibitors reported this link 
o Though empagliflozin is not associated with increased risk of fracture in various 
studies, canagliflozin and other SGLT2i’s may increase bone resorption and decrease 
bone mineral density.(28)  
 
7.3.2 Blood sampling 
This is required to obtain blood laboratory values including HbA1c, creatinine, etc.  Blood 
sampling is done through temporary intravenous access, which may result in localized pain, 
bleeding, or bruising at the puncture site.  Participants may rarely feel dizzy or uneasy if they are 
prone to experience vasovagal responses from these procedures.  Rarely, infection, 
thrombophlebitis or nerve damage may occur.   
 
7.3.3 Glucose sensors and insulin infusion sets 
Glucose sensors and infusion sets are both inserted subcutaneously. It is recommended to change 
insertion site every 3 days for an infusion set, and every 7 days for a glucose sensor. Both pose a 
risk of pain with insertion, continued irritation, and rarely, contact dermatitis if the patient has an 
underlying hypersensitivity to the adhesive.  Rarely, use longer than suggested for the product 
may increase risk of local infection.  Lack of insulin site change as recommended may increase 
risk of lipo-hypertrophy, which may then result in hyperglycemia. 
 
7.3.4 Hypoglycemia 
Hypoglycemia refers to a blood glucose less than 4.0 mmol/L that may induce sympathetic and 
neuroglycopenic symptoms; some patients, depending on presence of autonomic neuropathy or 
frequency of hypoglycemia, may not develop these symptoms.  Severe hypoglycemia refers to an 
event of hypoglycemia which requires third party intervention, i.e. the participant is not able to 
treat hypoglycemia via fast carbohydrates or glucagon, which includes (but is not limited to) 
impaired level of consciousness, coma, or seizure.   
 
Hypoglycemia is mitigated by the use of continuous glucose monitoring with alarm sets which 
are triggered by hypoglycemia.  The threshold at which the alarm starts can be modified by the 
user.  Review of hypoglycemia treatment will be performed at the initial clinic visit and if not in 
the participant’s possession already, dextrose tablets and glucagon kit (from the emergency kit) 
will be offered for treatment of hypoglycemia.   
 
7.3.5 Hyperglycemia (and associated conditions) 
Mild hyperglycemia is any glucose level above 10 mmol/L, but severe hyperglycemia refers to 
excess glucose that results in symptoms of polyuria, polydipsia, and fatigue.   

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Diabetic ketoacidosis (DKA) refers to a low-insulin state where ketone bodies are produced, 
creating acidosis and severe electrolyte disturbances, which requires immediate attention.  This 
may range from mild presentation where adjunctive insulin and a change in insulin catheter is 
needed, to severe life-threatening presentation where hospitalization is required for intravenous 
insulin therapy.  DKA may be triggered by lack of insulin administration (compliance, catheter 
dehiscence, pump malfunction) or an underlying condition such as acute illness.  Symptoms 
include nausea, vomiting, abdominal pain, and dehydration.  The table below (created by the 
American Diabetes Association) demonstrates laboratory investigations suggestive of 
ketoacidosis: 
 
 
DKA (usual serum glucose > 13.8 mmol/L) 
HHS (serum glucose 
> 33 mmol/L) 
Mild  
Moderate   
Severe 
Arterial pH 
7.25 – 7.30 
7.00 – 7.24 
< 7.00 
> 7.30 
Serum HCO3 (mmol/L) 15 - 18 
10 – 14.9 
< 10 
> 18 
Serum ketone 
Positive 
Positive 
Positive 
Minimal if positive 
Urine ketone 
Positive 
Positive 
Positive 
Minimal if positive 
Serum osmolality 
(mOsmol/kg) 
Variable 
Variable 
Variable 
> 320  
Anion gap  
> 10  
>12 
> 12 
Variable 
Mental status 
Alert 
Alert to drowsy 
Stupor to 
coma 
Stupor to coma 
Table 1.  Diagnostic criteria for DKA vs HHS as per the American Diabetes Association (2009).(29)  
 
Hyperglycemic hyperosmolar state (HHS) is another syndrome which presents as persistent 
hyperglycemia > 33 mmol/L with severe dehydration in the absence of frank diabetic 
ketoacidosis (table 1); this is however more common in type 2 diabetes than type 1 diabetes. 
 
Empagliflozin, as described, may also contribute to ketoacidosis in an unknown mechanism, but 
uniquely, the hyperglycemia is not as obvious as the excess glucose is excreted through 
urination.  SGLT2i use poses an increased risk of DKA specifically in those with type 1 
diabetes.(18,19,24) The doses used in our study have the lowest risk for ketoacidosis.  Various 
studies have been performed to treat this unique form of ketoacidosis in type 1 and type 2 
diabetes, an example being the STICH protocol for type 1 diabetes patients using an SGLT2i as 
adjunctive treatment (Figure 6).(17) 
  

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A) 
  B) 
 
Figure 6(A-B).  Description of the STICH protocol for patients with type 1 diabetes on SGLT2i’s as adjunctive 
therapy to insulin.(17)  (A) The recommended steps as described in the article for treatment and monitoring of 
ketones.  (B) Sample wallet card (front) describing the STICH protocol to treat any possible ketoacidosis.  
 
7.3.6 Genito-urinary and soft tissue infections 
Empagliflozin increases the risk of genito-urinary infections (1 – 10%), in particular genital 
mycotic infections.  There have also been reports of increased risk of soft tissue infection, 
particularly in the genital area, the worst being necrotizing fasciitis of the peritoneum, i.e. 
Fournier’s gangrene (with a risk of < 1%).  Increased amputations were previously reported with 
canagliflozin, (14) but this has not been reported with empagliflozin. 
 
7.3.7 Dehydration  
Increased urinary frequency and urine volume is commonly seen with SGLT2i’s due to their 
mechanism of action, at a risk of 1 – 10%.  In severe cases where a participant is not able to 
remain hydrated, there is a risk of dehydration, and subsequently if left untreated, low blood 
pressure and dizziness.  Acute kidney injury may occur in the context of severe dehydration; the 
risk is increased if there is already existing kidney disease.  Most of these cases can be avoided 
with adequate hydration, and in severe cases, can be treated by intravenous fluids. 
 
7.3.8 Risks related to the MAP system  
7.3.8.1 Disruption in communication between the insulin pump device and iMAP: 
- 
If Bluetooth communication is disrupted between the two devices, the application will 
automatically attempt to reconnect.  If this is not successful after 20 minutes, the system will 
revert to a mode of open-loop insulin basal administration (i.e. administration of pre-
programmed basal rates).  If Bluetooth connection is lost during bolus delivery, participant 
will be alarmed by the system and manual bolus may be required.   
 
7.3.8.2 Error in glucose sensor accuracy: 
- 
The MAP uses Dexcom G5 or G6 for continuous glucose monitoring, that requires twice per 
day minimum calibration for accurate measurement.  If the interstitial glucose measurement 

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performed by the CGM is inaccurate, insulin recommendations by iMAP will be suboptimal. 
If there is a major discrepancy between CGM measurements and point-of-care glucose 
testing by capillary glucose (see table below), participant will be prompted to re-test for 
calibration with a separate measurement in 30 minutes.  If the second calibration 
demonstrates ongoing error, open-loop mode will commence. Participants will be asked to 
contact the research team if sensor error persists 30 minutes post calibration, as this may be 
due to sensor malfunction and may require sensor replacement.   
 
For BG <=7.5: 
For BG >7.5 
sensorError= |(BG - bgSensor)| 
Sensor error threshold = 2.0mmol/L 
sensorError = |(BG - bgSensor)|/ BG 
Sensor error threshold = 27% 
 
- 
Participants will also be recommended to avoid acetaminophen.  Taking medications 
containing acetaminophen may falsely raise the sensor readings, causing the MAP System to 
deliver more insulin than required.   
 
7.3.8.3 Disruption in communication with the glucose sensor  
- 
If Bluetooth communication of the CGM to the rest of the MAP system is lost for more than 
60 minutes, the insulin pump system will revert back to open-loop mode.  Closed-loop 
insulin delivery will restart once CGM communication has been re-established. 
 
7.3.8.4 Smartphone malfunction or shut-down  
- 
If there is any malfunction with the study phone preventing access to iMAP (e.g. insufficient 
battery), open-loop mode will commence within 20 minutes.   
 
7.3.8.5 Software error  
- 
Any termination of the iMAP software for any reason will result in reversion to an open-loop 
mode of insulin delivery. 
 
7.4 
Pregnancy  
Empagliflozin has not been previously tested in pregnancy, therefore it is a Category C class 
medication in pregnancy.  Furthermore, glycemic management during pregnancy requires 
tighter-than-average regulation and should be followed by a specialized multi-disciplinary team.  
Given the risks, any female participant who has menses is at risk of pregnancy (see prior 
definitions) and must be on appropriate contraception throughout the study and will be 
counselled on the risks of pregnancy in the study.  If a participant feels she may be pregnant, she 
should stop the study medication and contact the study group immediately for confirmation (i.e. 
pregnancy test) and will be withdrawn from the study if positive.  Serum beta-HCG (via blood 
test) will be measured at the Initial Clinic Visit in female participants with ongoing menses to 
biochemically rule out pregnancy.  Females who are post-menopausal or who have undergone 
removal of the uterus and/or ovaries will be exempt from taking a pregnancy test. 
8 
Statistical Analysis 
All study outcomes will be compared between placebo vs. empagliflozin 2.5 mg, as well as 
placebo vs. empagliflozin 5 mg.  Wherever applicable, outcomes will be calculated for 24 hours, 
daytime (6h00 – 24h00), and nighttime (24h00 – 6h00). 

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8.1 
Study Endpoints 
8.1.1 Primary endpoints 
• Time in target range (3.9 to 10 mmol/L)  
 
8.1.2 Secondary endpoints  
8.1.2.1 Glycemic level as per CGM readings 
1) Percentage of time spent in the following ranges of glucose levels  
a. Between 3.9 and 7.8 mmol/L 
b. Below 3.9, 3.3 and 2.8 mmol/L  
c. Above 7.8, 10, 13.9, and 16.7 mmol/L  
2) Mean glucose level 
3) Standard deviation of glucose levels as a measure of glucose variability  
4) Percentage coefficient of variation of glucose levels 
5) Proportion of participants with TIR between 3.9 - 10.0 mol/L > 70% 
 
8.1.2.2 Quality of life measures  
1) Average scores between interventions for the following questionnaires 
a) Type 1 Diabetes Distress Scale 
b) Hypoglycemic Fear Survey – II 
c) INSPIRE questionnaire for adults 
 
8.1.2.3 Other secondary endpoints 
1) Total daily insulin dose  
2) Average point-of-care ketone level per intervention 
3) Rise in ketone level between interventions  
 
8.1.3 Safety endpoints 
The following will be evaluated for all interventions: 
1) Number of episodes of severe hypoglycemia (as defined previously) 
a. Requiring emergency room visit 
b. Requiring hospitalization 
c. Not requiring medical attention 
2) Number of episodes of diabetic ketoacidosis  
a. Requiring emergency room visit 
b. Requiring hospitalization 
c. Not requiring medical attention 
3) Number of infections 
a. Genito-urinary 
b. Other infections 
4) Forms of dehydration, defined as drop in blood pressure, dizziness, increased thirst or 
urination, or symptomatic feeling of dehydration  
5) Gastro-intestinal side effects 

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8.2 
Sample Size and Power Calculations  
The power calculations aim to compare the effects of the following interventions on the primary 
endpoint (time in target range), made at the α= 0.05 significance level: 
i) 
placebo vs. empagliflozin 2.5 mg; 
ii) 
placebo vs. empagliflozin 5 mg. 
 
Sample size was calculated based on the smallest clinically significant difference, which we 
assume as 6.25% (i.e. 90 min per day) of time in target range.  The standard deviation of the 
paired differences in the percentage of time in target range is assumed to be 10% from our 
previous studies.(7,8,11)  Given these parameters, and with an aim for power of 80%, a sample 
size of 23 patients was calculated using the sample size formula for paired t-test.  However, to 
accommodate uncertainty within the power calculation, 25 participants will be recruited.   
 
8.2.1 Level of significance 
5% significance threshold will be used to assess statistical significance. No formal correction 
will be applied for the secondary comparisons. 
 
8.2.2 Statistical analysis  
A linear mixed effect model will be used to assess the effect of these treatments on the described 
endpoints.  An approximate normal distribution will be examined from residual values from the 
regression model.  If there are any major outliers in the values, a transformation or non-
parametric analysis will be performed.  Carry-over effects will be tested via hypothesis of no 
sequence effect. 
 
This type of analysis will also be used to assess the results of individual survey items and 
composite scores to account for the types of interventions and their sequences.  Reverse scoring 
will be used in the direction of greater worries or higher treatment satisfaction.  Descriptive 
analysis will also be done for survey ratings, for e.g. percentage of patients that check off 
“disagree”, “agree”, etc. Pearson correlation and analysis of variance will be used to assess for 
any correlation with participant characteristics (e.g. sex, age, duration of diabetes). 
9 
Ethical and Legal consideration  
9.1 
Good clinical practice  
This study will be performed as per good clinical practice, as described in the International 
Conference of Harmonisation (ICH) E6: Guideline for Good Clinical Practice (1 May 1996), in 
agreement with the Declaration of Helsinki and regulations met locally, by the Institutional 
Research Board of Advarra at the Clinique Médicale Hygea, and by McGill University. 
 
9.2 
Delegation of investigator’s duties 
The primary investigator will ensure the following: 
- 
That all study members of the research team are qualified, informed of the protocol and study 
treatments and its subsequent changes, and the overall function of the trial  
- 
That the timeline of the study is respected  
- 
That co-investigators and other personnel are delegated appropriate duties 
 

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9.3 
Participant’s Informed Consent  
A participant will only be included in the study if informed consent has been obtained.  At the 
initial visit, reading material concerning details of the trial (including possible risks) will be 
given to the participant; this will also be discussed verbally to the participant by the study 
member at the visit.  Both the study member and the participant will sign and date the document 
of consent.  The original copy of this document will be kept with the study team, and a copy will 
be given to the participant.  Only after consent has been contained will the rest of the study be 
continued.  A letter will be sent concerning the study to the participant’s primary physician 
undertaking care of their diabetes.  Consent may also be withdrawn as per Section 3.2. 
 
9.4 
Confidentiality  
Confidentiality will be respected as per routine practice as mandated by the Royal College of 
Canada.  Participant’s personal identifiers, including names, date of birth, and address, will be 
concealed, and replaced by a study number.  This will be used to record participant’s results as 
used by the investigator and team members; these results will be stored on a protected computer 
as per regulations of the Institutional Review Board of the clinic and McGill University. 
 
9.5 
Approval of the clinical study protocol and amendments 
An application will be sent to the clinic’s Institutional Review Board for assessment and 
approval prior to start of the study.  If any changes are made to the study protocol, the IRB will 
be informed and the study will continue once the amendment has been approved.  The primary 
investigator will keep track of all communication with the IRB. 
 
9.6 
Record retention 
The study will follow guidelines as per ICH where all information will be collected and kept 
securely for 25 years. 
10 Data Safety and Monitoring Board 
10.1 Roles and Responsibilities 
The Data and Safety Monitoring Board (DSMB) is an independent group of experts that advises 
the study team. The members of the DSMB serve in an individual capacity and provide their 
expertise and recommendations. The DSMB is responsible for safeguarding the interests of study 
participants, assessing the safety and efficacy of study procedures, and for monitoring the overall 
conduct of the study.  
 
The primary responsibilities of the DSMB are to 1) periodically review and evaluate the study data 
for participant safety, study conduct and progress, and, when appropriate, efficacy, and 2) make 
recommendations concerning the continuation, modification, or termination of the trial.  
 
10.2 Membership 
The membership of the DSMB should reflect the disciplines and medical specialties necessary to 
interpret the data from the clinical trial and to fully evaluate participant safety. For this trial, the 
DSMB is composed of two adult endocrinologists that are independent of the study.  
 
 

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10.3 Conflict of Interest 
No member of the DSMB should have direct involvement in the conduct of the study. Furthermore, 
no member should have financial, proprietary, professional, or other interests that may affect 
impartial, independent decision-making by the DSMB.  Letters of invitation to prospective DSMB 
members will include the following: "Acceptance of this invitation to serve on the Low Dose Empa 
trial, protocol 2021-6542 DSMB confirms that I do not have any financial or other interest with 
any other organizations involved in the study that constitute a potential conflict of interest."  
 
10.4 Meetings 
The DSMB will meet: 
(1) After the first 10 participants are finished their interventions.  
(2) After P011 to P025 have finished their interventions. 
(3) After any serious adverse event. 
 
Items reviewed by the DSMB include: 
• 
Individual and cumulative data for evidence of study-related adverse events; 
• 
Individual and cumulative data for evidence of efficacy; 
• 
Adherence to the protocol; 
• 
Factors that might affect the study outcome or compromise the confidentiality of the trial 
data (such as protocol violations, etc.); and, 
• 
Factors external to the study such as scientific or therapeutic developments that may impact 
participant safety or the ethics of the study. 
 
The DSMB should conclude each review as to whether the study should continue without change, 
be modified, or be terminated. 
 
Recommendations regarding modification of the design and conduct of the study could include: 
• 
Modifications of the study protocol based upon the review of the safety data; 
• 
Suspension or early termination of the study because of serious concerns about subjects’ 
safety, inadequate performance, or rate of enrollment. 
 
10.4.1 Meeting Format 
The recommended meeting format consists of two sessions: Open Session and Closed Session: 
(1) Open session: issues relating to the general conduct and progress of the study are discussed 
including adverse events, demographic characteristics of enrollees, and protocol 
compliance. The principal and/or co-investigators and/or the study coordinator should be 
in attendance in order to present results and respond to questions.  
(2) Closed session: Grouped and individual safety data and efficacy data are reviewed at this 
session. This final session involves only DSMB members to ensure complete objectivity 
as they discuss outcome results, make decisions, and formulate recommendations 
regarding the study. 
 
10.4.2 Decisions 
After a thorough discussion of DSMB members' opinions and rationale, the final recommendations 
of each DSMB member should be solicited during the Closed Session. All decisions must be a 
consensus. If a consensus is not reached, the IRB will be notified.  

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10.4.3 Study Reports 
It is the responsibility of the PI to ensure that the DSMB is apprised of all new safety information 
relevant to the study. The DSMB should receive all protocol revisions and may receive other 
documents relating to the study. Reports are prepared by a member of the study team and 
distributed to the DSMB at least three days prior to the meeting. The data presented in the reports 
must reflect both the need for the fullest possible information on study results and the need to 
assure reliability and accuracy of the information included. The reports will include individual and 
cumulative data as well as any adverse events. 
 
10.5 Reports from the DSMB 
1. Verbal Report: At the conclusion of a DSMB meeting, the DSMB should discuss the findings 
and recommendations with the study team. 
2. Summary Report. The DSMB will approve written minutes that identify topics discussed by 
the DSMB and describe its individual findings, overall safety assessment, and 
recommendations. The rationale for recommendations will be included when appropriate. 
Minutes will generally not include information that was discussed in the Closed 
Session.  Additional reporting (e.g., IRB) is the responsibility of the study team.   
3. Immediate Action Report: The DSMB will notify the study team of any findings of a serious 
and immediate nature or recommendations to discontinue the study. Appropriate study staff 
will be notified immediately, including the PI and co-PIs. In addition to verbal 
communications, recommendations to discontinue or substantially modify the design or 
conduct of a study must be conveyed to the study team in writing within 48 hours. This written 
should include DSMB member's rationale for their recommendations.  
11 Adverse events 
11.1 Adverse events 
An adverse event is any unintended effect of either a medication or medical device, that may 
vary from mild discomfort to severe illness.  This includes medication overdose, exacerbation or 
worsening of a known illness, or development of new symptoms that relate to a separate 
mechanism of the medication.  Pertaining to a medical device, this also includes malfunction that 
may result in over-medication or under-medication that may cause deleterious effects to the 
patient.  Section 7.3 describes potential risks of the medications and devices being used, that may 
result in an adverse event. 
 
During the study, adverse events will be recorded in the following manner: 
- 
Active surveillance through each intervention questionnaire  
- 
Active surveillance via planned remote visit through the study team 
- 
Passive surveillance, where any participant may report (remotely or in person) to the study 
team 
 
Adverse events will be recorded as follows, from the time of signed consent to the end of the 
study (including wash-out period): 
- 
Record of the date of onset of symptoms 
- 
Severity of the symptoms (from discomfort to any need for hospitalization) 
- 
Causality (i.e. relation to the study drug itself or the insulin pump system) 

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The team will report to the primary investigator for any adverse events.  If the adverse event is 
severe enough that the participant’s health is significantly compromised, withdrawal from the 
study will be discussed.  
 
Furthermore, if any adverse event were to occur during the study, the patient will continue to be 
followed up after cessation of the study to ensure improvement and resolution, either in person or 
remotely (i.e. telephone, email, etc.), depending on the symptom itself and as per the primary 
investigator.   
 
11.2 Classification of specific adverse events 
The following adverse events are specific to the treatments of the study.  Below are described 
how these adverse events will be dealt with during the study. 
 
11.2.1 Hypoglycemia and hyperglycemia 
Given the intensity and complexity of treatment of insulin therapy in type 1 diabetes, hypo- and 
hyperglycemia are common.  Different therapies may influence the frequency and severity of 
these events for each participant.  See Sections 7.3.4 and 7.3.5 for more details. 
 
The iMAP system, given its autonomy in administration of insulin, and possibility of hardware 
malfunction, may result inadvertently in either hypoglycemia (if excess insulin is given in 
respect to the patient’s status activity and oral intake) or hyperglycemia (if not enough insulin is 
given, or if there is hardware malfunction).   
 
Empagliflozin may also influence glycemic control, though more likely hypoglycemia if the 
same amount of insulin is given for excess glucose that will be removed through urination.   
 
To mitigate this, treatment of hypo- and hyperglycemia will be discussed at the initial visit; for 
any significant or persistent hyperglycemia, assessment of ketoacidosis will be recommended 
(see Section 11.2.2).  Remote visits during the beginning of each intervention will ensure to 
discuss any excess hypo- or hyperglycemia.  Significant events of hypo- and hyperglycemia will 
be screened after each intervention, after which further discussion with a healthcare professional 
of the team will be held.  In the event of any severe hypoglycemia, a visit from the team will be 
held as soon as possible.   
 
Any significant episodes or recurring episodes causing impairment to the participant will be 
reported to the IRB and regularity authorities.  Note that non-severe hypo- and hyperglycemia 
will not be reported as adverse events. 
 
11.2.2 Ketoacidosis  
Any malfunction causing lack of insulin delivery can increase the risk of DKA in a patient with 
type 1 diabetes.  SGLT2i use in type 1 diabetes patients poses an addition unique risk.   
 
To ensure safety during the trial from severe hyperglycemia, DKA, and HHS, the following will 
be performed:  

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- 
Instructions on how to treat hyperglycemia and assess for ketoacidosis will be performed at 
the initial visit. 
- 
Continuous glucose monitoring will enable the participant to be alerted concerning 
hyperglycemia (the threshold set by the participant) as soon as possible, therefore any action 
is not delayed. 
- 
Regular point-of-care ketone measurements daily 
- 
Participants will be instructed to measure ketones if CGM measures above 16 mmol/L for 
more than 1 hour.   
 
11.2.3 Local skin reactions 
Adverse events related to local skin reactions range from mild reactions (local irritation, 
discomfort, mild bleeding, bruising, remaining indentation from site insertion) to dermatitis or 
lipo-hypertrophy (see section 7.3.3).  Though rarely would a soft tissue infection occur, the most 
life-threatening would be toxic shock syndrome, which is a systemic inflammatory response to 
Staphylococcus or Streptococcus soft tissue infection causing multi-organ damage; case reports 
of this have been reported in the past.(30)  This would only occur in the case of improper 
hygiene and a severe lack of recommended site change (recommended to be every 3 days). 
 
To prevent this, safe and clean insertion site technique is reinforced at the initial clinic visit.  
Recommendations will be given for change in pump catheter site every 3 days and change in 
sensor site every 7 days (note this is routine practice for any patient on insulin pump therapy).  
Any other mild reactions will be discussed at remote visits. 
 
Only skin reactions requiring medical attention (i.e. infection or concern for such, pain causing 
inability to go about daily activities, and any need to go to the emergency room) will be reported 
as adverse events.  Various ways to safely reduce risk of inflammation will be discussed in the 
case of contact dermatitis. 
 
11.2.4 Infection and soft tissue ischemia 
As previously discussed in Section 7.3.1, there is an increased risk of infection with SGLT2i use, 
in particular genito-urinary, but also soft-tissue infections, the worst (and extremely rare) being 
necrotizing fasciitis.  There is also an increased risk of ketoacidosis in those with type 1 diabetes 
who have an acute illness.(29)  Increased risk of amputation was only reported in the CANVAS 
trial,(14) but nonetheless due to this report, surveillance is heightened for other agents. 
 
At the initial clinic visit, participants will be screened for any recurrent or chronic infections or 
peripheral vascular disease and will be excluded from the study (see exclusion criteria) if 
applicable.   
 
Participants will be trained to immediately stop taking the study medication and to monitor for 
ketones during acute illness.  The participant is to seek medical attention for ketoacidosis or for 
any acute infection worse than a mild viral upper respiratory tract infection.  A prescription of 
clotrimazole 1% will be prescribed for each patient, to be filled out on an as-needed basis.  The 
participant is to seek immediate medical attention for any sudden onset numbness, pain, or lack 
of blood flow to any limb.   
 

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All of these adverse events (whether mild or severe) will be recorded during the study, and will 
be screened for with the end-of-intervention questionnaires.  If any severe infection requiring 
antibiotics or acute limb ischemia occur, then the patient will be withdrawn from the study as 
they cannot concomitantly be on the study medication.   
 
11.2.5 Dehydration 
Given the mechanism of action of SGLT2 inhibitors, increased urinary frequency is a common 
side effect.  In the extreme setting, this may result in dehydration and drop in blood pressure.   
Rarely, this could result in acute kidney injury.   
 
These symptoms will be screened for actively after each intervention.  During the initial clinic 
visit, participants will be advised about this effect and encouraged to stay hydrated.  Adverse 
events related to the above will be activated recorded by the questionnaire and end of visit 
survey.   
 
11.2.6 Phlebotomy 
At the initial visit, blood samples will be taken for baseline biochemistry.  This is a small amount 
of blood, with most common side effects being temporary discomfort, and bruising or redness at 
site of venipuncture.  Some patients may have more severe psychological discomfort, and rarely 
can develop a vasovagal response.  An adverse event will only be recorded if it is deemed severe 
by the primary investigator as per their clinical judgment. 
 
11.2.7 Closed-loop system device failure  
Possible malfunctions are described in Section 7.3.8.  Included in these adverse events is the 
need for any study personnel to override the MAP system due to any troubleshooting to avoid 
other adverse events.  Any MAP system failure will be recorded as a Technical Adverse Event 
(TAE) via a special form.  These will be recorded in addition to the other standard adverse 
events.   
 
11.3 Severity (intensity) and causality of adverse events  
A rough classification system will be used to describe the severity/intensity of adverse events in 
the study.  These are classified by medical judgment.  They are described as follows: 
- 
Mild: Discomfort is apparent but daily activities are not disrupted 
- 
Moderate:  
o Discomfort disrupts daily activities 
o Need to seek medical attention in an ambulatory or clinic setting (e.g. urinary tract 
infection)  
- 
Severe: Any medical occurrence that is beyond discomfort which includes any of the 
following: 
o An event that is life-threatening 
o Need to present to the emergency department  
o Requires inpatient hospitalization  
o Results in permanent disability 
o Results in death 
o Results in a possibility birth defect or obstetrical-related adverse event (if patient 
became pregnant inadvertently during the time of the study) 

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Once the adverse event occurs, causality by any agent in the study will be determined through 
medical judgment via temporal relationship, pattern of reaction, and confounding factors. 
 
11.4 Reporting serious adverse events 
11.4.1 Responsibilities of the principal investigator 
The principal investigator is responsible ultimately for adverse event evaluation.  These roles 
include: 
- 
Classification and evaluation of the adverse event that is recorded by the study team  
- 
Relationship to the study, and need for further protocol re-evaluation  
- 
Review of any possible factor in the study that could have caused the adverse event to find a 
potential way to reduce the risk to others 
- 
Documentation of the above analysis 
- 
Report to the research ethics board and regulatory authorities within 10 days of observation 
of this problem 
- 
Determination of the need to update risk analysis and other preventative measures, i.e. update 
of the protocol 
 
11.4.2 Definition of a Serious Adverse Event (SAE) 
A serious adverse event (SAE) is any adverse event that is labelled as severe, as described in 
Section 11.3, which includes any reaction that is life-threatening, requires admission to hospital, 
or would result in death, permanent disability, or congenital malformation.   
 
If an SAE occurs, it will be reported immediately to the local IRB (as per their local guidelines).  
If a drug (e.g. empagliflozin) or a device (e.g. any MAP system components) is suspected, SEA 
will also be reported to CTA or ITA division of Health Canada, respectively, within the 
timeframe defined in the guidelines.  
 
When an SAE occurs, medical attention and follow up by the study team will continue until the 
SAE has resolved, even after cessation or completion of the trial.  This is to record the course of 
the medical condition to ensure safety in other patients.  
 
 
 
 
 
 
 
 
 
 
 
 
 

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