Weekly Subcutaneous Semaglutide as Adjunct to Closed-loop Therapy in Type 1 Diabetes Care: a Double-blind, Cross-over, Randomized Controlled Trial
Phase: PHASE2
Conditions: Type 1 Diabetes, Diabetes Mellitus, Type 1
Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre

 
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Clinical Study Protocol  
 
 
 
 
 
 
 
 
 
Title 
Weekly subcutaneous semaglutide as adjunct to closed-loop therapy in type 1 
diabetes care: a double-blind, cross-over, randomized controlled trial [SEMA-AP] 
 
Principal investigator 
Dr. Michael TSOUKAS, M.D. 
Endocrinologist 
Division of Endocrinology & Metabolism 
Royal Victoria Hospital 
1001, boulevard Décarie  
Montreal (Quebec) Canada H4A 3J1 
 
Co-investigators 
Dr. Melissa-Rosina PASQUA, M.D. 
Endocrinologist 
Division of Endocrinology & Metabolism  
Royal Victoria Hospital 
1001, boulevard Décarie  
Montreal (Quebec) Canada H4A 3J1 
 
Dr. Ahmad HAIDAR, Eng., Ph.D. 
Scientist 
Research Institute of the McGill University Health Centre 
1001, boulevard Décarie  
Montreal (Quebec) Canada H4A 3J1 
 
Study site 
Research Institute of the McGill University Health Centre 
Royal Victoria Hospital 
1001, boulevard Décarie  
Montreal (Quebec) Canada H4A 3J1 
 
Funding 
Use of residual research funds, Canadian Research Chair in Artificial Pancreas 
Systems, and Fonds de la recherche en santé du Québec (FRQS) 
 
Sponsor 
Research Institute of the McGill University Health Centre (RI-MUHC) 

 
 
 
 
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Version Tracker/Revision History 
 
# 
Date 
Author 
 
Description 
REB 
ITA 
NOL 
Submission 
date 
Approval date 
Submission 
date 
Approval date 
Submission date 
Approval date 
1.0 
2021-
FEB-20 
Alessandra 
Kobayati 
Original draft development 
N/A 
N/A 
N/A 
1.1 
2021JUL-
23 
Melissa-
Rosina 
Pasqua 
Initial submission 
2021-JUL-26 
No approval - 
replaced by 
1.2 
2021-AUG-25 
No approval - 
replaced by 
1.2 
2021-AUG-25 
No approval - 
replaced by 1.2 
1.2 
2021-
SEP-22 
Melissa-
Rosina 
Pasqua 
Changes prior to approval by REB or Health 
Canada as requested by REB and Health 
Canada 
2021-SEP-23 
No approval - 
replaced by 
1.3 
2021SEP-30 
Screening 
clearance 
2021-OCT-07 
2021-OCT-1 
No approval - 
replaced by 1.3 
1.3 
2021-
OCT-20 
Melissa-
Rosina 
Pasqua 
Change recommended by REB to replace 
biobank with blood samples to be assessed 
for secondary use. 
2021-OCT-25 
No approval - 
replaced by 
1.4 
Had not yet 
been 
submitted  
2021-OCT-25 
No approval - 
replaced by 1.4 
1.4 
2021-
NOV-9 
Melissa-
Rosina 
Pasqua 
Clarification concerning acetaminophen use 
as per ITA, with addition of hydroxyurea use 
as exclusion criteria 
2021-NOV-29 
Awaiting 
ITA/NOL on 
2021-DEC-08 
2021-Dec-6 
No approval - 
replaced by. 
1.5 
2021-Nov-29 
Request for info 
2021-Dec-20 
1.5 
2021-
DEC-21 
Melissa-
Rosina 
Pasqua 
As per Health Canada: addition of ECG 
testing, change in GFR threshold for inclusion, 
titration schedule  
- 
2022-Jan-18 
 
2021-Dec-22 
NOL 2021DEC24 
1.6 
2021-
Dec-26 
Melissa-
Rosina 
Pasqua 
Option of different pump (YpsoMed) to be 
used for Automated Insulin Delivery 
(replacing McGill Artificial Pancreas) 
- 
2022-JAN-18 
 
2022JAN31 
(CTA-N) 
1.7 
2022-
Feb-14 
Melissa-
Rosina 
Pasqua 
As recommended by ITA: Participants will 
continue on same system throughout study 
- 
2022FEB116 
(changes 
requested) 
2022FEB21 
(CTA-N) 
1.8 
2022-
JUNE-22 
Melissa-
Rosina 
Pasqua 
More detail added to recruitment + ITA-
requested change: Clarification of insulin 
pump catheter change 
Approved 
2022-AUG-02 
iMAP 2022 
JUL28 
Euglide 
2022AUG30 
2022-JUN-28 
(CTA-N) 
2 
2022-
DEC-06 
Melissa-
Rosina 
Pasqua 
Laboratory changes: TNF-alpha removed, CRP 
(not hsCRP) to be measured, NT-pro-BNP 
specified, lipase/ amylase clarified, frozen 
sample processing specified.  Specified 
INSPIRE timing.  Clarified as needed follow up 
wording. 
 
 
 
 

 
 
 
 
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Table of Contents 
1.  Background & Rationales ................................................................................................... 6 
1.1 Prior GLP1-RA studies in T1D ...................................................................................................... 6 
1.2 Our prior studies using McGill's Automated Insulin Delivery (AID) .............................................. 7 
2.  Objectives, hypothesis, and design ..................................................................................... 8 
2.1. Objectives ................................................................................................................................. 8 
2.1.1 Primary objectives ...................................................................................................................................... 8 
2.1.2 Secondary objectives .................................................................................................................................. 8 
2.2 Hypotheses ................................................................................................................................ 9 
2.2.1 Primary hypotheses .................................................................................................................................... 9 
2.2.2 Secondary hypotheses ............................................................................................................................... 9 
2.3 Design overview ......................................................................................................................... 9 
3. Study population ................................................................................................................. 9 
3.1 Inclusion criteria ........................................................................................................................ 9 
3.2 Exclusion criteria ...................................................................................................................... 10 
3.3 Discontinuation criteria ............................................................................................................ 11 
3.4 Study withdrawal ..................................................................................................................... 11 
4.  Study centres and recruitment methods ........................................................................... 11 
5. Study drugs, devices, and materials .................................................................................. 12 
5.1 Study drugs .............................................................................................................................. 12 
5.1.1 Storage and handling ............................................................................................................................... 12 
5.1.2 Drug accountability .................................................................................................................................. 12 
5.2 Study devices and materials ..................................................................................................... 13 
5.2.1 Automated Insulin Delivery ...................................................................................................................... 14 
6. Trial Design ....................................................................................................................... 14 
6.1 Study timeline .......................................................................................................................... 14 
6.2 Randomization and allocation concealment ............................................................................. 15 
6.3 Blinding .................................................................................................................................... 15 
6.4 Anthropometric investigations ................................................................................................. 16 
6.5 Laboratory investigations ......................................................................................................... 16 
6.5.1 Laboratory measurement ........................................................................................................................ 18 
6.6 Questionnaires ......................................................................................................................... 18 
7. Study procedures .............................................................................................................. 20 

 
 
 
 
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7.1 Visit schedule ........................................................................................................................... 20 
7.2 Admission visit ......................................................................................................................... 21 
7.3 Training visit ............................................................................................................................ 22 
7.4 Semaglutide/ placebo titration period (Weeks 1 - 12) .............................................................. 22 
7.5 AID training (Visit 2) ................................................................................................................. 23 
7.6 Closed-loop therapy (Run-In) ................................................................................................... 23 
7.7 Closed-loop therapy (3 weeks) ................................................................................................. 23 
7.8 Laboratory and anthropometric measurements (Visit 3) .......................................................... 23 
7.8.1 Mixed meal tolerance test (MMTT) ......................................................................................................... 23 
7.9 Washout (2 weeks) .................................................................................................................. 25 
7.9 Second intervention ................................................................................................................. 25 
7.10 End of Study Visit (Visit 4) ...................................................................................................... 25 
7.11 Post-study follow-up .............................................................................................................. 26 
8. Risk and Risk Mitigation .................................................................................................... 26 
8.1 Semaglutide dose rationale ...................................................................................................... 26 
8.2 Medical and safety monitoring ................................................................................................. 26 
8.2.1 Concomitant and prohibited medications ............................................................................................... 26 
8.3 Risks associated with the study ................................................................................................ 26 
8.3.1 Semaglutide .............................................................................................................................................. 26 
8.3.2 Blood sampling ......................................................................................................................................... 27 
8.3.3 Glucose sensors and insulin infusion sets ................................................................................................ 28 
8.3.4 Hypoglycemia ........................................................................................................................................... 28 
8.3.5 Hyperglycemia (and associated conditions) ............................................................................................. 28 
8.3.6 Risks related to the AID system ................................................................................................................ 29 
8.4 Pregnancy ................................................................................................................................ 30 
9. Data Safety Monitoring Board (DSMB) .............................................................................. 30 
9.1 Roles and responsibilities ......................................................................................................... 30 
9.2 Membership ............................................................................................................................ 31 
9.3 Conflict of interest ................................................................................................................... 31 
9.4 Meetings .................................................................................................................................. 31 
9.4.1 Meeting format ........................................................................................................................................ 32 
9.4.2 Decisions .................................................................................................................................................. 32 
9.4.3 Study reports ............................................................................................................................................ 32 
9.5 Reports from the DSMB ........................................................................................................... 32 
10. Statistical analysis ........................................................................................................... 33 

 
 
 
 
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10.1 Study endpoints ..................................................................................................................... 33 
10.1.1 Primary endpoints .................................................................................................................................. 33 
10.1.2 Secondary endpoints .............................................................................................................................. 33 
10.1.3 Safety endpoints .................................................................................................................................... 34 
10.2 Sample size and power calculations ....................................................................................... 35 
10.2.1 Level of significance ............................................................................................................ 35 
10.2.2 Statistical analysis ................................................................................................................................... 35 
11. Ethical and legal considerations ...................................................................................... 36 
11.1 Good clinical practice ............................................................................................................. 36 
11.2 Delegation of investigator's duties ......................................................................................... 36 
11.3 Participant's informed consent ............................................................................................... 36 
11.4 Confidentiality ....................................................................................................................... 36 
11.5 Participant compensation ...................................................................................................... 36 
11.6 Approval of the clinical study protocol and amendments ....................................................... 36 
11.7 Record retention .................................................................................................................... 37 
12. Adverse events ................................................................................................................ 37 
12.1 Adverse events ....................................................................................................................... 37 
12.2 Classification of specific adverse events ................................................................................. 37 
12.2.1 Hypoglycemia ......................................................................................................................................... 38 
12.2.2 Hyperglycemia and affiliated conditions ................................................................................................ 38 
12.2.3 Local skins reactions ............................................................................................................................... 39 
12.2.4 Phlebotomy ............................................................................................................................................ 39 
12.2.5 Gastrointestinal symptoms, gallbladder disease and pancreatitis ......................................................... 40 
12.3 Technical adverse events ........................................................................................................ 40 
12.4 Severity (intensity) and causality of adverse events ............................................................... 40 
12.5 Reporting serious adverse events ........................................................................................... 41 
12.5.1 Responsibilities of the principal investigator ......................................................................................... 41 
12.5.2 Definition of a serious adverse event (SAE) ........................................................................................... 41 
References ............................................................................................................................ 42 
Appendix A: Ketone Management ........................................................................................ 48 
 
 
 
 
 

 
 
 
 
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1.  Background & Rationales 
Type 1 diabetes (T1D), which accounts for 5-10% of all cases of diabetes, is caused by 
autoimmune destruction of the insulin-producing cells of the pancreas (1).  This often occurs in 
childhood, and necessitates life-long intensive insulin therapy.  A goal of glycated hemoglobin 
(HbA1c) ≤ 7% is used to reduce the risk of micro- and macrovascular complications from chronic 
hyperglycemia (2–5).  Unfortunately, achieving tight glucose control is limited by hypoglycemia 
(low blood sugar), which can cause a range of symptoms from impaired judgment to loss of 
consciousness.  Throughout prior assessments in the United States and Canada, less than 25% 
of those with T1D are able to achieve target glycemic control (6,7). 
 
One of the most pertinent breakthroughs emerging into commercial use is closed-loop insulin 
therapy (8).  Closed-loop therapy is comprised of a continuous glucose monitor (CGM), an 
insulin pump, and an algorithm that is able to adjust subcutaneous insulin infusion based on 
glucose readings.  Closed-loop therapy has demonstrated (compared to CGM and insulin pump, 
or "sensor augmented therapy") increased time spent in target blood glucose levels of 3.9 to 10 
mmol/L , reduced hyper- and hypoglycemia, and reduced HbA1c levels (9–13).  Unfortunately, it 
does not perfect glucose control; in one of the largest closed-loop trials lasting 6 months, 
almost half of those on closed-loop therapy still had HbA1c levels below target.  One of the 
main barriers is post-prandial hyperglycemia, as nocturnal glycemia is well-controlled (14).  
 
Closed-loop therapy alone also does not address major gaps in T1D care.  There is a growing 
obesity epidemic in T1D (15–17), as well as a major gap in cardiovascular and renal protection 
compared to the recent pharmacological trials seen in type 2 diabetes (T2D) (18–21).  
Adjunctive therapies borrowed from T2D management have been used with variable efficacy 
and safety profiles (22).   
 
Glucagon-Like Peptide-1 Receptor Agonists (GLP1-RAs) are a class of medications that have 
been extensively studied in T2D and weight loss management (20,21,23).  GLP-1 is an intestinal 
hormone secreted by L cells which control glucose levels through reduced glucagon levels, 
increased insulin secretion, reduced beta cell apoptosis, increase satiety, and slowed gastric 
emptying (24).  GLP1-RAs mimic this effect, and have shown to not only improve glycemic 
control in T2D, but the use of liraglutide, dulaglutide, and semaglutide have shown in 
randomized clinical trials to lead to weight loss, reduced cardiovascular events, and reduction in 
diabetic nephropathy (20,21,25–27).  Of the GLP1RA's, semaglutide is the most potent in its 
weight loss and glycemic effects (28).   
 
1.1 Prior GLP1-RA studies in T1D 
The use of GLP1-RAs as adjunct has previously been used in T1D with variable effect, with 
agents studied being predominantly exenatide and liraglutide.  Adjunct-One and Adjunct-Two 
were two large studies in participants with T1D with HbA1c 7 - 10% (and body mass index (BMI) 
> 20 kg/m2) that resulted in weight loss and reduced HbA1c levels; there was a slightly more 

 
 
 
 
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pronounced effect in those with remaining C-peptide levels (29,30).  The Lira-Pump trial 
included only those with T1D on pump therapy with BMI ≥ 25 (i.e. overweight and obese), and 
resulted in HbA1c reductions of 0.5%, total daily insulin dose reductions of 16%, and body 
weight reduction of 6.3 kilograms (31).  Short studies have also been done using GLP1-RAs 
(liraglutide and exenatide) with closed-loop systems, which showed reductions in post-prandial 
hyperglycemia (32,33).  Other studies have looked at the use of GLP1-RAs in islet cell 
transplantation and beta cell preservation in early diagnosis of T1D with mixed results (34,35). 
 
Given the pathophysiology of T1D, the mechanism of GLP1-RA utility in T1D is still unclear.  It 
may be related to remaining beta cell protection, weight reduction in the context of insulin 
resistance, improvement in gastric emptying to aid glucose absorption, reduced glucagon 
secretion, or change in eating habits.  Given semaglutide was found to have more potent 
effects in T2D, its effects may then be more substantial in T1D. 
 
1.2 Our prior studies using McGill's Automated Insulin Delivery (AID) 
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 22 studies with more than 450 participants have been performed by our research 
group thus far (9,36–40).  These studies use McGill's Automated Insulin Delivery (AID) system, 
which is a hybrid closed-loop system, meaning participants must include carbohydrate 
counting.  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).(9,41)  
 
Multiple studies have been done using a bi-hormonal model with insulin and pramlintide, an 
analogue of the hormone amylin which is released by beta cells and improves glucose levels 
through increased satiety and delayed gastric emptying (42).  Our most recent study, an 
inpatient study using the rapid insulin-pramlintide closed-loop system, revealed that compared 
to insulin-alone, the novel system increased percentage of time spent in target and reduced 
mean glucose (41).  Despite the positive outcomes, barriers to the insulin-pramlintide closed-
loop system include gastrointestinal symptoms, the need to use two pumps at once, and the 
lack of an approved formulation for the two hormones.  However, pramlintide's mechanism of 
action are similar to GLP1-RA.  It would be beneficial to have these similar effects with easier 
administration and the added benefits of cardiovascular and renal protection. 
  

 
 
 
 
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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)        
2.  Objectives, hypothesis, and design 
2.1. Objectives 
2.1.1 Primary objectives 
The primary objective of our study is to assess the effect on time-in-target range (TIR) between 
3.9 to 10.0 mmol/L of the following: 
1) Semaglutide SC weekly at maximum tolerated dose in those with T1D on closed-loop 
therapy versus placebo with closed-loop therapy 
 
2.1.2 Secondary objectives 
The secondary objectives are to assess the following outcomes due to semaglutide SC weekly 
versus placebo on those with type 1 diabetes: 
1) Glycated hemoglobin (HbA1c) 
2) Anthropometric measurements: weight, body mass index, blood pressure 

 
 
 
 
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3) Total daily insulin requirements 
4) Daily carbohydrate intake  
5) Biochemical metabolic parameters such as lipid profile, cytokines, adipokines, biomarkers, 
urine albumin-creatine ratio (urine protein) 
6) Change in C-peptide, glucagon, and paracetamol levels during a mixed meal tolerance test 
7) Change in quality of life (such as fear of hypoglycemia, diabetes distress, treatment 
satisfaction, bowel symptoms) as assessed through questionnaires and semi-structured 
interviews 
 
2.2 Hypotheses 
 
2.2.1 Primary hypotheses 
Semaglutide SC weekly at maximum tolerated dose in those with T1D on closed-loop therapy 
will increase TIR of 3.9 to 10.0 mmol/L compared to those using placebo. 
 
2.2.2 Secondary hypotheses 
Semaglutide SC weekly at maximum tolerated dose in those with T1D will result in the 
following, compared to placebo: 
1) Reductions in HbA1c  
2) Reductions in total daily dose of insulin used 
3) Reductions in daily carbohydrate intake 
4) Reductions in weight, body mass index, blood pressure 
5) Improvement in lipid profile, cytokines, adipokines, biomarkers, urine protein 
 
2.3 Design overview 
This is a double-blinded, randomized, two-way crossover, outpatient trial.  Each arm will start 
with 12 weeks of titration of study drug tolerance (semaglutide or placebo) and insulin doses; 
the first 11 weeks will be on the participant's routine insulin pump therapy, and the last will be 
on the closed-loop insulin system.  This will be followed by 3 weeks of closed-loop therapy with 
the maximum tolerated dose of the study drug.  There will be 2 weeks of wash-out prior to the 
next intervention.  Laboratory and anthropometric measures will be done at the beginning as 
baseline, and then at the end of each intervention. 
3. Study population 
The trial will enroll 28 participants who meet the below criteria.   
 
3.1 Inclusion criteria 
1) At least 18 years of age 
2) A clinical diagnosis of T1D 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 up to 11% (inclusive), performed within the last 6 months prior to study inclusion 

 
 
 
 
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4) Insulin pump use (of any modality) for minimum 3 months  
5) Agreement to the use of highly effective method of birth control in persons of child-bearing 
age (if sexually active) and active avoidance of pregnancy during the trial.  Child-bearing 
potential 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. 
 
3.2 Exclusion criteria 
1) Current or < 2-week use of another GLP1-receptor agonist 
2) Less than 2 weeks use of any anti-hyperglycemic agent other than insulin  
3) Planned or ongoing pregnancy 
4) Breastfeeding individuals 
5) 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 
6) Severe diabetic ketoacidosis (DKA) within the last 6 months (“severe” referring to need to 
present to medical attention and requirement of intravenous insulin) 
7) Prior history of acute pancreatitis, chronic pancreatitis, or gallbladder disease 
8) Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 
2 
9) Severe impairment of renal function with eGFR <30 mL/min/1.73 m2 (using CKD-EPI 
formula), measured within the last 12 months 
10) Clinically significant diabetic retinopathy or gastroparesis, as per the clinical judgment of the 
investigator  
11) History of bariatric surgery within 6 months of screening 
12) 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) 
13) Prior adverse reaction to GLP1-RAs 
14) Body mass index ≤ 21 kg/m2 
15) Regular use of hydroxyurea during the expected time of Dexcom G6 use, as this medication 
is known to cause inaccurate measurements (43) 
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) Any demonstrate of difficulty in using the iAID system following training, as per 
investigator’s judgment 
19) Concern for safety of the participant, as per the clinical judgment of the primary 
investigator 

 
 
 
 
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Note that if any laboratory investigations required for screening are not available at the time of 
screening, conditional eligibility will be given so that baseline laboratory investigations can be 
performed at the initial admission visit.  These baseline laboratory investigations can be used 
for inclusion/exclusion criteria. 
 
3.3 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) Withdrawal of consent to participate or desire to no longer take part in the study  
3) Pregnancy 
4) The required use of medications listed in the exclusion criteria  
5) Severe hypoglycemia or diabetic ketoacidosis requiring hospitalization 
6) Acute pancreatitis or gallbladder disease 
7) Appearance of clinically significant diabetic retinopathy that threatens vision 
8) Severe hypersensitivity reaction 
9) Decision by the study group to prematurely terminate the clinical trial 
 
3.4 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 reasons 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 semaglutide) back to the participant’s usual regimen.     
4.  Study centres and recruitment methods 
The study will be conducted in Montreal, Quebec at the Centre for Innovative Medicine (CIM) 
of the Research Institute of the McGill University Health Centre (RI-MUHC).  Enrolment will 
consist of 28 adult participants.  Recruitment will predominantly take place among the clinic for 
adult T1D care seen by specialists in Endocrinology & Metabolism at the Royal Victoria Hospital, 
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.  Those who 
find the study through other means (e.g. the Clinical Trials website, CONNECT1D, REB-approved 
flyers, online platforms of diabetes organizations, other participants) will also be invited.  
 

 
 
 
 
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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.   
5. Study drugs, devices, and materials 
5.1 Study drugs 
Table 2. 
Investigational 
drug name 
Dose and formulation 
Blinding and preparation 
Semaglutide  
0.25mg (0.19ml), 0.5mg (0.37ml), 
1.0mg (0.74ml) injected 
subcutaneously once per week, 
colorless solution 
Liquid formulation prepared in blinded vials 
with an expiration date of 30 days (from the 
date of preparation) by the MUHC Research 
Pharmacy.  Injection needles will be provided 
to self-administer solution subcutaneously in 
the abdomen, thighs or upper arms once a 
week 
Placebo (saline)  0.19ml, 0.37ml, 0.74ml, injected 
subcutaneously once per week, 
colorless solution 
Liquid formulation prepared in blinded vials 
with an expiration date of 30 days (from the 
date of preparation) by the MUHC Research 
Pharmacy.  Injection needles will be provided 
to self-administer solution subcutaneously in 
the abdomen, thighs or upper arms once a 
week 
 
5.1.1 Storage and handling 
Participants will be instructed to store the vials of study drug (placebo and semaglutide) in the 
refrigerator at 2-8℃, though the vials can remain at room temperature once removed from 
refrigeration for up to 56 days. Participants may either keep the vial refrigerated or place it at 
room temperature (and away from direct sunlight) prior to each injection. 
 
5.1.2 Drug accountability  
Research personnel at the RI-MUHC pharmacy will complete a drug-dispensing log with 
enrolment ID, dispensing date and method, return date for each drug dispensation.  Participants 
will also be asked to record dose administration (or any possible missed dose) with time and date 
in a drug log.  Participants will be asked to communicate immediately to the research personnel 
if there are any missed dose > 24 hours or accidental additional/subtracted dose. 
 
 
 

 
 
 
 
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5.2 Study devices and materials 
Table 2 
Insulin pump by 
Tandem Diabetes Care 
or YpsoMed Diabetes 
Care, and associated 
materials 
This is the choice of continuous subcutaneous insulin infusion 
(CSII) administering compatible 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.   
The participant's study pump and supplies will either be from 
Tandem Diabetes Care or YpsoMed Diabetes Care; the participant 
will continue on the same brand of pump and appropriate 
corresponding AID system for the duration of the study. 
Dexcom 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.  No calibration is required. 
During the titration, CGM will be used.  If the participant does not 
have their own form of CGM, Dexcom G6 will be given. 
Study Smartphone 
The main algorithm for the closed-loop system is set on this 
device via the AID application.  The smartphone, pump, and 
sensor communicate via Bluetooth.  Each study participant is 
given one smartphone. 
Freestyle Precision Neo 
meter with glucose and 
ketone test strips 
Participants may use their own capillary point-of-care glucose and 
ketone measuring devices throughout the study.  In the event the 
participant does not have a glucose and/or ketone meter, 
participants will be given a Precision Neo meter with ketone and 
glucose test strips.  If a participant has already a Precision ketone 
and glucose measuring device (such as Precision Neo, Freestyle 
Libre or Freestyle Lite), capillary blood glucose and ketones will be 
provided.  Though Dexcom G6 does not require calibration, point-
of-care glucose testing may be required to ensure accuracy in the 
case of symptoms not corresponding to CGM glucose level.  
Ketone levels should also be tested in the setting of acute illness, 
nausea and vomiting, or glucose > 16 mmol/L more than 2 hours.   
Emergency kit 
The kit includes fasting-acting glucose tablets, insulin syringes, 
and intranasal glucagon.  This will be given to all participants.   
 

 
 
 
 
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5.2.1 Automated Insulin Delivery 
Automated Insulin Delivery (AID) 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 G6) 
2) A mobile application on a study smartphone 
3) An insulin pump 
 
Figure 2.  Depiction of McGill's Automated Insulin Delivery.   
 
For the ability to manipulate insulin administration via Bluetooth connection, the research 
team's own insulin pumps are required.  The algorithm is unique to our own research team, 
therefore it can be adjusted accordingly, therefore no commercial systems will be used in the 
study.  The application is certified only for these pumps and the Dexcom CGM. 
6. Trial Design 
6.1 Study timeline 
This is a double-blind, randomized, controlled, crossover, outpatient study comparing 
semaglutide SC weekly at maximum tolerated dose compared to placebo.  Further details on 
investigations performed and follow-ups are described below.   
 
The overall study length for each participant will be 32 weeks each.  
AID

 
 
 
 
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Figure 3.  Timeline of study interventions for each participant. 
 
6.2 Randomization and allocation concealment 
Block randomization using random block size of 4, 6, or 8 will be performed by a separate 
research team member.  This separate research member will create 2 envelopes: one for the 
investigator that includes the coded vials to be used for each arm of the study, and another that 
reveals which vial is which molecule.  The first envelope will be given to the investigator at the 
time of the initial admission visit when randomization is to occur; this is to be kept with 
participant documentation.  The second envelope will be placed (by the researcher who 
performs randomization) in separate documentation storage to be used after study completion 
or in the event of an emergency.   
 
6.3 Blinding 
This study will be double-blinded: the participant's study drugs will be vials that only include a 
code, and do not reveal if the medication is semaglutide or placebo.  The investigator will only 
know the code to be able to dispense vials, but will not know the molecule being administered.  
Both types of vials will be created by the RI MUHC research pharmacy, where the pharmacist is 
unblinded. 
 
Unblinding would occur in the event of a serious adverse event or in any other situation where 
it is pertinent for the participant's well-being to know if the participant was on the study drug.  
Prior to this, discussion will be held with the primary investigator for approval.  This will be 
Admission + Training
+ Randomization 
Visit
2 – 3 hours
Legend
Laboratory 
investigations
Anthropometrics
0.25 mg sema x 4 weeks
0.5 mg x 4 weeks
1 mg x 4  weeks
+ insulin titration
(last week on CL titration)
Placebo titration (mimic)
+ insulin titration (last 
week on CL titration)
12 weeks each
Sema = semaglutide
CL = closed loop
CL+ sema
CL +
placebo
3 weeks
Arm A
Arm B
End of Study 
Visit
Washout
2 weeks
(Labs within 
3 days of end)
Arm 
A
Arm 
B
Visit 2 – 6 hours
(labs to be done 
within 3 days of 
Arm A/B end)
15 weeks
MMTT

 
 
 
 
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done by one of the members of the team not involved in allocating medication.  Only the study 
drug in question for that participant will be reviewed. 
 
6.4 Anthropometric investigations 
Anthropometric measurements (except for height) will be taken at the Admission Visit, within 3 
days of the end of the first intervention, and at the End of Study Visit (which will be within 3 - 7 
days of the last intervention).  Body mass index will be calculated for each visit based on weight 
as well.  The following will be measured through the following instruments. 
 
Table 3 
Body weight 
A digital scale will be used to measure in kilograms. 
Height 
Height will be measured by a metal scale mount (or measuring tape if 
the other not available).  This measurement will be used for body 
mass index measurements.  Unlike the other measurements, it will 
only be taken at the admission visit. 
Waist circumference 
Measuring tape will be used to measure waist circumference at the 
top of the ischial crests as a landmark.  The measurement will be 
taken in centimetres when the participant exhales. 
Hip circumference 
Measuring tape will be used to measure hip circumference at the 
largest circumference around the buttock area; this will be taken in 
centimetres.    
Blood pressure 
An electronic sphygmomanometer will be used for blood pressure 
measurement above the brachial artery.  The patient should have 
sustained from smoking for 30 minutes, and emptied bladder prior.  
The participant should not be talking or cross their legs during the 
exam.  The mean of 3 measurements will be taken. 
Heart rate 
Heart rate will be taken by the same electronic sphygmomanometer 
as the blood pressure; the average heart rate will be taken as well. 
Calculated measurements 
Body mass index and hip: waist ratio will be calculated from the above 
measurements. 
Electrocardiogram  
An electrocardiogram (ECG) will also be performed due to risk of PR 
prolongation as describe in the product monograph (44). 
 
6.5 Laboratory investigations 
5 mL of serum via intravenous catheter will be taken at the same visits at anthropometric 
measurements (i.e. Admission Visit, end of first intervention, at End of Study Visit).  The 
description and rationale for each investigation is described below.  Note the study is not 
necessarily powered for changes in these parameters, but are exploratory in this setting. 
 
 
 

 
 
 
 
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Table 4 
Blood 
Glycated 
hemoglobin (HbA1c) 
Baseline and change in average glycemic control within the last 3- 4 months 
Liver profile 
 
At the MUHC, this includes bilirubin, alanine aminotransaminase (ALT), alkaline 
phosphatase (ALP).   
Screen and assess for change in possible cholestatic disease or liver disease (in 
particular non-alcoholic fatty liver disease).   
Lipid profile 
At the MUHC, includes total cholesterol, LDL-cholesterol, HDL-cholesterol, 
triglycerides. 
Screen and assess for change in dyslipidemia, in particular triglycerides and HDL-
c (markers of metabolic syndrome) and LDL-c (clinically important for 
cardiovascular protection) 
Creatinine 
Screen for and assess for change in renal function that may limit study drug use. 
Random (non-
fasting) blood 
glucose and C-
peptide 
Screen for beta-cell activity at the admission visit.  Prior studies have looked for 
effect of beta cell preservation on GLP1-RAs  (35), and Adjunct-One noted 
amplified glycemic effect in those with remaining C-peptide levels (29).  Random 
(non-fasting) C-peptide in prior studies has demonstrated to correlate with 
fasting C-peptide levels and the 90 minute mixed-meal tolerance test (45).   
Brain Natriuretic 
Peptide (NT-pro-
BNP) 
Screen for and assess for change in surrogate cardiovascular marker (46), given 
cardiovascular benefit seen in T2D in SUSTAIN6 trial (21).  
C-reactive protein 
(CRP), ferritin 
Screen and assess for change in markers of inflammation, influenced by 
metabolic syndrome (47,48).  Though metabolic syndrome is not key to T1D 
diagnosis, there are those with T1D who have concomitant metabolic syndrome.  
This is to assess for any possible metabolic effect influenced by this 
phenomenon. 
Lipase 
Screen for pancreatic inflammation with lipase and other relevant testing 
(adverse effect of GLP1-RAs). 
Interleukin(IL)-6 
This is an adipokine linked with metabolic syndrome, seen previously to be 
influenced by GLP1-RA (47,49).    
Thioredoxin-
interacting protein 
(TXNIP) 
TXNIP is a protein whose expression is increased in diabetes (50).  TXNIP 
downregulation has been linked with protective effects of the beta cell and 
organs susceptible to diabetes complications (50).  Prior GLP1-RAs (exendin-4) 
have  was shown to decrease TXNIP expression (50).  TXNIP can be measured in 
serum and correlates with diabetes status and nephropathy (51). 
Fructosamine 
Fructosamine is a measurement of glycosylated proteins, in particular albumin, 
which reflects glucose control within the last 2 - 3 weeks (52).  This will be used 
to compare more recent glucose control, similarly to glycated hemoglobin. 
Urine 

 
 
 
 
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Albumin:  creatinine 
ratio (uACR) 
Screen and assess for change in diabetic nephropathy, in particular given renal 
outcome results from SUSTAIN6 (21). 
Pregnancy screen 
An additional safety parameter to rule out pregnancy. 
Mixed-Meal 
Tolerance Test 
(MMTT) 
Description 
The mixed meal tolerance test is considered one of the goal standards for 
assessing beta cell activity in T1D (45,53,54).  It has also been previously used to 
assess for mechanistic of action of GLP1-RAs in prior trials (31,55).  See Section 
7.8.1 for details.   
14 participants (7 female and 7 male) will participate. 
Glucagon 
Glucagon is a counterregulatory hormone of insulin produced by the alpha cells 
of the pancreas; levels inappropriately rise post-prandially in those with T1D 
(56–58).  GLP-1 is known to suppress glucagon (24), and GLP1-RAs have shown 
to suppress glucagon with use in T1D previously (33,59,60).  Glucagon will be 
measured during the mixed-meal challenge and area-under-curve (AUC) will be 
used for secondary endpoints. 
C-peptide 
Will be measured as area-under-curve.  
Serum glucose 
Will be measured as area-under-curve. 
Paracetamol 
Given that gastric emptying rate is the rate-limiting step for paracetamol 
metabolism, this will be used to estimate changes in gastric emptying.  Area-
under-curve will be assessed. 
 
6.5.1 Laboratory measurement  
The majority of the laboratory investigations will be performed at the laboratory at the McGill 
University Health Centre.  Serum glucose measurements during the MMTT may be done 
through point-of-care testing (YSI Life Sciences).  TXNIP and glucagon measurements will be 
done via kit assays; TXNIP measurements will be done by chemiluminescence (Novus, NBP2-
68134), and glucagon will be measured by ELISA (Millipore, EZGLU-30K).  Processing of these 
samples will be done as recommended by manufacturer.  TXNIP analysis will be done with the 
collaboration of the laboratory of Dr George Fantus.  Plasma collection and storage for 
secondary use will be done at the timepoints of laboratory testing via centrifugation for 15 
minutes at 1000 x g, and storage within 30 minutes at ≤- 20oC.  This will be to further assess the 
hypotheses of the protocol or to further examine findings that were explored from the results 
of this study.   
 
6.6 Questionnaires 
Participants’ quality of life will be measured by the following validated questionnaires (note all 
of these have been used in prior projects within the research group): 
1) Type 1 Diabetes Distress Scale for adults: a validated 28-item questionnaire to assess 
distress concerning management, eating, and hypoglycemia for type 1 diabetes (61) 
2) Hypoglycemic Fear Survey – II: a validated 33-item questionnaire (62) 

 
 
 
 
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3) INSPIRE questionnaire for adults: a validated 22-item questionnaire assessing the following 
for those on insulin pumps: INsulin delivery Systems, Perceptions, Ideas, Reflections and 
Expectations) (63) 
o Note because this one reflects automated insulin delivery, it will not be used at the 
admission visit  
4) The Diabetes Bowel Symptom Questionnaire: A validated questionnaire used to assess 
gastro-intestinal symptoms specifically in type 1 diabetes (64) 
5) Diabetes Treatment Satisfaction Questionnaire (DTSQs): An 8-item validated questionnaire 
(65) 
 
Participants will fill out the questionnaires at the admission visit, and after each intervention. 
All questionnaires will be collected at the End-of-Study Visit.   
 

 
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7. Study procedures 
7.1 Visit schedule 
Table 5 
 
 
 
First Intervention 
 
 
Second Intervention 
 
 
Admission  
Visit a 
(Day 1) 
Training 
Visit b,c 
(Day1+) 
Drug  
insulin 
titration 
(Weeks 1-
11) 
AID 
training b 
(Visit 2) 
AID 
Run-in 
(Week 
12) 
AID  
(Weeks 
13 - 15)  
Visit 3 
(+ 3 days 
end of 
Week 15)a 
Washout 
(Weeks 
16 - 17) 
Drug and 
insulin titration 
(Weeks 18-28) 
AID 
Run-in 
(Week 
29) 
AID  
(Week 
30-32) 
Visit 4 
End of 
Study Visit 
(Week 32)b 
Consent & Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Full physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Anthropometrics (BP, HR, 
Weight, Height, BMI, WC)  
ECG testing 
X 
 
 
 
 
 
X 
 
 
 
 
 
Xa 
(3 days end 
of Week 32 
Basic Laboratory Investigations b 
Blood: HbA1c, liver profile, lipid 
profile, creatinine, blood glucose, 
C-peptide, NT-pro-BNP, CRP, 
ferritin, lipase+ 
Urine: uACR, pregnancy screenc 
X 
 
 
 
 
 
X 
 
 
 
 
 
Xa 
(3 days end 
of Week 32 
Extensive investigations (serum) 
TXNP, IL-6 
Mixed meal tolerance test (for 
the first consenting 7 females 
and males) 
 
 
 
 
 
 
X 
 
 
 
 
 
Xa 
(3 days end 
of Week 32 
Remote monitoring (contact by 
email, text, or telephone) 
 
 
Days: 7, 21, 
32, 56, 63, 
77 (± 2 
days) 
1 of last 3 
days of 
Week 11 
Days: 4, 
7 (±2 
days) 
Days: 14 
± 2  
 
Day 7 
±4 
Days: 7, 21, 32, 
56, 63, 77 (± 2 
days) 
Days: 
4, 7 (±2 
days) 
Days: 
14 ± 2 
 
 
 
 
a Must be done in person 
b Choice of in-person or remotely by teleconference (for AID training, only offered to those who are familiar with prior AID studies) 
c May be done at same time as Admission Visit  
d Blood glucose and C-peptide should be done non- fasting.  If the participant is hypoglycemic at time of laboratory investigations, the investigations will be done after correction.  This 
should be done prior to study drug administration.  
e If participant of childbearing potential 
BMI = body mass index, BP = blood pressure, HR = heart rate, LFTs = liver profile, WC = waist circumference  

 
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7.2 Admission 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. 
 
Table 6 
General procedures 
- 
Explanation of the study and answering of questions 
- 
Assessment of inclusion and exclusion criteria (if the participant fails 
this section, they can be re-assessed after 3 months) 
- 
Signing of consent form  
Medical history 
- 
Complete past medical history, both of their T1D and other medical 
conditions 
- 
Current diabetes care (frequency of glucose checks, recent difficulties 
in glycemic control, history of DKA, etc.) 
- 
Current diabetes regimen, doses and average carbohydrate count, 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 and heart rate 
- 
Height and weight 
- 
Waist and hip circumferences 
- 
Routine cardiovascular, respiratory, and abdominal examination 
- 
Foot and peripheral vascular exam  
- 
Signs of lipo-hypertrophy in areas of insulin catheter sites 
- 
An electrocardiogram (ECG) to assess heart rate and PR interval  
Blood and urine 
laboratory 
investigations  
5 mL of serum via intravenous catheter will be taken to measure the 
investigations.  A urine sample will also be required.  See Table 5 for 
details of investigations taken. 
Questionnaires 
 Participants will be given time to fill out quality of life questionnaires 
(except INSPIRE, which will only be done after each intervention) 
Randomization 
Randomization and allocation will be assigned.   
Emergency kit 
An emergency kit (see Section Error! Reference source not found.) 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 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 
 

 
 
 
 
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7.3 Training visit  
The training visit may be done the same day as the admission visit or on a different day given 
travel and time constraints. 
 
The participant will receive the following training.  AID training and training on its components 
(Dexcom CGM, insulin pump) will be done at a later date. 
 
Table 7 
Routine diabetes care 
Revision of hypo- and hyper-glycemic management, driving safely with 
diabetes, safe injection practices, sick day management, and ketone 
management.  A ketone management algorithm will be given.   
Participants will be expected to download their pump using their 
respective uploading software. 
Semaglutide SC weekly 
training 
The participant will be taught the titration schedule, how to administer the 
study drug, how to store, and how to record doses.  A drug log and 
symptom log will be given for them to fill each time the drug is used. 
Proper insulin titration on their own insulin pump while on the study drug 
(and the schedule of follow ups) will also be discussed. 
Along with the discussion of risks and benefits of semaglutide in the 
consent form, participants will be taught to identify the symptoms of 
nausea and vomiting, acute gallstone disease, and acute pancreatitis.    
The study drug will be given for Intervention 1 will be given once training 
is successfully completed. 
Dexcom G6 (if required)  If the participant does not use CGM in their usual diabetes care, Dexcom 
will be given.  Training will be given at the session concerning how to 
insert, use, and upload to the appropriate software. 
 
7.4 Semaglutide/ placebo titration period (Weeks 1 - 12) 
Titration of the study drug will be over a span of 12 weeks (i.e. the 1-week AID run-in is the 12th 
week), with each dose/volume increment every 4 weeks.  If there are intolerable symptoms, 
the participant will be asked to resume the last tolerated dose.  Follow-ups by remote 
monitoring will occur on the following days: Day 7, 21, 32, 56, 63, 77 (± 2 days of each for 
flexibility).  Given the long half-life of the drug and long time for steady state, there will be no 
prophylactic setting reductions unless preferred by the investigator to prevent hypoglycemia 
(for example, if the participant already has hypoglycemic events).  If the participant requires 
impromptu assistance or if increased surveillance is recommended at the discretion of the 
investigators, the research personnel responsible for medical care (i.e. insulin titration, side 
effects) will be available 24/7. 
 

 
 
 
 
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7.5 AID training (Visit 2) 
Within 3 days of the end of Week 11, training will be done on the AID system and its 
constituents.  Supplies and tools will be given during training. 
 
Table 8 
Dexcom G6 CGM  
Training on the Dexcom G6 sensors, transmitter, and reader will be 
performed. 
Insulin pump (Tandem 
Diabetes Care or 
YpsoMed Diabetes 
Care)  
Training on the insulin pump, including reservoir and catheter site 
insertion, will be done.  The participant's latest parameters will be 
programmed.  The participant's study pump and supplies will 
either be from Tandem Diabetes Care or YpsoMed Diabetes Care; 
the participant will continue on the same brand of pump and 
appropriate corresponding AID system for the duration of the 
study. 
Artificial Insulin 
Delivery application 
Training on the smartphone platform will be provided.  The User 
Guide will also be given to the participant. 
 
7.6 Closed-loop therapy (Run-In) 
The first week on the AID will occur during the 12th week of the titration.  Remote follow-up 
will occur on Day 4 and Day 7 (± 2 days) during Week 12, and as needed at the discretion of the 
participant and investigators.  CGM and pump data will be automatically uploaded via wireless 
connection to our database for analysis.  A separate researcher will create the graphs. 
 
7.7 Closed-loop therapy (3 weeks)  
The participant will continue their maximum tolerated dose of study drug and the AID for 3 
weeks.  Remote follow-up to review glucose data will be performed on Day 14 ± 2 and as 
needed.  The CGM data used for primary and secondary endpoints will be based on these 3 
weeks and the AID training week (a total of 4 weeks). 
 
7.8 Laboratory and anthropometric measurements (Visit 3) 
Participants will be required to perform laboratory investigations and anthropometric 
measurements (done by the research team) within 3 days of the end of the 4 weeks on closed-
loop therapy.  This can be done during the period of closed-loop therapy or during the washout 
period.   
 
7.8.1 Mixed meal tolerance test (MMTT) 
A MMTT will be in the first consenting 7 female and 7 male participants (for a total of 14 
participants).  It will be performed immediately after each intervention, preferably the same 
day as the post-intervention laboratory and anthropometric measurements (within 3 days of 
intervention end).  See Section 6.5 for more details of measurement. 
 

 
 
 
 
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Before the test:  
• Participants will be asked to continue using the McGill Artificial Pancreas, to be started 
minimum the evening before the MMTT, with a target glucose at 7 mmol/L.  
• Participants will need to fast overnight. 
• Upon arrival, the participant is to be weighed; if other anthropometrics are to be done, they 
can be done at this time as well. 
 
During the test (a total of 4 hours): 
• The glucose level should be between 3.9 and 11.5 mmol/L per CGM data prior to start of 
the study (if hypoglycemia, the participant can correct and wait 4 hours, or if hyperglycemic, 
can wait for the AID to reduce glucose levels)  
• An intravenous catheter is to be inserted and remain there throughout the examination. 
• The first blood draw will be at time 0 (upon catheter insertion), where glucagon, C-peptide, 
paracetamol and glucose will be drawn; other laboratory investigations (see Table 5) can be 
done at this time. 
• The mixed meal, i.e. Boost® (Complete Nutritional Drink High Protein, Nestlé Health 
Science) will be consumed at 6 mL/kg within 5 minutes.  1500 mg of paracetamol will be 
added to the drink as well. 
• For time 0 - 120 minutes:  
o Blood draws will be done at 30, 60, 90, and 120 minutes for glucose, C-peptide, 
paracetamol, and glucagon.   
o No pre-meal insulin bolus is to be administered; however, basal insulin via the McGill 
Artificial Pancreas will be continued. 
o No pre-meal insulin bolus is to be administered; however, basal insulin via the McGill 
Artificial Pancreas will be continued. 
• For time 120 - 240 minutes:  
o Paracetamol will be drawn at 180 and 240 minutes. 
o The participant can correct their glucose as per usual care, and carry on with usual 
diabetes care. 
o No restrictions on physical activity. 
• Reasons for premature cessation of test: 
o Concern for diabetic ketoacidosis (nausea, vomiting, abdominal pain with ketone 
level ≥ 0.6 mmol/L per point of care testing) 
o Hypoglycemia with glucose < 3.8 mmol/L 
o Withdrawal of consent from participant 
o Acute illness or increased risk as perceived by investigator 
 
After the test 
• Venous cannulation is removed.   
 

 
 
 
 
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If the MMTT is done during the intervention, then that day's CGM data will be removed from 
data used to calculate primary and secondary endpoints.   
 
Glucagon measurements will be processed and stored for measurement at a later date; these 
are to be processed, frozen and stored in a similar fashion to other laboratory tests (see Section 
6.5.1). 
 
7.9 Washout (2 weeks) 
The participant will be asked to stop the research medication for 2 weeks.  Prior to the washout 
period, the research personnel will give instructions (as per their clinical judgement) on how to 
safely go back to the participant's usual diabetes care.  Due to the long half-life of semaglutide, 
there will be no automatic prophylactic changes in pump settings.  However, if the participant 
had significant changes in pump settings during the last 4 weeks that may result in 
hypoglycemia, the research personnel will err on the side of caution and hypoglycemia 
reduction.  The participant will be given the second drug at this visit. 
 
If the participant does not use CGM in their usual diabetes care, Dexcom use will be 
recommended to aid with hypoglycemia reduction.   
 
On Day 7 (± 4 days), the research personnel will contact the participant to assess for any side 
effects off the study drug and any change in glycemia.  A quick and informal review of CGM 
data will be assessed to reduce the risk of hyperglycemia (> 13.9 mmol/L) and hypoglycemia (< 
3.9 mmol/L).    
 
7.9 Second intervention   
Drug titration over 12 weeks, AID run-in over 1 week, and the 3 weeks of AID use will be 
repeated with the following study drug as described previously.  
 
7.10 End of Study Visit (Visit 4) 
The last visit will take place within 3 days of the end of 4 weeks of using the AID and study drug.  
Final laboratory investigations and anthropometric measurements will be taken.  All study 
materials (questionnaires, logs, study drug bottles, diabetes care) will be returned.  A semi-
structured interview will be performed to assess items that may not be captured through 
questionnaires.  This will include the participant's overall experience the study, use of the 
closed-loop therapy, the study drug, and elements of T1D care that they are important to them.  
The interview will be audio-recorded with permission of the participant, and transcribed at a 
later date.  Ongoing consent during the recording process will be obtained.   
 

 
 
 
 
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7.11 Post-study follow-up 
Participants will ask to continue their usual follow-up with their own diabetes care team.  
However, a remote follow-up 1 week (± 3 days) will be done to informally ensure there are no 
adverse effects from the study. 
8. Risk and Risk Mitigation 
8.1 Semaglutide dose rationale 
The doses of semaglutide SC weekly used (0.25 mg, 0.5, 1 mg) in the the study are the same as 
those that are commercially available and have been used in the SUSTAIN trials (21,66–69).  The 
approach of using maximum tolerated dose is also used previously (23).  Though there is a long 
half-life to the drug, prior cross-over designs have successfully been used at 3 - 7 weeks of 
washout (70,71).  The dose titration is as reflected in the product monograph (44). 
 
8.2 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.   
 
8.2.1 Concomitant and prohibited medications 
• Concomitant medications that require observation (72) 
o Drugs that may enhance hypoglycemic effects: alpha-lipoic acid, androgens, 
directing acting antiviral agents (specifically for treatment of Hepatitis C), 
guanethidine, maitake, monoamine oxidase inhibitors, pegvisomant, prothionamide, 
quinolones, salicylates, selective serotonin reuptake inhibitors, other anti-
hyperglycemic agents (metformin, DPP4 inhibitors, sulfonylureas, SGLT2 inhibitors, 
acarbose) 
o Glucocorticoids: Potential for significant hyperglycemia 
o Drugs that may diminish hypoglycemic effects: ritodrine, thiazides 
o Other agents to be aware of: 
§ Levothyroxine: serum concentration of supplemental thyroid hormone levels 
may be modified in conjunction with semaglutide 
§ Sincalide: effect may be diminished due to impact of gallbladder motility 
 
8.3 Risks associated with the study 
8.3.1 Semaglutide 
The following side effects are reported in those who have used the drug primarily for T2D, as 
well as off-label use (72).  Similar effects are assumed to be seen in T1D.  The risks are divided 
by frequency as a percentage. 
 
 

 
 
 
 
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Table 9 
> 10%  
1 - 10% 
< 1% 
Not defined 
Abdominal pain 
Abdominal distension Acute pancreatitis 
Anaphylaxis, 
angioedema 
Nausea 
Cholelithiasis 
Discomfort at 
injection site 
Increased heart rate 
 
Constipation 
Dizziness 
Increased serum 
lipase and amylase 
 
Decreased appetite 
Fatigue 
Increase in PR 
interval on ECG  
 
Diabetic 
retinopathy* 
 
 
 
Emesis 
 
 
 
Eructation (i.e. 
belching) 
 
 
 
Flatulence 
 
 
 
Gastritis 
 
 
 
Gastroesophageal 
reflux 
 
 
 
Hypoglycemia 
 
 
* Increase in diabetic retinopathy, particularly in proliferative diabetic retinopathy, was seen in 
SUSTAIN6 (21).  Subsequent analysis revealed there is increased risk with existing diabetic 
retinopathy, and rapid decrease of hyperglycemia (73).  
 
Semaglutide was found in rodent studies to increase thyroid C cell hyperplasia and C cell 
tumours (72).  Because of this, semaglutide is contraindicated in patients with personal or 
family history of medullary thyroid cancer and Multiple Endocrine Neoplasia 2 (high risk for 
medullary thyroid cancer development). 
 
8.3.2 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.   
 

 
 
 
 
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8.3.3 Glucose sensors and insulin infusion sets 
Glucose sensors and infusion sets are both inserted subcutaneously. It is recommended to 
change insertion site every 2 - 3 days for an infusion set, and every 10 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. 
 
8.3.4 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.   
 
8.3.5 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.   
 
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 

 
 
 
 
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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 10.  Diagnostic criteria for DKA vs HHS as per the American Diabetes Association 
(2009).(74)  
 
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. 
 
8.3.6 Risks related to the AID system 
8.3.6.1 Disruption in communication between the insulin pump device and AID: 
- 
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.   
 
8.3.6.2 Error in glucose sensor accuracy: 
- 
The AID uses Dexcom G6 for continuous glucose monitoring, that requires twice per day 
minimum calibration for accurate measurement.  If the interstitial glucose measurement 
performed by the CGM is inaccurate, insulin recommendations by AID 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 doses of acetaminophen/paracetamol 
larger than 1 gram every 6 hours, which is more higher than maximum dose recommended 
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may falsely raise the sensor readings, causing the AID system to deliver more insulin than 
required.   
- 
Hydroxyurea is a known interfering substance that may cause falsely elevated glucose 
values; Dexcom G6 use is not advised with concomitant use of this drug as per the 
manufacturer.  This is encompassed in exclusion criteria, and participants will be asked to 
update research personnel on change in medications throughout the study. 
 
8.3.6.3 Disruption in communication with the glucose sensor  
- 
If Bluetooth communication of the CGM to the rest of the AID 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. 
 
8.3.6.4 Smartphone malfunction or shut-down  
- 
If there is any malfunction with the study phone preventing access to theh AID (e.g. 
insufficient battery), open-loop mode will commence within 20 minutes.   
 
8.3.6.5 Software error  
- 
Any termination of theAID software for any reason will result in reversion to an open-loop 
mode of insulin delivery. 
 
8.4 Pregnancy 
Semaglutide has not been previously tested in pregnancy, though studies in animals showed 
some potential toxicities (44).  The Food and Drug Administration had not released a specific 
category class for this drug, but it is recommended to not use during 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 participant who is at 
risk of pregnancy (see prior definitions) must actively avoid pregnancy throughout the study 
and will be counselled on the risks of pregnancy in the study.  If a participant feels they may be 
pregnant, they must 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 3 times throughout the study in those at risk to 
biochemically rule out pregnancy.  Those who are post-menopausal or who have undergone 
removal of the uterus and/or ovaries will be exempt from taking a pregnancy test. 
9. Data Safety Monitoring Board (DSMB) 
9.1 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.  

 
 
 
 
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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.  
 
9.2 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.  
 
9.3 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 SEMA-AP trial, protocol number [Research Ethics Board number here] 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."  
 
9.4 Meetings 
The DSMB will meet: 
(1) After P01-P06 (i.e. participants # 1 through 6) are finished their interventions.  
(2) After P07 to P014 have finished their interventions. 
(3) After any serious adverse event that is deemed potentially related to the intervention. 
 
Items reviewed by the DSMB include: 
• 
Individual and cumulative data for evidence of study-related adverse events; 
• 
Individual and cumulative data of glucose outcomes data; 
• 
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. 

 
 
 
 
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9.4.1 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. 
 
9.4.2 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 Research Ethics Board will be 
notified.  
 
9.4.3 Study reports 
It is the responsibility of the Primary Investigator 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. 
 
9.5 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., Research Ethics Board) 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 
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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.  
10. Statistical analysis 
• All glycemic outcomes based on CGM data will be compared between the 4 weeks on the 
AID using placebo vs. semaglutide (at maximum tolerated dose).  Wherever applicable, 
outcomes will be calculated for 24 hours, daytime (6h00 – 24h00), and nighttime (24h00 – 
6h00) 
• Mean values of TXNIP and IL-6 will be compared between each intervention 
• For any analyses done for the MMTT, area-under-curve will be compared between each 
intervention 
• All other measurements performed after each intervention will be compared to the 
baseline performed at the initial study visit 
 
10.1 Study endpoints 
10.1.1 Primary endpoints 
• Time in target range (3.9 to 10 mmol/L)  
 
10.1.2 Secondary endpoints 
10.1.2.1 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, 3.0 mmol/L  
c. Above 7.8, 10, and 13.9  
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% 
6) HbA1c 
 
10.1.2.2 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 
d) Diabetes Bowel Syndrome Questionnaire 
e) Diabetes Treatment Satisfaction Questionnaire 
 
10.1.2.3 Anthropometric measures 
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2) Heart rate 
3) Weight 
4) Body mass index 
5) Waist circumference 
6) Waist-to-hip circumference 
 
10.1.2.4 Laboratory measures 
1) Lipid profile, specifically: LDL-cholesterol, HDL-cholesterol, triglycerides 
2) NT-pro-BNP 
3) Inflammatory investigations: CRP, ferritin, IL-6 
4) uACR 
5) TXNIP 
6) Mixed-meal tolerance test 
a. Glucagon (area-under-curve) 
b. C-peptide (area-under-curve) 
c. Paracetamol (area-under-curve) 
 
10.1.2.5 Other endpoints 
1) Total daily insulin dose  
2) Units per kilogram 
3) Average daily carbohydrate count (as recorded from bolus calculator through pump) 
 
The semi-structured interview's analysis will be based predominantly on qualitative rather than 
quantitative data assessment, though some statistical analysis may be performed on 
prevalence of themes that arise during the coding of transcripts. 
 
10.1.3 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) Gastro-intestinal side effects 
a. Nausea 
b. Emesis 
c. Abdominal pain 
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e. Gallbladder disease 
f. Acute pancreatitis 
 
10.2 Sample size and power calculations 
The power calculations aim to compare the effects of placebo vs. semaglutide (at maximum 
tolerated dose) on closed-loop therapy on the primary endpoint (time in target range), made at 
the α= 0.05 significance level. 
 
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 (36,37,41).  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 for 20% drop-out, 28 participants will be recruited.   
 
10.2.1 Level of significance 
5% significance threshold will be used to assess statistical significance. No formal correction will 
be applied for the secondary comparisons. 
 
10.2.2 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).  A 
separate analysis will be used to assess if glycemic changes are linked with C-peptide levels 
(taken at admission visit) or weight reduction by end of intervention. 
 
The semi-structured interviews taken at the end of the study, after recording, will be 
transcribed and then coded by research personnel for themes using an inductive-deductive 
approach via encoding software (MAXQDA, version 22.1.1 for Macbook, or latest version at 
time of analysis).  There may be statistical analysis performed for prevalence of themes, but the 
assessment is ultimately qualitative in nature.     

 
 
 
 
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11. Ethical and legal considerations 
11.1 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 Research Ethics 
Board of the McGill University Health Centre. 
 
11.2 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 
 
11.3 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.  Consent can be withdrawn at any time by the participant. 
 
11.4 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 securely in paper 
format as per regulations of the Research Ethics Board of the McGill University Health Centre. 
 
11.5 Participant compensation 
All study materials (both non-perishable and perishable) will be provided to participants.  Given 
their time dedication, participants will be given $975: $25 for each in-person visit (initial study 
visit, examination after Intervention 1, and end of study visit), and $450 for each intervention 
completed.  This amount was decided based on prior studies and was felt reasonable from 
other participants. 
 
11.6 Approval of the clinical study protocol and amendments 
An application will be sent to the Research Ethics Board of the McGill University Health Centre 
for assessment and approval prior to start of the study.  If any changes are made to the study 

 
 
 
 
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protocol, the amended protocol will be submitted to Health Canada and the IRB will be 
informe.  The study will continue once the amendment has been approved.  The primary 
investigator will keep track of all communication with the Research Ethics Board. 
 
11.7 Record retention 
The study will follow guidelines as per ICH where all information will be collected and kept 
securely for 25 years. 
12. Adverse events 
12.1 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 participant. 
 
During the study, adverse events will be recorded in the following manner: 
- 
Active surveillance through the DSMB  
- 
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) 
 
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.   
 
12.2 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. 

 
 
 
 
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12.2.1 Hypoglycemia  
Given the intensity and complexity of treatment of insulin therapy in type 1 diabetes, 
hypoglycemia is common.  Different therapies may influence the frequency and severity of 
these events for each participant.   
 
The AID 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).   
 
Semaglutide 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 hypoglycemia will be reviewed at the training visit.  Real-time 
continuous glucose monitoring allows for alarms (as per participant preference) so participants 
are notified if hypoglycemia is occurring.  Remote visits during the beginning of each 
intervention will ensure to discuss any excess hypoglycemia.  Significant events of hypoglycemia 
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 (i.e. 
hypoglycemia requiring intervention by a third party due to altered mental status), immediate 
attention by medical personnel of the research group will be taken.  CGM data, pump settings, 
and the cause will be reviewed.  Revision by the primary investigator will confirm if the 
participant should be withdrawn from the city (as per their clinical judgment.  
 
Any significant episodes or recurring episodes causing impairment to the participant will be 
reported to the Research Ethics Board and regulatory authorities.  Note that non-severe 
hypoglycemia will not be reported as adverse events. 
 
12.2.2 Hyperglycemia and affiliated conditions  
Hyperglycemia is also a common feature of diabetes.  Different therapies may influence the 
frequency and severity of these events for each participant.   
 
A review of proper diabetes care (e.g. not overtreating hypoglycemia, meal bolus with 
carbohydrate counting) will be reviewed at the initial training visit, and brought up if need be 
throughout the study. 
 
The most concerning consequences of hyperglycemia (which is a lack of balance between 
glucose and insulin) is diabetic ketoacidosis (DKA).  Any malfunction causing lack of insulin 
delivery can increase the risk of DKA in a patient with T1D.  Hyperosmolar hyperglycemic state 
(HHS) is rare but still possible in T1D.   

 
 
 
 
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To ensure safety during the trial from severe hyperglycemia, DKA, and HHS, the following will 
be performed:  
- 
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. 
- 
Participants will be instructed to measure ketones if CGM measures above 16 mmol/L for 
more than 2 hours and no descent, in any acute illness, or symptoms of ketoacidosis 
(nausea, vomiting, abdominal pain). 
 
The following will be specific adverse events of interest during the study: 
- 
Point of care ketone levels above 1.5 mmol/L 
- 
Ketone-related events requiring presentation to medical attention 
- 
Diabetic ketoacidosis as previously defined. 
 
12.2.3 Local skins 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.  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.(76)  This would only occur in the case of improper hygiene and a 
severe lack of recommended site change (recommended to be every 3 days).  Local skin 
reactions to the injection of semaglutide or placebo may also occur. 
 
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. 
 
12.2.4 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 

 
 
 
 
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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. 
 
12.2.5 Gastrointestinal symptoms, gallbladder disease and pancreatitis  
Mild gastrointestinal symptoms such as abdominal discomfort, nausea, and vomiting have been 
previously reported.  Of the more severe gastro-intestinal adverse events are gallbladder 
disease (ranging from biliary colic to cholangitis, a life-threatening sepsis of an impacted 
gallstone) and acute pancreatitis. 
 
The following will be considered adverse events of specific interest: 
- 
Abdominal discomfort 
- 
Nausea 
- 
Vomiting 
- 
Diabetic retinopathy (de novo or progression) 
- 
De novo gallbladder disease of any kind (revision of the principal investigator will be 
required if withdrawal from the study is required) 
- 
Acute pancreatitis: if this occurs, withdrawal from the study will occur 
 
12.3 Technical adverse events 
Possible malfunctions are previously described.  Included in these adverse events is the need 
for any study personnel to override the AID system due to any troubleshooting to avoid other 
adverse events.  Any AID 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.   
 
12.4 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. 
 
12.5 Reporting serious adverse events 
12.5.1 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 
(though this may be delegated to MD co-investigator) 
- 
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 
 
12.5.2 Definition of a serious adverse event (SAE) 
A serious adverse event (SAE) is any adverse event that is labelled as severe, 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. semaglutide) or a device (e.g. any AID 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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Appendix A: Ketone Management 
 
Please be aware of the risks of diabetic ketoacidosis and the need to assess for this in the event 
of any of the following: 
- 
Glucose level above 16 mmol/L for more than 1 hour  
- 
Symptoms of hyperglycemia (increased urination, extreme thirst, fatigue, blurry vision) 
- 
Symptoms of ketones (nausea, vomiting, abdominal pain) 
- 
Sudden illness (such as infection) 
 
If any of the above occur, you must do the following: 
1) Measure blood sugar by finger-prick to confirm CGM reading  
2) Measure blood ketone levels immediately (and follow the table below) 
3) Confirm there is no damage or malfunction to the cartridge, catheter, or insertion site 
4) Drink at least 250 mL (or 1 cup) of water every 30 minutes.  Avoid drinks with sugar or 
caffeine. 
5) Follow the below recommendations, depending on the ketone level obtained 
 
If glucose is above 16 mmol/L, do the following depending on the described ketone level: 
Less than 0.6 mmol/L 
1. Calculate bolus estimated by the smartphone AID application and 
administer via the insulin pump 
2. Do not skip meals.  Try to have at least 30 g of carbohydrates at 
next meal   
3. Repeat blood glucose and ketone levels in 2 hours after bolus 
administration 
4. If glucose remains elevated and/or ketone levels rise (but are less 
than 0.6 mmol/L), change infusion site and continue to monitor 
5. If ketones rise above 0.6 mmol/L, follow instructions below 
0.6 to 1.5 mmol/L 
1. Contact your study lead as soon as possible. 
2. Calculate bolus estimated by the smartphone AID application and 
administer rapid acting insulin via insulin pen or syringe.  During 
closed loop setting, disconnect from pump and bolus the same 
amount so that pump is aware of insulin-on-board. 
3. Check that insulin in use from original was stored appropriately 
and not expired. 
4. Insert a new infusion catheter, with new insulin cartridge and 
tubing.  Fill with a new vial of insulin if there are any concerns 
from the prior vial. 
5. Examine the original pump catheter, tubing, and cartridge for any 
kinks or blockages.  If any identified, notify your study lead. 
6. Recheck blood glucose by finger-prick and ketones 2 hours after 
the injection 

 
 
 
 
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7. If glucose remains high and ketones remain above 0.6 mmol/L, 
further treatment will be discussed with your study lead.  You 
may need to go to the hospital. 
Above 1.5 mmol/L 
1. Contact your study lead.   
2. Calculate bolus estimated by the AID application and administer 
1.5x the calculated dose with rapid acting insulin via insulin pen 
or syringe (e.g. if 2 Units is suggested, give 3 Units instead).  
During closed loop setting, disconnect from pump and bolus the 
same amount so that pump is aware of insulin-on-board. 
3. Check that insulin in use from original was stored appropriately 
and not expired. 
4. Insert a new infusion catheter, with new insulin cartridge and 
tubing.  Fill with a new vial of insulin if there are any concerns 
from the prior vial. 
5. Examine the original pump catheter, tubing, and cartridge for any 
kinks or blockages.  If any identified, notify your study lead. 
6. It is possible if this persists, you may need to go to emergency 
department. 
 
If glucose is below 16 mmol/L but symptoms of ketoacidosis are present  
(e.g. nausea/vomiting/abdominal pain), this may be euglycemic ketoacidosis (high ketone 
levels with a normal blood sugar).  Do the following depending on the described ketone 
level: 
Less than 0.6 mmol/L 
1. If food can be kept down without vomiting: Eat 30 g of 
carbohydrates and bolus for this and any correction via the pump 
2. Repeat blood glucose and ketone levels in 2 hours after bolus 
administration 
3. If glucose and/or ketone levels rise (but are less than 0.6 
mmol/L), change infusion site and continue to monitor 
4. If ketones rise above 0.6 mmol/L, follow instructions below 
0.6 to 1.5 mmol/L 
1. Contact your study lead as soon as possible. 
2. If food can be kept down without vomiting: Calculate correction 
bolus and meal bolus for minimum 30 g of carbohydrates 
estimated by the AID smartphone app and administer rapid acting 
insulin via insulin pen or syringe.  During closed loop setting, 
disconnect from pump and bolus the same amount so that pump 
is aware of insulin-on-board.  Eat the carbohydrates after 
administering. 
3. If food cannot be kept down: administer any possible correction 
bolus applicable as estimated by the AID as #2 without 
carbohydrate bolus. 

 
 
 
 
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Protocol #: 2022-8097 
Version Date: 06 DEC 2022 
 
4. Check that insulin in use from original was stored appropriately 
and not expired. 
5. Insert a new infusion catheter, with new insulin cartridge and 
tubing.  Fill with a new vial of insulin if there are any concerns 
from the prior vial. 
6. Examine the original pump catheter, tubing, and cartridge for any 
kinks or blockages.  If any identified, notify your study lead. 
7. Recheck capillary blood glucose and ketones 2 hours after the 
subcutaneous injection 
8. If glucose remains high and ketones remain above 0.6 mmol/L, 
notify study physician  
Above 1.5 mmol/L 
1. Contact your study lead immediately.   
2. If food can be kept down without vomiting: Calculate 
carbohydrate bolus for minimum 30 g estimated from the AID, 
and 1.5 times any correction bolus (e.g. if 2 Units for 
carbohydrates, and 2 Units for correction, administer [2 + 2x1.5] = 
5 Units.  Administer rapid acting insulin via insulin pen or syringe.  
During closed loop setting, disconnect from pump and bolus the 
same amount so that pump is aware of insulin-on-board.  Eat 
carbohydrates after administering. 
3. If food cannot be kept down: administer any possible correction 
bolus applicable as estimated by the AID as #2 without 
carbohydrate bolus.   
4. Check that insulin in use from original was stored appropriately 
and not expired. 
5. Insert a new infusion catheter, with new insulin cartridge and 
tubing.  Fill with a new vial of insulin if there are any concerns 
from the prior vial. 
6. Examine the original pump catheter, tubing, and cartridge for any 
kinks or blockages.  If any identified, notify your study lead. 
 
If an event where this protocol is required, all actions, symptoms, and measurements of ketone 
and glucose levels should be recorded.   
 
Please note: This algorithm is based on protocols (the STICH and STOP-DKA protocols) created 
by experts to help patients to treat ketones while using SGLT2 inhibitors (67,77), and is also 
based on routine pump care for type 1 diabetes.  This algorithm has also been used in many of 
our previous studies, and was reviewed by a doctor (Dr Pasqua).  However, it is not in itself a 
validated algorithm and does not replace the need to contact qualified research personnel in 
the event of an emergency.