Clinical trial NCT05537233
Conditions: Type 1 Diabetes Obesity
Keywords: Type 1 diabetes Obesity HbA1c Time-in-range Weight loss Cardiovascular risk
Sponsor: Viral N. Shah
Start date: 2023-04-11; Completion date: 2024-08-06
Enrollment: 115 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the use of once weekly semaglutide injection in inadequately controlled obese adults with type 1 diabetes (T1D) using FDA-approved hybrid closed-loop therapies.

Detailed description:
After being informed about the study and potential risks, all patients given written informed consent will undergo a 2-week screening period to determine eligibility for study entry. At week 0, patients who meet the eligibility requirements will be randomized in a double-blind manner using computer generated randomization scheme to receive either semaglutide or placebo (1:1 ratio) for 26 weeks.

Arms: arm 1: Participants in this group will receive semaglutide once weekly injection in addition to their standard closed-loop therapy arm 2: Participants in this group will receive placebo once weekly injection in addition to their standard closed-loop therapy
Interventions: intervention 1: Semaglutide intervention 2: Placebo
Intervention descriptions: intervention 1: Semaglutide up to 1 mg per week in addition to standard closed-loop therapy intervention 2: Injection placebo up to 1 mg per week in addition to standard closed-loop therapy

Protocol documents:
Prot_SAP_001.pdf: 
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EFFICACY AND SAFETY OF ONCE WEEKLY SEMAGLUTIDE IN ADULTS WITH 
OBESITY AND INADEQUATELY CONTROLLED TYPE 1 DIABETES USING 
HYBRID CLOSED-LOOP SYSTEM 
Short title: ADJUnct Semaglutide Treatment in Type 1 Diabetes (ADJUST-T1D) 
INVESTIGATOR-INITIATED STUDY 
(Universal Trial Number- U1111-1269-8469) 
(Clinical Trial Number: NCT05537233) 


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Coordinating Center and PI 
Viral N. Shah MD 
Professor of Medicine, Division of Endocrinology and Metabolism 
Director of Diabetes Clinical Research, IU Center for Diabetes and Metabolic Diseases 
1120 W. Michigan Street CL380, Room 380F, Indianapolis, IN 46202-5209 
Phone (O)- 317-278-6017 
Email: shahvi@iu.edu 
Statistical Team:  
Giorgos Bakoyannis, Ph.D.  
Statistician, Department of Biostatistics and Health Data Science 
Indiana University Fairbanks School of Public Health and School of Medicine 
Laura Pyle, PhD  
Professor of biostatistics, department of pediatrics 
University of Colorado Anschutz Medical Campus  


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Clinical Sites and Site PI 
1) Barbara Davis Center for Diabetes
Halis K. Akturk, MD , Principal Investigator
Associate Professor,
Barbara Davis Center for Diabetes, University of Colorado
Janet K Snell-Bergeon, PhD  (T1D epidemiologist & Sub-investigator for exploratory
CV-renal outcomes) & Laura Pyle, PhD (Statistician)
Barbara Davis Center for Diabetes, University of Colorado
2) Henry Ford Hospital, Detroit, MI
Davida Kruger, NP and Arti Bhan, MD
Division of Endocrinology Diabetes and Metabolism,
Henry Ford Hospital, Detroit, MI
3) Iowa Diabetes Research Center
Anuj Bhargava, MD, Co-investigator and site PI
Founder and Director, Iowa diabetes reserch center
1031 Office Park Road, Suite 2,
West Des Moines, IA, 50265
4) OHSU Harold Schnitzer Diabetes Health Center
Andrew Ahmann, MD, Co-investigator and site PI
Professor of Medicine, Division of Endocrinology
Director,  Harold Schnitzer Diabetes Health Center
3181 SW Sam Jackson Park Rd,
Portland, OR 97239-3098


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Table of Contents 
1. Background and Significance  ..........................................................................................6 
2. Specific Objective  ..............................................................................................................8 
3. Research Design and Methods ..........................................................................................8 
3.1 Study Hypothesis ................................................................................................................ 8 
3.2 Endpoints ............................................................................................................................ 8 
3.3 Study Design  .................................................................................................................... 10 
3.4 Justification for Study Design  .......................................................................................... 11 
4. Clinical Research Sites  ...................................................................................................12 
5. Study Population  .............................................................................................................12 
5.1 Inclusion Criteria  ............................................................................................................. 12 
5.2 Exclusion Criteria  ............................................................................................................ 13 
5.3 Rationale for Inclusion/Exclusion Criteria  ...................................................................... 14 
5.4 Withdrawal Criteria .......................................................................................................... 14 
5.5 Subject Replacement  ........................................................................................................ 15 
5.6 Reminders ......................................................................................................................... 15 
6. Visit Procedures ...............................................................................................................15 
6.1 Screening  ......................................................................................................................... 18 
6.2 Randomization  ................................................................................................................. 18 
6.3 Semaglutide Dose, Titration, and Insulin Adjustment  ..................................................... 18 
6.4 Clinic and Phone Visits  .................................................................................................... 19 
6.5 Un-blinding  ...................................................................................................................... 19 
7. Statistical Plan  .................................................................................................................20 
7.1 Preliminary Data for Sample Size Calculation  ................................................................ 20 
7.2 Sample size calculation  .................................................................................................... 20 
7.3 Evaluability of subjects  .................................................................................................... 21 
7.4 Analysis Plan  ................................................................................................................... 22 
8. Data Handling and Record Keeping ..............................................................................22 
8.1 Data Management  ............................................................................................................ 22 
8.2 Source Data  ...................................................................................................................... 22 
9 Ethics  ................................................................................................................................22 
10 Study Drugs and Materials .............................................................................................23 
11 Concomitant Illness(es) and Medication (s)  .................................................................24 


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12 Adverse Events  ................................................................................................................24 
12.1 
 Definition  ........................................................................................................... 24 
12.2 
 Reportable Adverse Events ................................................................................. 25 
12.3 
 Non-reportable Adverse Events  ......................................................................... 26 
12.4 
 Reporting of Adverse Events  ............................................................................. 27 
13 Individual Subject Stopping Criteria  ............................................................................27 
14 Criteria for Suspending or Stopping ..............................................................................28 
15 Data Safety Monitoring Board (DSMB)  .......................................................................28 
16 Precautions/Over-dose .....................................................................................................29 
17 Risks and Discomforts .....................................................................................................29 
18 References .........................................................................................................................32 
Appendix 


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1. BACKGROUND AND SIGNIFICANCE:  
Due to complexity in managing type 1 diabetes (T1D) and hypoglycemia associated with 
intensive insulin therapy, only 30% of patients with T1D are able to achieve desirable glycemic 
goal; HbA1c <7% as recommended by the American Diabetes Association 1,2. Moreover, the 
prevalence of overweight and obesity is increasing among patients with T1D 3,4. Insulin 
resistance associated with obesity is also believed to be a contributing factor to inadequate 
glycemic control in T1D 5.  
Hybrid closed-loop systems (HCL), also known as artificial pancreas, where an insulin pump 
delivers insulin dose based on continuous glucose monitor (CGM) glucose values by means of 
controller (mathematical) algorithm 6. Studies with HCL have been shown to improve glycemic 
control and reduce hypoglycemia in children, adolescents, and adults with T1D 7,8,9,10. The HCL 
systems are the most advanced diabetes management tools in the armamentarium of diabetes 
management. The use of the HCL system is increasing among patients with T1D and it is 
becoming a standard of care in the management of T1D. With increasing use of diabetes 
technologies such as CGM and the HCL and limitation of HbA1c in managing of diabetes, 
diabetes care is now moving from HbA1c centric to CGM-based metrics such as time-in-range 
(TIR; sensor glucose between 70-180 mg/dL), time-below range (TBR; sensor glucose <70 
mg/dL) and time-above range (TAR; sensor glucose >180 mg/dL)11-13. Studies have also 
validated TIR as an outcome measure for diabetes clinical trials 14 and there is a strong inverse 
relationship between TIR and diabetes complications 15-21. International consensus recommends 
TIR>70% with TBR of <4% as optimal glycemic control for most adults with T1D and type 2 
diabetes 11.  
There are three HCL systems currently available in the US; Medtronic 670 G/ 770G, Tandem 
Control IQ and Omnipod 5 21-23.  On April 21, 2023, Medtronic 780 G was approved by the US 
FDA for management of T1D. Despite use of these most sophisticated diabetes technologies, not 
every HCL user with T1D is able achieve the recommended HbA1c or TIR goal 25-27. This is 
mainly due to inability of the currently available HCL systems to control post-prandial glucose 
excursions 28. Studies have shown improvement in glycemic control (HbA1c and time-in-range) 
due to mainly dramatic improvement in overnight glycemic control 8-10. The daytime control 


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between adults with T1D using HCL system and controls using insulin pump and CGM is only 
modestly different 8-10.  
Semaglutide is once a weekly glucagon-like peptide-1 receptor agonist (GLP-1RA). It has been 
approved for the management of type 2 diabetes and has been shown to improve glycemic 
control and is associated with significant weight loss without increasing hypoglycemia 29-31. 
GLP-1RA have potential to improve glycemic control in existing HCL uses with inadequately 
controlled T1D by improving daytime (mainly post-prandial) glycemic control and also may 
reduce insulin requirement due to weight loss. Small pilot studies have documented 
improvement in mean glucose and time-in-range with short-term use of liraglutide in patients 
with T1D using HCL 32,33. Moreover, liraglutide had no effect on plasma glucagon during mixed 
meal tolerance test 34 suggesting GLP-1RA may not blunt glucagon response during 
hypoglycemia. In addition, Semaglutide has been shown to improve cardiovascular and renal 
outcomes in patients with type 2 diabetes 35-38. Since cardiovascular disease is the leading cause 
of death in people with T1D 39-40, there is an interest in exploring effect of GLP-1RA in patients 
with T1D.  Further, as obesity is growing in prevalence among people with T1D, nonalcoholic 
fatty liver disease (NAFLD) is of concern in this population.  Semglutide may improve 
biomarkers of NAFLD, including hepatic steatosis index (HSI) and fibrosis score (FIB-4), based 
on easily obtained blood markers.  Further, assessment of NAFLD by magnetic resonance 
imaging corresponds well to livery biopsy data on steatosis and fibrosis.  Magnetic resonance 
elastrography (MRE) can be used to assess liver stiffness, a measure of fibrosis, and proton 
density fat fraction (PDFF), a measure of steatosis.  
Previous studies with the use of GLP-1RA in patients with T1D using HCL systems were limited 
by small sample size, and shorter duration (only for few days) 32,33, and therefore, unable to 
provide evidence for long-term efficacy and safety of GLP-1RA in patients with T1D using HCL 
systems. Semaglutide is a long-acting GLP-1RA with a once a weekly administration that makes 
it convenient for patients and shown to have high adherence rate in patients with type 2 diabetes 
41. Weight loss is more pronounced with semaglutide compared to liraglutide 42. Therefore, we 
plan to evaluate efficacy and safety of semaglutide as an add-on therapy in adults with T1D who 
are inadequately controlled despite the use of HCL therapy.  
 


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2. 
SPECIFIC OBJECTIVE  
Primary objective of the study is to evaluate improvement in a composite outcome (CGM-
measured TIR>70% with TBR of <4% and reduction in body weight by 5% at 26 weeks with the 
use of once weekly semaglutide in inadequately controlled obese adults with T1D using FDA-
approved HCL therapy.  
 
3. 
RESEARCH DESIGN AND METHODS 
3.1.Study Hypothesis 
We hypothesize that a significantly higher number of adults with T1D randomized to receive 
semaglutide (30-40%) will be able to achieve the primary composite outcome compared to adults 
with T1D randomized to the placebo group (≤5%).  
 
3.2 Endpoints 
3.2.1 Primary outcome  
Proportion of participants achieving composite outcome of time in range (TIR) 70-180 
mg/dl >70% and reduction in body weight by 5% with time below range (TBR) <70 
mg/dl of <4%. 
3.2.2 
Key secondary efficacy outcomes  
HbA1c  
TIR (70-180 mg/dL) 
Mean glucose  
TBR <70 mg/dL  
Time in tight target range (70-140 mg/dl)  
 
Change in Weight  
Change in BMI  
Time spent >180 mg/dL 
 
Time spent >250 mg/dL  
 
Standard deviation  
 
Coefficient of variation 
3.2.3 
Key Safety outcomes  
-SH events  


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-DKA events  
3.2.4 
Exploratory outcomes 
Proportion with hbA1c <7%  
Proportion with HbA1c <7.5% 
HbA1c improvement from baseline to 26 weeks  
HbA1c improvement of >0.4% from baseline  
Proportion of participants achieving TIR >70%  
Proportion of participants achieving TITR >50%  
Proportion of participants achieving TIR >80%  
Proportion of participants achieving TITR >60%  
Number of TBR<70 events (event is defined as <70 mg/dL lasting for at least 15 minutes)  
Number of TBR <54 events (event is defined as <54 mg/dL lasting for at least 15 minutes)  
Change in TDD (Units per day)  
Change in TDD (units/kg/day)  
Proportion achieving weight loss ≥5% 
Proportion achieving weight loss ≥10%  
Proportion of achieving BMI <30 kg/m2 
Proportion of achieving BMI <25  
Change in systolic blood pressure  
Change in diastolic blood pressure  
Change in pulse pressure  
Change in TG/HDL ratio  
Change in Brach D  
Change in cIMT  
Change in femoral to carotid pulse wave velocity (m/s)  
Change in ACR  
Quality of life (Diabetes Dependent QOL)  
CGM metrics (TIR, TITR, mean glucose, TBR, TAR >180, SD, CV) by daytime (6 AM to <11PM) 
and nighttime (11 PM to <6 AM)  
AID setting adjustment. Defined any adjustment in settings by provider or patient per person over 
the study period by two groups (number of adjustments (N) during trial) 
Change in basal insulin per day (Total basal insulin including autobasal delivery, units per day)   
Change in basal insulin per day (units/kg/day)  
Change in total boluses per day (frequency of boluses per day)  


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Achievement of primary outcome and key secondary outcomes by types of AID systems  
Change in Carbohydrate intake per day (grams/day) 
Change in total bolus insulin per day (units per day)  
Change in total bolus insulin (units/kg/day)  
Change in eGFR using CKD-EPI  
Change in Fib-4 score  
Change in HSI (hepatic steatosis index) 
Change in MRI measured pulse wave velocity and longitudinal strain  
Change in LDL-C  
Change in TC  
Change in TG  
Change in HDL-C  
Proportion with ACR <30 at 26 weeks  
Proportion with change in ACR from >30 to <30  
Achievement of primary outcomes by baseline BMI (BMI <35 vs >35)  
Achievement of primary outcomes by baseline A1c (A1c <7.5% vs >7.5%)  
3.3 Study design 
• 
This will be a multicenter (four centers), double blind, parallel-group, randomized, placebo 
controlled clinical trial in obese T1D adults with suboptimal glycemic control despite 3 
months use of FDA approved HCL technology.  Study design is summarized in the Figure 
below.   
 
Figure: An illustration of study design 


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• All participants will be randomized using computer generated block randomization 
and stratified by clinic research center. 
• There are up to 6 clinic visits and 3 phone call visits.  
• CVD assessments will take place at Randomization and at the week 26 visit. Brachial 
distensibility will be measured using the Dynapulse Pathway device at all centers, and 
pulse wave velocity (PWV), augmentation index by radial artery tonometry, cIMT 
and CMR assessments, along with ectopic fat measures of abdominal and pericardial 
fat, will take place at the BDC and OHSU sites. CVD assessments will be completed 
at an early discontinuation visit if a study participant drops out. 
• NAFLD assessments will be done in conjunction with CVD assessments, as part of 
the blood tests for all participants and as part of the MRI completed for participants at 
the BDC and OHSU. 
3.4 Justification for study design  
• HCL therapy is the standard of care managing T1D. Despite HCL use, not all patients 
with T1D are able to achieve recommended glycemic goals 25-27. Moreover, prevalence of 
obesity is increasing in this population 3-4, which is associated with insulin resistance and 
poor glycemic control 5. Therefore, adjunctive therapies such as GLP-1RA are needed in 
this population to improve glycemic control as well as improve weight management.  
• We propose a randomized, placebo controlled clinical trial, as a well-designed RCT, will 
provide a high level of evidence for efficacy and safety of semaglutide in obese adults 
with T1D.  
• We will have a 4 week titration period as recommended by the manufacturer. All subjects 
will be encouraged to titrate up to 1 mg a week. In case of intolerability, the dose will be 
titrated back to pre-tolerable dose and subjects will be encouraged to use max tolerable 
dose of at least 0.5 mg weekly.  
• This will be a first clinical trial to provide efficacy and safety of semaglutide in 
suboptimal glycemic control despite on optimal therapeutic regiment in adults with T1D.  
• 
We will try to screen subjects using different HCL systems (Medtronic 670/770 G/780G, 
Tandem control IQ and Omnipod 5).   


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• 
With increasing obesity and higher insulin resistance, cardiovascular risk is higher in 
people with T1D 43. Semaglutide has been shown to reduce Major Adverse 
Cardiovascular Events (MACE) in patients with type 2 diabetes with high cardiovascular 
risk 35,44. Therefore, it would be of interest to explore change in cardio-renal and NAFLD 
parameters over 26 weeks of treatment with Semaglutide in patients with T1D. Since 
enrolled patients are anticipated to have good glycemic control (due to HCL use) and 
because of the short duration of this clinical trial, we do not anticipate statistically 
significant differences in cardio-renal or NAFLD endpoints. However, these exploratory 
data would be useful for designing future clinical trials to reduce cardiovascular risk in 
people with T1D.  
4. CLINICAL RESEARCH SITES 
The study will be conducted at four US clinical sites. The Barbara Davis Center for Diabetes 
will be the lead primary site.  
5. STUDY POPULATION: 
5.1 Inclusion criteria  
For an eligible subject, all inclusion criteria must be answered “yes” 
1) Age ≥18 and ≤ 65 years at screening 
2) Patients with clinical diagnosis of T1D for at least 12 months 
3) Patient is on FDA- approved hybrid closed-loop system for ≥ 3 months  
4) Willing to use once weekly semaglutide 
5) Willing to share devices (HCL system) data uploads  
6) HbA1c >7.0% and <10.0%   
7) Body mass index ≥30 kg/m2 
8) Has current glucagon product to treat severe hypoglycemia  
9) Has current ketone meters to check ketones 
10) Ability to provide informed consent before any trial-related activities 
5.2 Exclusion criteria  
1) Age <18 years and > 65 years  
2) HbA1c ≤7.0 % or ≥ 10.0% at screening 
3) Less than 12 months of insulin treatment 


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4) Use of unapproved insulin for HCL system. E.g. use of Fiasp in the Tandem Control-IQ 
system  
5) Not willing to share the devices (HCL system) data uploads 
6) Non compatible devices (e.g. pump, CGM or smart phones) for data transfer  
7) Current use of multiple daily injection or inhaled insulin (Afrezza) 
8) Patients with T1D using any glucose lowering medications other than insulin at the time 
of screening  
9) Pregnancy, breast feeding, and positive pregnancy test during screening 
10) Women of childbearing age wanting to become pregnant  
11) Unwilling to use acceptable contraceptive methods (for both men and women) during the 
trial period 
12) Current use (≥ 2 weeks of continuous use) of any steroidal medication, or anticipated 
long-term steroidal treatment (>4 weeks continuously), during the study period 
13) Use of GLP-1RA or weight loss medications in the past 3 month  
14) Clinical diagnosis/history of gastroparesis or gastric motility disorders 
15) Serum triglycerides >500 mg/dL    
16) Planning for bariatric surgery during the study period  
17) eGFR below 45 ml/min/1.73 m^2 using CKD-EPI formula 
18) History of severe hypoglycemia in the previous 3 months 
19) History of diabetic ketoacidosis requiring hospitalization in the past 3 months 
20) History of allergy to any form of insulin, GLP-1RA or its excipients  
21) History of any form of pancreatitis    
22) History of stroke, myocardial infarction in the past 3 months  
23) History of congestive heart failure class III or IV 
24) History of acute or chronic liver disease  
25) History of malignancy requiring chemotherapy, surgery or radiation in previous 5 years  
26) Personal or family history of multiple endocrine neoplasia type 2 (MEN-2) or familial 
thyroid carcinoma or non-familial medullary thyroid carcinoma  
27) Have a pacemaker, metal implants, or aneurysm clips or weigh >330 lbs (exclusion only 
if doing MRI) 
28) Use of investigational drugs within 5 half-lives prior to screening 


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29) Participation to other intervention trials during the study period  
30) Any comorbidities or medical conditions such as severe psychiatric disorder that make a 
person unfit for the study at the discretion of the investigators 
5.3 Rationale for inclusion/ exclusion criteria: Only patients using FDA approved HCL system 
will be included. Many patients with T1D uses do-it-yourself (DIY) system that are not 
FDA approved and they will be excluded for safety reasons.  
 
5.4 Withdrawal criteria 
• Participation in this research is voluntary. Subjects may withdraw at will at any time. 
When withdrawing from the study, the participant should let the research team know that 
he/she wishes to withdraw. A participant may provide the research team with the 
reason(s) for leaving the study but is not required to provide their reason.  
• If subject is withdrawn after week-10, we will encourage participants to complete V6 
(week-26) or complete V6A/P3A.  
• Participants will be withdrawn from the study if they become pregnant, actively try to 
become pregnant, develop an allergic reaction to semaglutide or at the judgement of 
investigators due to safety concerns. 
• After withdrawal, the participant will be given instructions on how to safely stop using 
study medications and, eventually, on how to correctly and safely return to the previous 
treatment regimen. Instructions are also given on who to contact if there are any 
questions or concerns that arise after study withdrawal.  
• At the time of withdrawal, the research participant should let the research team know if 
he/she will allow the use of his/her health information and collected data by the 
researchers. 
5.5 Subject replacement 
Withdrawn subjects will not be replaced. However, re-screening is allowed within 
recruitment period at the investigator’s discretion.   
5.6. Reminders 
To minimize loss to follow-up, reminders (text message, phone call or email) will be sent 
to participants prior to each clinic visits.  


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6. VISIT PROCEDURES: 
 The details of the study visits and procedures are provided in the Table below. In brief, there 
are up to six in-person research visits and up to three phone call visits.  
 Before screening takes place, subjects will be provided with written information about the 
trial and the procedures involved. Subjects will be fully informed, both orally and in writing, 
about their responsibilities and rights while participating in the trial, as well as about possible 
advantages and disadvantages when participating in this trial. Subjects will have the 
opportunity to ask questions and have ample time to consider participation. The informed 
consent process will take place before the screening visit. Before signing the informed 
consent, the investigator will make sure that the potential subject has full knowledge of the 
study processes, and the possibility to withdrawal at any time during the study.  
 Subjects who wish to enroll in the trial must sign and date the informed consent form for the 
trial before participating in any trial-related procedures. All subjects will be provided with a 
copy of signed informed consent form. 


 
 
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Trial period 
Screening  
Randomization  Treatment period 
Follow-
up 
End-of-
treatment 
premature 
discontinuation  
Follow-up 
premature 
discontinuation  
Visit (V) or Phone (P) 
V1 
V2 
V34 
P1 
V44 
P2 
V5 
V6 
P3 
V6A2 
P3A3 
Weeks  
-2 
0 
4 
6 
8 
10 
20 
26 
28 
 
2 weeks from 
V6A 
Window (days) 
± 7 
- 
±3 
±3 
±3 
±3 
±7 
±7 
+7 
 
+7 
Subject-Related Information/ Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Screen fail/Withdrawal criteria  
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Medical history/concomitant medications/ 
Demography 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Trial-related efficacy and safety measures 
Height/Weight/BMI/ Waist & Hip circumference 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
CVD and NAFLD risk assessment6 
 
X 
 
 
 
 
 
X 
 
X 
 
Device downloads (CGM and pump data)1 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
Questionnaires8  
X 
 
 
 
X 
 
X 
X 
 
X 
 
AE/SAE assessment including assessment for severe 
hypoglycemia and DKA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory  
HbA1c (Central) 
X 
 
 
 
X 
 
X 
X 
 
X 
 
Lipid, CBC and CMP7 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
Random urine albumin to creatinine ratio 
 
X 
 
 
X 
 
X 
X 
 
X 
 
Pregnancy test (for premenopausal women)  
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
Fasting blood and urine collection (only for storage)  
 
X 
 
 
X 
 
X 
X 
 
X 
 
Trial Material 
Drug accountability  
 
 
X 
 
X 
 
X 
X 
 
X 
 
Drug Dispensing5  
 
X 
X 
 
X 
 
X 
 
 
 
 
Patient handouts/ reminders  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
1patients own devices. 2V6A to be scheduled at the discontinuation of the trial product; 3P3A to be conducted for those who complete their V6A. 4V3 and V4 can be done remotely if needed.  5In a 
situation needing subsequent visit to be done remotely, you can dispense extra IMPs. 6 CVD risk assessment includes brachial artery distensibility, pulse wave analysis and velocity, cIMT and CMR, 
MRE and PDFF. Brachial artery distensibility at all 4 sites. Other cardiac measures at BDC and OHSU sites, initial MRI and cIMT can be done prior to V2 after eligibility has been determined. 7At 


 
 
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screening, non-fasting plasma triglycerides and CMP will be measured. Randomization onwards, fasting lipids, CBC and CMP with be measured. 8 Questionnaires such as GOLD, QOL, physical 
activity measures.


 
 
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6.1 Screening  
 The subjects will be assigned a unique subject number, which will remain the same 
throughout the trial. The subject number will consist of 3 digits: first digit is site 
number (e.g. 1) followed by two digit subject number (e.g. 01).  
 All subjects will undergo review of inclusion and exclusion criteria. If any inclusion 
criteria is answered ‘no’ or any exclusion criteria is answered ‘yes’, the subject is a 
screen failure, and no further assessment will take place.  
 Patients will be told the importance of compliance of the pre-set study visit time 
schedules 
 All subjects will be assessed and reeducated on diabetes self-management, appropriate 
and safe use of their own diabetes devices, and its trouble shooting, prevention and 
treatment of hypoglycemia and sick day management.  
 All subjects must use appropriate insulin that is approved for their HCL system. For 
example, insulin Fiasp is not allowed to be used in Tandem Control-IQ HCL system.  
6.2. Randomization  
 Randomization visit will be done within 2 weeks from screening visit.  
 Subjects will be randomized using computer generated randomization scheme to receive 
either semaglutide or placebo (1:1 randomization). Patients or investigators will be 
blinded to either treatment modalities.  
 A pre-designated study personnel will be in-charge of allocating study drugs and 
keeping track of study drug distribution across all the sites.   
 A Directions For Use (DFU) will be provided by Novo Nordisk and will be given to 
each patient at the first dispensing visit (dosing details in Section 6.3) 
6.3. Semaglutide dose, titration, and insulin adjustment  
 Starting dose of semaglutide is 0.25 mg subcutaneously once a week.  
 All patients will be provided with verbal and written education on the use of 
semaglutide pen  
 Dose will be titrated after 4 weeks to 0.5 mg/ week and after 8 weeks to 1 mg/week. In 
case of intolerance to the medication, the dose can be scaled back. All patients will be 
encouraged to use maximally tolerable dose up to 1 mg/week.  


 
 
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 At randomization, and during drug titration (week 4 and week 8), study investigator or 
designated study personnel must review HCL settings, adjust it per the guidance 
provided in the Appendix A, and provide appropriate education to minimize 
hypoglycemia. HCL adjustment will be recorded in the study database (Redcap).  
 To achieve desirable glycemic control (>70% TIR and <4% TBR), HCL settings may 
be adjusted by the investigators per the guidance provided in the Appendix C after 
patient has reached the maximum tolerable dose (after week 10 or P2 study visit). HCL 
adjustment will be recorded in the study database (Redcap).  
6.4. Clinic and phone visits  
 All study procedures must be conducted as mentioned in the procedure table above.  
 In a situation where an in-person visit cannot be possible, research visits (V3 and V4) 
can be conducted remotely.  A study procedure manual will be provided to all sites.  
 If a subject is withdrawn after week-10, participants will be encouraged to complete V6 
(week-26) or complete V6A/P3A 
 
6.5 Un-blinding 
  The subject randomization list and IMP dispensation details will be stored at the BDC. 
Subject number will be matched with IMP assigned to the subject.  
 The designated independent personnel unblinded to the study drugs (Sarit Polsky, MD) 
will perform any un-blinding of study participants. 
 Un-blinding can be performed under the following circumstances: 
• 
Treatment of an individual in a medical emergency where knowledge of the 
treatment allocation is required. 
• 
Treatment of an individual for an AE. 
• 
In the event of a SUSAR. 
• 
In the event that the participant's study medication is accidentally taken by a 
member of their household e.g. a child. 
• 
If required by the DSMB committee or regulatory agencies.  
 
 


 
 
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7.   STATISTICAL PLAN  
7.1 Preliminary data for sample size calculation 
In SUSTAIN 1, 4 and 5 clinical trials, Semaglutide 0.5 mg and 1 mg per week for 30 weeks in 
patients with type 2 diabetes resulted in 2.5-4.5 kg, and 3.5-6 kg weight loss compared to 
baseline 44-46. 30-40% of patients with type 2 diabetes with baseline BMI between 30-35 kg/m2 
achieved weight loss of >5% using Semaglutide 0.5 mg weekly compared to comparator and 
45-60% had weight loss >5% using Semaglutide 1 mg weekly compared to comparator 47. 
Based on this data, we conservatively estimated that 30% of patients with T1D using HCL and 
randomized to semaglutide with BMI >30 kg/m2 will achieve >5% of weight loss at 26 weeks 
from baseline. None of the clinical trials in T1D demonstrated weight loss with the use of HCL 
therapy 8-10 and therefore, we don’t expect adults with T1D using HCL and randomized to 
placebo to lose >5% of body weight.  
Our previous real-life study of adults with T1D using Medtronic 670 G had mean percent TIR 
of 67%±1.2% after 3 months of using HCL. In our clinical experience of using semaglutide in 
adults with T1D with mean HbA1c of 7.7±1.4 at baseline had drop in HbA1c to 7.2±1.1 after 3 
months (unpublished data). Each 5% improvement in TIR approximates reduction in HbA1c by 
0.3-0.4% 48, 49 and therefore, based on our preliminary data, we expect that greater percentage of 
adults with T1D randomized to semaglutide would have improvement in TIR by at least 5% 
than adults with T1D randomized to placebo. Moreover, most adults with T1D using HCL 
system have TBR <4% and GLP-1 analogs have not found to increase TBR. Therefore, we 
expect that >75% of adults with T1D on HCL and randomized to either semaglutide or placebo 
would have TBR <4%.  
7.2 
Sample size calculation 
Using the Fisher’s exact test at an alpha level of 0.05, a sample size of 32 per group (intention to treat 
analysis) completing the study is expected to have power close to 80% to detect a 30% difference in the 
proportion of participants achieving the composite outcome if the proportion in the control group is 5%. If 
the proportion in the control group is 3%, then our power level is over 80% to detect a difference between 
groups of at least 29%, as shown in the table below.  
Power analysis for proportion of participants meeting primary composite outcome 
between two groups 


 
 
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Treatment 
group 
Control 
group 
Power 
35% 
5% 
78.4% 
30% 
5% 
64.2% 
25% 
5% 
47.1% 
20% 
 5% 
29.5% 
35% 
3% 
85.9% 
30% 
3% 
74.5% 
25% 
3% 
59.0% 
20% 
3%  
41.0% 
 
Power and Sample Size for secondary endpoints:  
 Power calculations for key secondary outcomes were conducted using PASS v24.02.  Differences in 
each variable from baseline will be calculated and compared by treatment group. We determined the 
detectable mean group difference for each secondary outcome, assuming the null hypothesis of no 
difference between the means.  With a sample size of 32 per group, we have 80% power to detect mean 
differences as shown in the table below, assuming the SD shown in the table.  
Outcome 
SD 
Detectable difference for 
comparison of means 
HbA1c (%) 
0.7 
0.5 
TIR (%), TITR, TAR>180 
15 
10.7 
Mean Glucose (mg/dL) 
18 
12.8 
TBR <70 (%) 
3 
2.1 
Weight (Kg) 
25 
8.07 
BMI (kg/m2) 
4 
2.8 
Glucose SD (mg/dL) 
10 
7.1 
Glucose CV (%) 
5 
3.6 
 
7.3 Evaluability of subjects 
 We will prepare two data sets for the analysis.  
 Per-Protocol (PP) analysis set: All exposed subjects who complete the 26-week trial 
without significantly violating the main aspects of the protocol. The Per-Protocol set will 
be used for sensitivity analyses.  
 Intention to treat (ITT) analysis set: All randomized subjects exposed to at least one dose 
of trial product. ITT data set will be used for efficacy and safety analysis.  


 
 
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7.4 Analyses plan 
Analysis plan is detailed in a separate statistical analysis plan. All statistical analysis plans were 
finalized prior to the completion of the study and analysis of any data.  
8. DATA HANDLING AND RECORD KEEPING 
8.1 Data management  
 Colorado Multiple Institutional Review Board (COMIRB) will serve as the IRB for the 
Barbara Davis Center.  The other sites will use their own IRB. 
 The data and specimens obtained from the subject will be identified by subject number.  
 The principal investigator will retain all data generated during the study. Data management 
is the responsibility of the investigator.  
 All electronic data from all four sites will be stored at the BDC, in a de-identified manner, 
which are secured by the University of Colorado servers. The data will be accessible only by 
the study team and if transfer of data needed, appropriate measures, including encryption of 
data files will be used to ensure security and subject confidentiality. 
 The records will be stored securely and kept for minimum of 9 years per the Standards 
Operating Procedures (SOP) of the University of Colorado 
(https://research.cuanschutz.edu/comirb/home/guidance-and-policies) 
8.2 Source data  
 
Source documents will be kept with the site investigators per local regulatory 
requirements. Source data must be available to the study monitors or regulatory agencies such 
as US FDA whenever asked for.  
 
All source data must be entered in the study data database electronically.  
9. ETHICS 
 The trial will be conducted in compliance with this protocol, ICH GCP, the University of 
Colorado COMIRB research policy, local site regulatory agencies, and in accordance with 
the Declaration of Helsinki. 
 The clinical trial protocol, consent form and appropriate study documents will be submitted 
to COMIRB for the approval before the start of any study related activity.  


 
 
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 Once the protocol is approved by COMIRB for the BDC and the IRBs for the other sites, 
the study team will be allowed to contact potential subjects. 
 Before any trial-related activity, the investigator/study team will give the subject verbal and 
written information about the trial and the procedures involved in a form that the subject 
can read and understand. 
 The subjects will be fully informed of their rights and responsibilities while participating in 
the trial as well as possible disadvantages of being treated with the trial products. 
 The investigator will ensure the subject is given ample time to come to a decision whether 
to participate in the trial. 
 A voluntary signed and personally dated informed consent will be obtained from the 
subject before any trial-related activity. 
 The process of informed consent process will occur in a clinical research place. The subject 
will sign the informed consent process in the presence of the investigator and witness. The 
confidentiality and HIPAA will be handled per the University of Colorado and local site 
regulatory research policies.  
 
10. STUDY DRUGS AND MATERIALS: 
Patients will be using their own insulin, and diabetes devices (HCL system and related supplies) 
Study medications 
 Injection semaglutide 1.34 mg/mL  
 Injection placebo (Clinic variant of marked product*)  
Packaging and labelling of study medication(s) 
 The BDC will receive study medications from Novo Nordisk A/S. 
 BDC pharmacist/designated person will distribute the drugs/placebo to other sites.   
 All sites will be provided guidance (study procedure manual) on medication packaging, 
labelling, storage and distribution.  
 All subjects will be provided written and verbal education on taking study medications 
appropriately.  
Storage and drug accountability of study medication(s) 
 All the study medication (including placebo) will be assumed as semaglutide and stored 
according to the approved label. 


 
 
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 The temperature log will be monitored at the site and any temperature fluctuation will be 
reported as deviation. 
Auxiliary supply 
 Pen needles will be provided to all subjects.    
 
11. CONCOMITANT ILLNESS(ES) AND MEDICATION(S) 
 
Concomitant illness is any illness that is present at the start of the trial (i.e. at the first visit).  
 
Concomitant medication is any medication other than the trial product(s) that are consumed during 
the trial.  
 
Details of all concomitant illnesses and medication will be recorded per protocol. All sites will be 
provided with source documents and instructions on recording concomitant illnesses and 
medications.  
 
* The clinic variant of the cartridge is produced with an army green closure cap compared to a dust green closure cap 
in the marketed Ozempic® product. Ozempic® are marketed in different pen variants for different intended dosing 
regimens. The push button and cartridge holder are light grey, and the pen can be found in both a 1.5 ml and 3 ml 
variant, dependent on the country. The clinical pen can be found in one variant to support 0.25mg, 0.5mg and 1mg 
doses in a 1.5 ml variant. The push button and cartridge holder are light brown. Neither closure cap nor the pen is in 
contact with the product and the differences in colours have no impact on the stability of the product. 
 
12. ADVERSE EVENTS 
12.1 Definition 
Adverse event (AE) 
Any untoward medical occurrence associated with the use of a drug 
whether considered drug related or not. AE can be unfavorable symptoms, 
sign (abnormality on physical exam or laboratory findings) or disease 
temporarily associated with the use of products whether or not related to 
the products. 
Serious adverse event 
(SAE) 
 
An adverse event or suspected adverse reaction is considered "serious" if, 
in the view of the investigator, it results in any of the following outcomes: 
 Results in death, or, 
 Is life-threatening, or, 
 Requires inpatient hospitalization or prolongation of existing 
hospitalization, or, 
 Results in persistent or significant disability/incapacity, or, 
 Is a congenital anomaly/birth defect, 
 Is a medically important event that may not result in death, be life 
threatening or require hospitalization may be considered an SAE 
when - based on appropriate medical judgement -they may 
jeopardize the subject and may require medical or surgical 


 
 
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intervention to prevent one of the outcomes listed in the definition 
of SAE 
Suspected transmission of an infectious agent should be considered as an 
SAE. 
Adverse Drug Reaction 
(ADR) 
An Adverse Reaction is an Adverse Event for which the causal 
relationship between the Product and the Adverse Event is suspected 
Serious Adverse 
Reaction (SAR) 
An Adverse event that fulfills both the criteria for a Serious Adverse event 
and the criteria for an Adverse Reaction. 
Medical event of special 
interest (MESI)  
 
A MESI is an event, which, in the evaluation of safety, has a special 
focus. A MESI is an AE (SAE or non-serious AE) which fulfils one or 
more of the below defined MESI criteria. 
–Medication errors concerning trial products: 
– Administration of wrong drug 
– Wrong route of administration, such as intramuscular instead of 
subcutaneous 
– Accidental administration of a lower or higher dose than intended, 
however the      administered dose must deviate from the intended dose to 
an extent where clinical consequences for the trial subject were likely to 
happen as judged by the investigator, although not necessarily did happen. 
Overdose and missed insulin injection resulting in severe hypoglycemia or 
hyperglycemia are considered as AE or SAE depending on severity.  
Suspected Unexpected 
Serious Adverse 
Reactions (SUSAR)  
 
An unexpected adverse reaction (UAR) is an adverse reaction that is not 
consistent with the product information in the summary of product 
characteristics (SPC, i.e.US prescribing information). The current version 
or any updated if available during the clinical trial for US prescribing 
information for study drugs will be used as SPC. If UAR is severe enough 
to define as SAE is called as SUSAR.  
Technical complaint 
 
A technical complaint is any written, electronic, or oral communication 
that alleges product (medicine or device) defects. The technical complaint 
may be associated with an AE but does not concern the AE itself. 
12.2 Reportable AE for Hypoglycemia and Hyperglycemia/Diabetic Ketoacidosis  
• Hypoglycemia: Hypoglycemia is common in people with T1D. Only severe 
hypoglycemia defined as “hypoglycemia event requiring medical assistance of another 
person due to altered consciousness, and required another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions” is reportable adverse event.  This 
means that the participant was impaired cognitively to the point that he/she was unable to 
treat himself/herself, was unable to verbalize his/ her needs, was incoherent, disoriented, 
and/or combative, or experienced seizure or coma. These episodes may be associated 
with sufficient neuroglycopenia to induce seizure or coma. If plasma glucose 


 
 
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measurements are not available during such an event, neurological recovery attributable 
to the restoration of plasma glucose to normal is considered sufficient evidence that the 
event was induced by a low plasma glucose concentration.  
• Hyperglycemic events/Diabetic Ketoacidosis (DKA): Hyperglycemic event is only 
reportable as an adverse event when one of the following four criteria is met:  
1) The event involved DKA, as defined by the Diabetes Control and Complication 
Trial (DCCT) and described here:   
 Hyperglycemic events are classified as DKA if the following are present 
(meeting all 4 criteria)  
a) Symptoms such as polyuria, polydipsia, nausea or vomiting  
b)  Serum ketones >1.5 mmol/L or large/moderate urine ketones  
c) Either arterial PH <7.30 or venous PH <7.24 or serum bicarbonate 
<15 
d) Treatment provided in a health care facility  
2) Evaluation or treatment was obtained at a health care provider facility for an acute 
event involving hyperglycemia or ketosis  
3) Blood ketone level ≥ 1.5 mmol/L and communication occurred with a health care 
provider at the time of the event  
4) Blood ketone level ≥ 2.5 mmol/L even if there was no communication with a 
health care provider  
12.3 Non-reportable adverse events  
 Hypoglycemia or hyperglycemia events not meeting above criteria are not required to be 
reported as an adverse event  
 Patients’ own devices (e.g. insulin pump, CGM, BG meters) related issues and skin issues 
arise from the use of these devices (such as skin rash due to adhesive or infusion site 
issues) are not reportable unless the event meets the definition of an SAE.   
 
 


 
 
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12.4 Reporting of adverse events   
 All events meeting the definition of an AE must be collected and reported. This includes 
events from the first trial-related activity after the subject has signed the informed consent 
until the end of the post-treatment follow-up period. 
 Once an AE is identified, assessment for severity (mild, moderate or severe), causality 
(probable, possible or unlikely) and outcome of an AE (recovered, recovering, recovered 
with sequelae, not recovered, fatal or unknown) must be provided.  Probable is defined as 
good reason and sufficient documentation to assume a causal relationship. Possible is 
defined as a causal relationship is conceivable and cannot be dismissed. Unlikely is defined 
as the event is most likely related to etiology other than the trial product. 
 Since patients are using their own diabetes devices, we do not intend to collect device 
issues. However, if a device issue results in SAE, it must be reported.  
 The investigator is responsible for reporting all AE to their IRB within five business days 
once they are aware of AE.  
 All non-severe and severe AE will be followed until the end of the study 
 Subjects must be instructed to notify the investigator immediately if they become 
pregnant. If a subject becomes pregnant during the study, the subject will be dropped from 
the study and followed until birth for pregnancy outcomes.  Pregnancy will be reported as 
an AE (or SAE if fulfills the criteria of SAE). The sponsor-investigator is responsible for 
reporting pregnancy to Novo Nordisk and reporting will occur within same timelines 
described below. Pregnancy complications will be recorded as an AE and if the infant has 
a congenital abnormality or birth defect, it will be reported and notified to the IRB  
 Site investigators are responsible to notify their IRB within 24 hours once they are aware 
of an SAE.  
 Sponsor-Investigators will be responsible for notifying COMIRB, DSMB, the FDA and 
Novo Nordisk of an AE/SAE within the stipulated time frame of each of the agencies.  
 Sponsor-investigator will report to NovoNordisk all SAEs, SUSARs and SADRs within 
15 days of the sponsor-investigator becoming aware of such adverse events. The Sponsor-
Investigator will provide the following information to NovoNordisk: study name, patient 
initials, sex, age, event (probable diagnosis), drug name (Semaglutide/placebo) and 


 
 
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reporter identification (name or initials) in addition to a description of the AE events such 
as causality and outcome.  
 Follow-up of adverse events: Investigator must provide adequate medical care to study 
subject for any study-related adverse events including clinically significant laboratory 
values related to the study and medical care of the subjects should be provided regardless 
of their insurance status. AE classified as serious or possibly/probably related to trial drug 
must be followed until the subject has been recovered and all queries have been resolved. 
For cases of chronic conditions follow-up until the outcome category is “recovered” is not 
required, as these cases can be closed with an outcome of “recovering” or “not recovered”. 
All other adverse events must be followed until the outcome of the event is “recovering” 
(for chronic conditions), or “recovered” or until the end of the post-treatment follow-up 
stated in the protocol, whichever comes first, and until all queries related to these AEs 
have been resolved. 
 
13.  Individual subject stopping criteria  
Study drug administration may be stopped for any of the following reasons: 
1) Two or more episodes of severe hypoglycemia as defined in the section 13.2  
2) Two or more DKA events not related to device malfunction. Definition of DKA is 
detailed in the section 13.2  
3) Investigator decides that, in the interest of the patient, it is not medically acceptable to 
continue participation in the study 
 
14. Criteria for suspending or stopping the study 
Greater than 10 cases of severe hypoglycemia or greater than 5 cases of DKA that are not 
due to device malfunction.  These criteria are based on exceeding the average incidence of 
severe hypoglycemia (11.8%) and DKA (4.8%) in patients with T1D as reported in the Type 
1 Diabetes Exchange Clinic Registry 50.  
15. Data Safety Monitoring Board (DSMB) 
A DSBM consisting of three members (two clinicians and one statistician) will independently 
monitor the study, including adverse events and study drug or device issues with potential to 
impact participant safety. A meeting will be held at the beginning of the study, and every six 


 
 
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months between the study teamsBDC and IU investigators) and the DSMB to review any 
adverse events. Following each safety review, a summary of recommendation from the 
DSMB will be collected.  
16. Precautions/over-dosage 
Inappropriate medication dose can cause severe hypoglycemia or hyperglycemia. The 
education on recognition of hypoglycemia or hyperglycemia and its treatment will be 
provided at screening and as needed during the study. 
17. Risks and Discomforts  
a) Blood Drawing Risks  
The risks of drawing blood from a vein include temporary discomfort from the needle stick 
(common), bruising (common), excessive bleeding (unlikely), lightheadedness (rare), 
infection (rare), and fainting (rare).   
 
b) Study procedure related discomfort  
The participant may feel some discomfort during height, weight, waist measurement and 
blood pressure measurements. All care will be taken to reduce discomfort.  
c) Side-effects related to semaglutide  
Semaglutide is a long-acting glucagon like peptide-1 (GLP-1). The most common adverse 
reactions, reported in ≥5% of patients treated with semaglutide are nausea, vomiting, diarrhea, 
abdominal pain, and constipation.  Nausea/ vomiting can sometimes lead to dehydration and 
acute kidney injury. Semaglutide causes a delay of gastric emptying and has the potential to 
influence the absorption of concomitantly administered oral medications, so caution should be 
exercised. Acute and chronic pancreatitis have been reported in clinical studies. 
Hypersensitive reactions have also been reported. Semaglutide is contraindicated in patients 
with a history or family history of medullary thyroid cancer and in patients with multiple 
endocrine neoplasia type 2 (MEN-2)  
d) Risk of Hypoglycemia (Low Blood Sugar)  
As with any person with diabetes who uses insulin, there is always a risk of having low blood 
sugar (hypoglycemia). GLP-1RA such as semaglutide is known to improve insulin action and 


 
 
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therefore, may increase risk for low blood sugar. Symptoms of low blood sugar can include 
sweating, jitteriness, and not feeling well. There is also the possibility of fainting or seizures 
(convulsions), brain damage, or death with a very low blood sugar. Since we will be closely 
monitoring participants during this study, a serious low blood sugar is less likely to occur in 
any study participant. Even if a low blood sugar does occur, it usually goes away quickly with 
treatment (carbohydrates) that raises the blood sugar. A severe low blood sugar may require 
that a participant get an injection of glucagon and/or have emergency services to help raise 
his/her blood glucose level. Hypoglycemia risk mitigation plan is discussed in the 
Appendices.  
e) Risk of Hyperglycemia (High Blood Sugar)  
Hyperglycemia usually does not cause many obvious symptoms, but participants may become 
thirsty, fatigued, or have a higher level of sugar in their urine. In severe cases of 
hyperglycemia, diabetic ketoacidosis (DKA) or coma may occur. Hyperglycemia leading to 
DKA can lead to renal failure (kidney failure), cardiac arrhythmia (irregular heartbeat), 
myocardial infarction (heart attack), rhabdomyolysis (muscle breakdown), and even death. A 
serious effect from hyperglycemia is not expected to occur in any study participant, as we will 
be monitoring blood glucose levels frequently.  
f) Psychosocial Questionnaires  
Answering questionnaires about thoughts, concerns, and distress related to diabetes and general 
quality of life assessments may result in undesired thought processes and/or emotions. These 
feelings may be transitory, recurrent, or permanent though most risks are minimal/transitory.  
g) Cardiac magnetic resonance imaging – during the MRI exam, some participants may 
experience claustrophobia and discomfort, due to being enclosed in a small tube.  In order to 
minimize the risk of this occurring, potential participants will be screened for claustrophobia or 
prior issues undergoing MRI and excluded if they have experienced claustrophobia or had other 
negative experiences with MRI.  In addition, participants will be excluded if they have a 
pacemaker, metal implants or aneurysm clips. 
h) Unknown Risks  


 
 
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In any study, there may be additional risks that we do not know about at this time. This is not 
likely but is always a possibility. If we become aware of any new risks, participants will be told 
about them. They will be able to decide if they want to continue to participate in this study. If a 
treatment or procedure has increased risks because it was not done according to study 
procedures due to error, participants will be informed, and the necessary steps will be taken to 
care for them.  
i) Confidentiality 
There is a risk of a breach in confidentiality. Thus, a confidential subject database will be 
established to maintain study data. Data will be entered into REDCap (Research Electronic 
Data Capture). REDCap is an internal secure, computerized database system at the University 
of Colorado Denver. This system allows data entry, survey/questionnaire building, data 
exportation to statistical packages, and is HIPAA compliant. Each subject will be assigned an 
identification number, which will be used to code and identify all of that subject’s records. 
This will avoid the continual use of subject names. REDCap surveys can be sent to study 
participants via e-mail for direct input into the database. All study data will be locked in the 
PIs’ offices and all relevant computer study files will be input on staff computers, which are 
password protected and contain encryption software. Data storage will be on a secured server 
maintained by the University of Colorado. The server is backed up nightly and a copy of the 
back-up file is kept off site in a secure facility. Data access will be limited to study personnel. 
Study results may be presented in the form of posters, abstracts, oral presentations, or 
publications at academic meetings or in journals. In all forms of study result reporting, subject 
identification will not be disclosed. A study subject may access his/her protected health 
information at any time by requesting said information in writing of the investigator. The 
investigative team has been trained in IRB and HIPAA compliance issues and will maintain 
confidentiality and protect health information. The above-stated procedures have been highly 
effective in preventing breaches of patient confidentiality for the prior and current research 
studies in which the PI has been and continues to be involved. 
 
 


 
 
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1. 
Miller KM, Foster NC, Beck RW, et al. Current state of type 1 diabetes treatment in the 
U.S.: updated data from the T1D Exchange clinic registry. Diabetes care 2015;38(6):971-
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2. 
Wood JR, Miller KM, Maahs DM, et al. Most youth with type 1 diabetes in the T1D 
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Society for Pediatric and Adolescent Diabetes clinical guidelines. Diabetes care 
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Shah VN, Bailey R, Wu M, et al. Risk Factors for Cardiovascular Disease (CVD) in 
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Shah VN, Grimsmann JM, Foster NC, et al. Undertreatment of cardiovascular risk factors 
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Tauschmann M, Thabit H, Bally L, et al. Closed-loop insulin delivery in suboptimally 
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Bergenstal RM, Garg S, Weinzimer SA, et al. Safety of a Hybrid Closed-Loop Insulin 
Delivery System in Patients With Type 1 Diabetes. Jama 2016;316(13):1407-1408. (In 
eng). DOI: 10.1001/jama.2016.11708. 
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Brown SA, Kovatchev BP, Raghinaru D, et al. Six-Month Randomized, Multicenter Trial 
of Closed-Loop Control in Type 1 Diabetes. The New England journal of medicine 
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Appendix A: General Guidance on HCL setting adjustments during drug up titration    
• 
Investigators must train subjects on diabetes self-management principles including 
hypoglycemia recognition, prevention, and treatment. This includes HCL specific 
training on hypoglycemia and hyperglycemia prevention and trouble shooting 
• 
At randomization and week 4 and Week 8, based on baseline glycemic control (time in 
range) and risk of hypoglycemia (time below range), investigators should adjust the HCL 
settings. The general guidance is provided below.  
 
 
 
 
*Each individual with type 1 diabetes is different in terms of response to GLP-1RA and risk for 
hypoglycemia. This is a general guidance and Investigators should adjust settings necessary to reduce the 
risk for hypoglycemia based on patient-related factors and clinical experience. 
#If needed, investigators can reduce the correction factors up to 10% (TIR>50% and TBR <4%) or 20% 
(TBR>4%) in addition to changes in basal rate or ICR. Moreover, investigators may recommend patients 
to use temporary manual mode, exercise mode/temporary target if above changes are not sufficient to 
TIR; time in range 70-180 mg/dL, TBR; time below 70 mg/dL, ICR: Insulin to carbohydrate ratio  


 
 
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mitigate hypoglycemia risk. For Omnipod 5 and Medtronic 780G, investigators may also adjust target 
glucose.  
 
Appendix B: Guidance on the functionality of the hybrid closed-loop systems 
 
 
Medtronic 
670/770G 
Medtronic 780G 
Tandem Control 
IQ 
Omnipod 
5 
How it works 
Automated basal 
insulin delivery 
every 5 minutes 
based on total 
daily dose from 
the past 2-6 days 
Automated basal 
insulin delivery 
every 5 minutes 
based on total 
daily dose 
Automated basal 
insulin delivery 
that increases or 
decreases patient’ 
programmed basal 
rate based on 
CGM glucose 
trends 
Automated 
basal 
insulin 
delivery 
every 5 
minutes 
based on 
total daily 
dose from 
the last 
pod 
change (2-
3 days)  
Algorithm target 
glucose 
level/range 
120 mg/dL (fixed) 3 target options: 
100, 110 and 120 
mg/dL 
112.5-160 mg/dL 
(fixed) 
110-150 
mg/dL 
(adjustable 
in 
increment 
of 10 
mg/dL) 
What you can 
adjust?  
 
(modifiable 
settings in HCL) 
Insulin: Carb ratio 
Active insulin 
time  
 
 
Insulin: Carb ratio 
Active insulin 
time  
 
Basal rate  
Insulin: Carb ratio 
Correction factor  
 
Insulin: 
Carb ratio 
Active 
insulin 
time  
Correction 
factor  
 
Auto bolus 
feature 
No 
Yes, every 5 
minutes based on 
algorithm 
calculations.   
Yes, automated 
boluses every 1 
hours (60% of 
calculated bolus) 
if needed.  
 
If patient takes 
bolus by 
him/herself, auto 
No 


 
 
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bolus clock resets 
to 60 minutes 
from the patient’s 
manual bolus.  
Additional 
features on 
closed-loop mode 
Temp target 
(during exercise 
or stress): 
increases the 
glucose target to 
150 mg/dL 
Temp target 
(during exercise 
or stress): 
increases the 
glucose target to 
150 mg/dL 
Exercise: Increase 
the glucose target 
to 140-160 mg/dL  
 
Sleep: changes the 
target to 112.5 to 
120 mg/dL but 
stops auto 
bolusing during 
this mode.  
Activity: 
changes 
the target 
to 150 
mg/dL  
 
All physicians will be trained on basic functionality of HCL, adjustable settings and trouble- 
shooting guidance per manufacturer instructions. For more information on comparisons of 
various HCL system, click this link- https://www.bdcpantherdiabetes.org/device-comparison  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix C: General Guidance on HCL setting adjustments after Week 10  
 
Glycemic goal for the most patients with T1D is TIR >70% and TBR <4%. Investigators are 
encouraged to review HCL settings and adjust if patient is not within the glycemic goal.  
 
 
 
 
 
*This is a general guidance and Investigators should adjust settings necessary to reduce the risk for 
hypoglycemia and improve glycemic control based on patient-related factors and clinical experience 
#If needed, investigators may strengthen correction factor (for Tandem Control IQ or Omnipod 5) or 
active insulin time (for 670/770G).  
$ Reduce the correction factors up to 10% (TIR>50% and TBR <4%) or 20% (TBR>4%) in addition 
to changes in basal rate or ICR. Moreover, investigators may recommend patients to use temporary 
manual mode, exercise mode/temporary target if above changes are not sufficient to mitigate 
hypoglycemia risk.  
 
 
 
 
 
 
TIR; time in range 70-180 mg/dL, TBR; time below 70 mg/dL, ICR: Insulin to carbohydrate ratio  


 
 
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Appendix D: General guidance on the management of hypoglycemia  
 
• 
Follows the guidance provided in the Appendix A-C to adjust HCL settings during drug 
up titration to minimize the risk for hypoglycemia. 
• 
Each subject must have glucagon product with them as a part of the standards of diabetes 
care. Subject and their caregiver (if any) must be trained on the use of glucagon product.  
• 
Subject should be advised to follow treatment for hypoglycemia. if glucose <70 mg/dL, 
take 15 grams of carbs (or less as HCL may have insulin suspension for anticipated 
hypoglycemia) and repeat glucose after 15 minutes till glucose is >70 mg/dL 
• 
If patient experience severe hypoglycemia, it should be reported as AE or SAE (if criteria 
for SAE are met). HCL setting should be adjusted to prevent another episode of 
hypoglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix E: Guidance on the checking for ketones