Obstructive Sleep Apnea and Glycemic Dysregulation in Adults With Type 1 Diabetes
Phase: NA
Conditions: Sleep Apnea, Obstructive, Type 1 Diabetes (T1D)
Sponsor: University of Chicago

 
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Protocol Title: Obstructive sleep apnea and glycemic dysregulation in adults with 
type 1 diabetes 
 
 
PI: Esra Tasali, MD 
 
 
Co-I(s): Louis Philipson, MD, PhD; Raghu Mirmira, MD, PhD 
 
 
Funding: NIH/NHLBI: 1R01HL174685 - 01 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table of Contents 
1 
INTRODUCTION ............................................................................................................. 6 
1.1 
BACKGROUND AND RATIONALE ........................................................................................... 6 
1.2 
OBJECTIVES .................................................................................................................... 6 
2 
STUDY DESIGN .............................................................................................................. 7 
2.1 
GENERAL DESCRIPTION ..................................................................................................... 7 
2.2 
NUMBER OF SUBJECTS ...................................................................................................... 8 
2.3 
DURATION OF PARTICIPATION ............................................................................................. 8 
2.4 
STUDY ENDPOINTS ........................................................................................................... 8 
3 
SUBJECT SELECTION AND WITHDRAWAL ........................................................................ 9 
3.1 
SUBJECT IDENTIFICATION AND RECRUITMENT .......................................................................... 9 
3.2 
INCLUSION ..................................................................................................................... 9 
3.3 
EXCLUSION .................................................................................................................... 9 
3.4 
EARLY WITHDRAWAL OF SUBJECTS ....................................................................................... 9 
4 
STUDY DRUG/DEVICE .................................................................................................. 10 
4.1 
DESCRIPTION ................................................................................................................ 10 
4.2 
CPAP ......................................................................................................................... 10 
5 
STUDY PROCEDURES ................................................................................................... 11 
5.1 
CONTINUOUS GLUCOSE MONITOR (CGM) .......................................................................... 11 
5.2 
INSULIN PUMP .............................................................................................................. 11 
5.3 
DIETARY TRACKING APP ‘LOSE IT’ ...................................................................................... 11 
5.4 
ACTIVITY MONITOR ......................................................................................................... 11 
5.5 
DIGITAL WEIGHT SCALE ................................................................................................... 11 
5.6 
HEART MONITOR ........................................................................................................... 12 
5.7 
BODY COMPOSITION ...................................................................................................... 12 
5.8 
INDIRECT CALORIMETRY .................................................................................................. 12 
5.9 
OVERNIGHT SLEEP STUDY ................................................................................................ 12 
5.10 
MEALS ........................................................................................................................ 12 
5.11 
QUESTIONNAIRES .......................................................................................................... 12 
5.12 
BLINDING .................................................................................................................... 13 
6 
STUDY SCHEDULE ....................................................................................................... 13 
6.1 
VISIT 1- SCREENING ....................................................................................................... 13 
6.2 
RANDOMIZATION ........................................................................................................... 13 
6.3 
VISIT 2 – CPAP TITRATION ............................................................................................... 13 
6.4 
UNTREATED STUDY PERIOD .............................................................................................. 13 
6.4.1 
Untreated Day 0 ( -1 week (-3days)) ......................................................................... 13 
6.4.2 
Untreated Days 1-14 .............................................................................................. 14 
6.5 
WASHOUT PERIOD ......................................................................................................... 15 
6.6 
CPAP TREATED STUDY PERIOD ......................................................................................... 15 
6.6.1 
Treated Day 0 ( -1 week (-3days)) ............................................................................. 15 
6.6.2 
Treated Days 1-14 .................................................................................................. 15 
7 
STATISTICAL PLAN AND CONSIDERATIONS ................................................................... 15 
7.1 
PRIMARY ANALYSES ........................................................................................................ 15 
7.2 
SECONDARY ANALYSES ................................................................................................... 17 
7.3 
MISSING DATA ............................................................................................................... 17 

 
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8 
RISKS AND BENEFITS ................................................................................................... 17 
9 
SAFETY AND ADVERSE EVENTS ..................................................................................... 19 
9.1 
DEFINITIONS ................................................................................................................. 19 
9.2 
RECORDING OF ADVERSE EVENTS ...................................................................................... 21 
9.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................ 21 
9.4 
REPORTING: NOTIFYING THE UNIVERSITY OF CHICAGO IRB ...................................................... 21 
9.5 
STOPPING RULES ........................................................................................................... 22 
9.6 
DATA AND SAFETY MONITORING PLAN ................................................................................ 22 
10 
DATA HANDLING AND RECORD KEEPING ...................................................................... 24 
10.1 
CONFIDENTIALITY .......................................................................................................... 24 
10.2 
RESEARCH MATERIAL AND CONFIDENTIALITY ........................................................................ 24 
10.3 
CASE REPORT FORMS ..................................................................................................... 24 
10.4 
RECORDS RETENTION ..................................................................................................... 24 
11 
ETHICAL CONSIDERATIONS ......................................................................................... 25 
12 
STUDY FINANCES ......................................................................................................... 25 
12.1 
FUNDING SOURCE ......................................................................................................... 25 
12.2 
SUBJECT PAYMENTS ....................................................................................................... 25 
13 
PUBLICATION PLAN ...................................................................................................... 25 
14 
REFERENCES ............................................................................................................... 25 
15 
APPENDIXES ................................................................................................................ 27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Study Summary 
TITLE  
OBSTRUCTIVE SLEEP APNEA AND GLYCEMIC 
DYSREGULATION IN ADULTS WITH TYPE 1 DIABETES 
SHORT TITLE 
OSA and T1D 
PROTOCOL NUMBER  
 
METHODOLOGY 
A WITHIN-SUBJECT, CROSS-OVER STUDY DESIGN IN 
ADULTS WITH TYPE 1 DIABETES (T1D) AND 
OBSTRUCTIVE SLEEP APNEA (OSA) WHO ARE USING 
AN INSULIN PUMP AND CONTINUOUS GLUCOSE 
MONITORING (CGM) 
STUDY DURATION  
3 MONTHS 
STUDY CENTER(S) 
SINGLE-CENTER  
OBJECTIVES 
TO DETERMINE TO WHAT EXTENT OSA CONTRIBUTES 
TO SUBOPTIMAL GLYCEMIC MANAGEMENT CONTROL 
IN ADULTS WITH T1D 
NUMBER OF SUBJECTS  
N=40 
DIAGNOSIS AND MAIN 
INCLUSION CRITERIA 
TYPE 1 DIABETES (T1D) AND OBSTRUCTIVE SLEEP 
APNEA (OSA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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List of Abbreviations 
 
 
UCMC 
 
UNIVERSITY OF CHICAGO MEDICAL CENTER 
IRB 
 
 
INSTITUTIONAL REVIEW BOARD 
NIH 
 
 
NATIONAL INSTITUTES OF HEALTH 
 
OSA  
 
OBSTRUCTIVE SLEEP APNEA 
T1D 
 
 
TYPE 1 DIABETES 
CPAP  
 
CONTINUOUS POSITIVE AIRWAY PRESSURE 
CGM   
 
CONTINUOUS GLUCOSE MONITOR 
CRC   
 
CLINICAL RESEARCH CENTER 
EHR  
 
ELECTRONIC HEALTH RECORD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1 Introduction  
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and the University 
of Chicago research policies and procedures.  
1.1 Background and Rationale 
Despite advances in diabetes care and technology, most adults with Type 1 diabetes 
(T1D) do not achieve optimal glycemic control, and consequently many are at risk for 
cardiovascular and other diabetes complications1-4. Thus, novel strategies are needed for 
improving glycemic control, in order to reduce cardiovascular complications and disease 
burden in adults with T1D. 
Obstructive sleep apnea (OSA) is a common sleep disorder characterized by recurrent 
collapse of the upper airway during sleep, resulting in intermittent hypoxia, sleep 
fragmentation by transient arousals, and poor sleep quality. Continuous positive airway 
pressure (CPAP), applied at night, is considered the treatment of choice for persons who 
are diagnosed with OSA. CPAP works by delivering continuous air pressure, preventing 
upper airway closures during sleep, eliminating hypoxia and sleep fragmentation, and 
restoring sleep quality.  
Current evidence suggests that ~50% of adults with T1D have OSA, and that 
cardiovascular and other diabetes complications are more common among those with 
OSA6-12. Moreover, cross-sectional studies suggest that adults with T1D and OSA, 
particularly those with moderate-to-severe OSA, have poorer glycemic control6-8,12.  
However, to what extent OSA contributes to suboptimal glycemic control in T1D is 
unknown. Also, the underlying mechanisms for glycemic dysregulation in T1D in the 
setting of OSA remain to be elucidated5-9.  
Our overall goal is to investigate the role of OSA in glycemic dysregulation in adults 
with T1D. We hypothesize that OSA exerts negative effects on glucose regulation in T1D, 
leading to suboptimal glycemic control and thus increasing cardiovascular risk in T1D. We 
further hypothesize that suboptimal glycemic control in adults with T1D occurs in part 
through OSA-induced alterations in counterregulatory hormone release and lipid 
metabolism, subsequently worsening glycemic control.  
Adult patients with T1D and OSA who are using an insulin pump and continuous 
glucose monitoring (CGM) will be studied in a within-subject, cross-over design. 
Participants will be studied under two 14-day study conditions in randomized order with a 
3-week (+/-1 week) washout period: untreated OSA condition (Untreated Study 
Period) and treated OSA condition (CPAP Treated Study Period). We will perform the 
same assessments in each study condition. 
    
1.2 Objectives  
The purpose of this study is to investigate to the role of OSA in glycemic dysregulation in 
adults with T1D. 
The primary objectives are: 
• 
to determine to what extent OSA contributes to suboptimal glycemic management 
(%CV) in adults with T1D. We will compare 14-day CGM profiles (at-home) 
between untreated OSA vs. treated OSA conditions to determine how the 
presence (or absence) of OSA affects standardized CGM metrics.Glycemic 
variability (% coefficient of variation i.e., % CV) will be the primary outcometo 
determine how alterations in counterregulatory hormone release and lipid 
metabolism in the setting of OSA account for suboptimal glycemic management in 

 
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adults with T1D. We will compare 24-hour blood profiles of counterregulatory 
hormones (in-lab), between untreated OSA vs. treated OSA conditions. 
2 Study Design  
This is a within-subject, cross-over study in adults with T1D and OSA (n=40) who are 
using an insulin pump and continuous glucose monitoring (CGM). Participants will be 
studied under two 14-day study conditions in randomized order with a 3-week (+/-1 week) 
washout: untreated OSA condition (Untreated Study Period) and treated OSA (CPAP) 
condition (CPAP Treated Study Period). We will perform the same assessments in each 
study condition. 
 
 
2.1 General Description 
Research Location: This research will be conducted in the research units located at the 
Clinical Research Center (CRC) on W5 floor and UChicago Sleep Center on W4 floor of 
the Mitchell building at the University of Chicago. This research will be conducted mainly 
in the UChicago Sleep Center, except for some cases where the 24-hour sampling may 
take place in Clinical Research Center (CRC). This will depend on nursing availability. 
 
 
Informed Consent: Subjects will be consented in clinic. Written informed consent will be 
obtained after a member of the research team has explained all details of the study, and 
the subject has received satisfactory answers to all of his/her questions. After informed 
consent, the subjects will undergo screening procedures. Details of all screening 
procedures are provided below under section 5. Study Procedures. 

 
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Screening Procedures: After informed consent, the subjects will undergo a single blood 
test (Visit 1) and home sleep apnea test (Visit 2). Details of all screening procedures are 
provided below under section 6. Study Schedule. 
 
Study Procedures: After screening, eligible subjects will be studied using a cross-over 
design under two conditions, untreated OSA (Untreated Study Period) and treated 
OSA (CPAP Treated Study Period), that will be done in random order with a 3-week 
(+/-1 week) washout period. Prior to the study, sleep condition order assignments will be 
prepared by the study statistician using block randomization, stratified by sex.10 Each 
study condition will be over a 14 day period. Over the 14-day period subjects will be 
asked to home monitor (wrist activity monitor & food logging, digital weight scale) and 
complete a daily questionnaire about their last night’s sleep.  The first three overnights 
(Days 1-3) will be spent in lab from 21:00h-7:00h. Days 4-12 will be spent at home, and 
the participants will continue to home monitor their activity/sleep and nutrition. On Day 
13 subjects will complete an overnight in lab sleep study. Upon waking (Day 14) subject 
will then complete 24-hour blood sampling in the research unit. Details of all study 
procedures are provided below under section 5. Study Procedures and 6. Study 
Schedule. 
2.2 Number of Subjects 
A total of 40 subjects will be enrolled (randomized) over 5-year period to achieve a final 
sample of 34 subjects completing the entire study after dropouts.  
2.3 Duration of Participation 
The duration of participation for each subject would take about 3 months, including 1 
screenings visit and 4 study visits with 3-week (+/- 1 week) washout periods between 
study visits. The overall recruitment and completion of the study would take about 5 
years.  
2.4 Study Endpoints 
Study endpoints will be:  
14-day CGM profiles (standardized CGM metrics) to assess glycemic management 
including mean glucose, glycemic management indicator (GMI), glycemic variability ((% 
coefficient of variation i.e., %CV), and time in ranges (time below, within, and above the 
established glycemic targets). Glycemic variability (% CV) will be the primary outcome.   
24-hour blood profiles (glucagon, adrenaline, noradrenaline, cortisol, growth hormone, 
free fatty acids, glycerol) measured under controlled in-lab conditions with standardized 
meals.  Additional biological and behavioral factors that may influence glycemic 
management: sleep stages by polysomnography (e.g., slow wave sleep), insulin dose 
(from pumps), self-reported sleepiness and subjective sleep quality (Morning Sleep Diary), 
diabetes self-management behaviors (i.e., self-monitoring of diet using ‘Lose It' a 
smartphone app, objective physical activity by accelerometry, validated questionnaires), 
resting metabolic rate (indirect calorimetry) and body composition (InBody 570 and daily 
weights on digital scale). We will also measure resting heart rate (Actiheart, wearable 
monitor), and fasting lipids to determine how presence (or absence) of OSA impact these 
intermediate markers of cardiovascular risk in adults with T1D. 

 
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3 Subject Selection and Withdrawal 
3.1 Subject identification and recruitment 
 
 
Subjects will be recruited in-person during routine clinic appointments in the Diabetes 
clinic and Sleep clinic. 
 
3.2 Inclusion 
• 
Age: 18 to 50 years old 
• 
Type 1 Diabetes (duration 3-20 years) on insulin pump therapy and using a CGM 
device with an GMI (glucose management indicator) between 5.5 and 8.5% with 
hemoglobin in the normal range at screening  
• 
Moderate to severe OSA by home sleep apnea test  
3.3 Exclusion 
• 
Regular and adherent CPAP use per clinical guidelines  
• 
Requiring oxygen or advanced positive airway pressure modalities during sleep 
• 
Having a ‘fall-asleep’ or ‘near miss’ accident in the past 6-months 
• 
Shift work 
• 
Severe hypoglycemia (≥1 episode in the past 3 months or diagnosis of 
hypoglycemic unawareness)  
• 
≥1 trip to emergency room for poor glucose management in the past 6 months 
• 
Proliferative retinopathy 
• 
Fasting triglycerides >400mg/dL,  
• 
Liver transaminases >2 times upper limit of normal,  
• 
Renal transplantation or serum creatinine >1.5 mg/dL 
• 
Anemia (hemoglobin <13.0g/dL in men or <11.6g/dL in women)  
• 
Acute coronary syndrome or stroke past 6 months 
• 
Severe hypertension (blood pressure>180/105 mmHg)  
• 
Any other significant health condition: unstable angina, heart failure requiring 
hospitalization in the past 6 months, significant heart block or arrhythmias, NYHA 
Class>2, pulmonary disease with dependence on oxygen or daily use of 
bronchodilators, active or chronic infection, thyroid disease and other endocrine 
disorders (e.g. Cushing syndrome, acromegaly)  
• 
Recent major surgery 
• 
Major psychiatric disorder 
• 
Subjects will also be excluded if taking medications that can confound metabolic 
assessments including systemic glucocorticoids, antipsychotics, thiazide diuretics, 
beta-blockers, daily use of aminophylline or theophylline, or use of any 
immunosuppressant.  
• 
Currently pregnant or trying to get pregnant or nursing 
• 
Smoking, alcohol or illegal drug abuse  
3.4 Early Withdrawal of Subjects 
When and How to Withdraw Subjects 
Subjects must be withdrawn from the study for any of the following reasons: 
• 
Withdrawal of informed consent 

 
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• 
Pregnancy 
• 
If the investigator concludes that it would be in the subject’s best interest for any 
reason 
Subjects may voluntarily withdraw from the study for any reason at any time. If withdrawal 
occurs for any reason, the investigator will document the reason for withdrawal in the 
source notes.   
 
Data Collection and Follow-up for Withdrawn Subjects 
Subjects who withdrew after enrollment will be replaced to complete the study. 
4 Study Drug/Device  
4.1 Description 
Subjects will complete both study periods (conditions), Untreated Study Period and 
CPAP Treated Study Period, in randomized order with a 3-week (+/- 1 week) 
washout period. 
4.2 CPAP 
During the CPAP Treated Study Period, all-night CPAP will be applied with 
bedtimes 23:00h to 7:00h. Days 1-3 will be in-lab under supervision for 3 nights to 
achieve complete resolution of OSA using optimal pressure and mask settings. On 
days 1-3 while sleeping in the research unit the overnight technician will be able to 
provide immediate help to the subjects for adjusting their mask and gain familiarity 
with the CPAP machine. Days 4-12 subjects will sleep at home with their CPAP 
machine and to follow regular bed and wake-up times 23:00h to 7:00h.  
 
CPAP treatment: CPAP masks can cause skin irritation from the mask and 
nose/mouth dryness.  
Risk Reduction: Our sleep technicians have extensive experience with CPAP 
therapy and these risks will be minimized with appropriate mask choice and 
adjustment of device humidity settings. 
 
Untreated severe sleep apnea: Untreated severe sleep apnea may carry risk of 
excessive daytime sleepiness and drowsy driving and car accidents.  
Risk Reduction: We will exclude subjects with high-risk occupation for drowsy driving 
(e.g. commercial truck driver or airline pilot). All subjects will be questioned regarding 
‘fall-asleep’ accidents or near miss accidents and such events will be notified to the 
DSMB before deciding on whether they should continue the study. The duration for 
study participation will be 3 months, and in large CPAP trials lasting from 6 months to 
more than 3 years (e.g. APPLES, SAVE trials), no increase in adverse events 
(cardiovascular or driving accident) were observed in patients with moderate or 
severe sleep apnea who were randomized to “non-treatment” arms, indicating overall 
safety of this protocol. All participants will be provided with a report summarizing the 
results of their sleep evaluations, a brochure on sleep apnea and its consequences, 
and information on available sleep centers to obtain further care. The standard 
clinical time from appointment to obtaining an at-home CPAP machine is anywhere 
from 3-6 months and subjects can be completing this process during the study. 

 
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5 Study Procedures 
5.1 Continuous Glucose Monitor (CGM) 
Glycemic management will be assessed over 14 days by CGM. Participants will 
have their own CGM device as a part of their standard clinical care. Commonly 
used standalone FDA-approved CGMs include several models of the Libre, 
including Libre 14-day, Libre 2, Libre 3, Libre 2 Plus, Libre 3 Plus;  Dexcom G6 
and G7, Eversense  E3 and 365 and Medtronic Guardian 3 and 4. Using CGM 
profiles, we will derive standardized CGM metrics14 that are used in clinical care 
to assess glycemic management.  The study team will request access to the data 
from the CGM directly from the participant.  The participant will be asked to share 
their CGM data with the research team (clinical research coordinators, clinical 
research nurse) using the connection methods that are available for their device 
in order to have data for the dates of the study. 
5.2 Insulin Pump 
Participants will have their own insulin pump as a part of their standard clinical 
care.  All insulin pumps are readily interrogated for a variety of daily and 
cumulative statistical measures, including bolus/basal ratio, percentages, and 
readily show boluses for each meal, changes in basal rates, how much insulin is 
delivered by the user and how much insulin is delivered by the pump. The study 
team will request access to the data from the insulin pump directly from the 
participant.  The participant will be asked to give the research team (clinical 
research coordinators, clinical research nurse) access through the product-
specific web-based portal in order to have data for the dates of the study. 
5.3 Dietary Tracking App ‘Lose It’ 
Diet will be captured using a standard, commercial smartphone app named “Lose 
it.” Participants will be instructed to record their daily dietary intake into the app. 
While marketed as a weight loss tool, it is used in this study because it is easy to 
use, tracks macronutrients, and data can be accessible to the research team. 
Importantly, the app has a scanner feature to track package barcodes and has 
integration with cell phone cameras to allow logging of food that might not have 
bar codes. Participants will be asked to download the data from the 14 days and 
give to the study team.  The data includes date, type of food, serving size and 
macronutrients.   
5.4 Activity Monitor 
Sleep, physical activity and heart rate will be continuously and objectively 
assessed by an 3-axis accelerosensor (Actigraph LEAP) worn on subject’s wrist 
during each 14-day study condition and 1 week preceding each study condition 
to also capture habitual patterns at home.   
5.5 Digital Weight Scale 
Body weight and composition will be measured by a take-home digital weight 
scale (Whitings BodyPro 2).  During each 14-day study condition subject will be 
asked to step on the scale within 15 minutes or wake and after they void. 

 
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5.6 Heart Monitor 
On Day 14 during the 24-hr blood sampling we will also collect data using a heart 
monitor, the Actiheart ECG device. The Actiheart is a very small, waterproof, 
ambulatory device consisting of a single-lead ECG and a tri-axis accelerometer 
to monitor heart rate, and physical activity and posture. It is worn on the chest 
(under the clothing) using standard disposable ECG electrodes. This data will 
allow us to continuously assess the resting heart rate and heart rate variability, 
which are strong prognostic markers of cardiovascular health. 
5.7 Body Composition 
To measure body composition we will use the InBody 570 Body Composition 
Analyzer located in the Clinical Research Center. This will be done in the 
morning, in a fasted state in a hospital gown to measure fat mass and fat-free 
mass.  
5.8 Indirect Calorimetry 
Resting energy expenditure will be measured for 20 min by indirect calorimetry in 
fasted state. 
5.9 Overnight Sleep Study 
Full polysomnography (overnight recording of sleep including EEG, oxygen 
saturation, respiration) overnight in the laboratory will be done to assess sleep on 
Day 13 of both the Untreated and CPAP Treated Study Periods. 
5.10 Meals 
All meals will be prepared under the supervision of a Registered Dietitian at 
UChicago Clinical Research Center’s Metabolic Kitchen. Caloric needs will be 
calculated for each participant based on indirect calorimetry. A diabetic breakfast 
will be provided every morning after overnight stays. In the evening on Day 13 
and 14, the participants will receive an in-lab weighed diabetic dinner at 19:00h 
and an evening snack before bed.  On Day 14 while subjects will be in lab for 24-
hr blood sampling, they will be provided isocaloric diabetic meals at 
08:00h,13:00h and 18:00h. Breakfast will be provided upon waking and after 
blood sampling is complete (08:00h).  Snacks/juice will be available at any time 
to prevent and/or in response to hypoglycemia. All meals will be consumed 
completely within 20 min. 
5.11 Questionnaires 
Upon awakening each morning, subjective sleep quality and daytime sleepiness 
will be assessed by the Morning Sleep Diary.  This is a combination of a 
validated a tool, Karolinska Sleep Diary15,16 and questions on any sleep 
disturbances due to CPAP mask/pressure, alarms from diabetes technologies 
(i.e., insulin pumps and CGM), and other factors related to lab/home environment 
that may influence subjects’ sleep. We will assess quality of life by Diabetes 
Quality of Life Measure17, diabetes self-care activities by Diabetes Self-
management Questionnaire18, hypoglycemia confidence by Hypoglycemia 
Confidence Scale19, and treatment satisfaction by Diabetes Treatment 
Satisfaction Questionnaire20 on Day 1 and Day 14. 

 
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5.12 Blinding 
Prior to the study, sleep condition order assignments will be prepared by the 
study statistician using block randomization, stratified by sex.13 The 
randomization order and sleep condition will be blinded to the resercah personnel 
who is responsible for data entry and data download. 
6 Study Schedule 
SEE SCHEMA APPENDIX B 
6.1 Visit 1- Screening 
This visit will be screening step 1, this visit will take up to 3 hours. Height and 
weight will be measured. Subjects will undergo screening fasted single blood 
draw (complete blood count, Lipid panel, metabolic panel, c-peptide level). 
Subjects will also undergo vitals, demographics, urine pregnancy test for women 
of childbearing potential and medical history and record of family history of any 
diabetes.  Study nurse will document any diabetes complications based on 
subject medical health record.  Subjects will undergo 20-min indirect calorimetry.  
This will allow subjects time to become familiar with the plastic hood that will be 
used during indirect calorimetry testing during study to ensure they tolerate this 
testing.   
 
Eligible subjects will then be given an at home sleep test (WatchPAT One) to 
diagnose OSA (moderate to severe OSA).  Subject will sleep with WatchPAT 
One device on for one night. WatchPAT One includes a snore/body position 
sensor worn as a sticker on the chest, small monitoring device worn on the wrist, 
and a finger probe worn on the index finger. Device is pre-programmed to record 
and is put on and worn by subject overnight at home then can be disposed of the 
next day. 
6.2 Randomization 
Randomization will occur after screening (Visit 1) is complete and subjects are 
determined to be eligible. The Untreated Study Period and CPAP Treated Study 
Period may happen in any order based on randomization assignment.  The first 
study visit will occur within 4 weeks of Visit 2.  If the timing exceeds 4 weeks then 
a single blood draw will be performed to assess no significant health changes. 
6.3 Visit 2 – CPAP Titration  
Subject will undergo an overnight sleep test (CPAP titration) by laboratory 
polysomnography to identify optimal CPAP pressure settings.  Subjects will be 
asked to sleep in the laboratory with 8-hour bedtimes from 23:00h to 7:00h. 
6.4 Untreated Study Period 
6.4.1 Untreated Day 0 ( -1 week (-3days)) 
Untreated Study Period Day 0 will be a 3-hr visit to the lab.  Subjects will meet 
with our certified diabetes care and education specialist to receive standard 
diabetes education, and review and optimize their pump/CGM use and to ensure 
that they are using the device and alarm settings properly and optimally. Alarm 
systems will be set to actionable levels to minimize sleep disruption.  Participants 

 
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will have their own CGM device and insulin pump as a part of their standard 
clinical care.  On this day participants will be asked to download the ‘Lose it’ app 
on their phones, if they don’t already have it, and asked to begin tracking their 
dietary intake.  Subjects will receive the wrist activity monitor (Actigraph LEAP). 
6.4.2 Untreated Days 1-14 
Subjects will be asked to wear wrist activity monitor and record their dietary 
intake into smartphone app ‘Lose it’ for the 14 days of study and for the week 
before study. During the 14 day study condition subjects  will be asked take their 
daily weights using the at-home digital scale. Subjects will spend the first three 
overnights (Days 1-3) in the laboratory with 8-hour bedtimes from 23:00h to 
7:00h, they will be asked to arrive at 21:00h. After the overnights (Days 1-3) the 
subject will be asked to step on the InBody 570 Body Composition Analyzer 
before leaving the laboratory. Each morning, upon wake, subjects will complete 
the Morning Sleep Diary online (RedCap) about their last night’s sleep. A diabetic 
breakfast will be provided every morning after overnight stays. Participants will 
leave the laboratory each morning after breakfast to engage in their daily routine 
activities. On days 4-12 subjects will be sleeping at home and sleep will be 
monitored at home by actigraphy.   
 
On day 13 subjects will arrive in the research unit at 20:00h and will receive an 
in-lab weighed diabetic dinner at 20:00h.  Subjects will stay in the research unit 
and sleep will be recorded by polysomnography with bedtimes 23:00h to 7:00h. 
The technician during calibration will ask the subject to complete a series of 
breathing maneuvers to evaluate neuropathy26.  Upon waking on Day 14, the 
clinical research nurse will then place a sterile intravenous catheter in the non-
dominant forearm for venous blood sampling and place the Actiheart on subject.  
Body composition will also be measured on the Bio570 Analyzer.  Blood samples 
will be collected beginning at 8:00h.  Blood samples will be collected every 15 
min for 90 min after each meal (detecting meal responses) and after bedtime 
(detecting major growth hormone pulse), and every 30 min at all other times until 
the next day 8:00h. During waking hours, blood samples will be collected at 
bedside while participants remain semi-recumbent at a 30o angle to avoid any 
influence of body position on hormone release (e.g., norepinephrine). During 
sleep hours, participants will be lying in bed and catheter line will be extended 
and fed through a port in the wall, allowing for disturbance-free blood drawing 
from an adjacent room.  On Day 14 (i.e., 24-hour sampling day), participants will 
receive 3 identical isocaloric diabetic meals served at 08:00h, 13:00h, and 
18:00h with snacks/juice available at any time to prevent and/or in response to 
hypoglycemia. Participants will be monitored for any signs and symptoms of 
hypo/hyperglycemia by the research staff. 
 
On day 14 the morning blood pressure will be measured and a 20 min indirect 
calorimetry in fasted state will be performed.  Upon the conclusion of blood 
pressure the research team will request access from the subject to the past 13 
days of data from the subjects CGM and insulin pump. 
 
After each night, subjects will be asked to complete the Morning Sleep Diary in 
the morning.  On Day 1 and Day 14 subjects will complete questionnaires as 
described in 5.9. These will take approximately 20 minutes to complete. All 
questionnaires will be completed on REDCap. 

 
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6.5 Washout Period 
During the 3 week washout period (+/- 1 week), subjects will be instructed to 
continue their typical daily routines.  No study related activites will happen during 
this time. 
6.6 CPAP Treated Study Period 
6.6.1 Treated Day 0 ( -1 week (-3days)) 
Treated Day 0 will be a 3-hr visit to the lab. All procedures described  above 
under Untreated Day 0 will be repeated.  In addition, subjects will also be fit for a 
CPAP mask and receive instruction on sleep apnea and the CPAP machine 
education to help them feel comfortable using at home. 
 
6.6.2 Treated Days 1-14 
The procedures involved in the CPAP Treated Study Period are the same as 
those during the Untreated Study Period, with the addition of the CPAP 
treatment.  For the CPAP treatment, all-night CPAP intervention (using each 
participant’s optimal pressure settings) will be applied under continuous 
supervision in-lab for the first three overnights (Days 1-3) to achieve complete 
resolution of OSA. While sleeping in the research unit, the overnight technician 
can help the subject adjust the mask and gain familiarity with the CPAP machine. 
Days 4-12 subjects will be sleeping at home with a CPAP machine (set at their 
optimal pressure settings). Successful treatment of OSA will also be verified from 
CPAP machine remotely and mask/pressure adjustment will be made as needed.   
 
Sleep will be monitored at home by actigraphy on Days 1-14.   
7 Statistical Plan and Considerations 
We propose to study n=40 individuals with T1D and OSA using a within-subject 
design. We will obtain the same metabolic and cardiovascular assessments 
under two 14-day study conditions in a randomized order with a 3-week washout 
period: untreated OSA condition vs. treated OSA condition (receiving CPAP 
intervention). Thus, this will be a 2-period cross-over study that is uniform within 
periods (i.e., half of the participants will do untreated condition first then treated 
condition, the other half will do treated condition first then untreated condition). 
Prior to study start, condition order assignments will be prepared by the study 
statistician using stratified, block randomization. Sex will be the only stratification 
factor. This randomization schedule will then be uploaded to REDCap.  
7.1 
Primary analyses  
The primary analytic approach will be to use a mixed-effects linear regression 
model to estimate the effects of treatment condition on outcomes along with 
inclusion of period, sequence, and period by treatment condition interaction and 
a random subject effect to account for the repeated measurements for each 
subject. Mean (standard deviation [SD]) values for all continuous variables, and 
frequency counts and percentages for all categorical variables will be used for 
descriptive analyses, overall and separately by treatment condition. Normality will 
be tested, using the Shapiro-Wilk test and Q-Q plots, for all continuous variables. 

 
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If there is evidence of non-normality, then a transformation such as the natural 
logarithm will be used. We hypothesize that OSA exerts negative effects on 
glucose regulation leading to suboptimal glycemic management and thus 
increasing cardiovascular risk in T1D. We further hypothesize that glycemic 
dysregulation in adults with T1D and OSA occurs in part through dysregulated 
counterregulatory hormone release and lipid metabolism, subsequently 
worsening glycemic management. To test these hypotheses, we will determine: 
to what extent OSA contributes to suboptimal glycemic management in adults 
with T1D (Aim 1) and to determine how alterations in counterregulatory hormone 
release and lipid metabolism in the setting of OSA account for suboptimal 
glycemic management in adults with T1D. (Aim 2). 
In Aim 1, the untreated OSA vs. treated OSA condition contrast in the mixed-
effects linear regression model (described above) will be of primary interest. We 
will compare 14-day CGM profiles between untreated OSA vs. treated OSA 
conditions to determine how the presence (or absence) of OSA affects glycemic 
management. The outcome variables (e.g., glycemic variability, time in range of 
glucose) will be derived from standardized CGM metrics that are used in clinical 
care to assess glycemic management.14 The number of days CGM worn, 
percentage of time CGM is active, mean glucose, glycemic management 
indicator (GMI), glycemic variability (% coefficient of variation, %CV), and time in 
ranges (time below, within, and above the established glycemic targets) will be 
derived based on consensus recommendations.14 Glycemic variability (%CV) will 
be the primary outcome. The glycemic variability metric will be calculated for 
each participant for each condition using three approaches: (1) using average 
data across all days, (2) using data only from day 13 (i.e., the final day prior to 
24-hour sampling), and (3) using data from individual days for each subject with 
inclusion of day number as a factor in the mixed-effects model. Each CGM metric 
will be calculated using data from the 24-hour, daytime, or nighttime periods, 
separately. 
 
In Aim 2, We will compare 24-hour hormonal/metabolic data between untreated 
OSA vs. treated OSA conditions and determine their relative contributions to 
glycemic management in T1D. These analyses will provide novel mechanistic 
insights into how OSA may contribute to glycemic dysregulation in T1D. The role 
of these potential mediators contributing to glycemic dysregulation will be 
assessed comparing untreated OSA vs. treated OSA conditions. The summary 
variables for each mediator (e.g., average values [24-h, daytime, nighttime], meal 
responses [area under the curve] from hormonal profiles) will be calculated, as 
previously described.11,12,21,22  First, we will determine the magnitude of the 
changes in the mediator variables (untreated – treated) using paired t-tests. We 
will then examine the correlation between the differences (untreated – treated) in 
our glycemic variables (e.g., glycemic variability [%CV]) and the differences in 
the mediator variables. With a sample size of n=40 and a two-sided alpha level of 
0.05, we will have 80%, 85%, and 90% power to detect correlation coefficients as 
small as 0.43, 0.46, and 0.49, respectively. A more formal estimation and testing 
of mediation (i.e. mechanisms that produce the effect) and moderation (i.e. 
factors that affect the magnitude of the effect) will also be performed using the 
linear regression framework, as described by Judd et al.52 In brief, a within-
subject analysis with a varying X (for example Glucagon) that can serve as both 
a moderator and a mediator will be conducted by assessing whether the 
magnitude of the treatment difference in Y (for glycemic variability, CV*) depends 

 
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on two different linear functions of the Xs: their sum and their difference as 
follows: (CV*treated – CV*untreated)= b0 + b1*(Glucagontreated + 
Glucagonuntreated) + b2*(Glucagontreated – Glucagontreated) + e, where e is 
an error term. Moderation will be indicated if the treatment difference in CV* 
depends on the sum of the two Glucagon measurements (i.e., the b1 coefficient 
is significant). Mediation will be indicated if the treatment difference in CV* 
depends on the difference between the two Glucagon measurements (i.e., the b2 
coefficient is significant), assuming an overall treatment effect in both Glucagon 
and CV*.  
7.2 
Secondary analyses  
We will calculate the untreated OSA vs. treated OSA condition contrast to 
examine the impact of OSA on additional factors that may influence glycemic 
management (e.g., insulin dose, physical activity) and determine to whether OSA 
impacts intermediate markers of cardiovascular risk (e.g., 24-hour ambulatory 
blood pressure). We will also examine the impact of variables (by including them 
in models as covariates) that could change between study conditions such as 
BMI, body composition, menstrual cycle, sleep duration, sleep stages (e.g., slow 
wave sleep), circadian phase53, and OSA indices (e.g., AHI, oxygen 
desaturation index [ODI], arousal index). We will also assess the impact of those 
variables that are stable over the study period (e.g., age, sex, race/ethnicity) on 
the magnitude of change in measured outcome variables. Models will also be fit 
separately to examine whether the treatment effects are significantly different by 
baseline OSA status (e.g., mild vs. severe OSA; hypoxic vs. non-hypoxic OSA) 
with the inclusion of the appropriate interaction terms in the mixed model.  
7.3 Missing data  
To account for missing data, multiple imputation using chained equations23-25  will 
be considered. To further address missing data (e.g., CGM data), a sensitivity 
analysis only including subjects with a given level of data completeness (70% of 
data from 14-day CGM per recommendations14) will be conducted.  
8 Risks and Benefits   
Blood sampling/Venous Catheter: There is minimal discomfort associated with 
venipuncture and slight risk of bruising, or rarely fainting and phlebitis with 
catheter placement. The hand or arm (in which an IV catheter has been inserted) 
will be wrapped in a heating pad that circulates warm water to facilitate frequent 
blood sampling during metabolic testing. With prolonged exposure to continuous 
heat, there is a potential risk of local skin irritation or a minor burn.  
Risk Reduction: The samples are collected using aseptic technique in designated 
areas of the research unit where facilities are available should untoward 
reactions occur. If phlebitis occurs, it will be treated conservatively with heat and 
when appropriate, with antibiotics. The catheter will be cared for by experienced 
research nurses. The amount of blood withdrawn will be in accordance with the 
University of Chicago IRB regulations. To minimize risk, subjects with anemia 
(hemoglobin <13.0g/dL in men or <11.6g/dL in women) will be excluded.  
 
Hyper/Hypoglycemia: During the study, subjects may have high or low blood 
sugars, which could cause a range of symptoms including possible flushing, 

 
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sweating, dizziness, confusion, racing heart, headache, blurry vision, thirst or 
excessive urination.  
Risk Reduction: The research center is equipped with rescue medications and 
equipment in the event that a subject would experience an adverse event during 
the test. Experienced nurses and physicians monitor all subjects during their 
participation in the study. In the event of excessive or symptomatic 
hypoglycemia, glucose may be given either through the IV or orally, as needed. If 
subject is experiencing symptoms or glucose approaches or is less than 
70mg/dL, the hypoglycemia will be treated by consuming 15 g of rapid acting 
glucose. Examples of 15 g of rapid acting glucose: 
              - 1/2C (4oz) juice 
              - 1 C (8oz) milk 
              - 4 pieces hard candy 
              - 4 glucose tabs 
The research nurse will monitor for 15 minutes then recheck blood sugar.  If 
blood sugar is still less than 70, the steps above would be repeated until 
resolved. 
 
 
InBody 570 Anaylzer:  Body Composition scan to measure fat free mass using 
electrical pulses. 
Risk Reduction: The amount of electrical pulses given during the InBody scan is 
very low.  Subjects with artificial electrical implants, like a defibrillator or 
pacemaker will not be included in study, but a safety questionnaire will be asked 
before every scan. 
 
Indirect calorimetry: This is a non-invasive measure of resting energy 
expenditure in which a clear plastic hood is placed over the head and shoulders 
for a period of time, during which the subject is asked to relax and remain still. 
The hood may cause feelings of claustrophobia.  
Risk Reduction: A research staff will be present throughout indirect calorimetry 
testing to ensure full comfort of the subjects during the test. To minimize risk, the 
subjects with claustrophobia will be excluded at screening.  
 
Untreated severe sleep apnea: Untreated severe sleep apnea may carry risk of 
excessive daytime sleepiness and drowsy driving and car accidents.  
Risk Reduction: We will exclude subjects with high-risk occupation for drowsy 
driving (e.g. commercial truck driver or airline pilot). All subjects will be 
questioned regarding ‘fall-asleep’ accidents or near miss accidents and such 
events will be notified to the DSMB before deciding on whether they should 
continue the study. The duration for study participation will be 3 months, and in 
large CPAP trials lasting from 6 months to more than 3 years (e.g. APPLES, 
SAVE trials), no increase in adverse events (cardiovascular or driving accident) 
were observed in patients with moderate or severe sleep apnea who were 
randomized to “non-treatment” arms, indicating overall safety of this protocol. 
Upon completion of the study, all participants will be provided with a report 
summarizing the results of their sleep evaluations, a brochure on sleep apnea 
and its consequences, and information on available sleep centers to obtain 
further care. The standard clinical time from appointment to obtaining an at-home 
CPAP machine is anywhere from 3-6 months and subjects can be completing 
this process during the study. 

 
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CPAP treatment: CPAP masks can cause skin irritation from the mask and 
nose/mouth dryness.  
Risk Reduction: Our sleep technicians have extensive experience with CPAP 
therapy and these risks will be minimized with appropriate mask choice and 
adjustment of device humidity settings. 
 
Confidentiality: It is possible that the information that we collect may be 
accessible to individuals that are not part of the research team.  
Risk Reduction: Data will be stored in a locked office and on a password 
protected computer at the University of Chicago. The CGM data will be accessed 
only by the research team for the two 14 days subjects are in the study. 
 
Alternative to participating: Subjects can decide not to participate in this study, 
this will not affect their standard of care.  During the study subjects’ standard of 
care will continue.  If there are any changes (i.e. medication, insulin dosage etc..) 
the study team will document. 
 
9 Safety and Adverse Events  
9.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• 
Serious: Serious problems or events that results in significant harm, (which 
may be physical, psychological, financial, social, economic, or legal) or 
increased risk for the subject or others (including individuals who are not 
research subjects). These include: (1) death; (2) life threatening adverse 
experience; (3) hospitalization - inpatient, new, or prolonged; (4) 
disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information 
(i.e. publications, DSMB reports, interim findings, product labeling change) 
that in the opinion of the local investigator may adversely affect the rights, 
safety, or welfare of the subjects or others, or substantially compromise the 
research data, AND 
• 
Unanticipated: (i.e. unexpected) problems or events are those that are not 
already described as potential risks in the protocol, consent document, not 
listed in the Investigator’s Brochure, or not part of an underlying disease. A 
problem or event is "unanticipated" when it was unforeseeable at the time of 
its occurrence. A problem or event is "unanticipated" when it occurs at an 
increased frequency or at an increased severity than expected, AND 
• 
Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
 
Adverse Event 
An untoward or undesirable experience associated with the use of a medical product 
(i.e. drug, device, biologic) in a patient or research subject. 
Serious Adverse Event 

 
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Adverse events are classified as serious or non-serious.  Serious problems/events 
can be well defined and include; 
• 
death 
• 
life threatening adverse experience 
• 
hospitalization 
• 
inpatient, new, or prolonged; disability/incapacity 
• 
persistent or significant disability or incapacity 
• 
birth defect/anomaly 
and/or per protocol may be problems/events that in the opinion of the sponsor-
investigator may have adversely affected the rights, safety, or welfare of the subjects 
or others, or substantially compromised the research data. 
All adverse events that do not meet any of the criteria for serious, should be 
regarded as non-serious adverse events.  
Adverse Event Reporting Period 
Any adverse event occurring during the course of the study period will be reported.  
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a 
preexisting condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the sponsor-investigator until 
the events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained.  At the last scheduled visit, the sponsor-investigator should 
instruct each subject to report, to the sponsor-investigator, any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be 
related to participation in this study.  
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should 
be documented and reported as a serious adverse event unless specifically 
instructed otherwise in this protocol.  Any condition responsible for surgery should be 
documented as an adverse event if the condition meets the criteria for an adverse 
event.  
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: (describe any 

 
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hospitalization situations which do not necessitate reporting as adverse events. 
Consider… 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
9.2 Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on 
all adverse events should be recorded immediately in the source document, and also 
in the appropriate adverse event section of the case report form (CRF) or in a 
separate adverse event worksheet.  All clearly related signs, symptoms, and 
abnormal diagnostic, laboratory or procedure results should be recorded in the 
source document. 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event should be followed until resolution, stabilization, or until it has 
been ultimately determined that the study treatment or participation is not the 
probable cause.  Serious adverse events that are still ongoing at the end of the study 
period must be followed up, to determine the final outcome.  Any serious adverse 
event that occurs during the Adverse Event Reporting Period and is considered to be 
at least possibly related to the study treatment or study participation should be 
recorded and reported immediately. 
9.3 Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriated 
action necessary to protect the study participant and then complete the Study 
Adverse Event Worksheet and log.  The principal investigator will evaluate the event 
and determine the necessary follow-up and reporting required. 
9.4 Reporting: notifying the University of Chicago IRB 
The principal investigator will report to the University of Chicago IRB any UPIRTSOs 
and Non-UPIRTSOs according to the University of Chicago IRB Policy and 
Procedures. 
 
According to the University of Chicago IRB Policy any serious adverse event (SAE) 
which the Principal Investigator has determined to be a UPIRTSO would be reported 
to the IRB as soon as possible but no later than 5 working days after the investigator 
first learns of the problem/event. The following information to collect when developing 
any forms for documentation of adverse events. 
 
Information collected on the adverse event worksheet (and entered in the research 
database):  

 
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• 
Subject’s name:  
• 
Medical record number:  
• 
Disease/histology (if applicable):  
• 
The date the adverse event occurred:  
• 
Description of the adverse event:  
• 
Relationship of the adverse event to the research (drug, procedure, or 
intervention*):  
• 
If the adverse event was expected:  
• 
The severity of the adverse event: (use a table to define severity scale 1-5**) 
• 
If any intervention was necessary:  
• 
Resolution: (was the incident resolved spontaneously, or after discontinuing 
treatment) 
• 
Date of Resolution:  
 
The principal-investigator will review all adverse event reports to determine if specific 
reports need to be made to the IRB.  For this protocol, only directly related 
SAEs/UPIRTSOs will be reported to the IRB. 
9.5 Stopping Rules  
The entire study may be discontinued at the discretion of the PI based on the 
occurrence of the following: 
• 
Adverse effects that seriously impact the risk-benefit ratio have been observed 
• 
Medical or ethical reasons affecting the continued performance of the study 
• 
Difficulties in recruitment of subjects 
• 
Any new information becomes available during the trial that necessitates stopping 
the trial 
• 
Other situations that may warrant stopping the trial 
 
Subjects will be informed that they are free to withdraw from the study at any time for 
any reason. The Principal Investigator (PI) may remove a subject from the study if, in 
the PI’s opinion, it is not in the best interest of the subject to continue the study.  
Subjects may be discontinued due to a change in compliance with an 
inclusion/exclusion criterion that is clinically relevant and affects subject safety, 
occurrence of AEs, occurrence of pregnancy, or administration of non-permitted 
concomitant 
medication 
that 
might 
affect 
subject 
safety 
or 
study 
assessments/objectives.  In case of premature discontinuation of study participation, 
efforts will be made to perform end of study/follow up assessments.  The date the 
subject is withdrawn from the study and the reason for discontinuation will be recorded 
on the subject’s Case Report Form (CRF).  All withdrawn subjects will be followed until 
resolution of any AEs or until any unresolved AEs are judged by the PI to have 
stabilized. 
9.6 Data and Safety Monitoring Plan 
The PI ensures that informed consent is obtained prior to performing any research 
procedures, that all subjects meet eligibility criteria, and that the entire study protocol 
is conducted according to the IRB-approved research plan.  
 
Additionally, the Data Safety Monitoring Board (DSMB) will monitor the study. DSMB 
members will be independent of the investigators and comprised of specialists in type 

 
Page 23 of 27                                                       Version 2025.03.14                                
1 diabetes, sleep medicine and metabolic studies who can oversee the study and offer 
guidance to the PI. The DSMB will have three voting members. The DSMB will 
convene in person or virtual every 6 months. will review adverse event data, other 
safety data, quality and completeness of study data, and enrollment data at each 
meeting to ensure proper study conduct. It will also conduct an ongoing assessment 
of clinical equipoise in the study. Study personnel should provide any new literature 
particularly pertinent to the study, along with their recommendation as to whether it 
affects the study conduct or design. The DSMB will review the informed consent form 
when it reviews the protocol. The DSMB will review the consent periodically and/or as 
needed and consider whether the consent form requires revision in light of any new 
findings or amendments. Based on an overall assessment of risk and review of the 
data, the Board will make recommendations, including whether the study should 
continue and/or be modified. 
 
In addition to regular meetings, it may be necessary to convene the DSMB urgently 
on an ad hoc basis to discuss new data or other information that raises questions 
about equipoise, safety, or anything else in the study. 
 
The expertise of the attending members should be appropriate for the agenda of the 
meeting. It’s expected that all DSMB members will attend every meeting, but, this may 
not always be possible. Therefore, the DSMB may establish a quorum for voting. A 
quorum is 2 members (usually half the members plus 1). The Board Chair and in most 
instances the Biostatistician, must be present at all meetings. All standing Monitoring 
Board members are voting members. The Board may also decide in advance whether 
ad hoc members can vote. 
 
Study data are accessible at all times for the team to review, and to the DSMB upon 
request. The PIs and co-investigators review study conduct, particularly accrual, drop-
outs, and protocol deviations on a quarterly basis. The team reviews adverse events 
(AEs) individually in real-time and in aggregate on a quarterly basis. The PIs review 
serious adverse events (SAEs) in real- time. The PIs ensure that all protocol 
deviations, AEs and SAEs are reported to the NHLBI and IRB according to the 
applicable regulatory requirements (see below).  
 
After the DSMB meets, the meeting minutes will be reviewed and approved by the 
DSMB Chair, then recommendations (if any) will be forwarded to the PI and to NHLBI 
staff. The minutes of the DSMB deliberations and recommendations (as approved by 
the Chair) will be submitted to the IRBs at the University of Chicago as well as to 
NHLBI during the annual renewals or sooner as per institutional requirements. The 
reports will include the following: a statement that a DSMB review of the data and 
outcomes across all performance sites took place on a given date; a summary of the 
DSMB review of the cumulative serious adverse events without specific disclosure by 
treatment unless safety considerations require such disclosure; and the DSMB’s 
conclusion with respect to progress or need for potential protocol modification (e.g., 
continue without changes to protocol, continue with changes (specified), or stop the 
study).  
 
Please see Appendix C for DMSB Charter. 

 
Page 24 of 27                                                       Version 2025.03.14                                
10 Data Handling and Record Keeping 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the 
subject of the following:  
• 
What protected health information (PHI) will be collected from subjects in this 
study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
The rights of a research subject to revoke their authorization for use of their PHI.  
This information is contained within the University of Chicago IRB Informed Consent.  
10.2 Research Material and Confidentiality 
Research material will be demographic data, wrist actigraphy recordings, sleep 
recordings, blood and muscle tissue samples, body weight, body composition, and indirect 
calorimetry data. Prescreening questions will be administered using University of Chicago 
REDcap, a secure portal, where the data is stored behind an encrypted firewall, and 
automatically backed up. All authorized study personnel at the University of Chicago will 
have a unique log in information to access study related data. All research material will be 
used only for research purposes and subject confidentiality will be protected according to 
guidelines. All data will be collected, stored, and managed in full compliance with HIPAA 
regulations as well as according to regulations by the IRB at the University of Chicago. All 
study personnel who will be authorized access to subject data will be trained in human 
subject’s research (e.g., CITI certified).  
10.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  If 
a space on the CRF is left blank because the procedure was not done or the question was 
not asked, write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All 
entries should be printed legibly in black ink.  If any entry error has been made, to correct 
such an error, draw a single straight line through the incorrect entry and enter the correct 
data above it.  All such changes must be initialed and dated. Do not erase or use “white-
out” for errors.  For clarification of illegible or uncertain entries, print the clarification above 
the item, then initial and date it.  If the reason for the correction is not clear or needs 
additional explanation, neatly include the details to justify the correction. 
10.4 Records Retention 
The principal investigator will maintain records and essential documents related to the 
conduct of the study.  These will include subject case histories and regulatory 
documents. Study documents will be retained for six years following the completion of 
the study. 
 

 
Page 25 of 27                                                       Version 2025.03.14                                
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study.  The decision of the IRB concerning the conduct of the study will be 
made in writing to the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for review 
and approval by the IRB for the study.  The formal consent of a subject, using the 
Approved IRB consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject or the subject’s legally 
authorized representative, and the individual obtaining the informed consent. 
12 Study Finances 
12.1 Funding Source 
The study is financed through a grant from the US National Institute of Health.  
12.2 Subject Payments 
Subjects will be paid: 
- $50 for completing the Visit 1 Screening in-clinic activities  
- $50 for completing the Visit 1 Screening at-home sleep study (Only subjects who 
qualify for the study after completing the screening in-clinic visit will be asked to 
complete the at home sleep study). 
- $50 for completing Visit 2 CPAP Titration 
- $1000 to complete The Untreated Study Period  
- $1000 for completing CPAP Treated Study Period.  
 
Subjects may be paid up to $2150 if they complete the entire study. Payments will be 
made after each study visit.  
 
13 Publication Plan 
The study team at the University of Chicago holds the primary responsibility for publication 
of the results of the study. 
14 References  
1. Wilmot EG, Choudhary P, Leelarathna L, Baxter M. Glycaemic variability: The under-
recognized therapeutic target in type 1 diabetes care. Diabetes Obes Metab. Dec 
2019;21(12):2599-2608. doi:10.1111/dom.13842 

 
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2. Peng CS, Cao YA, Tian YH, Zhang WL, Xia J, Yang L. Features of continuous glycemic 
profile 
and 
glycemic 
variability 
in 
patients 
with 
obstructive 
sleep 
apnea 
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Epub 2021 Aug 14. 
 
 
 
15 Appendixes 
 
A. INFORMED CONSENT FORM 
 
B. SCHEDULE OF EVENTS (SCHEMA) 
 
C. DSMB CHARTER 
 
D. QUESTIONNAIRES