Yale-Harvard Hotel-based Closed-Loop Studies in Children (HY-GRAID)
Phase: NA
Conditions: Type1 Diabetes
Sponsor: Yale University

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A Closed-Loop Study to Evaluate Safety of 
Zone MPC based Artificial Pancreas in 
Pediatric Subjects 
 
Clinical Protocol 
NCT04255381 
November 29, 2018 
Principal Investigators: 
Stuart Weinzimer, M.D. 
Professor of Pediatrics 
Yale University School of Medicine 
New Haven, CT 06520 
Email: stuart.weinzimer@yale.edu, Phone: 203-785-7924, Fax: 203-737-2829 
 
 
Eyal Dassau, Ph.D. 
Senior Investigator & Diabetes Team Research Manager 
Harvard John A. Paulson School of Engineering and Applied Sciences, 
29 Oxford St. 
Cambridge, MA 02138 
Email: dassau@seas.harvard.edu, phone: 617-496-0358, fax: 617-496-5264 

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Table of Contents: 
1. Background and Rationale ............................................................................................. 4 
2. Objectives ...................................................................................................................... 5 
3. Study Overview ............................................................................................................. 5 
4. Study Subjects ............................................................................................................... 6 
a. Eligibility Criteria .................................................................................................... 6 
b. Exclusion Criteria .................................................................................................... 6 
c. Sources of Subjects .................................................................................................. 7 
d. Consent Process ....................................................................................................... 7 
e. Sample Size ............................................................................................................. 7 
5. Study Procedures ........................................................................................................... 7 
a. Enrollment Visit ....................................................................................................... 7 
1) Medical History.................................................................................................. 7 
2) Physical Examination ......................................................................................... 8 
3) Laboratory Data ................................................................................................. 8 
4) CGM Placement ................................................................................................. 8 
5) Blood Glucose Meter.......................................................................................... 8 
b. Hotel Visit ............................................................................................................... 8 
1) Initiation of Closed-Loop ................................................................................... 8 
2) Activities During Hotel Visit .............................................................................. 9 
3) Exercise ............................................................................................................. 9 
4) Diabetes Management During Hotel Visit .......................................................... 9 
5) Hypoglycemia and Hyperglycemia Management ................................................ 9 
6) Remote monitoring ............................................................................................. 10 
7) Stopping criteria ................................................................................................. 10 
8) Treatment Protocol Table ................................................................................... 11 
9) End of Hotel Visit .............................................................................................. 12 
10) Surveys and Interviews ...................................................................................... 12 
6. Data 
Analysis ......................................................................................................................... 13 
a. Primary Endpoint ..................................................................................................... 13 
b.   Secondary Endpoints…………………………………………………………….. 
13 
c. Stopping .................................................................................................................. 13 
d. Continuation… ........................................................................................................ 14 
7. Financial Considerations ............................................................................................... 14 
a. Subject Compensation… .......................................................................................... 14 
b. Meal Stipend… ........................................................................................................ 14 

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8. Adverse Event Reporting and Safety Monitoring…........................................................ 14 
a. Definition… ............................................................................................................. 14 
b. Recording of Adverse Events ................................................................................... 15 
c. Reporting Serious or Unexpected Device-Related Adverse Events ........................... 15 
d. Unanticipated Adverse Device Events ...................................................................... 15 
e. Data Safety Monitoring Board (DSMB) ................................................................... 15 

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1. Background and Rationale 
The management of type 1 diabetes (T1D) can be complex, burdensome, and frustrating, 
requiring multiple tests of blood glucose levels daily, multiple injections of insulin (or 
manual dosing of an insulin pump), and monitoring of physical activity and carbohydrate 
intake. Real-time adjustments must be made on a daily basis for unplanned activities or 
foods, illness, and emotional factors that impact blood glucose levels; and even with 
adherence to the most rigid food, exercise, blood glucose, and insulin administration 
schedules, inherent pharmacological and physiological variability results in glucose swings 
out of desirable, or even safe, ranges. In no group of people is this more problematic than 
in young children, in whom eating and physical activity levels are highly variable and 
unpredictable, sensitivity to insulin renders small errors in insulin dosing prone to 
dangerous swings in blood glucose levels, and awareness of symptoms to warn of 
impending hypoglycemia or ability to effectively communicate this awareness is limited. 
Furthermore, most, if not all, diabetes management tasks in this age group must be 
performed by others: for the most part, parents (typically the mother), but also babysitters, 
other adult caregivers, and school personnel. At the same time, the demonstrated, well-
known adverse neurological effects of hypoglycemia, and the increasingly apparent 
adverse consequences of hyperglycemia on the developing brain, raise the stakes for good 
control even higher in this population, who must live the longest with the burden of 
diabetes. 
Many parents cope with these uncertainties by being very watchful and closely monitoring 
their child. Research with mothers of young children describes this state as one of “constant 
vigilance”. This sense of continuous responsibility to protect their child is especially 
burdensome during those early years, during which time pediatric parenting stress levels 
seem to be higher, particularly for mothers. Nighttime caregiving, including nocturnal 
blood sugar monitoring, is practiced by upwards of 40% of parents, and is associated with 
sleep deficit and increased anxiety and stress. Nearly a quarter of mothers of young children 
report clinically significant levels of anxiety and depression, the levels for which, not 
surprisingly, were highest for those who found it more upsetting to cope with T1D-related 
stress. Moreover, parents who experience more frequent and difficult T1D-related stress 
also tend to feel less confident in their capacity to perform these tasks, and have greater 
fear of hypoglycemia. There is evidence that over time, higher parental depressive 
symptoms, and parent stress, are associated with decreased parent involvement and greater 
family conflict. Taken together, these data raise many red flags about the impact the 
unremitting demands that T1D management can have on a parent’s well-being, particularly 
mothers who still tend to be primary caretakers. 
Modern technological improvements have had limited success in improving diabetes 
management in this age group. Despite the known benefits of long-term control of blood 
glucose, only 27% of children meet the current American Diabetes Association and 
International Society for Pediatric and Adolescent Diabetes A1c target of < 7.5%. 
The artificial pancreas platform employed under study is centered about the following four 
key innovations: 1) A zone model predictive control strategy that is at the same time very 
safe with respect to hypoglycemia, and can simultaneously and independently be 

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tuned with respect to its response to hyperglycemia; 2) Zone control with diurnal blood- 
glucose target zones; 3) Models of insulin-glucose physiology and insulin on board; 4) A 
system for alarming and notification of impending hypoglycemia and technical 
malfunctions: the Health Monitoring System. These features have been evaluated in several 
clinical trials in adults with unannounced meals and exercise. 
The proposed study will evaluate enhancements to our previous system tailored for the 
special needs of pediatric subjects: 1) A control strategy with responses to hyperglycemia 
and hypoglycemia spanning wide ranges, as is typical with children; 2) The use of time- 
dependent zones specific for pediatric subjects; 3) The development of models for young 
children, capturing the greater physiologic variability, and ensuring cautious insulin 
delivery; 4) remote alarming and notification systems that are useful to parents. 
 
 
2. Objectives 
The aim of this clinical study is to determine the feasibility, safety, and preliminary 
effectiveness of the Zone-Model Predictive Control Artificial Pancreas (ZMPC_AP) 
system in pediatric subjects with type 1 diabetes in an ambulatory semi-supervised 
environment over a short duration of 3 days and 2 nights, or up to 60 hours. 
 
 
Figure 1. Outline of the proposed clinical study. 
3. Study Overview 
We will assess the feasibility, safety, and preliminary effectiveness of a Zone-Model 
Predictive Control Artificial Pancreas (ZMPC_AP) system in children and adolescents 
with type 1 diabetes. The study will simulate children’s usual home environments, 
including meals of typical size and carbohydrate content, and will also include periods of 
afternoon exercise typical of after-school sports or other activities. This study will utilize 
a “hybrid” closed-loop paradigm, in which subjects (or parents) must count the 
carbohydrate content of the meals and announce this to the system at the time of the meal. 
Subjects and parents will be free to travel within a 15-minute walking distance of the study 
site, and they will sleep overnight in a local hotel, in which study personnel will provide 
on-site supervision. The duration of closed-loop control will be up to 60 hours. The initial 
cohort will be comprised of adolescent subjects, age 12-17y, and if successful (i.e. no 
stopping criteria are met), additional cohorts will consist of progressively younger-age 
children (8-<12y and then <8y). 
Admission 
based on 
eligibility 
criteria 
Baseline 
assessment 
of glucose 
control 
Day 1 
(Lunch, 
Dinner) 
Day 2 
( 
t, 
Breakfas 
Lunch, 
Dinner) 
Day 3 
(Breakfast, 
Lunch) 
Closed-loop study using AP 
 
Study 
conclusion 

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4. Study Subjects 
 
a. Eligibility Criteria 
Subjects will be eligible to participate in the study if they meet the following inclusion 
criteria: 
1) Age <18 years; for first cohort(s), subjects will be 12-17 years; additional age brackets 
will be 8-11 years and then <8 years 
2) Type 1 diabetes for ≥ 1 year duration – the diagnosis of type 1 diabetes will be based 
on the history of ketosis/ketoacidosis at diagnosis or laboratory evidence of islet-cell 
auto-immunity 
3) A1c level ≤ 10.0% 
4) Use of insulin pump and carbohydrate counting for ≥ 3 months 
5) Current or past use of CGM is desirable but NOT required 
6) Normal renal function as measured within 6 months of enrollment 
7) Normal thyroid function within 6 months of enrollment, or if previously diagnosed 
with hypothyroidism, documented within 3 months of enrollment 
8) Parent/guardian agrees to stay at hotel with subject for duration of hotel phase and has 
cell phone that can send/receive text messages 
9) Subject and participating parent/guardian speak and comprehend English 
 
b. Exclusion criteria 
Subjects will be ineligible to participate in the study if they meet any of the following 
criteria: 
1) Episode of diabetic ketoacidosis (DKA) within 6 months of enrollment 
2) Episode of severe hypoglycemia (seizure, loss of consciousness) within 6 months of 
enrollment 
3) Use of medications (other than insulin) known to affect BG levels within 4 weeks of 
enrollment – examples include systemic glucocorticoids, metformin, pramlintide, 
liraglutide, SGLT inhibitors) 
4) Current use of other medications, that in opinion of investigator, would interfere with 
safety or effectiveness of the study including acetaminophen 
5) Medical disorder, that in opinion of investigator, would be contraindication for 
inclusion; hypothyroidism and celiac disease are NOT exclusion if under good control 
6) Female subjects of childbearing potential unwilling to have pregnancy testing 
7) Female subject currently pregnant or lactating 
8) History of alcohol or drug abuse, documented eating disorder, or inpatient psychiatric 
treatment within 6 months of enrollment 
9) Subject is currently participating in another research study involving an 
investigational drug or device 
10) Parent/guardian unable or unwilling to comply with study protocol and stay at hotel 
with subject for duration of study 
11) Parent/guardian does not have cell phone with messaging capability 

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12) Parent/guardian does not comprehend written and spoken English 
 
c. Source of Subjects 
Subjects will be recruited from the clinic population at the Yale Children’s Diabetes 
Program who meet eligibility criteria. Additional subjects may be recruited from local 
advertising and/or the website clinicaltrials.gov. Potential subjects may be emailed 
information regarding the study, including copies of the consent forms, and if interested 
will be invited to the research center for formal enrollment. 
d. Consent Process 
The principal investigators, co-investigators, or study coordinators will introduce the 
studies to eligible participants and their caretakers during routine medical visits or in the 
form of a mailing or phone call. Prospective subjects/caretakers will have a face-to-face 
meeting with the investigator and/or study coordinator to address questions about the study 
rationale, procedures, risks and benefits. In order to identify and clarify any 
misconceptions, parents/caretakers will be encouraged to describe the research procedures 
and their associated risks in their own words, followed by correction of any errors by the 
investigator or study coordinator. All the subjects in the proposed studies will be minors; 
parent/guardian permission will be obtained for all subjects; additionally, for subjects age 
7 or older, subject assent will also be obtained, as per Yale IRB guidelines.   The 
parents/caretakers of participants will be encouraged to ask questions and will be clearly 
informed about the time required for these studies and their rights of non-participation 
and/or withdrawal. Caretakers/parents will be given copies of the signed consents to keep.   
Since personal health information will be collected as part of this research protocol, 
parents/caretakers will also be asked for authorization to collect this information in 
accordance with HIPAA and Yale IRB guidelines. 
e. Sample Size 
We will enroll a convenience sample of 24-48 subjects (8-16 in each of the three age 
cohorts), the final number depending on whether additional cohorts needed to be repeated 
at any given age group. There is no formal sample size calculation for this study. 
5. Study Procedures 
The study will consist of two visits, separated by no more than two weeks: an enrollment 
visit and a hotel visit. 
a. Enrollment Visit 
Subjects and parents/caregivers invited to participate in the study will undergo the consent 
process as described above, and then have the following study procedures: 
1) Medical History 
A medical history will be elicited from subjects/parents, focusing on current diabetes 
management issues, prior diabetes-related history (date of diagnosis, complications and co-
morbidities), history of adverse events (severe hypoglycemia, DKA), other past and 

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current medical problems, medications, and allergies. For subjects already attending the 
Yale Children’s Diabetes Program, electronic medical records will be available for each 
subject. For subjects not attending the Yale Children’s Diabetes Program, copies of 
medical records will be requested. Demographic data including age, sex, race/ethnicity will 
also be recorded. Current pump settings, glucose meter and continuous glucose monitor 
(CGM) logs, will be reviewed and recorded. 
2) Physical Examination 
A focused physical examination will be conducted on all subjects, including vital signs, 
anthropometrics, cardiac, respiratory, abdominal, and neurological systems, thyroid, skin 
(particularly infusion sites), and pubertal staging. 
3) Laboratory Data 
Subjects’ previous laboratory records will be reviewed, and a point-of-care A1c will be 
obtained at the visit, to confirm eligibility. Female subjects of childbearing potential will 
have a urine pregnancy test; those with a negative test will be invited to participate, and 
those with a positive test will be offered appropriate counseling. 
4) CGM Placement 
Subjects will be fitted with a DexCom sensor for collection of baseline glycemic 
profile data. Subjects already using a Dexcom CGM for their routine diabetes care 
may continue to use their own sensors; subjects not using Dexcom CGM will be 
provided with one and instructed on its proper use, including insertion, calibration, 
interpretation of data, recharging, and troubleshooting. Subjects/parents will be reminded 
that ALL insulin dosing decisions should continue to be made using capillary blood 
glucose testing with their usual meter, NOT the sensor. Subjects will be asked to collect 
baseline CGM data for up to two weeks. 
5) Blood Glucose Meter 
Subjects will be provided with a study glucose meter, which should be used for ALL BG 
testing during the baseline data collection period, as well as for calibration of the CGM. 
Subjects and parents will be instructed to test BG at least 4 times daily, more as needed, 
as per their usual home routine. Calibrations of the CGM should be done at least twice 
daily at appropriate times. 
 
 
b. Hotel Visit 
Approximately 1-2 weeks after the enrollment visit, subjects and at least one 
parent/guardian will return for a “hotel” visit, of up to 60 hours, during which time the 
following will occur: 
1) Initiation of Closed-Loop 
Subjects will return to study site in the morning of the day of admission, for review of 
interim diabetes control and uploading of pump, meter and CGM data. Subjects’ current 

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insulin pumps and sensors will be swapped for the study pump and sensor, and the system 
will be initialized and activated under study staff supervision. Study subjects will be trained 
on proper use of the system and will receive hard-copy training materials to use as 
reference. Before leaving the study facility, subjects will be required to demonstrate 
competency with basic system operations, and successful operation of the SMS alert 
system for subjects’ and staff cell phones will be ensured.   This training portion of the 
study may occur at the Yale Children’s Diabetes Research Program facility or at a 
conference room at the study hotel. 
2) Activities During Hotel Visit 
Subjects will be encouraged to participate in usual daily activities, including exercise, 
eating out, shopping, etc) as long as they remain within a 15-minute walking radius of the 
study site, and they have a functioning cell phone with messaging capabilities. There will 
be age-appropriate scheduled activities with the study group as well as personal “down- 
time.” During the entire duration of this phase, subjects will be under direct supervision 
of a parent or study staff member at all times. Subjects and parents will be required to 
return to hotel by 9 pm and have BG level checked at midnight each night they are at the 
hotel. A member of the study staff will be available at the hotel each night during the study 
to ensure subject safety and will check subjects’ BG levels at midnight each night. 
3) Exercise 
Subjects will be encouraged to participate in exercise activities each day during the hotel 
visit, such as walking, jogging, exercise room, or sports. Exercise will not be announced to 
the controller, but subjects that usually pre-treat exercise with small amounts of 
carbohydrate may continue to do so after discussion with study staff. All subjects will 
check BG levels prior to and after the planned exercise. 
4) Diabetes Management During Hotel Visit 
Subjects will continue to count carbohydrates for all meals and snacks and enter this 
amount into the controller of the closed-loop system. For youngest age group (<8 y), 
manual pre-meal boluses may not necessarily be given, at discretion of the investigator, to 
test the robustness of the system. Subjects will not utilize “correction doses” for 
hyperglycemia except if instructed by study staff. 
5) Hypoglycemia and Hyperglycemia Management 
Subjects and parents will be instructed to test BG on the study meter for any CGM readings 
under 70 mg/dL or if subject develops symptoms of hypoglycemia. For any documented 
BG <70 mg/dL or in the setting of symptoms of hypoglycemia, study staff will be alerted, 
subject will be treated with 15-30 gm rapid-acting carbohydrate (such as juice or glucose 
tabs), and BG will be rechecked in 15 minutes. Additional treatments for hypoglycemia 
will be given every 15 minutes as needed until BG levels are ≥ 70 mg/dL. For CGM 
readings ≥ 300 mg/dL for > 1 hour, subject will test BG, and if confirmed BG 
≥ 300 mg/dL, subject will test blood ketones. Subject or parent will contact investigator for 
any blood ketone level > 1.0 mmol/l for instructions on supplemental insulin, 

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changing insertion site, and continuation of closed-loop control, as per the Treatment 
Protocol (Table 1). 
6) Remote Monitoring 
Subjects’ parent/guardian and study staff will receive event-based SMS (text) alerts on 
their cell phones for low sensor readings, or for other operational issues affecting 
performance of the system. For these studies, the threshold for predictive hypoglycemia 
alerts will be set to 65 mg/dL. If the hypo- alert is activated, subjects will be required to 
test BG and communicate result to study staff.   If study staffs have received an SMS alert, 
they will call subjects on their cell phone if they have not received a call from them within 
15 minutes. Subjects will be instructed to treat symptomatic hypoglycemia or confirmed 
BG level < 70 mg/dL with 15-30 grams of rapid-acting carbohydrate (such as juice or 
glucose tabs), re-check BG level in 15 minutes, and repeat as necessary until BG level is 
over 70 mg/dL. Study staff will advise subject/caregiver whether to continue current 
diabetes management or exit closed-loop control, as per the Treatment Protocol (Table 1). 
7) Stopping Criteria 
If an individual subject has two episodes of a confirmed BG < 50 mg/dL (separated by at 
least 30 minutes), blood ketones > 1.0 mmol/L for over 2 hours, or any blood ketone level 
> 3.0 mmol/L, then the study will be stopped for that subject. Recall that subject will 
test for ketones after a confirmed BG ≥ 300 mg/dL following CGM readings ≥ 300 mg/dL 
for > 1 hour. If any subject has a seizure, loss of consciousness or ketoacidosis (CO2 < 15 
mEq/L, or pH<7.3) the study will be stopped for that subject and no additional subjects will 
be enrolled until the DSMB reviews the data. 
If for any subject the BG ≥ 300 mg/dL and blood ketones are > 1.0 mmol/L, the closed- 
loop control will be temporarily stopped, the infusion site will be changed, and 
supplemental insulin may be given at the discretion of the investigator. The closed-loop 
control will be restarted if BG <250 mg/dL and blood ketones < 0.6 mmol/L. 
If for any subject the BG ≥ 400 mg/dL for any ketone levels, the closed-loop control will 
also be temporarily stopped, the infusion site will be changed, and supplemental insulin 
may be given if the investigator concludes that the issue is related to a site failure and not 
due to malfunction of the controller. The closed-loop control will be restarted if BG <250 
mg/dL and blood ketones < 0.6 mmol/L. 
Additional information is shown in the Treatment Protocol table. 

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8) Treatment Protocol Table 
Table 1. Hypoglycemia and hyperglycemia monitoring and treatment procedures. 
 
Meter BG 
(mg/dL) 
Ketones 
(mmol/L) 
Clinical State 
Action 
Monitoring 
Any 
Seizure, loss of 
consciousness, 
or inability to 
consume oral 
treatment 
STOP system 
Treat with SQ glucagon 
Notify MD/NP 
End closed-loop 
STOP study for this patient 
Repeat BG every 
15 minutes until 
BG≥70mg/dL 
<70 
Conscious, 
well-appearing 
Treat with oral glucose 
Notify MD/NP 
Repeat MBG 
Continue closed-loop 
Repeat BG every 
15 minutes until 
BG≥70mg/dL 
70-299 
Asymptomatic 
and well 
Continue closed-loop 
Check BG 
(Premeal, pre 
and post exercise 
and midnight) 
300-399 
≤ 1.0 
Asymptomatic 
and well 
Continue with closed-loop 
Notify MD/NP 
May 
consider 
supplemental 
insulin 
Repeat BG and 
ketones in 1 hour 
300-399 
> 1.0 
Asymptomatic 
and well 
Notify MD/NP 
SQ insulin correction, set change 
Suspend closed-loop 
May restart if BG 80-250 mg/dL 
and ketones < 0.6 mmol/L. 
Encourage oral fluid intake. 
Repeat BG and 
ketones in 1 hour 
≥400 
Any 
Notify MD/NP 
SQ insulin correction, set change 
Suspend closed-loop 
May restart if the investigator 
concludes that the issue is related 
to a site failure and not due to 
malfunction of the controller, BG 
80-250mg/dL and ketones < 0.6 
mmol/L. 
Encourage oral fluid intake. 
Repeat BG and 
ketones in 1 hour 
Any 
>1.0 for 
>2h or 
>3.0 
once 
STOP system 
Notify MD/NP 
SQ insulin correction, set change 
End closed-loop 
STOP study for this patient 
Repeat BG and 
ketones in 1 hour 

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Any 
Any 
Abdominal 
pain, vomiting, 
altered level of 
consciousness 
STOP system 
Notify MD/NP 
SQ insulin correction, set change 
End closed-loop 
STOP study for this patient 
Transfer to ER for further Tx 
Per clinical 
scenario 
 
9) End of Hotel Visit 
At the conclusion of the hotel visit (afternoon of 3rd day), subjects will return to their usual 
pre-study insulin pump and regimen. Study devices will be returned and uploaded for data 
analysis. Subjects and parents will participate in semi-structured interviews and/or focus 
groups to give opinions about system usability, confidence in system safety, fear of 
hypoglycemia, and diabetes-related distress. Study staff will call subjects/parents 
approximately 24 hours after discharge to review BG control and assess for late adverse 
events. 
10) Surveys and Interviews 
Subjects and parents/caregivers will, at the conclusion of the hotel visit, complete several 
surveys/questionnaires to assess the effect of the closed-loop system on diabetes-related 
quality of life and distress, fear of hypoglycemia, and satisfaction with diabetes technology 
(see Table 2). Subjects and caregivers will also participate in focus groups or semi-
structured interviews related to human factors issues, and perceived burdens and benefits, 
of the closed-loop system. Only the interviewer and participant(s) will be present during 
the interview/focus group. 
Table 2. Surveys/questionnaires to assess effect of the closed-loop AP system. 
 
CONSTRUCT: 
MEASURE: 
CHILD/ADOLESCENT SURVEYS 
Fear of hypoglycemia 
Hypoglycemia Fear Survey 
Diabetes burnout/burden 
Problem Areas in Diabetes 
Quality of life–diabetes specific 
Pediatric QoL Inventory (PedsQL) – Diabetes Module (8-12) 
Quality of life–diabetes specific 
Pediatric QoL Inventory (PedsQL) – Diabetes Module (13-18) 
Automated Insulin Delivery Device Acceptance 
INSPIRE AID Acceptance (Draft) - Child 
Automated Insulin Delivery Device Acceptance 
INSPIRE AID Acceptance (Draft) – Teen 
PARENT OF YOUTH W T1D SURVEYS 
Fear of hypoglycemia 
Hypoglycemia Fear Survey – Parent version 
Diabetes burnout/burden 
Problem Areas in Diabetes – Parent version 
Quality of life–diabetes specific 
Pediatric QoL Inventory (PedsQL) – Diabetes Module (8-12)– 
Parent version 
Quality of life–diabetes specific 
Pediatric QoL Inventory (PedsQL) – Diabetes Module (13-18) – 
Parent version 

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CONSTRUCT: 
MEASURE: 
Automated Insulin Delivery Device Acceptance 
INSPIRE AID Acceptance (Draft) – Parent Version 
ALL AGES 
Technology Acceptance 
Comfort and Use of Technology Survey 
Glucose Monitoring Satisfaction 
The Glucose Monitoring Satisfaction Survey (GMSS) 
 
 
 
 
 
6. Data Analysis 
a. Primary Endpoint 
The primary endpoint for the short-duration hotel study is safety, as defined as: 1) no more 
than one confirmed BG < 50 mg/dL; 2) no more than two confirmed BG ≥ 300 mg/dL 
longer than 2 hours, unless determined to be from an infusion site failure; 3) no BG ≥ 400 
mg/dL; 4) no blood ketone level > 1.0 mmol/l for longer than 2 hours, or any ketone level 
>3.0 mmol/L, unless determined to be from an infusion site failure; and 5) no significant 
adverse events, such as severe hypoglycemia (seizure, loss of consciousness), diabetic 
ketoacidosis. 
 
b. Secondary Endpoints 
Efficacy endpoints of interest will include: 
a. Mean meter and sensor glucose 
b. % Time in range (70-180 mg/dL) 
c. % Time below range (<70 mg/dL) 
d. % Time above range (>180 mg/dL) 
e. % Time in hypoglycemia (<60 mg/dL) 
f. % Time in hyperglycemia (>250 mg/dL) 
g. % time AP system active 
 
The glycemic metrics will be calculated by total 24-hour period, and also broken down into 
daytime (6AM-11PM) and nighttime (11PM-6AM) periods. 
c. Stopping 
If an individual subject has two episodes of a confirmed BG < 50 mg/dL (separated by at 
least 30 minutes), blood ketones > 1.0 mmol/L for over 2 hours, or any blood ketone level 
> 3.0 mmol/L, then the study will be stopped for that subject. If any subject has a seizure, 
loss of consciousness or ketoacidosis (CO2 < 15 mEq/L, or pH<7.3) the study will be 
stopped for that subject and no additional subjects will be enrolled until the DSMB 
reviews the data. 

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d. Continuation 
If stopping criteria are NOT met for an age cohort, then after that cohort is completed we 
will proceed to next lower age cohort after DSMB review and approval.   However, even 
if stopping criteria are not met, additional cohorts at a given age range may be enrolled at 
discretion of investigators if adjustments to algorithm tuning parameters are desired based 
on glycemic results and comparison with subjects’ pre-study baseline glycemic profiles. 
 
 
7. Financial Considerations 
a. Subject compensation 
 
Subjects/parents will receive $50 for the enrollment visit and $100/day for the hotel visit, 
for a maximum of $350 compensation for participation. 
b. Meal Stipend 
All subject meals during the hotel stay will be covered by the study. Parents will receive 
$75 per day stipend for their meals and expenses during the hotel stay. Parking at the hotel 
will be covered by the study. 
 
 
8. Adverse Event Reporting and Safety Monitoring 
 
a. Definition 
Reportable adverse events in this study include any untoward medical occurrence that 
meets criteria for a serious adverse event or any medical occurrence (expected or 
unexpected) in a study participant that is study or device-related. 
Hypoglycemic events are recorded as adverse events if the event required assistance of 
another person due to altered consciousness and required another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions to prevent harm. This 
means that the subject was impaired cognitively to the point that he/she was unable to treat 
his or herself, was unable to verbalize his or 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 glucose measurements are not 
available during such an event, neurological recovery attributable to the restoration of 
glucose to normal is considered sufficient evidence that the event was induced by a low 
plasma glucose concentration. 
Hyperglycemic events are recorded as adverse events if the event involved diabetic 
ketoacidosis, as defined by the DCCT, and had all of the following: 
• 
Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
• 
Serum ketones or large/moderate urine ketones; 

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• 
Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
• 
Treatment provided in a health care facility 
 
b. Recording of adverse events 
Throughout the course of the study, all efforts will be made to remain alert to possible 
adverse events or untoward findings. The first concern will be the safety of the participant, 
and appropriate medical intervention will be made. The study investigator will assess the 
relationship of any adverse event to be related or unrelated by determining if there is 
reasonable possibility that the adverse event may have been caused by the study device 
or study procedures. 
The intensity of adverse events will be rated on a three-point scale: mild, moderate, or 
severe. It is emphasized that the term severe is a measure of intensity: thus a severe adverse 
event is not necessarily serious. For example, itching for several days may be rated as 
severe, but may not be clinically serious. 
Adverse events that continue after the participant’s discontinuation or completion of the 
study will be followed until their medical outcome is determined or until no further change 
in the condition is expected. 
c. Reporting serious or unexpected device-related events 
A serious adverse event is any untoward occurrence that: 
• 
Results in death 
• 
Is life-threatening; (a non life-threatening event which, had it been more severe, might 
have become life-threatening, is not necessarily considered a serious adverse event) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
d. Unanticipated adverse device event 
An unanticipated adverse device event is defined as an adverse event caused by, or 
associated with, a device, if that effect or problem was not previously identified in nature, 
severity, or degree of incidence. 
Serious or unexpected adverse events must be reported to the PI immediately.   The PI will 
notify the Yale IRB, DMSB, FDA, and device manufacturer of any adverse device event 
that is both serious and unexpected. Notification will be made within 5 days after the PI 
becomes aware of the event, as per Yale IRB requirements. 
e. Data Safety Monitoring Board (DSMB) 
Drs. Dassau and Weinzimer will convene a Data Safety Monitoring Board, (DSMB), 
comprised of independent clinicians experienced in the management of young children 
with type 1 diabetes, to review study protocols and safety reports with study 

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investigators. The DSMB will be responsible for oversight of the proposed protocol. The 
DSMB will monitor the ongoing safety of the studies through periodic reports, at least 
twice a year, provided by the clinical center, and any adverse event reports as described 
above requiring notification will also include the Chair of the DSMB. The DSMB will meet 
with Drs. Weinzimer and Dassau every six months, either in person or by conference call, 
to review study progress and adverse events. In addition, the DSMB will meet with study 
investigators before the initiation of successively younger subject cohorts, for their input 
on safety, before any subjects are enrolled, in order to approve the monitoring plans for 
each study phase at their start.