A Randomized Study to Compare a Fully-closed MPC Control Algorithm With a Commercial Hybrid Closed-loop Algorithm
Phase: NA
Conditions: Type 1 Diabetes
Sponsor: Oregon Health and Science University

OHSU IRB #24218 
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PROTOCOL TITLE: A randomized study to compare a fully-closed MPC control 
algorithm with a commercial hybrid closed-loop algorithm 
 
Brief Title: Two Way Crossover Closed Loop MPC vs Control IQ 
 
NCT Number: NCT05799781 
 
Unique Protocol Id: OHSU24218, Advarra Pro00067326  
 
Version 10.0 updated 10/14/2024 
 
 

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PROTOCOL TITLE: A randomized study to compare a fully-closed MPC control 
algorithm with a commercial hybrid closed-loop algorithm 
 
 
  
STUDY SITES: 
Oregon Health Science University 
3270 SW Pavilion Loop  
Portland, OR 97239 
 
UW Diabetes Institute 
750 Republican Street 
Building F, Floor 3 
Seattle, WA 98109 
 
 
FUNDING: 
NIDDK  
 
CLINICAL LEAD: 
Leah Wilson MD 
 
TECHNICAL LEAD: 
Peter Jacobs PhD  
 
OHSU CO-INVESTIGATOR:  
Diana Aby-Daniel PA-C 
 
UoW INVESTIGATOR:  
Subbulaxmi Trikudanathan MD 
 
 
 
 
Background: 
Closed-loop systems automate insulin delivery based on continuous glucose monitoring (CGM) 
values to minimize hypoglycemia and hyperglycemia. Closed-loop systems have been tested 
extensively in both the inpatient and outpatient settings. Our group has previously developed 
both an insulin-only closed-loop system and a dual-hormone (insulin and glucagon) closed-loop 
system[1-3]. The novelty of these closed-loop systems is their ability to automatically detect 
exercise and adjust dosing in response to the exercise. In preparation for the study outlined here, 
we have recently completed two closed-loop studies.  
 
The first study was an outpatient closed-loop study, which tested the OHSU insulin-only closed-
loop system using the Fading Memory Proportional Derivative (FMPD) algorithm which 
modulates insulin delivery using a Proportional-Integral-Derivative (PID) controller with 
exercise detection when metabolic expenditure goes above a set threshold as compared to a 
model predictive control (MPC) algorithm that modulates insulin delivery based on estimated 
activity level every 5 minutes based on accelerometry input. Participants underwent two 76-hour 
studies in randomized order, one using the FMPD and one using the MPC algorithm. Participants 
were in clinic for the first 12 hours of each study visit, eating meals and performing activities of 
daily living and exercise. Then participants went home using the system for the rest of the visit, 
completing one exercise at home. During the two hours after in-clinic exercise, both algorithms 

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yielded good results, but the MPC yielded a higher percent time in range (70-180 mg/dl) at 
87.5% vs. 76.3% (p=0.0462) and lower time in hypoglycemia (<70 mg/dl) 1.9% vs. 4.6% 
(p=0.09). The MPC and FMPD arms were not significantly different from each other across the 
76 hour visit with time in range for MPC vs FMPD of 74.5% vs. 75.7% and time in 
hypoglycemia (<70 mg/dL) 1.0% vs. 1.4%. 
 
The second study was performed in clinic and tested the MPC algorithm described above against 
a modified MPC algorithm with missed meal insulin detection. Participants underwent two 8 
hour studies in randomized order, one with and one without missed meal insulin detection. 
Participants ate two meals four hours apart without administering a meal bolus. During the study 
using missed meal insulin detection algorithm, the system was designed to identify the meal 
without an accompanying insulin bolus based on CGM data and give a suggestion for a bolus. 
The primary endpoint was the positive incremental area under the curve (iAUC) after breakfast. 
The mean (SD) iAUC was 253.9 (105.9) [mg/dl]*h with the use of the missed meal insulin 
algorithm vs. 277.5 (159.4) [mg/dl]*h without it. Secondary outcome metrics included % time in 
hypoglycemia (<70 mg/dL), % time in range (70-180 mg/dL), and time in hyperglycemia (>180 
mg/dl). Time in hypoglycemia was less than 2% for both arms. Time in range was higher with 
the use of the missed mealtime insulin algorithm 33.4 (22.8)% vs. 24.3 (20.2)% without it. Time 
in hyperglycemia was lowest with the missed mealtime insulin algorithm 64.8 (24.1)% vs. 75.7 
(20.2)% without it. The algorithm accurately detected 83.3% of the meals with median detection 
time of 26 minutes (range = [25,30] minutes).  
 
The study described within this protocol is designed to test the safety and efficacy of the OHSU 
model predictive control (MPC) algorithm that modulates insulin delivery based on estimated 
activity level combined with the OHSU missed meal detection algorithm. The potential benefit 
of this type of algorithm is that it handles exercise not as a discrete event, but it automatically 
adjusts insulin delivery based on estimated activity level and notifies users of rises in glucose 
levels that may have been related to a missed mealtime insulin bolus and automatically delivers 
an insulin dose to reduce post-prandial hyperglycemia. Participants will be enrolled who 
currently use the t:slim X2 pump with Control IQ or Omnipod 5 closed loop system. 
  
Primary Objective: 
• To confirm non-inferiority of the OHSU MPC exercise-enabled closed-loop system with 
missed mealtime insulin detection algorithm as measured by percent of time 70-180 
mg/dL on Dexcom G6 CGM as compared to use of the participant’s personal closed loop 
delivery system. 
Secondary Objective: 
• To confirm non-inferiority of the OHSU MPC exercise-enabled closed-loop system with 
missed mealtime insulin detection algorithm as measured by other glucose metrics as 
compared to use of the participant’s personal closed loop delivery system. 
Study Hypothesis: 

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We propose that the use of the OHSU MPC exercise-enabled closed-loop system with missed 
mealtime insulin detection algorithm will be non-inferior within a time in range margin of 7% as 
compared to the participant’s closed loop delivery system in patients with elevated baseline A1C 
values.  
 
Endpoints 
Primary Endpoint:  
• Percent of time with sensed glucose between 70-180 mg/dl across the study duration 
Secondary Endpoints:  
• Percent of time with sensed glucose between <70 mg/dl across the study duration 
• Percent of time with sensed glucose <54 mg/dl across the study duration 
• Percent of time with sensed glucose >180 mg/dl across the study duration 
• Mean sensed glucose across the study duration 
• Coefficient of variation of glucose across the study duration 
• Mean amount of insulin delivered per day (in units/kg) across the study duration 
Study Type  
This is a multi-center, randomized, two treatment, crossover non-inferiority trial designed to 
compare the glucose control resulting from the use of the OHSU MPC exercise-enabled AP 
system with missed mealtime insulin detection algorithm (Intervention Period) as compared to 
usual care using a closed loop insulin delivery system, either the t:slim X2 pump with Control IQ 
or Omnipod 5 system (Control Period).  
 
Study Population 
Study population will be participants with type 1 diabetes, ages 18 years of age and older. Up to 
36 participants will be recruited to participate in studies across two sites.  
 
Power Analysis 
A sample of 28 subjects provides at least 80% power for testing our primary endpoint in a non-
inferiority framework comparing the exercise-enabled MPC algorithm with missed meal insulin 
detection to use of participant’s personal closed loop system. Assumptions informing this 
calculation were derived from simulations showing an expected mean percent time in range (70-
180 mg/dL) for control IQ that was 3.7% lower (as a difference rather than a ratio) and standard 
deviations (SDs) for the two conditions of approximately 16 to 19. From this, we assume the SD 
of the within-subject difference will be approximately 17% and use a one-sided paired t test at 
the 0.025 level of significance for a mean difference of 3.7% time in range versus 6% as the non-
inferiority margin. We plan to recruit up to 36 subjects with goal enrollment of 30 subjects 
(about 15 at each center). 
 
Protocol Summary: 

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Participants will undergo one 7-day Intervention Period and one 7-day Control Period in 
randomized order. During the 7-day intervention study, participants will wear an Omnipod to 
deliver Fiasp insulin and a Dexcom G6 CGM. The CGM system will provide sensed glucose 
data every 5 minutes. Sensed glucose data will be wirelessly transmitted via Bluetooth Low 
Energy (BTLE) from the Dexcom G6 transmitter to the smartphone master controller every five 
minutes. The smartphone will wirelessly communicate via BTLE to an Omnipod through a 
Personal Diabetes Manager (Insulet Corp.). The closed-loop system will receive activity data 
through a Polar M600 watch worn by the participant. Participants will eat one meal in clinic and 
complete system training on Day 1 and then spend the rest of the 7 days at home. During the 7-
day Control Period, the participant will continue their usual diabetes care regimen using a t:slim 
X2 pump with Control IQ enabled or the Omnipod 5 closed loop system.  
 
 
 
 
 
Participant Criteria 
Inclusion Criteria:  
1. Diagnosis of type 1 diabetes mellitus for at least 1 year.  
2. Age 18 years and older.  
3. Current use of a t:slim X2 insulin pump with the use of Control IQ or the Omnipod 5 
system with closed loop enabled with Dexcom G6 or G7 for at least 12 weeks. 
4. Willingness to use Fiasp insulin during intervention study 
5. Lives with another person age 18 or older who will sleep in the house at night and that 
can attend the training on using the system. 
6. HbA1c or GMI ≥ 7.5% at screening. GMI (%) = 3.31 + 0.02392 × [mean glucose in 
mg/dL] based on prior 30 days of Dexcom CGM data.[4] 
7. Total daily insulin requirement is less than 139 units/day.  
8. Current use of a smartphone so can be contacted by study staff off-campus 
9. Willingness to follow all study procedures, including attending all clinic visits.  
10. Willingness to sign informed consent and HIPAA documents.  
 
Exclusion Criteria:  
1. Female of childbearing potential who is pregnant or intending to become pregnant or 
breast-feeding, or is not using adequate contraceptive methods. Acceptable contraception 
includes birth control pill / patch / vaginal ring, Depo-Provera, Norplant, an IUD, the 
double barrier method (the woman uses a diaphragm and spermicide and the man uses a 
condom), or abstinence. 
2. HbA1c >10% or ≤6.5% at screening.   
3.  Percent time < 54 mg/dL of >2% based on prior 30 days of Dexcom CGM data. 
4. Any cardiovascular disease, defined as a clinically significant EKG abnormality at the 
time of screening or any history of: stroke, heart failure, myocardial infarction, angina 
pectoris, or coronary arterial bypass graft or angioplasty. Diagnosis of 2nd or 3rd degree 
heart block or any non-physiological arrhythmia judged by the investigator to be 
exclusionary. 

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5. Renal insufficiency (GFR < 60 ml/min, using the MDRD equation as reported by the site 
laboratory). 
6. Liver failure, cirrhosis, or any other liver disease that compromises liver function as 
determined by the investigator.  
7. History of severe hypoglycemia during the past 12 months prior to screening visit or 
hypoglycemia unawareness as judged by the investigator. Participants will complete a 
hypoglycemia awareness questionnaire. Participants will be excluded for four or more R 
responses.  
8. History of diabetes ketoacidosis during the prior 6 months prior to screening visit, as 
diagnosed on hospital admission or as judged by the investigator. 
9. Adrenal insufficiency. 
10. Any active infection. 
11. Known or suspected abuse of alcohol, narcotics, or illicit drugs.  
12. Seizure disorder. 
13. Active foot ulceration. 
14. Severe peripheral arterial disease characterized by ischemic rest pain or severe 
claudication. 
15. Major surgical operation within 30 days prior to screening. 
16. Use of an investigational drug within 30 days prior to screening. 
17. Chronic usage of any immunosuppressive medication (such as cyclosporine, 
azathioprine, sirolimus, or tacrolimus). 
18. Bleeding disorder, treatment with warfarin, or platelet count below 50,000. 
19. Allergy to Fiasp insulin. 
20. Current administration of oral or parenteral corticosteroids. 
21. Any life-threatening disease, including malignant neoplasms and medical history of 
malignant neoplasms within the past 5 years prior to screening (except basal and 
squamous cell skin cancer).  
22. Current use of beta blockers or non-dihydropyridine calcium channel blockers. 
23. Current use of any medication intended to lower glucose other than insulin (ex. use of 
metformin or liraglutide) or SGLT-2 inhibitors (for diabetes or other indications, ex. use 
of empagliflozin or ertugliflozin). 
24. Gastroparesis 
25. Low carbohydrate diet at the time of screening defined as less than 50 grams of 
carbohydrate per day.  
26. Any clinically significant disease or disorder which in the opinion of the Investigator may 
jeopardize the participant’s safety or compliance with the protocol.  
Participant Recruiting: 
Participants will be recruited from 2 sites in the United States, one of which will be Oregon 
Health & Science University (OHSU). Non-English speaking participants will not be recruited 
since this protocol would require the use of medical devices and mobile software that do not 

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have non-English versions available. Up to 60 participants may be screened in this study. Goal 
enrollment is 30 participants across both sites with up to 6 replacements as needed to collect data 
from 28 participants. However, re-screening is allowed up to one time per individual, no sooner 
than 2 weeks and no longer than 3 months and after initial screen.  It is anticipated that each site 
will enroll about 15 participants, but this may be adjusted if needed to complete enrollment in a 
timely fashion.  
 
Withdrawal Criteria 
The participant may withdraw at will at any time or at the discretion of the Investigator.  
A participant must be withdrawn if the following applies: 
• Severe Hypoglycemia during the treatment period (control or intervention period). Severe 
hypoglycemia is defined as any event that required the assistance of another person to 
administer carbohydrate, glucagon, or other resuscitative actions.  
• Diabetic ketoacidosis during the treatment period (control or intervention period). 
Diabetic ketoacidosis is classified as: symptoms such as polyuria, polydipsia, nausea, or 
vomiting, serum ketones >1.5 mmol/L or moderate/large urine ketones, either arterial 
blood pH<7.3 or venous pH<7.24 or serum bicarbonate <15, and treatment provided 
in a health care facility 
• Other circumstances that would endanger the health of the participant if they were to 
continue participation in the study 
• Protocol deviation having influence on efficacy or safety data as judged by the 
Investigator.  
• Substantial and repeated non-compliance with trial procedures.  
• Pregnancy.  
• Intention of becoming pregnant.  
Visit Procedures 
Screening (Visit 1) 
Screening will take place within 12 weeks prior to the first 7-day Visit. The participant will be 
sent the consent form prior to the screening by email so that they can have time to read it fully at 
their leisure and prepare any questions they might have. Upon arrival and prior to any 
procedures, study staff will explain the study, give the participant ample time to ask questions 
and consider participation, and ensure that the participant voices understanding of the informed 
consent and study requirements. To minimize the possibility of coercion and to ensure that 
participant is signing the appropriate version of the consent, an informed consent checklist will 
be used by study staff. After the participant has signed the consent, a copy of the 
consent/authorization form will be given to the participant. The original will be kept for the 
source document.  
 
Study personnel will review medical history, and medications. Height, weight, pulse, and blood 
pressure will be obtained. A study investigator will perform a physical examination, excluding 

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breast and pelvic exams. Females of child-bearing potential will take a urine pregnancy test, 
which must be negative to participate. A venous blood sample will be taken for the following 
tests: hemoglobin A1C, complete blood count, and complete metabolic set (including creatinine, 
liver set, and electrolytes). A study investigator will assess inclusion/exclusion criteria and 
review the participant’s medical record for clarification as needed.  When feasible, the 
participant’s insulin pump and glucose sensor, if applicable, will be downloaded before 
enrollment to obtain the prior 4 weeks of data. A three-digit participant ID number will be 
assigned to the participant. This visit will take approximately 1.5 hours.  
 
The treatment order will be randomized. The two periods, which are the 7-Day Control Period 
and 7-Day Intervention Period, will be a minimum of 7 days and a maximum of 8 weeks apart 
counting from the first day of the first period to the first day of the second period.  
 
A complete list of times when participants will be instructed to take SMBG readings is listed 
below. 
 
Participants will be instructed to take SMBG readings under the following conditions: 
1. If the sensor glucose is <70mg/dL, the system will prompt a SMBG be entered. 
(intervention period only) 
2. If the sensor glucose is ≥ 300 mg/dl for 30 minutes within the last 45 minute period, 
the system will prompt a SMBG be entered. (intervention period only) 
3. If participant’s symptoms (such as symptoms of hypoglycemia or hyperglycemia) are 
discrepant with the Dexcom CGM reading, then the participants will be instructed to 
perform a SMBG and use this value to make treatment decisions and to calibrate the 
Dexcom device. (Intervention and control period) 
4. If CGM value is unavailable, a SMBG will be required to calculate a correction bolus. 
(Intervention and control period) 
5. Before driving to clinic for study visits. (Intervention and control period) 
6. On arrival to clinic for study visits. (Intervention and control period) 
7. Before and after exercise if they choose to exercise during the study period. 
(Intervention and control period) 
8. On discharge from clinic for study visits. (Intervention period) 
 
7-Day Control Period  
For the 7-Day Control Period, women of childbearing potential will receive a urine pregnancy 
test if the last pregnancy test was more than 7 days prior. This test must be negative before 
further participation is allowed. A capillary blood glucose (CBG) will be measured. Participants 
will complete a virtual visit by WebEx or Microsoft Teams or in person to start this visit. The 
purpose of this visit is to assist the participant with downloading: 1) the Dexcom Clarity app and 
sharing their data with the site, 2) the t:connect app and pairing it to their pump on their personal 
phone 3) Tidepool uploader app or 4) for Omnipod 5 users, logging in to their account at 
https://insuletid.com/ from a computer/laptop/mobile browser and selecting to connect to 

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Glooko. If participants already have these apps on their phones, the visit will be used to confirm 
that data sharing is in place. The participants will continue to use their personal closed loop 
system, either the t:slim X2 pump with Control IQ or Omnipod 5, and their own insulin during 
the 7-Day Control Period. They will be instructed to take boluses prior to meals as they usually 
would. Participants will be asked to check their capillary blood glucose for symptoms of 
hypoglycemia or hyperglycemia if discrepant with CGM reading and in response to CGM alerts.  
 
 
Participants will be given an instruction card (see Appendix C) for carbohydrate treatment before 
exercise to follow, if participants choose to exercise as part of their week. On the seventh day, 
participants will connect virtually by WebEx or Teams with study staff to share their pump 
download and confirm Dexcom Clarity data has been shared. A capillary blood glucose (CBG) 
will be measured. If the participant is not able to send the pump download and/or Clarity data is 
not being shared, the participant will come into clinic so that staff can download their devices.  
 
7-Day Intervention Period 
The participant will be asked to check his/her glucose before driving to the clinic and to bring a 
snack in the car in case hypoglycemia does occur (in which case, the participant must park and 
treat the hypoglycemia). For the 7-Day Intervention Period, women of childbearing potential will 
receive a urine pregnancy test if the last pregnancy test was more than 7 days prior. This test 
must be negative before further participation is allowed.  
 
An assessment will take place at the beginning of the 7-Day Intervention Period. We will inquire 
whether the participant has had changes in their medications and/or medical history to confirm 
the participant does not meet any study exclusion criteria. A capillary blood glucose (CBG) will 
be obtained and measured by a Contour Next glucose meter. When they arrive, participants will 
be given 15-20 grams of oral carbohydrate if the CBG reading is less than 70 mg/dl. CBG values 
> 300 mg/dl will be managed at the discretion of the investigator with a correction bolus and 
serum ketones will be checked. If serum ketones are ≥ 0. 6 mM, the study will not be started and 
insulin therapy will be guided by a study investigator.  
 
During the 7-Day Intervention Period, glucose will be controlled using the OHSU MPC exercise-
enabled closed-loop mode with missed mealtime insulin detection algorithm. The first 
approximately 6 hours of the visit will be conducted in clinic. The participants will then go 
home. The first 5 participants will be conducted at OHSU with remote monitoring. If safety 
criteria are satisfied, as outlined below, subsequent participants may be enrolled without remote 
monitoring at any of the sites.  
 
The wire glucose sensor is sterile and commercially available from DexcomTM and will be used 
for single use only as directed by the manufacturer. The participant will be trained on how to 
insert a Dexcom G6 sensor into the subcutaneous tissue of the abdomen after appropriate 
preparation of the abdominal skin per the manufacturer’s directions. Participants will be trained 
how to pair the Dexcom G6 transmitter to the iPancreas app on the smart phone, start and stop a 
new sensor session and how to enter calibrations. The Dexcom G6 does not require calibrations. 
As part of the training, study staff will review with the participants that Dexcom G6 values can 

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be inaccurate. In the event that the participant’s symptoms (such as symptoms of hypoglycemia 
or hyperglycemia) are discrepant with the G6 CGM reading, then the participants will be 
instructed to perform a CBG and use this CBG value to make treatment decisions and use the 
CBG value to calibrate the Dexcom G6 device. Participants will be provided with a copy of the 
Dexcom G6 user guide.  
 
An Omnipod (510K#042792) will be filled with Fiasp insulin. We will use only name brand 
insulin, not generic insulin. We will provide the participants with Omnipods to replace the 
Omnipod at home every 72 hours or earlier if needed along with a vial of Fiasp insulin and train 
participants how to perform this. The Omnipod will be primed and inserted as directed by the 
manufacturer. Research staff will train participants on the approved Omnipod placement options 
from the Omnipod User Guide. Participants will wear a Polar watch to inform the controller. 
Participants will disconnect his/her own pump and remove his/her own insulin infusion set once 
insulin delivery has started via the Omnipod. Since the Dexcom G6 sensor will require a two-
hour warm-up, the system will be started in open loop mode with the system delivering their 
programmed basal rate. Once a sensor value is available, the research staff will initialize the 
system and begin the closed-loop study using the iPancreas smart phone application. Two staff 
will review each of the settings to confirm the settings are inputted correctly. The participant will 
be given enough study supplies for the 7-day study period. A study investigator will be available 
in person or by phone for the entire 7-day study period.  
 
Study staff will complete a training with each participant on using the Dexcom G6, the Omnipod 
system, and the Polar watch. Participants will be shown how to use the smartphone user interface 
which includes: entering basal profiles, insulin carb ratios and sensitivity, activating and 
deactivating Omnipods, giving meal boluses, carb treatments, entering capillary blood glucose 
values and ketone levels, addressing alerts, troubleshooting the devices connection to the phone 
via Bluetooth, and pausing the study. Participants will be advised that they can take insulin prior 
to meals or they can allow the system to detect the meal and give insulin automatically. 
Participants will be instructed that taking insulin before meals will generally reduce 
hyperglycemia. Instruction will be given on identifying an Omnipod malfunction. The time 
required for this training will vary, depending on the experience of each participant, but will be 
sufficient to help him/her/they become comfortable using the smartphone and changing the 
Omnipod. If the participant experiences difficulties using the Omnipod during the study period, 
study staff will be available to educate and support by phone. Training will include that the smart 
bolus calculator available in open loop mode is a suggestion and that participants should use 
their judgement on what insulin dose to take as the bolus calculator is not aware of certain 
circumstances such as illness or alcohol use.  
 
The participant will need to demonstrate competency in operating the system before study staff 
leave the room. A competency assessment will be completed on day 1 of the closed-loop visit 
prior to discharge. Each participant will start the G6 sensor and start the Omnipod on their own 
during onboarding. Participants will need to show competency in entering fingerstick glucose 
values and announcing meals during the day on campus. Participants will demonstrate 
competency in the following using a simulated closed-loop study: pausing and resuming a study, 
using the smart bolus calculator and manual bolus while in pause mode. Participants will be 
given contact information to call for any problems during the 7-day study period. The companion 

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will accompany the participant to receive training (or be previously trained) on treatment in case 
of severe hypoglycemia episode, including administration of rescue carbohydrates and use 
of emergency glucagon kit. Companions will also be trained on the closed-loop system. This 
training may be completed virtually. Participants will be given an instruction card (see Appendix 
C) for carbohydrate treatment before exercise to follow, if participants choose to exercise as part 
of their week. The site investigator will monitor in real-time the first auto-bolus delivered in 
closed-loop mode for each subject. 
The algorithm will push data up to a cloud server that can be monitored remotely every 5 
minutes. A study coordinator will be available at all times for the visits with the ability to 
monitor the closed-loop system remotely via a cloud system on the web in the event of any 
issues. The closed-loop system will generate alerts on the smartphone according to Appendix B. 
The participants will all be trained as to the action required by each alert. Each alert has a 
specific condition to be met for it to be considered serviced (i.e. enter treatment with oral 
carbohydrates). The refractory period is also specific to each alert with shorter refractory periods 
for alerts that concern participant safety. The first 5 participants will be remotely monitored by 
study staff as described in more detail below. If the participant does not appropriately respond to 
the alert in the allotted timeframe, the alert will push to the study coordinator and the on-call 
investigator according to Appendix B for those studies being remotely monitored. At that time, 
the coordinator will pull up the web-based monitoring system. The study investigator and 
technician may intervene with a telephone call, text or a personal visit at any time. If staff is 
remote monitoring and the participant cannot be reached and sensor glucose is below 54 mg/dl, 
the companion will be contacted. If the alert is still un-serviced and study staff are unable to 
reach the participant or the companion, emergency medical services will be contacted (staff 
attempted to contact both participant and companion 2x each with less than 2 minutes between 
each call). If the companion is not able to assess of the participant’s status within 5 minutes, we 
will reach out to emergency services.. To facilitate this, the phone will track the participant’s 
location and push GPS coordinates to the cloud server approximately every 10 minutes. Cloud 
coordinates will be pushed with a known, fixed offset to allow for scrambling.  
 
In order to push alerts to study coordinators and study investigators, the cloud server used for 
remote monitoring will have a drop down menu for study staff to sign in and out for the duration 
of their monitoring shift.  Each study coordinator and investigator listed in the menu will have a 
cell phone number on file that can receive texts with pushed alerts.  
 
If at any time study staff determines that a sensor can no longer be used, a new sensor will be 
inserted. In order to ensure safety and to assess sensor accuracy, the participant will be asked to 
check their capillary blood glucose before and after exercise (if the participants selects to 
exercise), for symptoms of hypoglycemia, and in response to system alert (such as for low or 
high sensor alerts).  
 
For participant safety, if a sensor value is not available for 20 minutes or communication with 
the Omnipod is lost for more than 30 minutes, the Omnipod will begin insulin delivery according 
to a pre-set basal profile(s) inputted for the participant at study start. When this occurs for a lost 
sensor, iPancreas will activate the predictive low glucose suspend feature if the last known 
sensor value was within the range of 70-140 mg/dl and predicted to fall below 90 mg/dl within 

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thirty minutes or if the sensor glucose is less than 70 mg/dl. Insulin is suspended for 30 minutes, 
after which basal insulin delivery resumes. When communication with the sensor or Omnipod is 
restored, the system will automatically resume, updating the IOB accordingly.  
 
The food items will be self-selected by the participant.  
Safety assessment – first 5 participants  
We are proposing to remove remote monitoring after the successful completion of the first 5 
participants if the safety criteria are satisfied. We will complete an interim analysis after the first 
5 participants complete both arms of the study assessing time spent with CGM < 54 mg/dL, <70 
mg/dL, and > 300 mg/dL and any adverse events. The closed-loop system data will be compared 
to the equivalent data from the participant’s 7-Day Control period with the use of their personal 
closed loop system, either the t:slim X2 with Control IQ or Omnipod 5 system. If the interim 
analysis shows that the closed-loop system data is comparable to usual care studies and presents 
no safety concerns, we will proceed to enrolling participants without remote monitoring. If it 
does not or if there are any instances of severe hypoglycemia or DKA (unrelated to infusion set 
failure), then the study will be halted, changes will be made as appropriate to algorithm and the 
protocol and a plan will be submitted to FDA and IRB that will need to be approved before 
further studies are conducted. After the algorithm adjustments are made, an additional 5 
participants will then be completed with remote monitoring.  
 
Severe hypoglycemia is defined as any event that required the assistance of another person to 
administer carbohydrate, glucagon, or other resuscitative actions. Diabetic ketoacidosis is 
classified as: symptoms such as polyuria, polydipsia, nausea, or vomiting, serum ketones >1.5 
mmol/L or moderate/large urine ketones, either arterial blood pH<7.3 or venous pH<7.24 or 
serum bicarbonate <15, and treatment provided in a health care facility. If an event of severe 
hypoglycemia or diabetic ketoacidosis should occur, the study will be halted and a description of 
the serious adverse event and a new risk mitigation plan will be submitted to the FDA. The study 
will only resume once FDA approval is received.    
 
We are aware that there is a risk of severe hypoglycemia while the participants are at home. The 
system will alert if the sensed glucose values fall below 70 mg/dl prompting the participant to 
obtain a capillary blood glucose sample. Participants will be required to live with at least one 
other person age 18 or older and live within 40 miles of the study site that enrolled the 
participant.  
 
In case of a system error that cannot be corrected immediately with the participant off campus, 
the participant will be able to go into open-loop mode. This will allow the Omnipod to begin 
basal insulin delivery for a pre-set basal profile(s) inputted for the participant at the study start. 
Participants will be able to give meal boluses and corrections through the Omnipod while in 
open-loop mode. When the error is resolved, the participant can resume closed-loop mode and 
the system will resume. If the participant goes into open-loop mode, this will be visible on the 
cloud server and may prompt a telephone call from study staff to determine the issue and the best 
way to resolve it. The participant may contact study staff at any time during the outpatient 
portion of the visit.  

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Discharge from inpatient clinic 
At the completion of the 6-hour in-clinic visit, participants will be discharged from the clinic. 
Capillary blood glucose will be measured prior to discharge. Participants will wait to discharge 
home if capillary blood glucose is <85 and or >300 mg/dl or at the discretion of the study 
investigator, and treatment will be at the discretion of the study investigator. Once participant’s 
capillary blood glucose is between 85-300 mg/dl on two capillary blood glucose measurements 
completed at least 30 minutes apart, they can be discharged home. If the capillary glucose is less 
than 85mg/dL, participants will be asked to consume 15g of glucose tablets. They can then be 
discharged if the next capillary glucose measurement 30 minutes later is greater than 85mg/dL. If 
the capillary blood glucose is <70, participants will be asked to consume 15g of glucose tablets 
and recheck capillary blood glucose every 15 minutes until >70. If capillary blood glucose is 
greater than 300mg/dL, participants will be instructed to pause iPancreas closed loop mode, take 
a correction bolus from the bolus calculator after reviewing this dose with the study investigator 
who will modify dose if needed considering current insulin on board then resume iPancreas 
closed loop mode. The participant can then be discharged home if the next capillary blood 
glucose measurement 30 minutes later is less than 300 mg/dL or if the CGM glucose trend arrow 
shows flat arrow (Increasing/decreasing less than 1 mg/dL each minute) or a down arrow 
(decreasing >30mg/dL in 30 minutes).  Participants will be instructed to eat meals and snacks as 
they normally would at home. Participants will be instructed that his/her companion will be 
required to stay with them each night while an outpatient. 
 
Return to the Outpatient Clinic  
On the seventh day, participants will return to the outpatient clinic. The study will be terminated 
and the participant’s own insulin pump will be restarted. The study investigator will consult with 
the participant regarding appropriate insulin dosing for the remainder of the day. The Polar 
watch, Omnipod and Dexcom sensor will be removed from the participant. All infusion and 
sensor sites will be inspected for signs of irritation or infection. In addition, the sensor will be 
inspected for the possibility of breakage or fracture. If there is any evidence of sensor breakage, 
it will be recorded. If an area of inflammation of 1 cm or greater exists around the point of 
insertion, a de-identified photograph will be taken of the area and the participant will return 1-3 
days later for a follow-up visit. A capillary blood glucose value will be taken immediately prior 
to discharging the participant. Participants will be given oral carbohydrate for values below 85 
mg/dl, and if capillary blood glucose is greater than 180mg/dL, participants will be instructed to 
take a correction bolus from their home insulin pump per their usual home settings after 
reviewing this dose with the study investigator who will modify dose if needed considering 
current insulin on board. The participant can then be discharged home if the next capillary blood 
glucose measurement 30 minutes later is less than 300 mg/dL or if the CGM glucose trend arrow 
shows flat arrow (increasing/decreasing less than 1 mg/dL each minute) or a down arrow 
(decreasing >30mg/dL in 30 minutes). 
 
There is the option to complete this visit by WebEx or Microsoft Teams. Participants will be 
given shipping boxes for sending all devices back. Participants will connect with a study 
coordinator and investigator virtually to complete the visit.  

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If a study visit is stopped prematurely, such as due to technical problems, the participant will be 
asked if they can repeat the study visit that was terminated early with additional compensation 
provided. Repeating the study visit will be optional. 
 
Hypoglycemia Treatment Guidelines  
 CBG < 70 mg/dl 
• Give 15 grams of oral carbohydrate.  
• Repeat treatment every 15 minutes as needed to raise blood glucose ≥70 mg/dl.  
Presence of STUPOR, LOSS OF CONSCIOUSNESS, or SEIZURE 
• Administer rescue glucagon per the manufacturer’s instructions.    
• Verify that insulin is turned off.  
• Further management per study investigator.  
Hyperglycemia Treatment Guidelines  
If the sensed glucose is ≥ 300 mg/dl, the participant will be instructed to check their blood 
glucose and to check the Omnipod for malfunction. This would include checking for insulin 
leaks, making sure Omnipod is securely adhered to skin, and check for error messages on the 
phone running the algorithm.  
 
If capillary blood glucose value is over 300 mg/dl for more than 2 hours or is ≥ 400 mg/dl at any 
time, the participant will be instructed to check serum ketones using the Abbott Precision Xtra 
meter and to change out the Omnipod. If serum ketones are over 0.6 mM, the participant will be 
instructed to contact the study investigator to discuss proper management, including delivering a 
correction bolus. (see Appendix C ‘Safety Instructions for Participants’ for instructions provided 
to participants on when to contact study staff) In addition, the participant will be encouraged to 
drink sugar-free liquids. If serum ketones are above 1.5 mM at any time, the study will be 
stopped and insulin will be administered as directed by the on call investigator.  
  
Cleaning and Disinfecting  
All devices will be cleaned and disinfected between participants. The smart phone, Dexcom G6 
transmitter, heart rate monitor and Omnipod PDMs are cleaned by study staff. Technicians who 
are disinfecting units will wash hands thoroughly and wear gloves. All items will undergo 
intermediate-level disinfection using Oxivir TB disposable wipes. The disinfectant will be 
applied and allowed to air dry. After disinfection, when the units are completely dry, they will be 
placed in a sealed bag labeled with participant information.  
 
Stopping Rules 
Individual study stopping rules 
The closed-loop study will be stopped and the participant’s own pump will be resumed under the 
guidance of the on call study investigator if any of the following occur after the start of the study: 

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the participant requests that the treatment be stopped, participant pregnancy, one episode of 
diabetic ketoacidosis as defined as symptoms such as polyuria, polydipsia, nausea, or vomiting, 
serum ketones >1.5 mmol/L or moderate/large urine ketones, either arterial blood pH<7.3 or 
venous pH<7.24 or serum bicarbonate <15, and treatment provided in a health care facility, or 
one episode of severe hypoglycemia defined as a hypoglycemic event resulting in altered 
consciousness requiring another person to actively administer carbohydrate, glucagon, or other 
resuscitative actions.   
 
Entire study stopping rules 
Triggers for reporting unanticipated problems are seizure, hospitalization, death or any other 
occurrence considered serious by the PI and Medical Monitor. If any studies are stopped for 
severe hypoglycemia or diabetic ketoacidosis, then the entire study will be halted. Severe 
hypoglycemia is defined as any event that required the assistance of another person to administer 
carbohydrate, glucagon, or other resuscitative actions. Diabetic ketoacidosis is classified as: 
symptoms such as polyuria, polydipsia, nausea, or vomiting, serum ketones >1.5 mmol/L or 
moderate/large urine ketones, either arterial blood pH<7.3 or venous pH<7.24 or serum 
bicarbonate <15, and treatment provided in a health care facility. If an event of severe 
hypoglycemia or diabetic ketoacidosis should occur, the study will be halted and a description of 
the serious adverse event and a new risk mitigation plan will be submitted to the FDA. The study 
will only resume once FDA approval is received. In addition, if there is any unexpected event 
such as death or patient hospitalization, the studies will be stopped until the root cause is 
evaluated. 
 
The Model Predictive Control (MPC) Algorithm 
Our MPC algorithm uses a glucoregulatory model to predict glucose outcomes over a predicted 
horizon  and mathematically solve for the optimal insulin doses across the control horizon to bring 
the participant to target. The model is updated at each timestep by a Kalman filter, which uses the 
difference between CGM observations and model predictions to update the physiologic model 
states. In short, a model-predictive controller uses a physiologic model to calculate how much 
insulin is required to bring someone to glucose target, and these predictions are adapted to the 
specific participant using a Kalman filter.  
 
For the MPC exercise-enabled mode, there is a model within the controller that takes as an input 
the aerobic metabolic expenditure in addition to the CGM and meal inputs. The algorithm uses 
heart rate and accelerometer data collected on the patient’s body to calculate metabolic 
expenditure. The metabolic expenditure then acts on the model for the insulin dynamics, 
whereby more energy expenditure and longer duration exercise can lead to a more substantial 
effect of insulin on the CGM (i.e. the CGM will drop more in response to more intense aerobic 
exercise and with longer duration exercise). In this way, the model within the MPC control 
algorithm is always aware of exercise as a continuous input to the system and can respond 
dynamically to short or long, light, moderate, or intense exercise bouts. We expect that the MPC 
controller will be able to dynamically adapt to either short or long exercise bouts. We also expect 
the MPC to dynamically adapt to in-home exercise better, which can be more variable than static 
exercise that is performed within a clinic under controlled conditions.  

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The MPC algorithm shall be capable of automating the detection of meals and delivering a 
portion of the meal insulin.  If a meal is detected that has not been reported by the user (i.e. meal 
carbohydrates entered with insulin bolus delivered), this shall be called a missed meal insulin.  
When missed meal insulin is detected by the MPC algorithm, the app shall calculate the amount 
of meal insulin that will be dosed and deliver that insulin without an announcement to the user.   
 
Statistical methods 
The primary study endpoint is percent of time in range defined as glucose measured by Dexcom 
G6 or G7 in the range of 70-180 mg/dL. The hypothesis to be tested is if the MPC exercise-
enabled closed-loop system with missed mealtime insulin algorithm will be non-inferior as 
compared to the participant’s personal closed loop system. As our main approach, we will 
perform a two-sided Wilcoxon test for the paired differences. This test is widely used and easily 
interpreted. However, it cannot accommodate missing data or estimate crossover effects, and 
while we do not anticipate that these will affect our study outcomes, we plan to conduct a 
supplemental analysis using a linear regression model with bootstrapped standard errors, which 
do not require distributional assumptions. In resampling for the bootstrap, we will use study 
subjects as the sampling unit to account for correlation between their repeated observations. The 
general model is as follows:  
(1)  
𝑌!" = 𝛽# + 𝛽$𝑇𝑟𝑡" + 𝛽%𝑆𝑒𝑞! + 𝛽&𝑃𝑒𝑟𝑖𝑜𝑑" 
In this model, the outcome Yij is the percent of time with sensed glucose 70-180 mg/dL for 
person i in observation period j. Trtj represents the treatment arm (MPC=1, Control IQ=0). Seqi 
is an indicator for sequence (AB vs BA) and Periodj indicates when Trtj occurred in the 
sequence. The coefficient β0 represents the mean response for Control IQ, and the coefficient β1 
represents the difference between treatments to be tested. The coefficients β2 and β3, mean 
differences for sequence or period, are both expected to equal zero; a large effect or significance 
test with p-value <0.05 will be considered evidence of a carryover effect. Hypothesis tests will 
be two-sided with type I error set to 0.05. Because statistical tests are specified and prioritized a 
priori and our proposed endpoints are highly related, we will follow recommendations to report 
p-values and confidence intervals rather than adjust for multiple comparisons. 
Model fit and alternatives: Goodness of fit statistics and model fitting diagnostics will be used to 
assess for influential points and to evaluate alternative model specifications. If needed to 
compensate for some skew and heteroscedasticity in secondary outcomes, we will use 
bootstrapped variance estimators and compare these against robust estimates.  
Missing data: Our primary approach will include all available data as an intention-to-treat 
analysis, regardless of whether study subjects completed both arms. An observation will be 
included if at least 24 hours of data are available. However, we expect very low levels of 
missingness; in our previous four-arm crossover study, only one subject withdrew before 
completing at least two arms. Dropped CGM values will be interpolated over short time periods, 
using capillary values for calibration when available. In the event of ≥10% missingness in either 
subject data or CGM values, we will analyze outcomes under multiple imputation to compensate 
for potential bias. 
Additional considerations for selected secondary endpoints: The coefficient of variation of 
glucose is non-normal without an obvious probability distribution, so that bootstrapping will be 

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our primary approach for this endpoint. Data for percent of time with sensed glucose <54 mg/dl 
may be sparse; if so, we will present counts of events where glucose went below this level, 
counting as separate events when the time between them is ≥ 30 minutes.  
 
Confidentiality and Protection of Human Participants 
RISKS and BENEFITS 
Risks: Given pumps and sensors used within automated glucose control systems are imperfect, 
there is a risk for hyperglycemia and hypoglycemia, which is mitigated by use of CGM alarms, 
protocols for managing hypoglycemia and hyperglycemia, and remote monitoring of the first 5 
participants. A study investigator will be on call at all times.  
Rarely, there can be allergic responses to insulin, such as skin redness, hives, itching of the skin, 
swelling of the mouth, or breathing difficulties. These reactions are considered very unlikely. 
The following events have been identified as possible anticipated device-related adverse events 
of Dexcom G6 sensor insertion and wear: 
• Excessive pain or discomfort from either system deployment or during wear period (8 or 
greater on a 10-point Likert scale)  
• Excessive bleeding, defined as requires removal of the device to stop bleeding 
• Hematoma, defined as induration at the sensor insertion location (ecchymosis is a known 
consequence of needle skin puncture or pressure from sensor pod and will not be captured 
as an AE) 
• Edema from sensor and/or adhesive tape that is significant and non-resolving within 48 
hours of sensor pod removal 
• Erythema from sensor and/or adhesive tape that is significant and non-resolving within 48 
hours of sensor pod removal 
• Local infection, defined as presence of pus at either sensor wire or sensor pod site  
• Sensor or introducer needle fracture during insertion/wear/removal. For this reason, the 
study investigator will inspect each removed sensor for the possibility of breakage or 
fracture. Any evidence of sensor breakage will be recorded and reported to FDA and the 
sensor company. 
 
Benefits: The participant may not directly benefit from being in this study; however, their 
participation may help to advance automated insulin delivery technology. 
 
COSTS:   
If a participant withdraws early from the study, compensation will be given as follows: $150 for 
the usual care arm, $100 for a confirmed download for t:slim or Omnipod 5 pump and Dexcom 
sensor from the usual care arm and $350 for the closed-loop arm. If a participant is asked to 
repeat a study due to technical problems, he/she will receive an additional $250 for usual care 
arm with download, $350 for the closed-loop arm. There is no compensation for the screening 
visit.  
 
Safety Oversight: 

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Diana Aby-Daniel PA-C will be the study Medical Monitor. Diana Aby-Daniel has no 
commercial interest in any of the companies which manufacture any of the devices used in this 
study.  
 
A Data and Safety Monitoring Board (DSMB) will provide safety oversight. The DSMB will 
meet a minimum of every 3 months. The DSMB will be informed of all cases of severe 
hypoglycemia and diabetic ketoacidosis irrespective of device relationship, all device-related 
SAEs, and all UADEs at the time that they occur during the study and will review compiled 
safety data at periodic intervals. The DSMB also will be informed of any ADEs not meeting 
criteria for a UADE if the Medical Monitor requests the DSMB review. The DSMB can request 
modifications to the study protocol or suspension or complete halting of the study if deemed 
necessary based on the totality of safety data available. Details regarding the DSMB’s role are 
documented in a separate DSMB document. 
 
Data Collection: 
Participant privacy will be protected by using a three-digit identifying number to code study 
documents. All paper source documents will be kept in a locked cabinet for a minimum of five 
years.  
 
Recording of Data: 
Investigators and staff will record data collected during the clinical trial on the CRF’s in a secure 
HIPAA compliant system run by Prelude Dynamics. The CRFs will include: 
1. Screening form 
2. iPancreas Training 
3. Companion Training 
4. Day 1 Intervention Period Study Visit  
5. Day 7 Intervention Period Study Visit 
6. Day 1 Control Period Study Visit  
7. Day 7 Control Period Study Visit 
8. Phone Update Form 
9. Adverse Event form 
10. Serious Adverse Event form 
11. Concomitant Medications 
 
The Principal Investigators may authorize other personnel to make entries in the CRF. The coded 
data collected during this study will be used for analysis of the primary and secondary endpoints 
listed in this protocol. The key to the code for this study will not be stored in the repository and 
only named study members on this project will have access to the key for this study. Researchers 
who request data from the repository will not receive any identifiers aside from date and we do 
not anticipate that the date will allow those researchers to re-identify the data. However, some of 
the researchers named on this project may use the data from the repository which would mean 
that the repository data will still be potentially identifiable to those who have access to the key as 
part of this project. The coded data will also be stored in the OregonAPC repository according to 
OHSU IRB protocol 19858. During screening, all new participants will sign the consent form to 

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store their study data in the data repository. The data to be collected includes: 1) glucose sensor 
data, 2) blood glucose data, 3) insulin data, 4) physical activity data, and 5) food and exercise 
data. All data, except for blood glucose, is aggregated by the iPancreas app. The blood glucose 
data is collected through downloading the Contour Next BG meters and exporting data as an 
excel file. There are no biological specimens collected during this study. 
 
Monitoring Procedures: 
This protocol is written in accordance with the principles established by the 18th World Medical 
Assembly General Assembly (Helsinki, 1964) and amendments and clarifications adopted by the 
29th (Tokyo, 1975), 35th (Venice, 1983), 41st (Hong Kong, 1989), 48th (Somerset West, South 
Africa, 1996), 52nd (Edinburgh, 2000), 53rd (Washington, 2002), 55th (Tokyo, 2004), 59th 
(Seoul, 2008), and 64th (Brazil, 2013) General Assemblies. The investigator will ensure that the 
study described in this protocol is conducted in full conformance with those principles, the 
protocol, current FDA regulations, ICH Good Clinical Practices (GCP) guidelines, Good 
Laboratory Practices (GLP) guidelines, local ethical and regulatory requirements, including the 
Federal Food, Drug and Cosmetic Act, U.S. applicable Code of Federal Regulations (title 21), 
any IEC requirements relative to clinical studies.  
Should a conflict arise, the investigator will follow whichever law or guideline affords the 
greater protection to the individual participant. The investigator will also ensure thorough 
familiarity with the appropriate use and potential risks of use of the study device, as described in 
this protocol, prior to the initiation of the study. 
 
Adverse Event Reporting 
At all study visits, study staff will determine if any adverse events (AEs) have occurred. Disease 
related events that are chronic in nature and occur as part of the progression of the diabetes disease 
state (i.e. diagnoses of retinopathy, nephropathy, and neuropathy) will not be captured as adverse 
events in this study. Hypo- and hyperglycemia will not be considered AEs unless participant has 
positive ketones or displays symptoms of hypoglycemia such as: loss of consciousness, slurred 
speech, hospitalization or EMS services called.  
One of the investigators will write up a description of the adverse event/unanticipated problem. 
All reportable new information (RNI) will be reported to the IRB within five calendar days after 
the PI learns of the event. RNI is any information that might meet the regulatory definition of an 
unanticipated problem involving risks to subjects or others or serious or continuing noncompliance 
that might impact the criteria for IRB approval. The report will be submitted to the IRB by the 
principal investigator or study coordinator. A summary of all UP's and adverse events, including 
those that do not meet the requirement for RNI, will be submitted with the continuing review. All 
AEs will be monitored until adequately resolved or stable. Information regarding AEs that occur 
during the study will be entered into appropriate CRFs. Such information will include, at a 
minimum: 
• Date of event 
• Severity 
• Outcome 
• Resolution of event 
 

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Definition of Adverse Event 
An AE is any clinically significant undesirable experience (sign, symptom, illness, or other 
medical event) meeting the causality definition above that appears or worsens in a participant 
during a clinical study. A clinically significant event is any event (sign, symptom, lab/imaging 
abnormality, or diagnosis) that is noteworthy enough to merit documentation in standard medical 
records (e.g. history and physical, progress notes, clinic visit notes, etc.). Other non-clinically 
significant events (e.g. colds, minor headaches, etc.) may be documented on the comments CRF. 
Mild hypoglycemia is expected in persons with diabetes using insulin and are typically self-
limiting in nature; thus, this will not be captured as an AE. The Medical Monitor will have the 
final say in determining the causality. 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. 
 
Serious Adverse Events  
A serious adverse event (SAE) is defined as any untoward medical occurrence that: 
• Results in death 
• Is life-threatening; (substantial risk of dying at the time of the adverse event or suspicion 
that continued use of the device would result in a participant’s death  
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions  
• Requires medical or surgical intervention to prevent permanent impairment or damage  
Exceptions to the SAE definition will include the following: 
• Elective surgery 
• A planned hospitalization for pre-existing condition, without a serious deterioration in 
health 
Any SAE, including death, due to any cause (related or unrelated to the device), that may occur 
during a clinical study will be reported to the PI and Medical Monitor immediately (within 1 
working day of learning of the event).  
 
Severity of Adverse Events  
The following definitions may be used to rate severity of AEs: 
• Mild 
Awareness of signs or symptoms, but easily tolerated; are of minor irritant type that is 
outside the norm for the disease state or subject; causing no loss of time from normal 
activities; symptoms would not require medication or a medical evaluation; signs and 
symptoms are transient. Mild hypoglycemia is expected in diabetes and will not be 
captured as an AE.  
Example: ketosis not requiring an ER visit. 
• Moderate 

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Discomfort severe enough to cause interference with usual activities, requiring treatment  
by family member or emergency personnel  
Example: infusion site infection requiring antibiotics prescribed at urgent care. 
• Severe 
Incapacitating, causing inability to do work or usual activities; signs and symptoms may 
be of systemic nature or require medical evaluation and/or treatment at a health care 
facility 
Example: severe hypoglycemia defined as hypoglycemic event resulting in altered 
consciousness requiring another person to actively administer carbohydrate, glucagon, 
or other resuscitative actions.  
Relationship of Adverse Events to Study or Study Device 
The investigator will categorize the relationship of the event to the study or study device as 
follows:  
• Not Related 
AE is due to an underlying disease state or concomitant medication or therapy not related 
to the device, disease or study. 
• Unlikely Related 
AE has minimum or no temporal relationship to the study device, disease or study 
participation and/or a more likely alternative etiology exists. 
• Possibly Related 
AE has a strong temporal relationship to the study device, disease or study procedures 
and alternative etiology is equally or less likely compared to the potential relationship to 
the device, disease or study. 
• Probably Related 
AE has a strong temporal relationship to the study device, disease or study and another 
etiology is unlikely. 
• Definitely Related 
AE has a strong temporal relationship to the study device, study procedures or disease 
and another etiology does not exist. 
Unanticipated Problems 
Unanticipated problems, including study, disease or device-related problems will be detected by 
reviewing descriptions of known or foreseeable adverse events and risks in the IRB-approved 
research protocol and the current IRB approved consent form, any underlying disease or 
conditions of the subject experiencing the adverse event, a careful assessment of whether the 
adverse event is related or possibly related to the subject’s participation in the study or if root 
cause or associations is with study devices.  
 
Unanticipated Adverse Device Effect (UADE) 

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An unanticipated adverse device effect (UADE) is not expected to occur. An UADE is defined as 
any serious adverse effect on health or safety or any life-threatening problem or death caused by 
– or associated with – the device, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the investigational plan (including documents such as 
the protocol, the informed consent document, other study-related documents), or any other 
unanticipated serious problem associated with the device that relates to the rights, safety, or 
welfare of participants.  
During the review of a reported SAE, if the PI and Medical Monitor input determines the 
severity or extent of the event was not cited in this protocol or associated protocol materials, and 
the event was classified as, ‘possibly related’ to the device, the event will be documented as an 
UADE. If the event is classified as an UADE, the Investigator must notify the IRB and the FDA 
within ten (10) working days of the original SAE notification. 
If determined that the UADE presents an unreasonable risk to participants, we will terminate all 
investigations or parts of investigations presenting that risk as soon as possible, but not later than 
5 working days after such determination is made and not later than 15 working days after we first 
receives notice of the original SAE. We will not resume a terminated study without IRB and 
FDA approval. 
Medical Device Reporting (MDR)  
A device issue, whether related to a complaint or not, is an allegation from the participant or 
study personnel regarding an indication of the failure of a device to meet user expectations for 
quality or performance specifications. Device issues will be recorded onto appropriate CRFs by 
site personnel. The CGM and Omnipod devices are currently marketed. Therefore, the PI will 
follow the required reporting regulations to Dexcom or Insulet if an MDR reportable event 
occurs.  
MDR reportable events are events that manufacturers become aware of that reasonably suggest 
one of their marketed devices may have caused or contributed to a death or serious injury, or has 
malfunctioned and the malfunction of the device would likely cause or contribute to a death or 
serious injury if the malfunction were to recur (21 CFR 803.3). 
 
Confidentiality Procedures: 
Staff will maintain the confidentiality and security of data collected in this study. Paper files will 
be stored in locked filing cabinets in restricted access offices at site. After the study, source 
documents will be maintained at the participating clinical center (or offsite record storage 
facilities) 2 years after a marketing application is approved for our group's decision support 
device or discontinuance of pursuit of marketing approval. Electronic data will be stored on 
encrypted: computers, laptops and study smartphones. Electronic data is stored in OneDrive and 
on a secure HIPAA compliant system run by Prelude Dynamics. Sites will be invited to upload 
data using a password protected folder in Microsoft OneDrive. iPancreas data will be housed in a 
custom cloud database on an OHSU secure server called the GRM (see below). Access to 
data/specimens is restricted to study personnel. Access to data requires ID/password 
authentication.  
 
iPancreas Guidance Remote Monitoring (GRM) Cloud Server 

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All of the data collected will be streamed over the Internet (using secure sockets encryption) to 
an OHSU secure instance of an AWS cloud storage server every 5 minutes. Authentication 
between the phone and the AWS server is done using OAuth2. Data transmitted between the 
phone and the AWS server is encrypted using HTTPS/SSL. The code managing authentication 
and data transfer is Python version 3.7.0. Data acquired from the app is displayed via a physician 
web portal. The physician web portal user interface is written in Javascript version 1.8.5. There 
is no personally identifiable data stored with the data sent to the AWS server. The server shall be 
capable of receiving the following types of data (1) CGM data, (2) blood glucose and ketone 
data, (3) insulin dosing data, (4) insulin on board, (5) alerts, (6) exercise data, and (7) settings. 
All types of data shall be indexed by participant ID and by date/time. Data shall be stored on the 
server in a secure database. Each data packet shall be accompanied by an authentication 
identifier determined through oauth.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix A: Hypoglycemia Awareness questionnaire 
This survey item will be used to categorize awareness or having reduced awareness of 
hypoglycemia. 
 
1. Check the category that best describes you: (check one only) 
 
 I always have symptoms when my blood sugar is low (A) 
 I sometimes have symptoms when my blood sugar is low (R) 
 I no longer have symptoms when my blood sugar is low (R) 
2. Have you lost some of the symptoms that used to occur when your blood sugar was low? 
 
 Yes (R) 
 No (A) 
3. In the past 6 months how often have you had episodes where you might feel confused, 
disoriented, or lethargic and were unable to treat yourself? 
 
 Never (A) 
 Once or twice (R) 
 Every other month (R) 
 Once a month (R) 
 More than once a month (R) 
4. In the past year, how often have you had episodes where you were unconscious or had a 
seizure and needed glucagon or intravenous glucose? 
 
 Never (A) 
 1 time (R) 
 2 times (R) 
 3 times (R) 
 4 times (R) 
 5 times (R) 
 6 times (R) 
 7 times (R) 
 8 times (R) 
 9 times (R) 
 10 times (R) 
 11 times (R) 
 12 or more times (R) 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
 
5. How often in the last month have you had readings < 70 mg/dl with symptoms?  
 
 Never 
 1 to 3 times 
 1 time/week 
 2 to 3 times/week 
 4 to 5 times/week 
 Almost daily 
6. How often in the last month have you had readings < 70 mgdl, without symptoms? R: 5<6, A: 
6<5; 
 
 Never 
 1 to 3 times 
 1 time/week 
 2 to 3 times/week 
 4 to 5 times/week 
 Almost daily 
7. How low does your blood sugar need to go before you feel symptoms? 
 
 60-69 mg/dl (A) 
 50-59 mg/dl (A) 
 40-49 mg/dl (R)  
 < 40 mg/dl (R) 
 
8. To what extent can you tell by your symptoms that your blood sugar is low? 
 
 Never (R) 
 Rarely (R) 
 Sometimes (R) 
 Often (A) 
 Always (A) 
 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
Appendix B: iPancreas Alerts Table 
# 
NAME: Activation 
criteria 
Clearing Criteria 
Algorithm 
specifics 
Notification to 
participant 
Re-fire 
Time  
Refractory 
Period (min) 
Coordinator 
push (remote 
monitoring 
only) 
Investigator 
push  
(remote 
monitoring 
only) 
Waiting 
period 
4 
cbg_equal_or_under
_40: CBG ≤ 40 mg/dl 
AND alert 4 not 
active  
User enters CBG > 
40 mg/dL after 15 
minutes. Once 
rescue carb are 
entered, the 
waiting period 
starts. 
   If CBG ≥70 at any 
time, alert clears. 
None 
 "Blood glucose is 
below 40 mg/dl. 
Please take 30 gm 
of rescue 
carbohydrates and 
recheck your blood 
glucose level in 15 
minutes." 
5 min 
- 
Immediately 
Immediately 
Waiting 
period ends 
when alert 
13 is serviced 
OR clear 
criteria is 
met 
5 
cbg_under_70: CBG 
< 70 mg/dl AND 
alert 5 not active 
AND alert 4 not 
active 
CBG entry ≥70 
clears alert.  
 Once rescue carbs 
are entered, the 
waiting period 
starts. 
Alert clears if 
activation of alert 4 
is met 
Future: look back 
in time to see if 
taken rescue carbs 
within 15 min, 
then don’t require 
rescue carbs.  
None 
"Blood glucose is 
below 70 mg/dl. 
Please take 15 gm 
of rescue 
carbohydrates and 
recheck your blood 
glucose level in 15 
minutes." 
15 min 
- 
After 1st re-
fire 
After 2nd re-
fire 
Waiting 
period ends 
when alert 
13 is serviced 
OR clear 
criteria is 
met 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
6 
sensor_glucose_low: 
Sensor glucose < 
LOW_THRESH 
AND alert 4 AND 
alert 5 AND alert 6 
not active or 
refractory & no CBG 
within last 15 
minutes 
sensor ≥ 
LOW_THRESH OR 
extreme_low_senso
r_glucose is active. 
For MPC, 
LOW_THRES
H = 70 mg/dL 
 
"Sensor glucose is 
below 
LOW_THRESH 
mg/dl. Please 
perform a blood 
glucose check 
now." 
15 min 
60 
After 1st re-
fire 
After 2nd re-
fire 
- 
7 
cbg_equal_or_over_
300: CBG ≥ 300 
mg/dl AND alert 27 
not active or 
refractory AND alert 
7 not active or 
refractory 
Ketone check 
 
None 
"Blood glucose is 
above 300 mg/dl. 
Please check the 
insulin pod for 
leaking or 
detachment and 
check ketone levels 
now." 
30 min 
120 
After 1st re-
fire 
After 2nd re-
fire 
- 
8 
sensor_glucose_high
: Sensor glucose ≥ 
300 mg/dl for 30 
minutes within the 
last 45 minute 
period AND alert 8 
AND alert 7 AND 
alert 27 not active or 
refractory AND no 
CBG in last 30 
minutes 
CBG check. 
OR sensor < 300 
None 
"Sensor glucose is 
over 300 mg/dl. 
Please perform a 
blood glucose 
check now." 
30 min 
60 
After 1st re-
fire 
After 2nd re-
fire 
- 
10 
Insulin_user_bolus_
failure: If 50% of 
user bolus is still not 
delivered after 20 
minutes. 
User 
acknowledgement  
None 
Insulin pump may 
have failed. At least 
50% of your insulin 
bolus failed to 
deliver.   
- 
- 
Immediately 
Immediately 
- 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
13 
recheck_cbg: Alert 4 
OR alert 5 in 
waiting period for 
15 minutes  
CBG recheck 
 
"Please perform a 
blood glucose 
check now." 
20 min 
- 
After 1st re-
fire 
After 2nd re-
fire 
- 
14 
no_data_connection
: No connection to 
the internet or data 
for 40 minutes 
Phone connects to 
a wifi network or 
regain cell service 
 
There is no 
connection of the 
phone to the 
internet. Please 
move back into cell 
phone or wifi 
range.  
40 min 
- 
- 
- 
- 
17 
sensor_not_reportin
g: Sensor is out of 
date for > 20 
minutes AND alert 
17 AND alert 19 
AND alert 20 not 
active or refractory 
Clears with valid 
sensor.  
Alert  refires 
every 12 hours   
"A sensor reading 
has not been 
received in the last 
20 minutes. Please 
ensure that the 
phone is within 
range of the sensor. 
Click here for 
trouble-shooting 
guidelines" 
12 
hours 
- 
- 
- 
- 
19 
sensor_not_reportin
g_correctly: will 
populate 20 minutes 
after a temporary 
sensor issue is 
received AND 
alert 17 AND alert 
19 AND alert 20 not 
active or refractory 
Clears with valid 
sensor.  
Alert  refires 
every 12 hours   
"Sensor value is not 
reporting correctly. 
Please check your 
sensor site for 
problems. Click 
here for trouble-
shooting 
guidelines.” 
12 
hours 
- 
- 
- 
- 
20 
replace_sensor: 
iPancreas sends 
message to replace 
the sensor 
immediately after 
Clears with valid 
sensor  
Alert  refires 
every 12 hours. 
Other sensor 
alerts will not 
fire during the 
"The sensor is no 
longer functioning. 
Please replace it 
immediately." 
12 
hours 
120 
- 
- 
- 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
receiving a 
permanent sensor 
error.  
refractory 
period of 120 
minutes.   
21 
Insulin_pump_com
munication_failure: 
Basal Insulin Fails to 
deliver correct 
amount for 60 
minutes OR insulin 
suspend required 
and no connection 
to pump 
Successful basal 
insulin is 
delivered  OR 
insulin is 
successfully 
suspended 
 
“Insulin 
communication 
failure. Please move 
PDM and POD 
closer to phone”  
60 min 
If alert fires 
after 
10:59PM, 
refractory 
lasts until 
6:59AM. No 
refractory 
other hours of 
the day. 
After 1st re-
fire 
After 2nd re-
fire 
- 
25 
phone_battery_low: 
Phone battery falls 
below 20% AND is 
not charging 
If phone is charging 
or level goes above 
20% 
 
"Phone battery low. 
Please charge" 
10 min 
- 
After 1st re-
fire 
After 2nd re-
fire 
- 
26 
maximum_insulin_e
xceeded: Insulin 
Delivery ≥ 35% 
TDIRadj on last hour 
User 
acknowledgement  
 
"Max insulin has 
been exceeded" 
- 
60 
Immediately 
Immediately 
- 
27 
cbg_equal_or_over_
400: CBG ≥ 400 
mg/dl AND alert 27 
not active or 
refractory 
Ketone check 
 
"Blood glucose is 
above 400 mg/dl. 
Please change the 
insulin pod and 
check ketone levels 
now." 
15 min 
60 
Immediately 
Immediately 
- 
28 
ketone_level_high: 
Ketones ≥ 0.6 
mmol/L 
User 
acknowledgement 
 
“Ketone levels are 
high. If not already 
done, please change 
the insulin pod. Do 
not exercise.” 
- 
- 
Immediately 
Immediately 
- 
29 
Insulin_pump_reser
voir_low: Omnipod 
Pod with greater 
than 10% volume is 
 
Your insulin pod is 
low. Please 
120 
min 
- 
After 1st re-
fire 
After 2nd re-
fire 
- 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
has less than 10% of 
fluid volume 
remaining. 
connected (i.e. pod 
is changed) 
deactivate your 
current pod and 
activate a new 
insulin pod. 
30 
External_insulin_de
tected_alert: 
iPancreas has 
determined that 
more insulin has 
been delivered than 
expected by 
observing the 
insulin pump’ pulse 
count  
None, this alert 
only goes to the 
study coordinator 
and investigator. 
The app 
determined by 
the pump’s 
pulse count 
that more 
insulin than 
was expected 
was delivered. 
We determined 
that X.X units of 
insulin above the 
expected amount 
was delivered. 
Please switch to 
open loop mode 
and call study 
team. 
- 
- 
Immediately 
Immediately 
- 
31 
Sensor_glucose_extr
emely_low:  This 
alert fires when 
CGM is measured to 
be <= 54 mg/dL. 
Measured CGM > 
54 mg/dL. 
This alert fires 
if CGM is 
measured to be 
< 54 mg/dL.  
When this 
alert is active, 
the 
sensor_glucose
_low is 
suppressed.  If 
CGM goes 
from <= 54 to 
between 70-54 
mg/dL, the 
sensor_glucose
_low alert will 
fire again after 
the refractory 
period of 30 
minutes expires 
“Sensor value is 
extremely low” 
“Sensor glucose is 
below 54 mg/dL.  
Please perform a 
blood glucose 
check now.” 
10 min 
30 
After first re-
fire 
After second 
re-fire 
- 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
on the recently 
cleared  
sensor_glucose
_extremely_lo
w alert 
32 
extreme_hypoglyce
mia_predicted: fires 
when CGM is 
predicted to be <= 
54 mg/dL within the 
next 30 minutes. 
CGM is no longer 
predicted to be <= 
54 mg/dL within 
the next 30 
minutes, or CGM is 
measured to be <= 
54 mg/dL. 
This alert fires 
if the LSTM 
predicts that 
the CGM will 
drop < 54 
mg/dL.  
Your blood glucose 
is predicted to drop 
below 54 mg/dl 
within 30 minutes. 
Please consider 
taking a rescue 
carbohydrate. 
15 min 
30 
After first 
re-fire 
After 
second re-
fire 
- 
33 
Watch_not_commu
nicating 
 
This alert fires 
if the watch 
hasn’t 
communicated 
for last 30 
minutes. Alert  
refires every 12 
hours   
Your watch hasn’t 
communicated in a 
while. Please check 
the connection.  
12 
hours 
- 
- 
- 
 
34 
Missed_meal_alert 
 
This alert is 
triggered if the 
missed meal 
detection 
algorithm 
detects a meal 
and the safety 
layer for the 
missed meal 
detection 
algorithm calls 
for a reduction 
of 50% or more 
of the meal 
Did you consume a 
meal? Your glucose 
appears to be rising. 
Did you consume a 
meal that you want 
to dose insulin for? 
 
- 
- 
- 
 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
insulin 
calculated by 
the missed 
meal detection 
algorithm. 
35 
Pdm_low_battery_al
ert 
Alert clears when 
PDM battery goes 
above 2.5 V.  
If the Insulet 
PDM battery 
level drops 
below 2.5V, 
then this alert 
triggers. Alert  
refires every 12 
hours   
The battery on the 
PDM is low.  Please 
change the 
batteries on the 
PDM. 
12 
hours 
2 hours 
- 
- 
 
36 sensor_session_e
nded alert 
Alert clears with 
new sensor 
session start 
 
Your sensor 
session has 
ended. Please 
replace your 
sensor 
immediately. 
12 
hours 
- 
 
 
 
37 automated_meal
_bolus_delivered
      
 
 Clears 
immediately 
 
 
- 
- 
Immediately Immediatel
y 
 
38 replace_transmit
ter:  Dexcom 
reports that the 
currently 
activated 
transmitter is no 
longer 
usable.                 
     
User 
acknowledgeme
nt 
 
The transmitter 
is no longer 
functional. 
Please replace it. 
12 hrs 
- 
- 
- 
 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
39 calibrate_sensor
: Dexcom reports 
that a calibration 
is 
required.              
   
User 
acknowledgeme
nt 
 
Sensor 
calibration is 
due. Please 
perform a blood 
glucose check 
now. 
30 min - 
- 
- 
 
40 closed_loop_per
manently_pause
d: The Insulet 
Omnipod pump 
controller reports 
an unexpected 
error. 
User 
acknowledgeme
nt 
 
An unexpected 
error has 
occurred and 
closed loop has 
been 
permanently 
paused. Please 
contact the study 
coordinator. 
- 
- 
Immediately Immediatel
y 
 
41 insulet_pod_not
_usable: The 
Insulet PDM 
Device reports 
that the currently 
activated 
Omnipod is no 
longer usable. 
User 
acknowledgeme
nt 
 
Your pod is no 
longer usable. 
Please replace 
the pod. 
- 
- 
- 
- 
 
42 pump_time_out_
of_sync: This 
alert is triggered 
if the time on the 
phone and PDM 
differ by greater 
than 5 
minutes.               
                   
User 
acknowledgeme
nt 
 
A time 
discrepancy 
between the 
phone and tHe 
pUMP HAS BEEN 
DETECTED. 
CLOSED LOOP 
CONTROL HAS 
BEEN 
- 
- 
Immediately Immediatel
y 
 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
PERMANENTLY 
PAUSED.  
43 re_pair_pdm: 
The app detects 
an issue with the 
Bluetooth 
connection to the 
PDM.  
User 
acknowledgeme
nt 
 
Your PDM 
seems to be 
having trouble 
communicating 
and needs to be 
un-paired / re-
paired. Please 
disconnect the 
device from 
iPancreas. Then 
go to the 
Android 
Bluetooth menu, 
forget the device, 
then re-pair it. 
- 
- 
- 
- 
 
44 insulin_pod_em
pty: The app 
detects the pod is 
empty.  
 
 
Your insulin pod 
is empty. Please 
replace it 
immediately.  
30 
minute
s 
none 
never 
never 
 
45 insulin_pod_expi
res_soon: the app 
detects that it has 
been 71 hours 
since pod was 
started.  
 
 
Your insulin pod 
will expire soon. 
Please replace it 
immediately.  
60 
minute
s 
none 
never 
never 
 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
Appendix C:  Safety instruction cards for participants for checking ketones, to take 
additional carbs at the start of exercise as needed based on CGM and trend to avoid post-
exercise hypoglycemia, for study stopping rules.  
 
Instruction cards:  
 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
 
 
 

OHSU IRB #24218 
Advarra Pro00067326 
Version 10.0 updated 10/14/2024 
Appendix D: Instruction card for participants outlining how to properly replace pods  
 
 
References Cited in this Document 
 
[1] 
P. G. Jacobs et al., "Randomized trial of a dual-hormone artificial pancreas with dosing 
adjustment during exercise compared with no adjustment and sensor-augmented pump therapy," 
Diabetes Obes Metab, vol. 18, no. 11, pp. 1110-1119, Nov 2016, doi: 10.1111/dom.12707. 
[2] 
J. R. Castle et al., "Randomized Outpatient Trial of Single- and Dual-Hormone Closed-
Loop Systems That Adapt to Exercise Using Wearable Sensors," Diabetes Care, p. dc180228, 
2018/5/9 2018, doi: 10.2337/dc18-0228. 
[3] 
L. M. Wilson et al., "Dual-Hormone Closed-Loop System Using a Liquid Stable 
Glucagon Formulation Versus Insulin-Only Closed-Loop System Compared With a Predictive 
Low Glucose Suspend System: An Open-Label, Outpatient, Single-Center, Crossover, 
Randomized Controlled Trial," Diabetes Care, vol. 43, no. 11, pp. 2721-2729, Nov 2020, doi: 
10.2337/dc19-2267. 
4] 
R. M. Bergenstal et al., "Glucose Management Indicator (GMI): A New Term for 
Estimating A1C From Continuous Glucose Monitoring," Diabetes Care, vol. 41, no. 11, pp. 
2275-2280, Nov 2018, doi: 10.2337/dc18-1581.