A Crossover Study to Evaluate Insulin/Pramlintide Versus Insulin Alone Delivery Strategy
Phase: NA
Conditions: Type 1 Diabetes
Sponsor: Oregon Health and Science University

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PROTOCOL TITLE: A crossover study to evaluate insulin and pramlintide versus insulin alone 
delivery strategy 
 
Brief Title: Pramlintide AP study  
 
NCT Number: NCT06422325 
 
Unique Protocol Id: OHSU25279 
 
Version 5.0 updated 30Oct2024 

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PROTOCOL TITLE: A crossover study to evaluate insulin and pramlintide versus insulin 
alone delivery strategy 
 
  
STUDY SITE: 
Oregon Health Science University 
3181 SW Sam Jackson Park Rd 
Portland, OR 97239 
 
FUNDING: 
NIH 
 
PRINCIPAL INVESTIGATORS: 
Leah M. Wilson MD; Peter Jacobs PhD  
 
CO-INVESTIGATORS:  
Diana Aby-Daniel PA-C, Andrew Ahmann MD, Roula Zahr MD 
 
 
 
Background: 
Type 1 diabetes (T1D) is a complex disease and people with T1D are at high-risk of both hyper- 
and hypoglycemia which can lead to severe acute and chronic complications. Due to the burden 
and complexity of managing T1D, the vast majority of people with T1D do not reach the target 
HbA1c of <7% as recommended by the American Diabetes Association. Data from the T1D 
Exchange, which includes 64 diabetes centers, demonstrated that 69% of patients in the 
exchange had HbA1c levels of >7.5% [62]. The benefits of optimal glycemic control are well 
documented, including significant reductions in microvascular disease [63] and to a lesser degree 
macrovascular disease [64]. Achieving optimal glycemic control requires frequent glucose 
monitoring by finger-stick and/or continuous glucose monitoring (CGM) in combination with 
either multiple daily injection (MDI) or insulin pump therapy, or most recently, with an artificial 
pancreas (AP) system. AP systems automate insulin delivery based on CGM values to minimize 
hypoglycemia and hyperglycemia, and in some cases also deliver glucagon to prevent and treat 
hypoglycemia. AP systems have been tested extensively in both the inpatient and outpatient 
settings [54, 65-69].  
 
Current commercial closed loop systems such as the Medtronic 670g and more recently 
Tandem’s Control-IQ [70, 71] have demonstrated a modest improvement in the percent time in 
glucose target range (70-180 mg/dL) of 5% for the 670g [72] and 10% for the Control-IQ [71]. 
However, the benefit is almost entirely due to improved glycemic control overnight when meals 
are not being consumed as shown by Kovatchev and colleagues [73]. Our group has developed a 
multi-hormone (glucagon and insulin) closed loop system that improved time in range by 7.6% 
overall; but as with the commercial systems the majority of benefit was during the overnight 
hours where it exhibited 100% time in target range (70-180 mg/dL) compared with 62.5% time 
in range for the control open loop system with predictive low glucose suspend [31] Commercial 
closed-loop systems and the systems developed by our group are unable to effectively handle 
meals because the kinetics of subcutaneously delivered insulin are sufficiently slower than the 

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body’s absorption of carbohydrates [36]. This delay in kinetics of insulin relative to meal 
absorption results in a rapid increase in glucose immediately following a meal that cannot be 
prevented, even if the appropriate amount of insulin is given at the time of the meal or even prior 
to meal consumption. 
 
Compounding this problem is the fact that many people struggle to adequately estimate their 
carbohydrates because they simply do not know the amount of carbohydrates in the food that 
they are consuming [37]. Our group recently showed that 49% of smaller meals (carbs <30 g) are 
overestimated by an average of 25.7 +/- 17.2 g while 64% of larger meals (>60 g) are 
underestimated by an average of 53.6+/-33.8 g by people with T1D under free-living conditions 
[74]. Furthermore, people with T1D oftentimes forget to announce meals to the closed loop 
system altogether, leading to insufficient insulin at meal time, followed by possible over-dosing 
of insulin by the control algorithm immediately after the meal when glucose levels spike, which 
can then lead to both short-term hyperglycemia and also hypoglycemia hours after the meal [37]. 
This is why the current commercial closed loop systems require users to announce meals to the 
system prior to eating. Hybrid closed loop systems use the carbohydrate amount entered by the 
user to dose the appropriate amount of insulin based on preset insulin to carbohydrate ratios. 
Requiring a person with T1D to announce meals is both a burden to the person, and as discussed 
above, missed doses and errors in carbohydrate estimations can lead to serious postprandial 
hypo- and hyperglycemic outcomes after a meal. The failure of hybrid closed loop systems to 
appropriately handle meals is the primary reason why these systems do not show a benefit during 
the daytime compared with manual control.  
 
Integrating pramlintide into a dual hormone hybrid closed loop system is effective at 
substantially improving time in target range (70-180mg/dL) during the daytime as shown by 
Haidar and colleagues [75]. When people with T1D dosed a combination of rapid acting insulin 
and pramlintide, their time in target range was substantially lower following the meal compared 
with rapid acting insulin alone. Haidar et al. found that time in target range could be increased 
from 74% (SD 18%) to 84% (SD 13%) when incorporating pramlintide dosed with insulin prior 
to meals. Pramlintide is a synthetic form of amylin which is released with insulin from the beta 
cell in normal physiology. People with T1D loose both insulin and amylin secretion due to 
autoimmune beta cell destruction [38]. Pramlintide is known to substantially blunt rate of 
appearance of glucose after a meal in T1D as shown by our group in Riddle et al [39] by 
suppressing glucagon production to prevent hepatic glucose release [40] and delaying gastric 
emptying [41] via central nervous system effects. The slowing of gastric emptying by 
pramlintide controls the influx of glucose from the meal to better match the relatively slower 
kinetics of subcutaneous insulin for disposal of glucose.  There is now a co-formulation in 
development of insulin with pramlintide that will allow for ease of dosing (Adocia 
Pharmaceuticals). M1Pram contains A21G human insulin analog (“M1”), which most closely 
matches pharmacokinetics of regular human insulin, along with the amylin analog pramlintide 
manufactured by AstraZeneca.  
 
We have developed a meal detection and carb-estimation algorithm[2]  and we have integrated 
this algorithm within the context of a dual-hormone insulin and pramlintide closed loop system 
to enable fully automated closed loop control without requiring people with T1D to enter 

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carbohydrates to the system. This meal detection and carb-estimation algorithm was shown in a 
clinical study to detect meals within 25.9 minutes of meal consumption with sensitivity of 83.3% 
and a false discovery rate of 16.6%. It was shown to reduce time above 180 mg/dL by 10.8%[2]. 
 
The clinical study described in this protocol is a safety and efficacy study in order to develop a 
non-hybrid, fully automated closed loop system that does not require the person to announce 
meals to the system, and which utilizes the hormone analog pramlintide in combination with 
insulin to potentially reduce the meal related hyperglycemia and increase the time spent in target 
range during the daytime.   
 
Primary Objectives: 
• To evaluate safety and efficacy of a fixed co-ratio insulin and pramlintide delivery 
strategy under closed loop control after a meal is detected by the meal detection 
algorithm 
• To evaluate performance of the fully closed-loop system with (1) insulin+pramlintide as 
compared to (2) insulin-only as measured by incremental area under the curve (iAUC) in 
the 6 hours following the first meal period 
Secondary Objective: 
• To evaluate performance of the fully closed-loop system with insulin+pramlintide as 
compared to insulin-only for other glycemic outcomes 
Study Hypothesis: 
Our hypothesis is that pramlintide and insulin delivered after a meal by a closed loop system in 
response to automated meal detection will be well tolerated and will allow for a reduction in the 
postprandial glucose response as measured by the incremental area under the CGM curve 
(iAUC)  compared with an insulin-only fully closed loop system. 
 
Endpoints 
Primary Endpoints:  
• Incremental area under the curve (iAUC) of postprandial glucose as measured by CGM 
in the 6 hours following the start of first meal. iAUC (mg/dL*min) will be calculated 
using a trapezoidal method [76], which sums all CGM values in the 6 hour period 
following the meal above the starting glucose. 
• Percent of time with sensed glucose between 70 – 180 mg/dl in the 6 hours following the 
start of first meal. 
Secondary Endpoints  
• Incremental area under the curve (iAUC) of postprandial glucose as measured by CGM 
in the 6 hours following the start of second meal. iAUC (mg/dL*min) will be calculated 
using a trapezoidal method [76], which sums all CGM values in the 6 hour period 
following the meal above the starting glucose. 

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• Percent of time with sensed glucose between 70 – 180 mg/dl in the 6 hours following the 
start of second meal. 
(The following secondary outcomes will be measured in the 6 hours following (1) the start 
of the first meal, (2) the start of the second meal, and (3) full study duration):  
• Net area under the curve (netAUC) of postprandial glucose as measured by CGM in 
the 6 hours following the start of first meal. netAUC (mg/dL*min) will be calculated 
using a trapezoidal method [76], which sums all CGM values in the 6 hour period 
following the meal above the starting glucose and subtracts CGM values below the 
starting glucose. 
• Percent of time with sensed glucose <70 mg/dl  
• Percent of time with sensed glucose between 70 – 140 mg/dl 
• Mean sensed glucose 
• Percent of time with sensed glucose <54 mg/dl 
• Percent of time with sensed glucose >180 mg/dl 
• Percent of time with sensed glucose >250 mg/dl 
• Mean amount of insulin delivered (in units and units/kg) 
• Mean amount of pramlintide delivered (in mcg and mcg/kg) 
• Coefficient of variation 
• LBGI 
• HBGI 
• Safety endpoints (over full study duration): 
o Adverse events  
▪ Number of adverse events probably or possibly associated with 
pramlintide administration (see ‘Causality Relationship’ below) 
▪ Baxter Retching Faces (BARF)/VAS scale for gastrointestinal issues 
after first and second meal, see Protocol Appendix D. 
▪ Mean duration of gastrointestinal issues after first and second meal as 
reported by participant on BARF/VAS scale, see Protocol Appendix 
D. 
o Episodes of carbohydrate intake to treat hypoglycemia (defined as 15g 
carbohydrate intake) 
o Episodes of hypoglycemia defined as CGM <70mg/dL for 10 minutes or more 
o Number of provider-administered insulin injections due to hyperglycemia  
Study Type  
This is a single-center, crossover trial designed to evaluate glucose outcomes of a fully closed-
loop system with insulin+pramlintide dosed in response to meal detection as compared to an 
insulin alone fully closed loop system. 
 
Study Population 

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Study population will be adults with type 1 diabetes, ages 18 – 70 years of age. Younger 
participants are excluded as it is appropriate to assess safety first in the over 18 year old 
population. We are targeting a total of 35 participants to complete the full study protocol.   
 
Power Analysis  
A sample size of 35 participants provides 90% power to detect a standardized paired mean 
difference of 0.56 SD, or 80% power to detect a 0.49-SD difference with a two-sided test at the 
.05 level of significance. This is calculated using a paired t test to approximate a mixed model 
with treatment, period, and sequence effects. Data from a previous study [24] showed a 0.64-SD 
reduction with pramlintide in 4-hour postprandial AUC for participants with >40 U bolus insulin 
per day. We plan to recruit more than half of our study participants from this population and so 
we expect to observe a slightly smaller reduction in AUC.  
 
Protocol Summary: 
Participants will undergo two study visits to evaluate (1) insulin+pramlintide versus (2) insulin-
only delivery strategies. The order of the visits will be randomized.  Meal scenarios will be 
identical across all study arms. Participants will arrive at approximately 7:30 am for all visits, be 
monitored through the afternoon and discharged at approximately 8 pm. During each study visit, 
participants will wear Omnipod(s) to deliver insulin and/or pramlintide and a Dexcom G6 CGM 
to measure glucose and a Polar M600 to measure activity levels. See Figure 1 and 2 below.  
Figure 1: Study flow diagram
 
Visit 1: 
Screening 
visit
1 ½ hours
Visit 2: 
Dexcom G6 
run-in visit
30-60 min
Visit 3: Clinic 
Visit #1
12.5 hours
Visit 4: Clinic 
Visit #2
12.5 hours
Time between visits 1&2: 
same day if passes screening or 
1-12 weeks
Time between visits 2&3: 
1-8 days
Time between visits 3 & 4:
3-28 days

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Figure 2: Treatment visit timeline 
 
Subject Criteria 
Inclusion Criteria:  
1. Diagnosis of type 1 diabetes mellitus for at least 1 year.  
2. Participants 18 to 70 years of age.  
3. Current use of an insulin pump for at least 3 months with stable insulin pump settings for 
>2 weeks. OR Current use of multiple day injection insulin therapy with stable doses for 
>2 weeks.  
4. Uses a carbohydrate ratio, at least occasionally, to dose meal time insulin  
5. HbA1c ≤ 10.5% at screening.   
6. Total daily insulin requirement is less than 139 units/day.  
7. Willingness to follow all study procedures, including attending all clinic visits.  
8. Willingness to sign informed consent and HIPAA documents.  
Exclusion Criteria:  
1. Individual 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. Any cardiovascular disease, defined as a clinically significant EKG abnormality 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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3. Renal insufficiency (GFR < 60 ml/min, using the MDRD equation as reported by the 
OHSU laboratory). 
4. Liver failure, cirrhosis, or any other liver disease that compromises liver function as 
determined by the investigator.   
5. History of severe hypoglycemia during the past 3 months prior to screening visit or 
hypoglycemia unawareness as judged by the investigator.  
6. Participants will complete a hypoglycemia awareness questionnaire.  Participants will be 
excluded for four or more R responses.  
7. History of diabetes ketoacidosis during the prior 3 months prior to screening visit, as 
diagnosed on hospital admission or as judged by the investigator. 
8. Adrenal insufficiency. 
9. Any active infection requiring treatment (example soft tissue infection requiring 
antibiotics) . 
10. Known or suspected abuse of alcohol, narcotics, or illicit drugs.  
11. Seizure disorder. 
12. Major surgical operation within 30 days prior to screening. 
13. Use of an investigational drug within 30 days prior to screening. 
14. Chronic usage of any immunosuppressive medication (such as cyclosporine, 
azathioprine, sirolimus, or tacrolimus). 
15. Bleeding disorder, treatment with warfarin, or platelet count below 50,000. 
16. Allergy to aspart insulin. 
17. Allergy to NPH insulin. 
18. Allergy to pramlintide. 
19. Current administration of oral or parenteral corticosteroids. 
20. 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).  
21. Current use of any medication that may lower glucose other than insulin or pramlintide 
(ex. use of liraglutide, metformin etc) including the use of GLP1RA medications for 
weight loss (ex. Wegovy or Zepbound). 
22. Gastroparesis 
23. Diets consisting of less than 50 grams of carbohydrates per day.  
24. Dietary restrictions or allergies to all of the study meal options 
25. Any clinically significant disease or disorder which in the opinion of the Investigator may 
jeopardize the participant’s safety or compliance with the protocol.  
Subject Recruiting: 
Participants will be recruited from OHSU clinics, from flyers to be posted in approved places at 
OHSU or posted on the web to the clinical trials page for the OHSU Schnitzer Diabetes Clinic, to 
the clinic’s Facebook group, ads on Facebook, electronic newsletter or from the OHSU Subject 
Recruitment website. Handouts may also be made available to faculty at Tuality, Providence, 

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Kaiser and Legacy to pass along to patients/participants who show interest in the study. Records 
from OHSU Schnitzer Diabetes Clinic patients may be screened to find potential participants. 
Participants will also be recruited from a list of participants who participated in past OHSU 
studies who have agreed to be contacted regarding future studies, from the OHSU diabetes 
research registry and/or www.clinicaltrials.gov. Participants will be contacted using the approved 
telephone screening script and email template. Non-English speaking participants will not be 
recruited since this protocol would require the use of medical devices and mobile software that 
do not have non-English versions available.  
This study will use Epic MyChart® to recruit potential participants. Researchers will work with 
ITG to identify potential participants based upon the above eligibility criteria. Researchers will 
create a Reporting Workbench query in epic based on inclusion and exclusion criteria. Potential 
participants will be sent a MyChart® recruitment message asking them to participate. There is no 
risk of duplicate invitations as it is based on MyChart® accounts combined with Epic records and 
no duplication is possible.  
 
Up to 50 participants may be screened in this study.  Goal enrollment is 35 participants. 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. 
Visit Procedures 
Screening (Visit 1) 
Screening will take place within 12 weeks prior to the Dexcom G6 training visit (Visit 2). This 
visit will take approximately 1.5 hours.  
 
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 their 
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 
breast and pelvic exams. Individuals 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, complete metabolic set (including creatinine, liver 
set, and electrolytes).  If a participant had any of these labs drawn with in the last 6 months and 
results are available for review within Epic or CareEverywhere for the study investigator to 
review, then those labs do not need to be drawn at the Screening Visit. A study investigator will 
assess inclusion/exclusion criteria and may review the participant’s medical record for 
clarification as needed.  Participants will complete a hypoglycemia awareness questionnaire, see 
Protocol Appendix B.  The participant’s insulin pump, and if applicable glucose sensor, will be 

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downloaded at the time of the screening visit to assess the participant’s insulin settings. A three-
digit participant ID number will be assigned to the participant.   
Dexcom CGM training visit (Visit 2) 
The purpose of this visit is to have the participants learn how to use the Dexcom G6 CGM device 
using the iPancreas smart phone application on a provided study phone. This visit will take 30-60 
minutes depending on user experience. This visit can occur directly after the screening visit if all 
screening criteria are met OR anytime within 12 weeks of the screening visit. After arrival, 
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. 
 
There is the option to make this visit virtual with supplies, including a pregnancy test, shipped to 
the participant at home.  Participants will meet with study staff via WebEx video software.  
 
Participants will receive training on how to use and calibrate the Dexcom G6 CGM system 
including changing out the sensor every 10 days.  The wire glucose sensor is sterile and 
commercially available from DexcomTM and will be used for single use only as directed by the 
manufacturer.  Participants will be trained to insert the sensor into the subcutaneous tissue of the 
abdomen after appropriate preparation of the abdominal skin per the manufacturer’s directions.  
Participants will be trained on 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 calibration. As part of the training, study staff will review with the participants 
that Dexcom G6 values can 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 capillary blood glucose (CBG) and use this value to 
make treatment decisions and to calibrate the Dexcom G6 device.  Participants will be provided 
with a copy of the Dexcom G6 user guide.    
 
The CGM alerts will be set at 70 mg/dL and 300 mg/dL. Participants will be given a Dexcom G6 
transmitter and sensor to insert the day before each treatment visit along with a Contour Next 
meter for measuring their capillary blood glucose.  
 
Run-in Period 
For the three days prior to the pramlintide treatment visit, participants will be instructed to use 
pramlintide 15 mcg injected subcutaneously via a pen device up to three times daily before each 
main meal for 1 day then increase to 30mcg before each main meal if tolerating in terms of GI 
side effects. They will be instructed to initially reduce their usual mealtime insulin doses by 10-
20% to accommodate the use of pramlintide, then can increase mealtime insulin dose as needed 
to target post meal glucose levels <180 or participants preferred post meal glucose levels. The 
last dose of pramlintide administered at home prior to the treatment visit should be at least 8 
hours before the visit. 
For participants using basal insulin (such as glargine, Tresiba, or Toujeo insulin) as an evening 
dose, they will be instructed to take about 1/3 ± 10% of their usual basal insulin dose as a dose of 
NPH insulin no later than 7 pm the night before each study visit, and to withhold any basal 

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insulin on the morning of the study. They will be instructed to bring their home basal insulin to 
the study visit to take a dose prior to discharge.  
  
For participants using basal insulin as a morning dose, they will be instructed to take usual 
morning basal insulin dose the day prior to each study visit, and to withhold any basal insulin on 
the morning of the study. The study investigator will calculate a dose to be given a dose of about 
1/3 ± 10% of their usual basal insulin dose as a dose of NPH insulin prior to discharge from the 
study visit. They will be instructed to give their home basal insulin the morning after the study 
visit as they normally do.  
  
For participants using basal insulin as a twice daily dose, they will be instructed to take usual 
morning basal insulin dose the day prior to each study visit. On the evening before the study 
visit, they will be instructed to take 2/3 ± 10% of their usual basal insulin dose as a dose of NPH 
insulin no later than 7 pm the night before each study visit, and to withhold any basal insulin on 
the morning of the study. They will be instructed to bring their home basal insulin to the study 
visit to take a dose prior to discharge.  
 
Insulin Treatment Visit  
Participants will be asked to check glucose from CGM at 2am each morning before their 
treatment visit. If the CGM value is above 150 mg/dl, participants will be asked to take 80% of 
the correction bolus. If the glucose is less than 100 mg/dL they will be instructed to take 15 
grams of carbohydrate. 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).  After the first treatment visit, the washout 
period will be at least 3 days calculated from the day of admission until the start of the next 
admission.  After arrival, 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 each of the participant’s closed-loop studies. 
We will inquire whether the participant has had changes in their medications and/or medical 
history to confirm the participant hasn’t developed any study exclusion criteria. A CBG will be 
obtained and measured by a Contour Next glucose meter.  When they arrive, participants will be 
given 15 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 the onsite investigator.  The order of the visits will be randomized.  
 
An Omnipod will be filled with aspart insulin. We will use only name brand insulin, not generic 
insulin. The Omnipod will be primed and inserted into the skin of the participant’s abdomen or 
flank as directed by the manufacturer through the iPancreas smart phone application on a 
provided study phone.  If applicable, participants will disconnect his/her own pump and remove 
his/her own insulin infusion set once insulin delivery has started via the Omnipod. If, applicable 
for participants on multiple daily injection therapy at baseline, we will verify time of last long 

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basal insulin administration. Participants will wear a Polar M600 fitness watch to inform the 
controller about physical activity. The research staff will initialize the system, input insulin 
settings and begin the closed-loop study. See Appendix A for a picture of the closed-loop 
system. Two staff will review each of the settings to confirm the settings are entered correctly. 
Participant will receive training on using the iPancreas smart phone application. A member of 
the study staff will remain near to the participant for the duration of the study to address any 
alerts or issues that arise. The study investigator will be on call for the duration of the study.  
 
The algorithm will push data up to an encrypted, secure Amazon Web Services cloud server that 
can be monitored remotely every 5 minutes. The iPancreas software will generate alerts on the 
smartphone. 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 the server that can receive texts with pushed alerts.  
 
During all studies, sensed glucose data will be wirelessly transmitted via BTLE from the 
Dexcom G6 transmitter to the insulin-delivery algorithm every five minutes.  The insulin-
delivery algorithm will calculate insulin doses and will run on a Samsung smart phone. The 
smart phone will wirelessly communicate via BTLE to a PDM communicating to an Omnipod 
for automated insulin delivery. Participants will wear a Polar watch for collecting heart rate and 
accelerometry data. The Polar watch transmits this data to the smartphone controller via 
Bluetooth. iPancreas will convert the heart rate and accelerometry data into an estimated energy 
expenditure.  
 
If at any time the study staff determines that a sensor can no longer be used, a new sensor will be 
inserted. If the participant’s blood glucose is < 70 mg/dl or is experiencing symptoms of 
hypoglycemia, he/she will be instructed to treat with 15 grams of carbohydrates. Glucose tablets 
will be provided to the participants.  
 
For participant safety, if communication is lost between the iPancreas app and the Dexcom G6 
CGM for ≥20 minutes or the insulin pod ≥30 minutes, the insulin pump shall deliver basal 
insulin according to pre-set basal rates designated within the iPancreas settings according to 
given times of day. 
 
When either the CGM or the insulin pump is out for the above time durations, the iPancreas 
system will activate a 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 thirty minutes or if 
the sensor glucose is less than 70 mg/dl. Maximum insulin suspension time is 2 hours. Prediction 
of sensor glucose is based on data long short term memory neural network (LSTM) 
algorithm[77]. When communication with the sensor or Omnipod is restored, the system will 
automatically resume delivering insulin according to the control algorithm, and IOB will be 
updated accordingly.  
 
Meal Description 

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After the closed loop study has started, participants will eat the assigned breakfast meal around 
8am. The assigned lunch meal will be given six hours later around 2 pm. The meal time may be 
delayed for safety if participant had a recent low glucose. The selected breakfast and lunch 
option will be identical across both study arms for each participant. The participant will be 
requested to complete their meal within 10 minutes. There will not be a premeal insulin bolus. 
 
The participant will select between two or three breakfast and lunch meals options and have 
these same meals at each study visit. If a food item is unavailable, it will be substituted with the 
closest available substitute. The caloric size of the meal will be based on DRI Estimated Energy 
requirement formulas.  The meals will be made by the OHSU Bionutrition kitchen. The breakfast 
meal options will each provide approximately 33% of participants daily energy requirement, 
with macronutrient composition of 50% carbohydrate, 15% protein and 35% fat. The lunch meal 
options will provide approximately 40% of the participants daily energy requirement with the 
same macronutrient composition as the breakfast meal.  
 
Meal detection will be enabled for the study. If iPancreas does not auto-detect the meal after 30 
minutes of when they start eating, the study coordinator will assist the participant to enter a meal 
with a reduction to the amount of carbs entered based on the amount of time since the meal 
occurred, at the investigator’s discretion.  Participants will complete a pictorial nausea rating 
scale for reported nausea at study start and at approximately 6 hours after the first and second 
meal to report the worse nausea/vomiting they experienced over the prior 6 hours (the Baxter 
Retching Faces [BARF] scale) (see Protocol Appendix D)[78] and the approximate duration of 
the nausea.  
 
The MPC closed loop system with the meal detection algorithm can detect if a meal has been 
eaten, estimate the grams of carbohydrates consumed then dose an insulin bolus based on the 
estimated grams of carbs, user’s carb ratio and estimated time since the meal was consumed. The 
bolus is delivered automatically. The system reduces the bolus (per calculation below) by 25% as 
the detection occurs on average 25 minutes after meal is consumed.  
 
𝐵𝑜𝑙𝑢𝑠(𝑢𝑛𝑖𝑡𝑠) = 𝑒𝑠𝑡𝑖𝑚𝑎𝑡𝑒𝑑 𝑐𝑎𝑟𝑏𝑜ℎ𝑦𝑑𝑟𝑎𝑡𝑒𝑠 (𝑔)
𝑐𝑎𝑟𝑏 𝑟𝑎𝑡𝑖𝑜 ( 𝑔
𝑢𝑛𝑖𝑡)
 
 
If CBG >300mg/dL before the lunch meal, then the study will be stopped early and the 
participant will be given the option to return on a different day for the second meal.  
 
The meal detection algorithm can be enabled or disabled through the insulin profile settings for a 
given time period. In order to avoid a meal detection before the two scheduled meals, the meal 
detection algorithm will be disabled through the insulin profile in between the meals.   
 
If stopping criteria for hyperglycemia is reached, the study investigator will calculate a meal 
bolus with correction dose as in the equation below if no meal bolus was given by the system, 
otherwise, the investigator will calculate a correction bolus based on current glucose, target 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
glucose, and correction factor. The final dose that is delivered to the participant will be adjusted 
if needed by a study investigator considering insulin-on-board, time since meal consumption, and 
CGM trend. The Omnipod site will be assessed to determine if the insulin should be delivered 
via the Omnipod, syringe, or via the participant’s own insulin pump after it is reconnected.  
 
𝑇𝑜𝑡𝑎𝑙 𝐼𝑛𝑠𝑢𝑙𝑖𝑛 𝐵𝑜𝑙𝑢𝑠= 
𝐶𝑎𝑟𝑏𝑜ℎ𝑦𝑑𝑟𝑎𝑡𝑒 (𝑔)
𝐶𝑎𝑟𝑏𝑜ℎ𝑦𝑑𝑟𝑎𝑡𝑒 𝑅𝑎𝑡𝑖𝑜+
𝐶𝑢𝑟𝑟𝑒𝑛𝑡 𝑔𝑙𝑢𝑐𝑜𝑠𝑒−𝑇𝑎𝑟𝑔𝑒𝑡 𝐺𝑙𝑢𝑐𝑜𝑠𝑒
𝐶𝑜𝑟𝑟𝑒𝑐𝑡𝑖𝑜𝑛 𝐹𝑎𝑐𝑡𝑜𝑟
 - IOB                   
 
Discharge from inpatient clinic 
The study will be terminated and the participant’s own insulin pump or home basal insulin will 
be restarted. The study investigator will consult with the participant regarding appropriate insulin 
dosing for the remainder of the day. The Polar watch and Omnipod will be removed from the 
participant. The participant will wear Dexcom sensor until just prior to discharge to track the 
glucose and trend arrow.  Participants will complete a pictorial nausea rating scale (the Baxter 
Retching Faces [BARF] scale), if applicable (see Protocol Appendix D)[78]. 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 measured. 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 or via home insulin pen/vial 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). 
 
Participants who will be taking an NPH dose prior to discharge from the clinic and who currently 
do not use a CGM or are not actively using their personal CGM will continue to use the study 
CGM for approximately 12 hours after the visit completes.  Study staff will complete a phone 
check-in the next day to remove the CGM.  For safety for avoiding hypoglycemia, all  
participants who take NPH prior to discharge will be asked to check glucose from CGM at 2am 
the morning after their treatment visit, if the glucose is less than 100 mg/dL they will be 
instructed to take 15 grams of carbohydrate. If the CGM value is above 150 mg/dl, participants 
will be asked to take 80% of the correction bolus. 
 
Participants will be given a snack to take with them for the trip home. Participants will also be 
advised to monitor their glucose for any symptoms of hyperglycemia or hypoglycemia, before 
their next meal, and at bedtime.  
 
Insulin + Pramlintide Treatment Visit  

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
Participants will be asked to check glucose from CGM at 2am each morning before their 
treatment visit. If the CGM value is above 150 mg/dl, participants will be asked to take 80% of 
the correction bolus. If the glucose is less than 100 mg/dL they will be instructed to take 15 
grams of carbohydrate. 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).  After the first treatment visit, the washout 
period will be at least 3 days calculated from the day of admission until the start of the next 
admission.  After arrival, 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 each of the participant’s closed-loop studies. 
We will inquire whether the participant has had changes in their medications and/or medical 
history to confirm the participant hasn’t developed any study exclusion criteria. A CBG will be 
obtained and measured by a Contour Next glucose meter.  When they arrive, participants will be 
given 15 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 the onsite investigator.  The order of the visits will be randomized.  
 
An Omnipod will be filled with aspart insulin. We will use only name brand insulin, not generic 
insulin. Additionally, a second Omnipod will be filled with Pramlintide (Symlin, AstraZeneca). 
The iPancreas system will deliver pramlintide in a fixed ratio to insulin at 6 mcg of pramlintide 
delivered for every 1 unit of insulin.  The Omnipod(s) will be primed and inserted into the skin 
of the participant’s abdomen or flank as directed by the manufacturer.  The pods will be placed at 
least 4 inches apart.  If applicable, participants will disconnect his/her own pump and remove 
his/her own insulin infusion set once insulin delivery has started via the Omnipod(s). If, 
applicable for participants on multiple daily injection therapy at baseline, we will verify time of 
last long basal insulin administration. Participants will wear a Polar M600 fitness watch to 
inform the controller about physical activity. The research staff will initialize the system, input 
insulin settings and begin the closed-loop study. Two staff will review each of the settings to 
confirm the settings are entered correctly. Participants will receive training on using the 
iPancreas smart phone application. A member of the study staff will remain near to the 
participant for the duration of the study to address any alerts or issues that arise. The study 
investigator will be on call for the duration of the study.  
 
The algorithm will push data up to an encrypted, secure Amazon Web Services cloud server that 
can be monitored remotely every 5 minutes. The iPancreas software will generate alerts on the 
smartphone. 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 the server that can receive texts with pushed alerts.  
 
During all studies, sensed glucose data will be wirelessly transmitted via BTLE from the 
Dexcom G6 transmitter to the insulin-delivery algorithm every five minutes.  The insulin-

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
delivery algorithm will calculate insulin doses and will run on a Samsung smart phone. The 
smart phone will wirelessly communicate via BTLE to a PDM communicating to an Omnipod 
for automated insulin and pramlintide delivery. Participants will wear a Polar watch for 
collecting heart rate and accelerometry data. The Polar watch transmits this data to the 
smartphone controller via Bluetooth. iPancreas will convert the heart rate and accelerometry data 
into an estimated energy expenditure.  
 
If at any time the study staff determines that a sensor can no longer be used, a new sensor will be 
inserted. If the participant’s blood glucose is < 70 mg/dl or is experiencing symptoms of 
hypoglycemia, the procedure noted below will be followed. Glucose tablets will be provided to 
the participants.  
o If CBG <70mg/dL occurs during pramlintide treatment visit: 
▪ Give 15 grams of oral carbohydrate. 
▪ Repeat treatment every 15 minutes with 15 grams oral carbohydrate as 
needed to raise blood glucose ≥70 mg/dl.  
▪ Repeat CBG checks every 15 minutes for 45 minutes to ensure glucose is 
persistently ≥70 mg/dl. 
 
For participant safety, if communication is lost between the iPancreas app and the Dexcom G6 
CGM for ≥20 minutes or the insulin pod ≥30 minutes, the insulin pump shall deliver basal 
insulin according to pre-set basal rates designated within the iPancreas settings according to 
given times of day and the pramlintide pump will deliver a fixed ratio of pramlintide to match 
the pre-set basal rate for insulin. 
 
When either the CGM or the insulin pump is out for the above time durations, the iPancreas 
system will activate a 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 thirty minutes or if 
the sensor glucose is less than 70 mg/dl. Maximum insulin suspension time is 2 hours. Prediction 
of sensor glucose is based on data long short term memory neural network (LSTM) 
algorithm[77]. When communication with the sensor or Omnipod is restored, the system will 
automatically resume delivering insulin according to the control algorithm, and IOB will be 
updated accordingly.  
 
Meal Description 
After the closed loop study has started, participants will eat the assigned breakfast meal around 
8am. The assigned lunch meal will be given six hours later around 2 pm. The meal time may be 
delayed for safety if participant had a recent low glucose. The selected breakfast and lunch 
option will be identical across both study arms for each participant. The participant will be 
requested to complete their meal within 10 minutes. There will not be a premeal insulin bolus. 
 
The participant will select between two or three breakfast and lunch meals options and have 
these same meals at each study visit. If a food item is unavailable, it will be substituted with the 
closest available substitute. The caloric size of the meal will be based on DRI Estimated Energy 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
requirement formulas.  The meals will be made by the OHSU Bionutrition kitchen. The breakfast 
meal options will each provide approximately 33% of participants daily energy requirement, 
with macronutrient composition of 50% carbohydrate, 15% protein and 35% fat. The lunch meal 
options will provide approximately 40% of the participants daily energy requirement with the 
same macronutrient composition as the breakfast meal.  
 
Meal detection will be enabled for the study. If iPancreas does not auto-detect the meal after 30 
minutes of when they start eating, the study coordinator will assist the participant to enter a meal 
with the amount of carbs provided by Bionutrition.  Participants will complete a pictorial nausea 
rating scale for reported nausea at study start and at approximately 6 hours after the first and 
second meal to report the worse nausea/vomiting they experienced over the prior 6 hours (the 
Baxter Retching Faces [BARF] scale) (see Protocol Appendix D)[78] and the approximate 
duration of the nausea.  
 
The MPC closed loop system with the meal detection algorithm can detect if a meal has been 
eaten, estimate the grams of carbohydrates consumed then dose an insulin bolus based on the 
estimated grams of carbs, user’s carb ratio and estimated time since the meal was consumed. The 
bolus is delivered automatically. The system reduces the bolus (per calculation below) by 25% as 
the detection occurs on average 25 minutes after meal is consumed. Pramlintide will be delivered 
at the fixed ratio of 6 mcg for every 1 unit of insulin delivered. 
 
𝐵𝑜𝑙𝑢𝑠(𝑢𝑛𝑖𝑡𝑠) = 𝑒𝑠𝑡𝑖𝑚𝑎𝑡𝑒𝑑 𝑐𝑎𝑟𝑏𝑜ℎ𝑦𝑑𝑟𝑎𝑡𝑒𝑠 (𝑔)
𝑐𝑎𝑟𝑏 𝑟𝑎𝑡𝑖𝑜 ( 𝑔
𝑢𝑛𝑖𝑡)
 
 
If CBG >300mg/dL before the lunch meal, then the study will be stopped early and the 
participant will be given the option to return on a different day for the second meal.  
 
The meal detection algorithm can be enabled or disabled through the insulin profile settings for a 
given time period. In order to avoid a meal detection before the two scheduled meals, the meal 
detection algorithm will be disabled through the insulin profile in between the meals.  If the 
participant experiences significant GI side effects after the first meal, the study investigator will 
decrease the aggressiveness of the participant’s carb ratio 30% such that the participant will 
receive less pramlintide with their second meal. 
 
If stopping criteria for hyperglycemia is reached, the study investigator will calculate a meal 
bolus with correction dose as in the equation below if no meal bolus was given by the system, 
otherwise, the investigator will calculate a correction bolus based on current glucose, target 
glucose, and correction factor. The final dose that is delivered to the participant will be adjusted 
if needed by a study investigator considering insulin-on-board, time since meal consumption, and 
CGM trend. The Omnipod site will be assessed to determine if the insulin should be delivered 
via the Omnipod, syringe, or via the participant’s own insulin pump after it is reconnected.  
 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
𝑇𝑜𝑡𝑎𝑙 𝐼𝑛𝑠𝑢𝑙𝑖𝑛 𝐵𝑜𝑙𝑢𝑠= 
𝐶𝑎𝑟𝑏𝑜ℎ𝑦𝑑𝑟𝑎𝑡𝑒 (𝑔)
𝐶𝑎𝑟𝑏𝑜ℎ𝑦𝑑𝑟𝑎𝑡𝑒 𝑅𝑎𝑡𝑖𝑜+
𝐶𝑢𝑟𝑟𝑒𝑛𝑡 𝑔𝑙𝑢𝑐𝑜𝑠𝑒−𝑇𝑎𝑟𝑔𝑒𝑡 𝐺𝑙𝑢𝑐𝑜𝑠𝑒
𝐶𝑜𝑟𝑟𝑒𝑐𝑡𝑖𝑜𝑛 𝐹𝑎𝑐𝑡𝑜𝑟
 - IOB                   
 
Discharge from inpatient clinic 
The study will be terminated and the participant’s own insulin pump or home basal insulin will 
be restarted. The study investigator will consult with the participant regarding appropriate insulin 
dosing for the remainder of the day, considering pramlintide on board as tracked by the iPancreas 
system. If this level is elevated,, the participants will be offered an additional meal to eat before 
they discharge. The study investigator will consult with the participant in regards to a safe 
mealtime insulin dose given from their home pump or insulin pen.  
 
The Polar watch and Omnipods will be removed from the participant. The participants will wear 
Dexcom sensor until just prior to discharge to track the glucose and trend arrow.  Participants 
will complete a pictorial nausea rating scale (the Baxter Retching Faces [BARF] scale), if 
applicable (see Protocol Appendix D)[78]. 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 measured. Participants will be given oral carbohydrate for 
values below 85 mg/dl with a repeat capillary blood glucose every 15 minutes until glucose is ≥ 
85 mg/dL. If capillary blood glucose is greater than 180mg/dL, participants will be instructed to 
take a correction bolus from their home insulin pump or via home insulin pen/vial per their usual 
home settings after reviewing this dose with the study investigator who will modify dose if 
needed considering current insulin on board.  
 
If the initial capillary blood glucose was > 85 mg/dL, 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). If the initial capillary blood 
glucose was < 85 mg/dL, then the participant will be given oral carbohydrates and we will repeat 
a fingerstick every 15 minutes until glucose is ≥ 85mg/dL and the CGM trend arrow is flat or 
trending up, then patient can be discharged. 
 
Participants who will be taking an NPH dose prior to discharge from the clinic and who currently 
do not use a CGM or are not actively using their personal CGM will continue to use the study 
CGM for approximately 12 hours after the visit completes.  Study staff will complete a phone 
check-in the next day to remove the CGM.  The participants will be asked to check glucose from 
CGM at 2am the morning after their treatment visit. If the CGM value is above 150 mg/dl, 
participants will be asked to take 80% of the correction bolus. If the glucose is less than 100 
mg/dL they will be instructed to take 15 grams of carbohydrate. 
 
Participants will be given a snack to take with them for the trip home. Participants will also be 
advised to monitor their glucose for any symptoms of hyperglycemia or hypoglycemia, before 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
their next meal, and at bedtime. Study staff will call the participant approximately 1 hour after 
discharge and participant will obtain a fingerstick glucose at that time. 
 
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. 
 
Adverse Events 
Causality relationship to Pramlintide administration 
The causality of each AE should be assessed by the Investigator according to the following 
classification:  
 
Probable: Good reason and sufficient documentation to assume a causal relationship.  
 
Possible: A causal relationship is conceivable and cannot be dismissed.  
 
Unlikely: The event is most likely related to etiology other than the pramlintide administration. 
 
Not related: The event occurs before any pramlintide has been started. 
 
 

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Table 1: Schedule of Events 
Automated insulin delivery system abbreviated AID 
1 ins/pram visit 
 
Screening  
 
Active Treatment 
End of Treatment 
Description of visit procedures  
  
  
Screening 
visit 
Dexcom CGM 
insertion visit 
1st AID visit 
2nd AID visit 
Visit Number 
1 
2 
3 
4 
Visit Window 
  
1-84 days 
1-8 days 
3-28 days  
Informed Consent 
X 
 
 
 
Medical history/ 
X 
X 
X 
X 
Focused physical 
X 
 
 
 
Eligibility assessment 
X 
  
  
  
Download data from participant's 
existing insulin pump and glucose 
sensor (if applicable) 
X 
  
  
  
Review medications and doses 
X 
X 
X 
X 
Hypoglycemia awareness survey 
X 
  
  
  
Measure BP, pulse, height and 
weight 
X 
  
  
  
Pregnancy Test (Urine) 
X 
X 
X 
X 
Hemoglobin A1c 
X 
 
 
 
Complete Blood Count (CBC) 
X 
  
  
  
Comprehensive Metabolic Panel 
(CMP) 
 X 
  
  
  
Adverse Event Reporting 
  
X 
X 
X 
Dexcom G6 CGM and iPancreas 
usage training 
 
X 
  
  
Examination of sensor site after 
removal (if applicable) 
  
  
X 
X 
Hypoglycemia Treatment Guidelines 
CBG < 70 mg/dl 
• Give 15 grams of oral carbohydrate.  

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
• Repeat treatment every 15 minutes as needed to raise blood glucose ≥70 mg/dl. 
o If CBG <70mg/dL occurs during pramlintide treatment visit: 
▪ Give 15 grams of oral carbohydrate. 
▪ Repeat treatment every 15 minutes with 15 grams oral carbohydrate as 
needed to raise blood glucose ≥70 mg/dl.  
▪ Repeat CBG checks every 15 minutes for 45 minutes to ensure glucose is 
persistently ≥70 mg/dl. 
 
Presence of STUPOR, LOSS OF CONSCIOUSNESS, or SEIZURE 
• Give 3 mg glucagon intranasal  
• Verify that insulin and pramlintide are turned off.  
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 by study investigator to discuss proper management, including delivering a correction 
bolus. 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, Polar watch 
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 or basal insulin will be 
resumed under the guidance of the on call study investigator if any of the following occur after 
the start of the study: 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 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
provided in a health care facility including in the absence of hospitalization, severe GI symptoms 
(i.e. to the point of not being able to tolerate food or liquids 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. 
 
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: 
• Hypoglycemia during the treatment period posing a safety problem as judged by the 
investigator.  
• Hyperglycemia during the treatment period posing a safety problem as judged by the 
investigator. 
• 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.  
Description of the MPC algorithms 
Our exercise-aware model predictive control (exMPC) algorithm uses a glucoregulatory model 
to predict glucose outcomes over a predicted horizon (Np), and mathematically solve for the 
optimal insulin doses across the control horizon (Nc) 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.  Exercise is 
represented by heart rate data collected from a wrist-worn fitness watch.  Elevated heart rate is 
represented by increased glucose disposal in the form of increased insulin sensitivity. In 
summary, 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 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
participant using a Kalman filter.  The exMPC algorithm has been described previously and has 
been clinically evaluated in multiple outpatient studies [79-81]. 
 
The Meal Detection feature in the algorithm includes a model for missed meal insulin detection 
and carbohydrate size estimation[2].  The model includes estimations for carbohydrate 
consumption based glucose patterns to determine if that person has consumed a meal without 
announcing it to the system. We refer to this algorithm as the Meal Detection algorithm.  
 
Statistical methods 
The primary study endpoints are (1) incremental area under the curve (AUC) of glucose in the 6 
hours following unannounced meals and (2) percent of time with glucose sensor 70-180 mg/dL.  
The hypothesis to be tested is that pramlintide and insulin delivered after a meal by a closed loop 
system in response to automated meal detection will improve postprandial glucose control over 
insulin delivered alone in response to automated meal detection.   
 
Incremental AUC (iAUC) of postprandial glucose (mg/dL*min) will be calculated using a 
trapezoidal method which sums all CGM values in the 6 hour period following the meal above 
the starting glucose. (M. M. Tai, "A Mathematical Model for the Determination of Total Area 
Under Glucose Tolerance and Other Metabolic Curves," Diabetes Care, vol. 17, no. 2, p. 152, 
1994, doi: 10.2337/diacare.17.2.152.)  
 
We will estimate the difference between systems using a fixed effect in a standard 2x2 crossover 
model with a random participant effect. We will also control for sequence (AB or BA) and 
period (1 or 2), though we do not anticipate statistically significant effects for these parameters.  
 
We anticipate that the primary outcomes will be approximately normally distributed. We will 
review the appropriateness of this assumption using both goodness-of-fit tests and diagnostic 
plots, such as quantile-normal plots. If the normality assumption holds, possibly with a 
transformation of the outcome, we will test the difference between the study arms using a paired 
t-test. In the case of mild departures from normality or unequal variances at the two time points, 
we will re-analyze the primary outcome as the difference between the two visits using 
bootstrapped standard errors, which avoid distributional assumptions. We will use two-sided 
tests at the 0.05 level of significance. 
 
Missing data: Missing sensed glucose values will be interpolated for up to 30 min segments. 
Longer periods of missing data will be omitted if they represent <3% of observation time (which 
will be truncated if a participant leaves the study early). If the missing data are >3% of 
observation time, we will use available CBG values to interpolate or impute using 
measurements. In the case that >2 participants fail to complete the study, we will analyze the 
primary outcome under multiple imputation using baseline values.  
 
Confidentiality and Protection of Human Subjects 
RISKS and BENEFITS 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
Risks: The risks of the protocol procedures are considered minor. Nonetheless, since pumps and 
sensors used within automated glucose control systems are imperfect, there is a risk for 
hyperglycemia and hypoglycemia. All studies will have frequent glucose and ketone samplings 
and a member of the study staff will be present for studies with a study investigator on call at all 
times.  
There is a risk that the meal detection and dosing algorithm will be incorrect (false positive) and 
dose meal insulin even if a meal has not occurred. While this is a rare event that we have found 
occurs only about once every 5 days of continuous usage, this does introduce the risk of a 
hypoglycemia event occurring. We have incorporated an additional safety layer for the meal 
detection and dosing algorithm that uses the person’s correction factor to limit the amount of 
meal insulin dosed to prevent the person’s glucose from dropping below 70 mg/dL, even in the 
event that the algorithm incorrectly detects a meal. 
Pramlintide can cause nausea and more rarely vomiting. These reactions are considered to be 
somewhat likely. These symptoms may be lessened by the run in period using a low dose of 
pramlintide. Pramlintide can increase the likelihood of hypoglycemia after a meal. Continuous 
glucose monitoring will be running at all times to reduce the likelihood of severe hypoglycemia. 
Rarely, there can be allergic responses to insulin or pramlintide, such as skin redness, hives, 
itching of the skin, swelling of the mouth, or breathing difficulties. These reactions are 
considered very unlikely. 
There is a small risk of sensor fracture, and in such a case, a piece of the sensor could be left in 
the tissue after sensor 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. 
There is risk of IV access site problems such as extravasation, bleeding, irritation, infection. 
These are generally low risk and will be minimized by employing trained phlebotomy staff, and 
ensuring that strict sterile and/or antiseptic procedures are followed. 
 
 
Benefits: The participant may not directly benefit from being in this study; however, their 
participation may help to advance automated insulin delivery technology. 
 
COSTS:   
Participants will receive $600 for completion of all study visits.  If a participant withdraws early 
from the study, compensation will be given as follows: $50 for the run-in visits and $250 for 
each of the 2 study visits. There is no compensation for the screening visit. If a participant is 
asked to repeat a study due to technical problems, he/she will receive an additional $250.    
 
Monitoring Entity: 
This investigation will be monitored by the co- investigator Diana Aby-Daniel PA. Diana has no 
commercial interest in any of the companies which manufacture any of the devices used in this 
study. Dr. Leah Wilson and Dr. Peter Jacobs are inventors on patents regarding the algorithms. 
 
Data Collection: 

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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. The CRFs 
will include: 
• Screening form 
• G6 Training Visit 
• First Closed-loop Study Assessment 
• First Closed-loop Study Visit  
• Second Closed-loop Study Visit  
• Adverse Event form 
• Serious Adverse Event form 
• 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 IRB protocol 19858.  During screening, all new participants 
will sign the consent form to store their study data in the data repository. The data to be collected 
includes: (1) glucose sensor data, (2) blood glucose data, (3) insulin and pramlintide data, (4) 
physical activity data, and (5) food 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 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
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. 
Unanticipated 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 participant experiencing the adverse 
event, a careful assessment of whether the adverse event is related or possibly related to the 
participant’s participation in the study. 
 
Any adverse event (AE) and/or unanticipated problem (UP) will be reported to the investigator 
monitor immediately by one of the investigators. 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 always be on-call during the closed-loop studies and 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 participants 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. The FDA will be notified of 
any unanticipated adverse event related to the use of the study device. Notification will be made 
within 10 days after the Principal Investigator becomes aware of the event. 
 
Confidentiality Procedures: 
To protect confidentiality, standard institutional practices will be followed as described in the 
OHSU Information Security and Research Data Resource Guide 
(http://ozone.ohsu.edu/cc/sec/isg/ressec.pdf) to maintain the confidentiality and security of data 
collected in this study. Study staff will be trained regarding these procedures. See IRB protocol 
19858 for a complete description of the confidentiality and security of the study data collected 
during this study to be stored in the OregonAPC repository.  
Data for this project will be stored in an AWS server developed by our group that has undergone 
a security review.  
Paper files will be stored in locked filing cabinets in restricted access offices at OHSU. 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. iPancreas data will be housed in a custom cloud database 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
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 
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 and pramlintide 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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
Protocol Appendix A: Devices 
iPancreas smart phone app with Insulet Omnipod and relay PDM, Dexcom G6 Continuous 
Glucose Monitoring system, Polar M-600 fitness watch and AWS cloud server 
 
Contour Next Blood Glucose Meter 
Abbott Precision Xtra Meter 
 
 
  
 
  
 
 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
Protocol Appendix B: 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 moderate hypoglycemia episodes? (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 severe hypoglycemia episodes? (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) 
 
 
 

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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) 
 
 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
Protocol Appendix C: DRI Estimated Energy Requirement (EER) formulas 
  
BMI 
category 
Age Range 
EER equation 
Physical Activity 
Factor 
BMI <25 
normal weight 
Boys 3-8 yrs 
88.5-
(61.9*age)+PA*(26.7*wt+903*ht)+20 
PA=1 if sedentary 
PA=1.13 if low 
active 
PA=1.26 if active 
PA=1.42 if very 
active 
Boys 9-18 
88.5-
(61.9*age)+PA*(26.7*wt+903*ht)+25 
Girls 3-8 yrs 
135.3-
(30.8*age)+PA*(10*wt+934*ht)+20 
 
PA=1 if sedentary 
PA=1.16 if low 
active 
PA=1.31 if active 
PA=1.56 if very 
active 
Girls 9-18 
135.3-
(30.8*age)+PA*(10*wt+934*ht)+25 
 
BMI>25 
Overweight/obese 
Boys 3-18 
114-
(50.9*age)+PA*(19.5*wt+1162.4*ht) 
PA=1 if sedentary 
PA=1.12 if low 
active 
PA=1.24 if active 
PA-1.45 if very 
active 
Girls 3-18 
389-
(41.2*age)+PA*(15*wt+701.6*ht) 
PA=1 if sedentary 
PA=1.18 if low 
active 
PA=1.35 if active 
PA-1.6 if very 
active 
BMI <25 
normal weight 
Men >19 yr  
662-
(9.53*age)+PA*(15.91*wt+539.6*ht) 
PA=1 if sedentary 
PA=1.11 if low 
active 
PA=1.25 if active 
PA=1.48 if very 
active 
Women >19 yr 
354-
(6.91*age)+PA*(9.36*wt+726*ht) 
PA=1 if sedentary 
PA=1.12 if low 
active 
PA=1.27 if active 
PA=1.45 if very 
active 

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BMI>25 
Overweight/obese 
Men >19 yr for 
Weight 
maintenance 
1086-
(10.1*age)+PA*(13.7*wt+416*ht) 
PA=1 if sedentary 
PA=1.12 if low 
active 
PA=1.29 if active 
PA=1.59 if very 
active 
Women >19 yr 
for 
Weight 
maintenance 
448-
(7.95*age)+PA*(11.4*wt+619*ht) 
PA=1 if sedentary 
PA=1.16 if low 
active 
PA=1.27 if active 
PA=1.44 if very 
active 
 
[82] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

OHSUIRB #25279                                                                             version v5.0 30OCT2024 
 
 
Protocol Appendix D: Pictorial Nausea Rating Scale (the Baxter Retching Faces 
[BARF]/VAS scale)[78] 
Investigative Site Instructions: The participant should complete the BARF/VAS for 
nausea/vomiting discomfort at approximately 6 hours after the first meal (prior to second meal) 
and six hours after the second meal (prior to discharge) to indicate the worse nausea/vomiting 
discomfort they have had over the prior 6 hours. Instruct the participant that the facial 
expressions represent the nausea severity they are experiencing. The face starts as neutral (shown 
below), but the animation becomes more nauseated as you proceed from 0 to 10.  
The participant completes the VAS by drawing a single vertical line through the scale 
corresponding to the perceived intensity (severity) of discomfort matching the facial scale. The 
goal is for the subject to report the amount of discomfort, if any, remaining at each time point. 
Note: If a subject is unable to physically complete the questionnaire, the subject will indicate the 
point on the VAS corresponding to their level of discomfort, and study staff will enter a vertical 
line at that point. Documentation will be provided on each completed questionnaire as to who 
completed the form. 
Please verify the length of the VAS line to be 100-mm before providing it to the subject. 
Subject Instructions: Discomfort could include cramping, abdominal pain, nausea or vomiting. 
The further to the right you make indicate, the more intense discomfort you are feeling. 
You should normally draw a straight line across the scale to indicate your maximum level of 
discomfort over the prior 6 hours. However, if you felt no discomfort, you should circle the 
vertical line on the left end of scale (above the word “no”). If you are currently feeling the worst 
discomfort possible, you should circle the vertical line on the right end of the scale. 
 
 
   ├                                                                                    ┤ 
No Discomfort 
 
 
 
 
 
          Worst Possible Discomfort 
 
About how long did the nausea last? (please approximate the number of minutes of nausea 
out of the prior 6 hours)  
 
____________ (minutes)