A Crossover Study to Assess the Efficacy of a Robust AP Closed Loop System vs MPC Closed Loop System
Phase: NA
Conditions: Type 1 Diabetes
Sponsor: Oregon Health and Science University

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PROTOCOL TITLE: A crossover study to assess the efficacy of a Robust AP closed loop 
system vs MPC closed loop system 
 
  
STUDY SITE: 
Oregon Health Science University 
3181 SW Sam Jackson Park Rd 
Portland, OR 97239 
 
FUNDING: 
NIH 
 
PRINCIPAL INVESTIGATORS: 
Jessica R. Castle MD; Peter Jacobs PhD  
 
CO-INVESTIGATORS:  
Leah Wilson MD 
Joseph El Youssef MBBS 
 
 
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% [1] The benefits of optimal glycemic control are well 
documented, including significant reductions in microvascular disease [2] and to a lesser degree 
macrovascular disease [3]. There are a multitude of barriers to improved glycemic control, 
including fear of hypoglycemia, particularly in those with hypoglycemia unawareness, which can 
lead patients to under-dose insulin despite the known benefits of improved glycemic control [4, 
5]. In addition to fear of hypoglycemia, the process of determining the correct insulin dose is 
challenging and can lead to errors. Ahola et al. found that 64% of patients miscalculated their 
prandial insulin need, often resulting in repeated hypoglycemia and hyperglycemia [6]. Severe 
hypoglycemia and hyperglycemia can have significant consequences, including hospitalization. 
Data from the T1D exchange demonstrated that 11.8% of adults had one or more severe 
hypoglycemic events and 4.8% developed diabetic ketoacidosis (DKA) in the prior 12 months 
[7], with an even higher rate of DKA in children [8].  
 
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 [9-14]. In a multi-center 
study by the AP@home consortium, adults with type 1 diabetes completed two months each of 
insulin pump therapy and sensor-augmented pump with AP use from dinner to waking up in a 

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cross-over design [15]. This study was the first to show a reduction in HbA1c, with a reduction 
of -0.2% between conditions favoring the AP system (p=0.047). In a study by Thabit et al, 24 
adults and 16 adolescents each participated for 2 months with use of sensor-augmented pump 
therapy during the day and for half of the nights used an AP system overnight and the other 
nights continued sensor-augmented pump therapy [13]. Mean HbA1c for participants was 8.1%. 
The use of the AP system improved time in target range overnight by 18.4% (61.2% vs 73.2%, p 
= 0.0004), improved mean glucose by 14.4 mg/dL (p=0.0013), and had no impact on time <70 
mg/dL (1.7% vs 1.7%). In a subsequent study, Thabit et al. showed that for 58 adults with T1D 
who used a single-hormone AP over 12 weeks, better glucose control and lower hypoglycemia 
were observed as well as a reduced HbA1c (-0.3%) compared with sensor-augmented pump 
therapy [14].  
 
These studies have proven that AP systems are safe, but they have only demonstrated modest 
reductions in HbA1c in the patient populations that have been studied thus far. It is very likely 
that a reduction of HbA1c of 0.2-0.3% is not sufficient to reduce hyperglycemia-related 
complications. As a comparison, long term complications were significantly reduced in the 
Diabetes Control and Complications Trial [2] in the case where peoples’ HbA1c levels were 
lowered by 2% in the intensively treated group as compared to the conventional group. 
Additional data is clearly needed to identify which populations will most benefit from AP 
systems. The intent of this protocol is to target a high-risk patient population and determine the 
most effective treatment options.  
 
The study described within this protocol is designed to test the efficacy of a new insulin-only 
closed-loop algorithm using a model predictive control (MPC) framework that will incorporate a 
new feature to handle meals that are consumed without a pre-bolus of insulin called the Robust 
AP (R-AP) system. Model predictive control (MPC) is a control strategy whereby a model is 
used to predict the response of a system to a receding horizon of inputs.  MPC uses the model to 
predict how the system will respond to current and future inputs and selects an optimal control 
output based on how well the predicted output of the system matches an optimal control 
trajectory. The power of MPC is in its predictive ability such that systems, which have very long 
response times, can be modelled to avoid over or under-delivery of control outputs of the MPC 
algorithm to the system which thereby lead to instability.  An early paper describing an approach 
to MPC using a glucoregulatory model was Hovorka et al. [16]. This group has gone on to use 
MPC within their single-hormone control system, which has been evaluated clinically [14].  The 
group at University of Virginia developed an MPC for use within an AP [17] and they have 
published results on this algorithm within a multi-center trial [18]. The Padova group has also 
done work on MPC algorithms within an AP including an algorithm that uses an auto-regressive 
model that adapts over time called a run-to-run algorithm [19].   
 
The robust R-AP system used in this protocol has been designed to handle a variety of real-world 
scenarios that are critical to a high-risk patient population. We will test how well the new 
algorithm handles missed or inaccurate meal announcements. This type of algorithm may 
significantly improve glucose control over the standard model predictive control (MPC) closed-
loop algorithm without these new algorithm features for patients with type 1 diabetes.    
  

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Primary Objectives: 
• To evaluate performance of the OHSU Robust R-AP closed-loop system as measured by 
area under the curve (AUC) in the 4 hours following first meal period, versus the OHSU 
MPC closed-loop system. 
• To evaluate performance of the OHSU Robust R-AP closed-loop system as measured by 
percent of time with sensed glucose between 70 – 180 mg/dl in the 4 hours following the 
first meal period, versus the OHSU MPC closed-loop system. 
Secondary Objective: 
• To evaluate performance of the OHSU Robust R-AP closed-loop system versus the 
OHSU MPC closed-loop system in the 4 hours following the first meal period, as 
measured by other glycemic outcomes.  
Study Hypothesis: 
We propose that the use of the OHSU Robust R-AP closed-loop system as compared to the 
OHSU MPC closed-loop system will decrease AUC and increase the time in range as measured 
by sensed glucose values.   
 
Endpoints 
Primary Endpoint:  
• Incremental AUC of postprandial glucose in the 4 hours following the start of first meal. 
AUC (mg/dL*min) will be calculated using a trapezoidal method [20], which sums all 
CGM values in the 4 hour period following the meal above the starting glucose. 
• Percent of time with sensed glucose between 70 – 180 mg/dl in the 4 hours following the 
start of first meal. 
Secondary Endpoints (all measured in the 4 hours following the start of meals):  
• Percent of time with sensed glucose <70 mg/dl across the study duration 
• Number of carbohydrate treatments (defined as 15 or 20 grams of carbohydrate)   
• Number of provider-administered insulin injections due to hyperglycemia  
• 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 per day (in units/kg) 
Study Type  
This is a single-center, crossover trial designed to compare the glucose control resulting from the 
use of the OHSU Robust R-AP system as compared to the OHSU MPC AP system.  
 
Study Population 

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Study population will be adults with type 1 diabetes, ages 18 – 65 years of age. Younger 
participants are excluded as it is appropriate to assess safety first in the adult population. Fifteen 
participants will be recruited to participate in studies.   
 
Power Analysis 
This study is to obtain feasibility and assessment of variability in the primary outcomes that will 
inform a future larger, sufficiently powered efficacy study. A sample size of 15 is a feasible 
number to recruit and complete the study in timely fashion. This sample size will allow adequate 
estimation of the outcomes and variability of those estimates. 
 
Protocol Summary: 
Participants will undergo two visits at OHSU that will evaluate missed meal bolus detection.  
Participants will arrive at approximately 7am for all visits, be monitored through the afternoon 
and discharged before dinner. See Figure 1 for a diagram of the study flow. During each of these 
intervention visits, participants will wear an Omnipod to deliver insulin and a Dexcom G6 CGM 
to measure glucose.  The closed loop system will receive activity data through a Polar M600 
watch worn by the participant. The studies will test the ability of the system to adapt to a missed 
meal bolus. For one missed meal bolus study, glucose will be controlled using the Robust R-AP 
closed-loop mode.  During the other missed meal bolus study, glucose will be controlled using 
the MPC closed-loop mode.  For the R-AP study, participants will eat self selected meals at 10 
am and 2pm. The 10am meal will be the only meal given during the MPC study. The 10am meal 
will be the same across both arms. A meal bolus will not be given before any meals.  
 
Figure 1: Study Flow Design 
 
 
 
 
 
Subject Criteria 
Inclusion Criteria:  
1. Diagnosis of type 1 diabetes mellitus for at least 1 year.  
2. Male or female participants 18 to 65 years of age.  
3. Current use of an insulin pump for at least 3 months with stable insulin pump settings for 
>2 weeks.   

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4. HbA1c ≤ 10.5% at screening.    
5. Total daily insulin requirement is less than 139 units/day.  
6. Willingness to follow all study procedures, including attending all clinic visits.  
7. 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 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. 
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. Hematocrit of less than 36% for men, less than 32% for women. 
6. 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.  
7. History of diabetes ketoacidosis during the prior 6 months prior to screening visit, as 
diagnosed on hospital admission or as judged by the investigator. 
8. Adrenal insufficiency. 
9. Any active infection. 
10. Known or suspected abuse of alcohol, narcotics, or illicit drugs.  
11. Seizure disorder. 
12. Active foot ulceration. 
13. Severe peripheral arterial disease characterized by ischemic rest pain or severe 
claudication. 
14. Major surgical operation within 30 days prior to screening. 
15. Use of an investigational drug within 30 days prior to screening. 
16. Chronic usage of any immunosuppressive medication (such as cyclosporine, 
azathioprine, sirolimus, or tacrolimus). 
17. Bleeding disorder, treatment with warfarin, or platelet count below 50,000. 
18. Allergy to aspart insulin. 
19. Current administration of oral or parenteral corticosteroids. 

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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. Beta blockers or non-dihydropyridine calcium channel blockers. 
22. Current use of any medication intended to lower glucose other than insulin (ex. use of 
liraglutide). 
23. Gastroparesis 
24. Diets consisting of less than 50 grams of carbohydrates per day.   
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 newletter or from the OHSU Subject 
Recruitment website. Handouts may also be made available to faculty at Tuality, Providence, 
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.  
 
Up to 18 participants may be screened in this study.  Goal enrollment is 15 participants.  
 
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.  
Visit Procedures 

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Negative COVID-19 screening is required for face-to-face visits.  Study staff will perform 
COVID-19 screening on all participants and participant households, to ensure that there is no 
COVID-19 or COVID-19 symptoms. OHSU COVID-19 policy provides the option to complete 
visits virtually in order to minimize face-to-face contact with participants. 
 
Screening (Visit 1) 
Screening will take place within 12 weeks prior to the 1 week run-in period (Visit 2).  All 
screening visits will take place at OHSU’s Oregon Clinical Translational Research Institute 
(OCTRI) outpatient clinic, the Biomedical Engineering Point of Care (BME POC) Laboratory or 
at the Harold Schnitzer Diabetes Health Center. 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.  
 
A capillary blood glucose (CBG) will be obtained and measured by a Contour Next glucose 
meter and recorded after consenting. Prior to measurement of any blood samples, the meter will 
undergo quality control testing with two different glucose levels, one high and one low, and both 
values must fall within the accepted range for a meter to be used.  
 
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, than 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.  
The participant’s insulin pump, and if applicable glucose sensor, may be 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 insertion visit 
The purpose of this visit is to have the participants learn how to insert the Dexcom G6 CGM 
device. This visit will take 30-60minutes. 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 at 

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the OHSU OCTRI outpatient clinic, the Biomedical Engineering Point of Care (BME POC) 
Laboratory or Harold Schnitzer Diabetes Health Center clinic, 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. 
 
Participants will receive training on how to use and calibrate the Dexcom G6 CGM system. 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 or flank after appropriate preparation of the 
abdominal skin as per the manufacturer’s directions.  Participants will be trained how to pair the 
Dexcom G6 transmitter to the Dexcom app on a provided study smart phone to start and stop a 
new sensor session and how to enter calibrations. 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. The transmitter and sensors can be given to the participant at the CGM insertion visit or 
delivered via courier. 
 
To reduce the risk of COVID-19 and to comply with OHSU modified operations, sensor 
insertion visits can be completed using Webex video conferencing software. Study devices, 
including a urine pregnancy test, will be delivered to participants via a courier. Using the Webex 
platform, study staff can connect virtually with participants for training on the devices and study 
procedures while they are at home.  
 
1 day Treatment Visits  
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 enter this 
value into his/her pump calculator and take 80 percent of the correction bolus. 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 3 to 30 days calculated 
from the day of admission until the start of the next admission.  After arrival at the OHSU 
OCTRI outpatient clinic, the Biomedical Engineering Point of Care (BME POC) Laboratory or 
Harold Schnitzer Diabetes Health Center clinic at approximately 7am, 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 participant’s first closed-loop study. 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 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 the onsite investigator.   

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During each visit, glucose will be controlled using either: 1) the OHSU Robust R-AP closed-
loop mode or 2) the OHSU MPC closed-loop mode. The order of the visits will be randomized. 
A code team is available by page at all times in all locations. 
 
An Omnipod will be filled with Novolog or Humalog insulin for all studies. The Omnipod will 
be primed and inserted into the skin of the participant’s abdomen or flank as directed by the 
manufacturer.  Participants will disconnect his/her own pump and remove his/her own insulin 
infusion set once insulin delivery has started via the Omnipod. Participants will wear a Polar 
watch to inform the controller. The research staff will initialize the system and begin the closed-
loop study. Two staff will review each of the settings to confirm the settings are inputted 
correctly. A member of the study staff will remain with the participant for the duration of the 
study with the study investigator on call. Research staff will set up and run the system and 
respond to all alerts. 
 
The algorithm will push data up to a cloud server that can be monitored remotely every 5 
minutes. The iPancreas will generate alerts on the smartphone according to Appendix D. 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.  
 
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 a sensor value is not available for 20 minutes or communication with 
the Omnipod is lost for more than 30 minutes, the insulin 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, 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 linear regression of the prior 

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ten minutes of sensor glucose data. When communication with the sensor or Omnipod is 
restored, the system will automatically resume, updating the IOB accordingly.  
 
After a run-in period of 2 hours whereby the participants are using the AP algorithms, 
participants will eat self selected meals around 10 am. During the R-AP study only, another meal 
will be given four hours later around 2 pm. The self selected meals will have a minimum of 45 g 
of carbohydrates, and a maximum of 120 g of carbohydrates. These self selected breakfasts will 
be identical across both study sessions. Participants will not enter a meal bolus for the meals. 
CBG and blood ketone measurements will be taken every 30 min (for safety purposes only, not 
for input into the AP systems) until study discharge. If CBG >250mg/dL before the lunch meal, 
then study will be stopped early and the participant will be given the option to return on a 
different day for the second meal.  
 
The study will be stopped if: 
(1) the CBG reaches > 300 mg/dL with ketones > 0.5 mM,  
(2) the CBG reaches > 300 mg/dL for over an hour (even when ketones are <0.5 mM),  
(3) the CBG reaches > 450 mg/dL,  
(4) participants exhibit nausea or vomiting or both.  
The Robust-AP system will use the Missed Meal Detection algorithm to identify a missed meal 
bolus. If the R-AP system detects a missed meal, the system will send an alert to the user 
indicating that a meal was detected, and the system will also return the estimated carbohydrate 
content of the detected meal. The user will be required to acknowledge this alert. The user can 
modify the carbohydrate content that was estimated by the R-AP system. Then the R-AP will use 
that carbohydrate content to calculate a meal bolus, which will then be dosed by the R-AP 
system via insulin pump as described in the equation below. A study investigator will evaluate 
the meal insulin dose prior to delivery, considering insulin-on-board and time since meal 
consumption, and the investigator will modify the insulin dose if needed for participant safety. 
Otherwise, if stopping procedures (1)-(3) are reached, the study investigator will calculate a meal 
bolus with correction dose as in the equation below. 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 investigator will check the Omnipod site and 
determine if the insulin should be delivered via the Omnipod, syringe, or via the participant’s 
own insulin pump after it is reconnected. The study team will monitor the participants CGM  
levels and ketones will be checked every 30 minutes until ketone levels are less than or equal to 
0.2 mmol/L. Participants will be provided with plenty of water to drink to avoid dehydration. 
Additional subcutaneous insulin doses will be given approximately every three hours to treat 
hyperglycemia at the investigator’s discretion. Participants will be evaluated by investigator for 
possible transfer to the emergency room if ketone level is 3.0 mmol/L or higher or earlier at the 
discretion of the study investigator.  
 
𝑇𝑜𝑡𝑎𝑙 𝐼𝑛𝑠𝑢𝑙𝑖𝑛 𝐵𝑜𝑙𝑢𝑠= 
𝐶𝑎𝑟𝑏𝑜ℎ𝑦𝑑𝑟𝑎𝑡𝑒 (𝑔)
𝐶𝑎𝑟𝑏𝑜ℎ𝑦𝑑𝑟𝑎𝑡𝑒 𝑅𝑎𝑡𝑖𝑜+
𝐶𝑢𝑟𝑟𝑒𝑛𝑡 𝑔𝑙𝑢𝑐𝑜𝑠𝑒−𝑇𝑎𝑟𝑔𝑒𝑡 𝐺𝑙𝑢𝑐𝑜𝑠𝑒
𝐶𝑜𝑟𝑟𝑒𝑐𝑡𝑖𝑜𝑛 𝐹𝑎𝑐𝑡𝑜𝑟
 - IOB                   
 

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Participants can be discharged after 4pm when: (1) CBG >80 and < 250 mg/dl, (2) ketones ≤ 0.2 
mM and (3) the participant is feeling well. For values outside this range, treatment will be at 
the discretion of the study investigator. 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.  
 
Discharge from 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, Omnipods and Dexcom sensor will be removed from the 
participant. All infusion sites and the sensor site 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.  
 
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 
Give 1 mg glucagon IM  
Verify that insulin is turned off.  
Further management per study investigator.  
 
Cleaning and Disinfecting  
All devices will be cleaned and disinfected between participants.  The smart phone, Dexcom G6 
transmitter 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 open-loop control will be resumed under the guidance 
of the on call study investigator if any of the following occur after the start of the study: 1) 

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capillary blood glucose falls to < 40 mg/dl at any time point, 2) serum ketones are above 1.5 mM 
at any time and 3) seizure or unconsciousness associated with hypoglycemia.  
Entire study stopping rules 
Triggers for reporting unanticipated problems are seizure, hospitalization, death or any other 
occurrence considered serious by the PI. If any studies are stopped for severe hypoglycemia or 
diabetic ketoacidosis, then the entire study will be halted. Severe hypoglycemia is defined as 
event that required the assistance of another person due to altered consciousness, and required 
another person to actively 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. 
 
Description of the MPC and R-AP algorithms 
Our MPC 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.  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.  
 
The R-AP is a modified MPC algorithm. A new feature in the algorithm includes a model for 
missed meal insulin detection.  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 Missed Meal Insulin Detection. Our Missed Meal 
Insulin Detection algorithm is unique in that it presumes that the patient will generally announce 
their meals to the system. However, if the participant does not announce, the algorithm will 
detect it using machine learning methods, and then adjust dosing based on this detected meal.  
 
Statistical methods 
The primary study endpoints are (1) incremental area under the curve (AUC) of glucose in the 4 
hours following unannounced meals and (2) percent of time with glucose sensor 70-180 mg/dL. 
The hypothesis to be tested is the R-AP closed-loop system will increase time in range and 
decrease AUC as compared to the MPC-AP closed-loop system. We will estimate the difference 
between systems using a fixed effect in a standard 2x2 crossover model with a random 
participant effect. While we do not anticipate statistically significant effects for the following, we 
will also control for sequence (AB or BA) and period (1 or 2).  
 

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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 robust-AP and standard 
MCP visits 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 
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.  
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. 
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. 
 
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 $340 for completion of all study visits.  If a participant withdraws early 
from the study, compensation will be given as follows: $40 for the run-in visit and $150 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 $150.    
 
Monitoring Entity: 
This investigation will be monitored by the co- investigator Leah Wilson MD. Dr. Wilson has no 
commercial interest in any of the companies which manufacture any of the devices used in this 

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study. Drs. Jessica Castle, Peter Jacobs and Joseph El Youssef are inventors on patents regarding 
the algorithms. 
 
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. All data from the study files on the smart phone master controller will subsequently be 
entered into the authorized electronic OCTRI Cloud database.  
 
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 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 

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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. 
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/res_sec.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.   

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Appendix A: Devices 
Insulet Omnipod insulin management system  
 
 
iPancreas with Dexcom G6 Continuous Glucose Monitoring System which includes Sensor 
and Sensor Transmitter  
 
 
 
 
 
 
 
 
 
 
 

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Contour Next Blood Glucose Meter 
Abbott Precision Xtra Meter 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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)

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Appendix C: Alert Manager Specifications  
 
# NAME: Activation criteria 
Clearing Criteria 
Algorithm 
specifics 
Notificati
on to 
participa
nt 
Re-
fire 
Time 
(min
) 
Refrac
tory 
Period 
(min) 
Coordin
ator 
push 
Investi
gator 
push 
Waiti
ng 
perio
d 
4 
cbg_equal_or_under_4
0: 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 
carbohyd
rates and 
recheck 
your 
blood 
glucose 
level in 
15 
minutes.
" 
5 
- 
Immedi
ately 
Immedi
ately 
Waiti
ng 
perio
d 
ends 
whe
n 
alert 
13 is 
servi
ced 
OR 
clear 
crite
ria 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 
None 
"Blood 
glucose 
is below 
70 
mg/dl. 
Please 
take 15 
gm of 
rescue 
carbohyd
15 
- 
After 
1st re-
fire 
After 
2nd re-
fire 
Waiti
ng 
perio
d 
ends 
whe
n 
alert 
13 is 
servi

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rates and 
recheck 
your 
blood 
glucose 
level in 
15 
minutes.
" 
ced 
OR 
clear 
crite
ria is 
met 
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 
CBG check 
OR sensor ≥ 
LOW_THRESH OR 
extreme_low_sen
sor_glucose is 
active. 
For MPC, 
LOW_THRESH = 
70 mg/dL 
 
"Sensor 
glucose 
is below 
LOW_TH
RESH 
mg/dl. 
Please 
perform 
a blood 
glucose 
check 
now." 
15 
60 
After 
1st re-
fire 
After 
2nd re-
fire 
- 
7 
cbg_equal_or_over_30
0: 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 
detachm
ent and 
check 
ketone 
30 
120 
After 
1st re-
fire 
After 
2nd re-
fire 
- 

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levels 
now." 
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 
60 
After 
1st re-
fire 
After 
2nd re-
fire 
- 
1
0 
Insulin_meal_bolus_fail
ure: If 50% of meal bolus 
is still not delivered after 
20 minutes. 
Auto clears  
None 
Insulin 
bolus 
failed to 
deliver, 
please 
contact 
the study 
investiga
tor.  
- 
- 
Immedi
ately 
Immedi
ately 
- 
1
3 
recheck_cbg: Alert 4 OR 
alert 5 in waiting period 
for 15 minutes  
CBG recheck 
 
"Please 
perform 
a blood 
glucose 
check 
now." 
20 
- 
After 
1st re-
fire 
After 
2nd re-
fire 
- 
1
4 
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 
connecti
on of the 
phone to 
the 
internet. 
Please 
move 
40 
- 
- 
- 
- 

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back into 
cell 
phone or 
wifi 
range.  
1
7 
transmitter_not_reporti
ng: Sensor is out of date 
for > 20 minutes AND 
alert 17 AND alert 18 AND 
alert 20 not active or 
refractory 
Clears with valid 
sensor 
 
"A 
sensor 
reading 
has not 
been 
received 
in the 
last 20 
minutes. 
Please 
ensure 
that the 
phone is 
within 
range of 
the 
sensor." 
20 
- 
After 
1st re-
fire 
After 
2nd re-
fire 
- 
1
8 
replace_transmitter: 
iPancreas sends message 
to replace the transmitter 
immediately 60 minutes 
after activation criteria for 
alert 17 if clear criteria has 
not been met 
User 
acknowledgement 
 
"The 
transmitt
er is no 
longer 
functiona
l. Please 
replace it 
immediat
ely." 
- 
120 
- 
- 
- 
1
9 
sensor_glucose_invalid: 
Sensor value is invalid for 
> 20  Minutes AND alert 
19 AND alert 18 AND alert 
20 not active or refractory 
Clears with valid 
sensor 
 
"Sensor 
value is 
not 
reporting 
correctly. 
Please 
20 
- 
After 
1st re-
fire 
After 
2nd re-
fire 
- 

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check 
your 
sensor 
site for 
problems
. Contact 
the study 
coordinat
or if 
needed." 
2
0 
replace_sensor: 
iPancreas sends message 
to replace the sensor 
immediately 60 minutes 
after activation criteria for 
19 if clear criteria has not 
been met  
User 
acknowledgement 
 
"The 
sensor 
may no 
longer be 
functioni
ng. 
Please 
replace it 
immediat
ely." 
- 
120 
- 
- 
- 
2
1 
Insulin_pump_commun
ication_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 
communi
cation 
failure. 
Please 
move 
PDM and 
POD 
closer to 
phone”  
60 
min
utes 
If 
alert 
fires 
after 
10:59
PM, 
refrac
tory 
lasts 
until 
6:59A
M. No 
refrac
tory 
other 
hours 
After 
1st re-
fire 
After 
2nd re-
fire 
- 

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of the 
day. 
2
5 
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 
- 
After 
1st re-
fire 
After 
2nd re-
fire 
- 
2
6 
maximum_insulin_exce
eded: Insulin Delivery ≥ 
35% TDIRadj on last hour 
Auto clears  
 
"Max 
insulin 
has been 
exceeded
" 
- 
60 
Immedi
ately 
Immedi
ately 
- 
2
7 
cbg_equal_or_over_40
0: 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 
60 
Immedi
ately 
Immedi
ately 
- 
2
8 
ketone_level_high: 
Ketones ≥ 0.6 mmol/L 
User 
acknowledgement 
 
“Ketone 
levels 
are high. 
If not 
already 
done, 
please 
change 
the 
insulin 
pod. Do 
- 
- 
Immedi
ately 
Immedi
ately 
- 

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not 
exercise.
” 
2
9 
Insulin_pump_reservoir
_low: Omnipod has less 
than 10% of fluid volume 
remaining. 
Pod with greater 
than 10% volume 
is connected (i.e. 
pod is changed) 
 
Your 
insulin 
pod is 
low. 
Please 
deactivat
e your 
current 
pod and 
activate 
a new 
insulin 
pod. 
120 
- 
After 
1st re-
fire 
After 
2nd re-
fire 
- 
3
0 
External_insulin_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 coordinato. 
The app 
determined by 
the pump’s pulse 
count that more 
insulin than was 
expected was 
delivered. 
Alert for 
over-
insulin 
delivery:  
The 
actual 
insulin 
exceeded 
the 
expected 
insulin 
by XX 
units. 
- 
- 
Immedi
ately 
Immedi
ately 
- 
3
1 
Extreme_low_sensor_gl
ucose:  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_lo
w is suppressed.  
“Sensor 
value is 
extremel
y low” 
“Sensor 
glucose 
is below 
54 
10 
30 
After 
first re-
fire 
After 
second 
re-fire 
- 

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If CGM goes from 
<= 54 to between 
70-54 mg/dL, the 
sensor_glucose_lo
w alert will fire 
again after the 
refractory period 
of 30 minutes 
expires on the 
recently cleared  
extreme_low_sen
sor_glucose alert 
mg/dL.  
Please 
perform 
a blood 
glucose 
check 
now.” 
3
2 
Missed_meal_detection
_alert:  This alert triggers 
if the Missed Meal 
Detection algorithm 
detects that carbohydrates 
were consumed 
approximately 25 minutes 
ago. 
The user 
acknowledges the 
alert and either 
doses insulin or 
declines that  a 
missed meal. 
 
20 minutes have 
passed since the 
alert trigger. 
The missed meal 
detection alert 
will trigger if 
glucose is rising 
rapidly and the 
prior 
carbohydrate 
intake is indicated 
by the algorithm.  
The algorithm 
presumes the 
meal was 
consumed 25 
minutes prior to 
the trigger.  The 
alert will expire 
after 20 minutes 
from triggering. 
“Your 
glucose 
appears 
to be 
rising.  
Did you 
consume 
a meal 
that you 
want to 
dose 
insulin 
for?” 
 
- 
- 
- 
- 
- 

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References  
 
 
[1] 
K. M. Miller et al., "Evidence of a strong association between frequency of self-
monitoring of blood glucose and hemoglobin A1c levels in T1D exchange clinic registry 
participants," Diabetes care, vol. 36, no. 7, pp. 2009-14, Jul 2013, doi: 10.2337/dc12-1770. 
[2] 
C. Diabetes et al., "The effect of intensive treatment of diabetes on the development and 
progression of long-term complications in insulin-dependent diabetes mellitus," The New 
England journal of medicine, vol. 329, no. 14, pp. 977-86, Sep 30 1993, doi: 
10.1056/NEJM199309303291401. 
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