Conditions: Type1diabetes
Keywords: glucagon closed-loop Omnipod exercise
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 23
Healthy volunteers: no

Brief summary:
Closed-loop systems are an emerging technology that automate hormone delivery. They are quickly paving the way to revolutionize the treatment of type 1 diabetes. Several categories have emerged: dual-hormone (insulin and glucagon) closed-loop systems and closed-loop systems with insulin only, one variety of which is the low glucose suspend safety feature now available from Medtronic (MiniMed640G with SmartGuard). The study described within this protocol is designed to test the efficacy of a new closed-loop algorithm for managing blood glucose in people with type 1 diabetes before and after exercise. The new algorithm will have 3 modes: a single hormone insulin only mode, a dual-hormone insulin and glucagon mode and an insulin only mode with predictive low glucose suspend, all with an exercise detection algorithm. The purpose of this study is to determine whether a dual hormone AP using a stable investigational glucagon with an exercise detection algorithm outperforms both single hormone AP and a low glucose suspend algorithm.

Detailed description:
Subjects will undergo three approximately 76 hour studies. During each of these intervention visits, subjects will wear an Omnipod to deliver insulin and a Dexcom G5 CGM to measure glucose. In the dual-hormone closed-loop study, participants will wear a second Omnipod filled with XeriSol™ glucagon. The first day of intervention visit will be a 12 hour inpatient visit with the subsequent time spent as an outpatient. The subject will come back to the research center on Day 4 in the morning to remove all devices. The blood glucose control system is called the Artificial Pancreas Controller (APC). During one of the studies, glucose will be controlled using the dual hormone mode. During another study, glucose will be controlled using the single hormone mode. The single and dual hormone modes of the APC controller determine insulin only and insulin with glucagon delivery rates based on proportional and derivative error and contain an exercise detection component. During the other study, glucose will be controlled using a predictive low glucose suspend (PLGS) mode. In the PLGS mode, the APC will be programmed with the subject's basal profile(s) which will be transmitted to the Omnipod Personal Diabetes Manager (PDM) and allow for boluses to be inputted by the subjects for meals and corrections using their typical carb ratios and correction factors. However, this system will have a safety feature to suspend insulin delivery when sensor glucose is predicted to go below a threshold. Treatment order will be randomized.

Subjects will arrive at the clinic at approximately 7 or 8am for the inpatient visits. Subjects will eat breakfast and lunch at approximately 8:30am, noon and 6pm respectively. The dinner meal will be consumed while the subject is at home. Subjects will exercise on a treadmill for 45 minutes. Subjects will be discharged 9 hours after admission. The subject will then go home for the remainder of the study visit. Studies will be remotely monitored. Subjects will return to OHSU on Day 4 for removal of all devices.

During each study, the subject will wear one subcutaneous DexcomTM G5 continuous glucose monitoring (CGM) system. The CGM system will provide sensed glucose data every 5 minutes. The accuracy of the sensed data will be obtained by reference measurements of capillary blood glucose. Sensed glucose data will be wirelessly transmitted via Bluetooth Low Energy (BTLE) from the Dexcom G5 transmitter to the Nexus 5 master controller every five minutes. The controller for all 3 modes is a Google Nexus 5 phone. The smart phone will wirelessly communicate via BTLE to an Omnipod through a PDM (Insulet Corp. ) for automated insulin delivery or in the case of dual-hormone AP, one used for automated insulin delivery and one for automated glucagon delivery.

A physician or nurse practitioner will be present for study start-up, will be on campus for exercise on Day 1 and will be immediately available on call at all other times.

Arms:
arm 1: Subjects will undergo a 76 hour study with 9 hours inpatient and 67 hours outpatient using the closed-loop artificial pancreas controller in dual hormone mode and XeriSol glucagon to manage blood sugar that includes an exercise detection component that includes a reduction in insulin delivery and an increase in glucagon delivery upon detection. arm 2: Subjects will undergo a 76 hour study with 9 hours inpatient and 67 hours outpatient using the closed-loop artificial pancreas controller in single hormone mode to manage blood sugar that includes an exercise detection component that includes a reduction in insulin delivery upon detection. arm 3: Subjects will undergo a 76 hour study with 9 hours inpatient and 67 hours outpatient using the closed-loop artificial pancreas controller in predictive low glucose suspend mode. The system will run through the closed-loop system but will utilize the patient's optimized basal rates, correction factors and carb ratios as they would normally run on their own insulin pump. But the mode will have the additional safety net of the pump suspending insulin when it predicts a hypoglycemic event.

Interventions: intervention 1: Artificial Pancreas Controller in Dual Hormone Mode intervention 2: Artificial Pancreas Controller in Single Hormone Mode intervention 3: Artificial Pancreas Controller in Predictive Low Glucose Suspend Mode intervention 4: XeriSol glucagon
Intervention descriptions: intervention 1: The artificial pancreas controller contains an algorithm for managing blood glucose in people with type 1 diabetes which includes an exercise detection component. The algorithm has 3 modes: a single hormone closed-loop insulin only mode, a dual-hormone closed-loop insulin and glucagon mode and an insulin only mode with predictive low glucose suspend. The Closed-loop Artificial Pancreas Controller includes insulin and glucagon delivery algorithm implemented on a smart phone, utilizing sensor glucose values from a Dexcom G5 sensor and sending delivery commands to two Omnipod insulin pumps, one filled with insulin and one with glucagon. intervention 2: The artificial pancreas controller contains an algorithm for managing blood glucose in people with type 1 diabetes which includes an exercise detection component. The new algorithm will have 3 modes: a single hormone closed-loop insulin only mode, a dual-hormone closed-loop insulin and glucagon mode and an insulin only mode with predictive low glucose suspend. The Closed-loop Artificial Pancreas Controller includes insulin delivery algorithm implemented on a smart phone, utilizing sensor glucose values from a Dexcom G5 sensor and sending delivery commands to one Omnipod pump filled with insulin. intervention 3: The artificial pancreas controller contains an algorithm for managing blood glucose in people with type 1 diabetes which includes an exercise detection component. The new algorithm will have 3 modes: a single hormone closed-loop insulin only mode, a dual-hormone closed-loop insulin and glucagon mode and an insulin only mode with predictive low glucose suspend. The Closed-loop Artificial Pancreas Controller includes insulin delivery algorithm implemented on a smart phone, utilizing sensor glucose values from a Dexcom G5 sensor and sending delivery commands to one Omnipod insulin pump filled with insulin. intervention 4: XeriSol glucagon is an investigational drug that is a stable, soluble liquid glucagon formulation that can be injected or administered through an insulin pump. XeriSol glucagon will be used to fill the Omnipod to deliver glucagon for the Artificial Pancreas Controller in Dual Hormone mode.

Protocol document:
Prot_SAP_000.pdf: 
IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
PROTOCOL TITLE: A randomized, three-way, cross-over study to assess the efficacy of a 
dual-hormone closed-loop system with XeriSol™ glucagon vs closed-loop system with 
insulin only vs a predictive low glucose suspend system 
 
  
STUDY SITE: 
Oregon Health Science University 
3181 SW Sam Jackson Park Rd 
Portland, OR 97639 
 
FUNDING: 
National Institute of Health 
 
PRINCIPAL INVESTIGATORS: 
Jessica R. Castle MD; Peter Jacobs PhD  
 
CO-INVESTIGATORS:  
Joseph El Youssef MBBS 
Leah Wilson MD 
Roula Zahr MD 
 
 
Background: 
 
Closed-loop systems are an emerging technology that automate hormone delivery.   They are 
quickly paving the way to revolutionize the treatment of type 1 diabetes.   Several categories 
have emerged: dual-hormone (insulin and glucagon) closed-loop systems and closed-loop 
systems with insulin only.  Already, the benefit of improved glycemic control compared to 
current open-loop pump therapy has been demonstrated in several trials.  Hovorka et al.  recently 
showed that for people with T1D, glucose control could be improved when using a single-
hormonal AP system for 12 weeks under free living conditions compared with sensor-augmented 
pump (SAP) therapy in a randomized multicenter cross-over trial (1). Participants were in 
euglycemia for 11% more time using the AP system as compared to SAP therapy.  Kropff et al.  
also recently published results from a long-term single-hormone study showing that when 
patients with T1D used an AP during evening hours and while sleeping, using SAP during the 
day, the time spent in euglycemia was increased compared with participants who used SAP 24-
hours per day (2). HbA1c dropped more significantly when using the AP (-0·3%) compared with 
SAP (-0·2%), though the improvement was modest.   
 
Dual-hormone APs that deliver glucagon as well as insulin have also shown promise, especially 
in helping to prevent hypoglycemia.  Glucagon works by breaking down hepatic glycogen, 
resulting in an increase in circulating glucose.  Russell et al.  showed how use of a dual-
hormonal AP improved time spent in euglycemia and reduced time spent in hypoglycemia and 
hyperglycemia (3). Our group has shown that the OHSU dual-hormone system effectively 
manages blood glucose in a clinic setting with great progress using glucagon to reduce 
hypoglycemic episodes (4, 5).  
 
One of the downfalls of using glucagon is that currently available glucagon formulations can 
only be used for a short time after reconstitution due to issue of protein aggregration and 
degradation.   For dual-hormone closed-loop systems to become fully automated in the outpatient 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
setting, it is necessary to develop a stable glucagon solution that can remain in a pump reservoir 
for several days.  Xeris Pharmaceuticals Inc. has developed a stable, soluble liquid glucagon 
formulation (XeriSol™) that can be injected or administered through an infusion pump (6).   
 
The study described within this protocol is designed to test the efficacy of a dual-hormone 
closed-loop system utilizing XeriSol™ glucagon over a 3 day period as compared to an insulin-
only closed-loop system and to a predictive low glucose suspend system.    
  
Primary Objectives: 
 To confirm superiority of the OHSU dual hormone closed-loop system as measured by 
frequency of hypoglycemia after exercise as compared to the insulin only closed-loop 
system and the predictive low glucose suspend system.    
 
Secondary Objectives: 
 To confirm superiority of the OHSU dual hormone closed-loop system as measured by 
percent of time with sensed glucose between 70 – 180 mg/dl as compared to the insulin 
only closed-loop system and the predictive low glucose suspend system.    
 To confirm superiority of the OHSU dual hormone closed-loop as measured by other 
glucose metrics as compared to the insulin only closed-loop system and the predictive 
low glucose suspend system.    
 
Study Hypothesis: 
We propose that the use of the OHSU dual hormone closed-loop system as compared to an 
insulin only closed-loop system and a predictive low glucose suspend system, will reduce the 
time spent in the hypoglycemic range after exercise as measured by sensed glucose values.   
 
Endpoints 
Primary Endpoint (duration: 4-hours post exercise):  
 Percent of time with sensed glucose <70 mg/dl  
 
Secondary Endpoints (duration: entire study):  
 Percent of time with sensed glucose between 70 – 180 mg/dl 
 Number of carbohydrate treatments (defined as 15 or 20 grams of carbohydrate)   
 Mean sensed glucose 
 Percent of time with sensed glucose <50 mg/dl 
 Percent of time with sensed glucose >180 mg/dl 
 Mean amount of insulin delivered in one day (in units/kg) 
 Mean amount of glucagon delivered in one day (in mcg/kg)  
 
Study Type  
This is a single center, randomized, three treatment, crossover trial designed to compare the 
glucose control resulting from the use of a dual and single-hormone closed-loop system as 
compared to a predictive low glucose suspend system.   
 
 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
Study Population 
Study population will be adults with type 1 diabetes, ages 21 – 50 years of age.  Older subjects 
are excluded due to higher risk of unrecognized coronary artery disease.  Younger subjects are 
excluded as it is appropriate to assess safety first in the adult population.  Nineteen subjects will 
be recruited to participate in studies.   
 
Power Analysis 
A Paired Means Power Analysis was used to carry out a sample size power analysis.  A total 
sample size of 19 achieves 80% power to detect a reduction in percent time in hypoglycemia of 
62% when using the dual-hormone (DH) artificial pancreas during the 4 hours after the start of 
aerobic exercise compared to predictive low glucose suspend (PLGS). Based on prior data in our 
previous experiments, we found that subjects spent an average of 9.8% time in hypoglycemia 
(standard deviation of 9.5%) under PLGS and 3.7% time in hypoglycemia using DH (standard 
deviation of 4.8%).  
 
Protocol Summary: 
Subjects will undergo three approximately 76 hour studies.  See Figure 1 below for a diagram of 
the study flow. During each of these intervention visits, subjects will wear an Omnipod to deliver 
insulin and a Dexcom G5 OR G6 CGM to measure glucose.  In the dual-hormone closed-loop 
study, participants will wear a second Omnipod filled with XeriSol™ glucagon.  The first day of 
the intervention visit will be an 11 hour inpatient visit with the subsequent time spent as an 
outpatient.  The subject will come back to the research center on Day 4 in the morning to remove 
all devices.  During one of the studies, glucose will be controlled using the FMPD dual hormone 
mode.  During another study, glucose will be controlled using the FMPD single hormone mode.  
The single and dual hormone modes of the controller determine insulin only and insulin with 
glucagon delivery rates based on proportional and derivative error and contain an exercise 
detection component.  During the other study, glucose will be controlled using a predictive low 
glucose suspend mode.   In this mode, the APC will be programmed with the subject’s basal 
profile(s) which will be transmitted to the Omnipod Personal Diabetes Manager (PDM) and 
allow for boluses to be inputted by the subjects for meals and corrections using their typical carb 
ratios and correction factors.  However, this system will have a safety feature to suspend insulin 
delivery when sensor glucose is predicted to go below a threshold.  Treatment order will be 
randomized.    
 
Subjects will arrive at the clinic at approximately 7am for the inpatient visits.  Subjects will eat 
breakfast, lunch and dinner at approximately 8:30am, noon, and 6pm respectively.  Subjects will 
exercise on a treadmill for 45 minutes. Subjects will be discharged approximately 4 hours after 
exercise begins. The subject will then go home for the remainder of the study visit.  Subjects will 
be given a standardized meal for dinner on Day 1. Subjects will return to OHSU on Day 4 for 
removal of all devices.   During each study, the subject will wear one subcutaneous DexcomTM 
G5 OR G6 continuous glucose monitoring (CGM) system.  The CGM system will provide 
sensed glucose data every 5 minutes.  The accuracy of the sensed data will be obtained by 
reference measurements of capillary blood glucose.  Sensed glucose data will be wirelessly 
transmitted via Bluetooth Low Energy (BTLE) from the Dexcom G5 OR G6 transmitter to the 
Nexus 5 master controller every five minutes.  The controller for all 3 modes is a Google Nexus 
5 phone.  The smart phone will wirelessly communicate via BTLE to an Omnipod through a 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
PDM (Insulet Corp. ) for automated insulin delivery or in the case of dual-hormone AP, to 
another Omnipod and PDM to be used for automated glucagon delivery.    
 
 
 
 
 
 
A physician or nurse practitioner will be present for study start-up, will be on campus for 
exercise and will be immediately available on call at all other times.  The study investigators 
retain the authority to modify any aspects of the protocol at his/her discretion if he/she believes 
the subject’s safety is a concern.   During the outpatient portion of the study visits, a study 
coordinator will be able to access the cloud for monitoring purposes.  For safety purposes, all 
system alerts that are not serviced by the subject will be pushed to the study coordinator/study 
investigator according to Appendix D.    
 
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 subjects 21 to 50 years of age.  
3. Physically willing and able to perform 45 min of exercise (as determined by the 
investigator after reviewing the subjects activity level)  


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
4. Current use of an insulin pump for at least 3 months with stable insulin pump settings for 
>2 weeks.   
5. Lives with another person age 18 or older who will be present while subject exercises at 
home and that can attend the training on using the system. 
6. Lives within 40 miles of OHSU main campus. 
7. HbA1c ≤ 10% at screening.    
8. Total daily insulin requirement is less than 139 units/day.  
9. Current use of a phone or other device so can be contacted by study staff off-campus 
10. Willingness to follow all study procedures, including attending all clinic visits.  
11. Willingness to sign informed consent and HIPAA documents.  
 
Exclusion Criteria:  
1. Female of childbearing potential who is pregnant or intending to become pregnant or 
breast-feeding, or is not using adequate contraceptive methods. Acceptable 
contraception includes birth control pill / patch / vaginal ring, Depo-Provera, Norplant, 
an IUD, the double barrier method (the woman uses a diaphragm and spermicide and the 
man uses a condom), or abstinence. 
2. 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. Hypertensive subjects with systolic blood pressure ≥ 160 mmHg or diastolic blood 
pressure ≥ 100 mmHg despite treatment or who have treatment-refractory hypertension 
(e.g. requiring four or more medications).  
7. History of severe hypoglycemia during the past 12 months prior to screening visit or 
hypoglycemia unawareness as judged by the investigator. Subjects will complete a 
hypoglycemia awareness questionnaire.  Subjects will be excluded for four or more R 
responses.  
8. History of Diabetes Ketoacidosis during the prior 6 months prior to screening visit, as 
diagnosed on hospital admission or as judged by the investigator. 
9. Adrenal insufficiency. 
10. Any active infection. 
11. Known or suspected abuse of alcohol, narcotics, or illicit drugs.  
12. Seizure disorder. 
13. Active foot ulceration. 
14. Severe peripheral arterial disease characterized by ischemic rest pain or severe 
claudication. 
15. Major surgical operation within 30 days prior to screening. 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
16. Use of an investigational drug within 30 days prior to screening. 
17. Chronic usage of any immunosuppressive medication (such as cyclosporine, 
azathioprine, sirolimus, or tacrolimus). 
18. Bleeding disorder, treatment with warfarin, or platelet count below 50,000. 
19. Allergy to aspart insulin. 
20. Allergy to glucagon. 
21. Need for uninterrupted treatment of acetaminophen. 
22. Current administration of oral or parenteral corticosteroids. 
23. 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).  
24. Beta blockers or non-dihydropyridine calcium channel blockers. 
25. Current use of any medication intended to lower glucose other than insulin (ex. use of 
liraglutide). 
26. Diagnosis of pheochromocytoma, insulinoma, or glucagonoma, personal or family 
history of multiple endocrine neoplasia (MEN) 2A, MEN 2B, neurofibromatosis or von 
Hippel-Lindau disease.   
27. History of severe hypersensitivity to milk protein.  
28. Current use of any medication with strong anticholinergic properties, such as 
antihistamines, sleep aids, and antidiarrheal medications.  
29. Current use of indomethacin.  
30. Conditions that may result in low levels of releasable glucose in the liver and an 
inadequate reversal of hypoglycemia by glucagon such as prolonged fasting, starvation 
or chronic hypoglycemia as determined by the investigator.  
31. A positive response to any of the questions from the Physical Activity Readiness 
Questionnaire with one exception: subject will not be excluded if he/she takes a single 
blood pressure medication that doesn’t impact heart rate and blood pressure is controlled 
on the medication (blood pressure is less than 140/90 mmHg).  
32. Any chest discomfort with physical activity, including pain or pressure, or other types of 
discomfort.  
33. Any clinically significant disease or disorder which in the opinion of the Investigator 
may jeopardize the subject’s safety or compliance with the protocol.  
 
Subject Recruiting: 
Subjects 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, electronic newletter or from the OHSU Subject Recruitment 
website. Handouts will also be made available to faculty at Providence 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 subjects. Subjects will also be recruited from a 
list of subjects who participated in past OHSU studies who have agreed to be contacted 
regarding future studies involving Drs. Castle or El Youssef, from the OHSU diabetes research 
registry and/or www.clinicaltrials.gov. Non-english speaking subjects will not be recruited since 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
this protocol would require the use of medical devices and mobile software that do not have non-
english versions available.  
 
Up to 50 subjects may be screened in this study.  Goal enrollment is 19 subjects.  Up to four 
subjects will be replaced if needed, with a total enrollment of up to 23 subjects.  
 
Withdrawal Criteria 
The subject may withdraw at will at any time or at the discretion of the Investigator.  
 
A subject must be withdrawn if the following applies: 
1. Hypoglycemia during the treatment period posing a safety problem as judged by the 
investigator.  
2. Hyperglycemia during the treatment period posing a safety problem as judged by the 
investigator.  
3. Protocol deviation having influence on efficacy or safety data as judged by the 
Investigator.  
4. Substantial and repeated non-compliance with trial procedures.  
5. Pregnancy.  
6. Intention of becoming pregnant.  
 
Visit Procedures 
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 or at the Harold Schnitzer Diabetes Health Center. The subject 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 subject ample time to ask questions and 
consider participation, and ensure that the subject voices understanding of the informed consent 
and study requirements. To minimize the possiblity of coercion and to ensure that subject is 
signing the appropriate version of the consent, an informed consent checklist will be used by 
study staff. After the subject has signed the consent,a copy of the consent/authorization form will 
be given to the subject. The original will be kept for the source document.  
 
VO2max testing will take place at the Human Performance Lab, which is located within OHSU 
and is attached to the main hospital. A code cart is on site within the Human Performance Lab 
and a code team is available by page at all times. Subjects will be asked to fast before the 
screening visit for 3 hours. 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. 
After the CBG is obtained, the study investigator may adjust the subject’s basal insulin rate as 
necessary in preparation for VO2max testing to avoid hypoglycemia. 
 
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 


IRB 17225 Protocol v12  
 
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breast and pelvic exams. Females of child-bearing potential will take a urine pregnancy test, 
which must be negative to participate.  A venous blood sample will be taken for the following 
tests: hemoglobin A1C, complete blood count, complete metabolic set (including creatinine, liver 
set, and electrolytes).   In addition, for subjects with signs and symptoms suggestive of 
pheochromocytoma, fractionated plasma metanephrines will be measured. An EKG will be 
completed. A study investigator will assess inclusion/exclusion criteria and review the subject’s 
medical record for clarification as needed.  The subject’s insulin pump will be downloaded at 
this visit. The pump download will allow the investigator to assign an appropriate Total Daily 
Insulin Requirement (TDIR) to the subject during dosing visits. A three-digit subject ID number 
will be assigned to the subject.   
 
Subjects will undergo VO2max testing at the end of the screening visit if all inclusion criteria are 
met and no exclusion criteria are met, with the exception of blood test results which will not be 
immediately available. A study investigator will be present for the entire VO2max testing 
procedure. Additional CBG samples will be taken immediately before and after completion of 
the VO2max test. Subjects will be given juice and the VO2max test will either be delayed by 
approximately 1 hour for CBG values of <80 mg/dL, or rescheduled for a different day.  Subjects 
will be given 15-20 grams of carbohydrates for CBG values of <70 mg/dL at any point during 
the screening visit. CBG values will be reviewed by an investigator and subjects will be provided 
with a snack after VO2max testing as needed to avoid post-testing hypoglycemia. Subjects that 
screen fail by meeting any of the exclusion criteria prior to proceeding to the VO2max test will not 
complete the VO2max test. This visit will take approximately 2.5 hours.  
 
One Week Run-in Period 
The purpose of this run-in period is to teach subjects how to use the Dexcom CGM system using 
the APC software. For those new to CGM, it is also designed to provide them exposure prior to 
starting the intervention visits. The one week run-in period will take place within 6 weeks prior 
to the first 76 hour treatment visit.  After arrival at the OHSU OCTRI outpatient clinic 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. This visit will take approximately 1 hour. 
 
Subjects will receive training on how to use and calibrate the Dexcom G5 OR G6 CGM system 
including changing out the sensor every 7 or 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.   Subjects 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.  Subjects will be trained how to pair the Dexcom transmitter to the APC app on the 
Nexus 5 smart phone, start and stop a new sensor session, how to enter calibrations and how to 
begin a simulated study.  
 
The Dexcom G5 OR G6 CGM system will be calibrated at home according to the manufacturer’s 
directions.  The CGM alerts will be set at 70 mg/dL and 300 mg/dL. Subjects will begin a run-in 
study at home after two hours when the sensor warm-up is completed. Subjects will be given a 
Dexcom a transmitter and sensor to insert the day before each treatment visit along with a 
Contour Next meter for measuring their capillary blood glucose in order to calibrate the Dexcom 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
CGM system.  Subjects will be instructed to discontinue the use of acetaminophen for all periods 
when wearing the Dexcom CGM system.    
Each subject will be instructed on how to fill and insert the Omnipod, adjust their basal through 
the Nexus smart phone, give meal boluses and corrections through the Nexus smart phone and 
change out the pods. Instruction will be given on identifying infusion malfunction. The time 
required for this training will vary, depending on the experience of each subject, but will be 
sufficient to help him/her become comfortable using the Nexus smart phone and changing out 
the infusion pod. If the subject experiences difficulties using the Omnipod during the study 
period, study staff will be available to educate and support by phone. 
 
The companion accompany the subject to the start of the training visit to receive training on 
treatment in case of severe hypoglycemia episode, including administration of rescue 
carbohydrates and use of emergency glucagon kit.   
 
76 hour Treatment Visits  
The subject will be asked to check his/her CBG before driving to the clinic and to bring a snack 
in the car in case hypoglycemia does occur (in which case, the subject must park and treat the 
hypoglycemia).  After the first treatment visit, the washout period will be 6 to 45 days calculated 
from the day of admission to the research center until the start of the next admission.  Subjects 
will be asked to avoid vigorous activity within the 24 hours prior to all treatment visits.  The 
subject will arrive at the research center 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 
 
 
A capillary blood glucose (CBG) will be obtained and measured by the Contour Next glucose 
meter given to the subject for prior two visits.  When they arrive, subjects 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.   Serum ketones will 
also be checked.  If serum ketones are ≥ 0. 6 mM, the study will be halted and insulin therapy 
will be guided by the onsite investigator.   
 
During each treatment visit, glucose will be controlled using either: 1) the single hormone insulin 
only mode 2)  the dual hormone insulin and glucagon mode or 3) the insulin only mode with 
predictive low glucose suspend.  The first 11 hours of the visit will be conducted in the OCTRI 
inpatient research unit, the Harold Schnitzer Diabetes Health Center or the Medicine Specialties 
clinic.  The subjects will then go home for the remainder of the intervention period, returning on 
Day 4 to the clinic to return all devices.  A code cart is on site at all locations and a code team is 
available by page at all times. 
 
Inpatient Visits (11 hours) 
An Omnipod will be filled with aspart insulin for all studies, but the dual hormone study will 
also have an Omnipod filled with XeriSol™ glucagon.   Each pod and corresponding PDM will 
be labeled with a sticker indicating either "insulin" or "glucagon" for clear identification. We will 
provide the subjects with kits to replace the pods at home in case of pod malfunction or 
dislodgement at home. We will provide the pods with respective labels ("insulin" or 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
"glucagon") attached to the outside of the sterile packaging of the pod with instructions to 
immediately affix to the pod upon opening. The respective insulin or glucagon medication, pods, 
and all supplies will be provided separate kits that are extensively labeled. During the training, 
we will instruct patients to fill one pod at a time with only the supplies from that kit out at that 
time.    
 
The pod will be primed and inserted into the skin of the subject’s abdomen or flank as directed 
by the manufacturer.  The subject will also wear a Zephyr heart rate monitor and accelerometer.  
For male subjects, two small areas may be shaved on either side of the sternum to allow proper 
placement of the Zephyr. Additionally, subjects will be asked to wear an activity watch, such as 
the Actigraph wGT3X-BT. The activity watch will be used in addition to the Zephyr to collect 
heart rate and activity data. The activity watch will not be connected to the APC system.  See 
Figure 2 below for a diagram of the system design.  Subjects will disconnect his/her own pump 
and remove his/her own insulin infusion set once insulin delivery has started via the Omnipod.    
 
Figure 2: Closed-loop System Design  
 
 
 
  


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
The research staff will initialize the system and begin the closed-loop study.  With the oversight 
of study staff, the subject will perform a CBG measurement and use this measurement to 
calibrate the glucose sensor at the start of the closed-loop study.  The subject will be given 
enough study supplies for the 76 hour visit.  The study investigator will then depart but remain 
on call.   
 
Study staff will remain to complete a training with each subject on using a Dexcom CGM, the 
Omnipod system, the Zephyr BioPatch heart rate and accelerometer with the APC app. Subjects 
will be shown how to use the Nexus 5 controller user interface which includes: entering basal 
profiles, insulin carb ratios and sensitivity, activating and deactivating pods, meals, carb 
treatments, blood glucose values and ketone levels, addressing alerts, troubleshooting the devices 
connection to the phone via Bluetooth, and pausing the study.   The subject will need to 
demonstrate competency in operating the system before study staff leave the room.  The subject 
will keep a journal of all occurrences and symptoms, such as hypoglycemic spells, carbohydrate 
administrations and device problems while study staff is absent. Subjects will be given a pager 
number to call for any problems during the 76 hour visit.   
 
The algorithm will push data up to a cloud server that can be monitored remotely every 5 
minutes. A study coordinator will be available at all times for the visits with the ability to 
monitor the APC remotely via a cloud system on the web in the event of any issues. The APC 
will generate alerts on the smartphone according to Appendix D. The subjects will all be trained 
as to the action required by each alert. Each alert has a specific condition to be met for it to be 
considered serviced (i. e.  enter treatment with oral carbohydrates).  The refractory period is also 
specific to each alert with shorter refractory periods for alerts that concern subject safety.   If the 
subject does not appropriately respond to the alert in the alotted timeframe, the alert will push to 
the study coordinator and the on-call investigator according to Appendix D. At that time, the 
coordinator will pull up the web-based monitoring system. The study investigator and technician 
may intervene with a telephone call or a personal visit at any time. For example, staff will call to 
remind the subject to calibrate the sensor. If the subject cannot be reached and sensor glucose is 
below 50 mg/dl, the emergency contacts provided by the subject will be contacted. If the alert is 
still unserviced and study staff are unable to reach the subject or either of the emergency 
contacts, emergency medical services will be contacted. To facilitate this, the Nexus 5 phone will 
track the subject’s location and push GPS coordinates to the cloud server approximately every 10 
minutes.  Cloud coordinates will be pushed with a known, fixed offset to allow for scrambling.  
 
In order to push alerts to study coordinators and study investigators, the cloud server used for 
remote monitoring will have a drop down menu for study staff to sign in and out for the duration 
of their monitoring shift.   Each study coordinator and investigator listed in the menu will have a 
cell phone number on file that can receive texts with pushed alerts.  
 
During all studies, sensed glucose data will be wirelessly transmitted via BTLE from the 
Dexcom transmitter to the FMPD algorithm every five minutes.  The single and dual hormone 
modes of the algorithm will calculate insulin only or insulin and glucagon doses and will run on 
a Google Nexus 5 phone.  The predictive low glucose suspend mode of the algorithm will deliver 
insulin according to a pre-set basal profile(s) for the subject, which the subject may change if 
needed for safety as he or she would normally do.  The smart phone will wirelessly communicate 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
via BTLE to a PDM communicating to an Omnipod for automated insulin delivery, and for the 
dual hormone closed-loop system, to a second PDM and Omnipod for automated glucagon 
delivery.    
 
During normal operation, the sensor will be calibrated approximately every 12 or 24 hours.   If at 
any time the study staff determines that a sensor can no longer be used, a new sensor will be 
inserted, which will be calibrated after two hours and then used to run the closed-loop system. 
The sensor will also be recalibrated per the manufacturer’s directions if the sensor becomes 
inaccurate. An inaccurate sensor is defined as either (1) a sensor whose value is 35% or more 
different than a CBG when the CBG ≥ 75 mg/dl or (2) when a sensor is more than 30 mg/dl 
different than a CBG when the CBG < 75 mg/dl.. Additional calibrations may be ordered at the 
discretion of the  investigator on call.  
  
In order to ensure safety and to assess sensor accuracy, the subject will be asked to check their 
blood glucose two times during the day (typically before breakfast and at bedtime), for 
symptoms of hypoglycemia, and in response to system alert (such as for low or high sensor 
alerts).  We will also instruct patients to perform capillary blood glucose immediately prior to 
and 30-60 minutes following exercise, and at 2-3am on the night following inpatient and 
outpatient exercise sessions. The subject will be able to check his/her capillary blood glucose 
more than 2 times a day if they feel they need to.  If the subject’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 and glucose tablets will be available for rescue treatment.   The study investigator 
retains the authority to check blood glucose at more frequent time points at his/her discretion.   
 
For subject safety, if a sensor value is not available for 20 minutes or communication with the 
insulin pod 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 subject at study start. When communication 
with the sensor or pod is restored, the system will automatically resume, updating the IOB 
accordingly. If sensor glucose values are not being acquired, glucagon delivery will be suspended. 
When this occurs for a lost sensor, the APC system will also activate the predictive low glucose 
suspend feature if the last known sensor value was within the range of 70-140 mg/dl and predicted 
to fall below 90 mg/dl within 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 ten minutes of sensor glucose data.  
 
Subjects will eat breakfast, lunch and dinner at approximately 8:30am, noon and 6pm 
respectively. Meals will be announced to the controller. For each meal, food items will be self-
selected from the hospital menu. The number of grams of carbohydrates will be counted by the 
subject and entered in the controller. Immediately before eating, each subject will receive 80% 
(nominal) of his/her typical pre-meal insulin dose based on their insulin to carbohydrate ratio. 
The same self-selected meal will be offered on subsequent inpatient visits, and in the event a 
particular food item is not available, a different item with a similar amount of carbohydrate will 
be provided.  
 
Subjects will exercise at approximately 2pm. Subjects will warm-up for 5 minutes then exercise 
for approximately 45 minutes on a treadmill. Subjects will exercise at the CTRC. A code cart is 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
on site within the unit and a code team is immediately available by page at all times. For subject 
safety, capillary blood glucose must be 80 mg/dl or higher to begin exercise. Subjects will 
exercise at a fixed intensity level to a target heart rate (±10%) based on the heart rate achieved at 
60% of their VO2max determined at screening.  This protocol will allow the exercise to be graded 
according to each participant’s relative capacity. The speed and grade of the treadmill will be 
adjusted by trained research personnel with a goal of keeping participants within their target 
heart rate range for the entire 45 minutes.  
During the exercise period, there will be defined rules for stopping exercise, including: 
1) If the subject feels unwell, 
2) If the subject develops hypoglycemic symptoms, such as excessive sweating, 
shaking/tremors, palpitations, feelings of dread or panic, light-headedness, nausea, 
difficulty concentrating or the like, 
3) If the subject develops chest pain/pressure, 
4) If the subject develops undue shortness of breath (SOB), 
5) Signs of poor perfusion: light-headedness, confusion, ataxia, pallor, cyanosis, nausea, or 
cold and clammy skin  
6) If the maximum heart rate of the subject (MHR) is exceeded, 
7) For patient preference. 
 
If the exercise is stopped prematurely, the duration of exercise will be noted by the study staff 
and if the subject is deemed safe to participate in future studies, the exercise will be stopped after 
that same time duration for subsequent studies. For subject safety, if capillary blood glucose is < 
70 mg/dl at any point during the exercise period, the subject will consume 15 g of carbohydrates 
and delay completion of exercise until blood glucose raises above 80 mg/dl. If glucose fails to 
rise above 80 mg/dl after a carbohydrate treatment during exercise, a second treatment of 15 
grams will be given. Since insulin will be turned off briefly, exercise will be delayed for subjects 
with ketones above 0.6 mM to minimize hyperglycemia until levels drop below this threshold. 
 
The Fading Memory Proportional Derivative (FMPD) algorithm will determine the insulin and 
(when applicable) glucagon delivery rates for the closed-loop studies. The FMPD algorithm 
determines insulin and glucagon delivery rates based on proportional error, defined as the 
difference between the current glucose level and the target level, and the derivative error, defined 
as the rate of change of the glucose. Each of these errors is calculated over a time interval. The 
“fading memory” designation refers to weighting recent errors more heavily than remote errors. 
This weighting provides an adaptive component to the algorithm. In simple terms, the insulin 
rate is increased for high or rising glucose levels and glucagon is given for low or falling glucose 
levels (at times of impending hypoglycemia). Gain factors determine the degree to which 
proportional or derivative errors lead to changes in hormone delivery rates. There are separate 
gain factors for proportional and derivative error for both insulin and glucagon. Positive 
proportional errors (glucose level above target) and positive derivative errors (rising glucose 
level) call for an increase in the insulin delivery rate.  
 
When in predictive low glucose suspend mode, the system will deliver insulin based on the basal 
profile(s) entered for each subject. The subjects will manually enter in boluses for meals and 
corrections into the APC user interface. Using this system, the subjects will manage their blood 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
glucose as they  normally would. The advantage is that the system is integrated with a glucose 
sensor to give advanced diabetes control.  
 
The predictive suspend feature will activate within the range of 70-140 mg/dl if sensor glucose is 
predicted to fall below 90 mg/dl within thirty minutes. If this occurs on a consecutive turn, the 
APC system will activate a minimum 30 minute suspension and a maximum of 120 minutes 
within any 150 minute window.  Suspension will be limited to 180 minutes during the nighttime 
(11pm-7am).  After this minimum 30 minutes has lapsed, insulin delivery will resume if sensor 
glucose is above 70 mg/dl and predicted to rise above 120 mg/dl within the next 30 minutes. As 
long as sensor glucose is above 140 mg/dl, the predictive suspend feature will not activate. 
Prediction of sensor glucose is based on linear regression of the prior ten minutes of sensor 
glucose data. During the predictive low glucose suspend mode arm of the study, subjects will not 
be allowed to change their insulin dosing prior to the start of the exercise. This is being done to 
allow for equal comparison of dosing and subsequent glucose control across arms.  
 
Subjects will wear a Zephyrlife BioPatch monitoring device for collecting heart rate and 
accelerometry data. The Zephyr transmits this data to the Nexus 5 master controller via 
Bluetooth. The APC system will convert the heart rate and accelerometry data into an estimated 
energy expenditure to determine if the subject is exercising. If the communication is not working 
between the Zephyr and the Nexus 5 at the time of exercise during the inpatient visit, exercise 
may be delayed until communication is restored.  Energy expenditure (EE) is estimated every 
minute using a time series approach.  This time series model uses the inputs of heart rate (HR) 
and physical activity (PA). The EE estimation is further personalized by incorporating 
anthropometric characteristics of the individual. If the communication is not working between 
the Zephyr and the Nexus 5 at the time of exercise during a visit, exercise may be delayed until 
communication is restored.  
 
The exercise threshold will be set to 4 METs/min for every subject at the start of the study. If the 
corrected MET value is greater than 4 METs for a period of 5 consecutive minutes during the 
first exercise period, exercise is considered to be ongoing.  An exercise dosing adjustment 
algorithm will be used when exercise is detected that has been previously tested and published 
(7).   When exercise is detected while in single or dual-hormone mode, and the subject confirms 
he/she is exercising, insulin will be turned off for 30 minutes (nominal) immediately after 
detection of exercise. Subsequently, the insulin infusion rate will be reduced to 50% (nominal) 
for a period of 1 hour (nominal). During use of the dual-hormone closed-loop system, the 
glucagon set point during exercise will also be set higher to 110 mg/dl (nominal). This will result 
in glucagon being called for at an earlier point with an increase in the amount of glucagon 
delivered. Also, the maximum amount of glucagon allowed to be delivered in a 50 minute time 
period will be increased by double, which will allow for more glucagon to be delivered during 
and immediately after exercise if glucose levels are dropping rapidly.  The maximal amount of 
glucagon that can be delivered in a 24 hour period will remain unchanged. These adjustments 
will continue during the same period of time that insulin adjustments are being made (nominal 
1.5 hours) after exercise. After the initial adjustment in glucagon target, the investigator will 
evaluate the subject’s response to glucagon during exercise and may change the target further, 
within the range of nominal values, based on whether the subject still went hypoglycemic (< 70 
mg/dl) or hyperglycemic (>180 mg/dl) within 3 hours from the start of exercise. 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
With regards to the daytime and nightime glucose target, % of premeal insulin bolus and exercise 
insulin and glucagon adjustment parameters: these are current nominal values that may be 
adjusted within the FDA approved minimum and maximum range for each adjustable parameter.   
 
During predictive low glucose suspend mode, a Zephyr BioPatch will transmit heart rate and 
accelerometry values to the APC for the purposes of exercise detection, but exercise detection 
will not trigger any changes in insulin delivery while in this mode. 
 
The exercise detection algorithm will prompt the participant if exercise is occurring prior to 
adjusting dosing.  For example, if the participant’s METs exceed a threshold of 4 METs, the AP 
will detect this and ask the participant if they are exercising.  If the participant acknowledges this 
and says “Yes”, the AP will adjust the dosing.  If the subject selects that they are not exercising, 
the APC will present a dropdown menu from which the subject can select their current activity 
for logging purposes (e. g.  housework).  It will also present several choices for the amount of 
time that exercise detection will be suspended so that the subject will not continuously receive 
detection alerts during that activity (15, 30 or 60 minute suspension).  If the participant says 
“No”, this is considered a false alert because the algorithm has detected exercise, but the 
participant was not actually exercising.  Because these false alerts can be annoying to the 
participants, the AP includes an adjustable exercise detection threshold.  The adjustable exercise 
detection threshold works as follows:  
 At the start of the study, the participants’ exercise detection threshold will be set to 4 
METs. 
 On the first day of the study, when the participant exercises at the hospital, the AP 
records the participants’ METs during exercise and also records the participants’ METs 
during activities of daily living and other non-exercise events.   
 Based on data from this controlled setting, a “lower bound MET” for that subject will be 
calculated based on a lower-bound confidence interval set around their METs recorded 
during exercise. 
 If that participants’ lower bound MET during exercise is greater than 4, their maximum 
allowable exercise threshold value (MAETV) will be set to the lower bound MET.  
Otherwise, the MAETV will remain at 4. 
 Every time a false alert occurs for detecting exercise, the participants’ exercise detection 
threshold will increase by 0.25 MET.  However, the exercise detection threshold will 
never exceed the MAETV described above.  
 
We are aware that there is a risk of hyperglycemia if the subject stops exercising after a short 
time with continued adjustments to insulin or insulin/glucagon.  Therefore, an exercise 
cancellation option is available on the user interface for up to 30 minutes after the start of 
exercise that will revert insulin and glucagon parameters to their nominal values. If exercise is 
not detected by the algorithm when the subject is actually exercising, an exercise announcement 
button on the APC user interface will be used.  
 
 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
Discharge from inpatient clinic 
If the subject’s schedule does not allow them to return to the clinic before the 72 hour mark from 
the time the first pod was activated, then a new insulin pod (and new glucagon pod if applicable) 
will be placed as described above approximately 1-2 hours prior to discharge to avoid use of any 
single pod beyond 72 hours. At the completion of the 11 hour inpatient visit, subjects will be 
discharged from the clinic.  Subjects will complete a VAS injection site discomfort assessment 
for the glucagon infusion site, if applicable (see Appendix E). Capillary blood glucose will be 
measured with two consecutive blood glucose measurements at least 15 minutes apart prior to 
discharge. Subjects will wait to discharge home if capillary blood glucose is <85 and or >300 
mg/dl or at the discretion of the study investigator, treatment will be at the discretion of the study 
investigator. Once subject’s capillary blood glucose is between 85-300 mg/dl, they can be 
discharged home. Subjects will be given enough supplies to continue running the study while at 
home for 2 days. Subjects will be given a glucose and exercise diary to record the specifics of 
his/her activities at home. After the subject is discharged on Day 1, he/she will return home for 
Day 2 and Day 3 and return to OHSU on the morning of Day 4 to return all devices and end the 
study.  
 
We are aware that there is a risk of severe hypoglycemia while the subjects are at home. The 
system will alert if the sensed glucose values fall below 70 mg/dl without exercise detection and 
below 85 mg/dl with exercise detection, prompting the subject to obtain a capillary blood 
glucose sample. Subjects will be required to live with at least one other person age 18 or older 
and live within 40 miles of OHSU. All subjects will provide two emergency contacts to study 
staff and will be given an emergency glucagon hypokit if they don’t already have one.  
In case of a system error that cannot be corrected immediately with the subject off campus, the 
subject will be able to to pause the APC system. Pausing will allow the Omnipod filled with 
insulin to begin basal insulin delivery for a pre-set basal profile(s) inputted for the subject at the 
study start. If there is a pending meal bolus in the insulin back log, the pause mode will be 
delayed to allow the bolus to finish delivering. Subjects will be able to give meal boluses and 
corrections through the Omnipod while in pause mode. When the error is resolved, the 
participant can exit pause mode and the closed loop system can be resumed.  If the subject 
pauses the system, this will be visible on the cloud server and may prompt a telephone call from 
study staff to determine the issue and the best way to resolve it.  
 
Subjects will be given sufficient blood glucose testing supplies, ketone testing supplies and 
Omnipods for 2 days of closed-loop treatment at home. Study staff will check in with the subject 
each morning. The subject may contact study staff at any time during the outpatient portion of 
the visit. Subjects will be asked to perform 45 minutes of an aerobic exercise of his/her choice 
(excluding swimming) on Day 3 while at home. Subjects will be reminded to check their blood 
glucose before and after exercise. For subject safety, capillary blood glucose must be 100 mg/dl 
or higher to begin exercise while subject is at home. Subjects will be required to have a person 
age 18 or older who attended a training session on the study present while the subject exercises 
at home. The companion will stay after the exercise until the subject’s CBG is > 100 mg/dl or for 
60 minutes after exercise is completed-whichever is longer. 
 
 
 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
Return to the Outpatient Clinic at OHSU 
On the fourth day, subjects will return to the OCTRI inpatient clinic, the Harold Schnitzer 
Diabetes Health Center or the Medicine Specialties clinic in the morning.  Subjects will be asked 
to arrive early enough to provide sufficient time to allow the pods to be removed before the 72 
hour mark of pod use. Subjects will complete another VAS injection site discomfort assessment 
for the glucagon infusion site before removal of the Omnipod, if applicable. The study will be 
terminated and the subject’s own insulin pump will be restarted. The study investigator will 
consult with the subject regarding appropriate insulin dosing for the remainder of the day. The 
HR monitors, Omnipods and Dexcom sensor will be removed from the subject. All infusion sites 
and the sensor site will be inspected for signs of irritation or infection. The study investigator 
will complete the Draize scale assessment for the glucagon infusion site, if applicable (see 
Appendix F). 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 subject will return 1-3 days later for a follow-up visit. A capillary blood glucose 
value will be taken immediately prior to discharging the subject. Subjects will be given oral 
carbohydrate for values below 85 mg/dl, and will be given an insulin bolus if deemed appropriate 
by the study investigator for values above 150 mg/dl.  
 
If a study visit is stopped prematurely, such as due to technical problems, the subject 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 
o Give 15 grams of oral carbohydrate.  
o Repeat treatment every 15 minutes as needed to raise blood glucose ≥70 mg/dl.   
 Presence of STUPOR, LOSS OF CONSCIOUSNESS, or SEIZURE 
o Give 1 mg glucagon SC.  
o Verify that insulin is turned off.  
o Further management per study investigator.  
 
Hyperglycemia Treatment Guidelines 
If the sensed glucose is ≥ 300 mg/dl, the subject 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 for closed-loop studies, making sure there 
are no 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 subject will be instructed to check serum ketones using the Abbott Precision Xtra meter 
and to change out the infusion set. If serum ketones are over 0.6 mM, the on call study 
investigator will be alerted to discuss proper management, including changing Omnipod and 
delivering a correction bolus. In addition, the subject 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.  


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
Cleaning and Disinfecting  
All devices will be cleaned and disinfected between subjects.  The smart phone, Dexcom 
transmitter, heart rate monitors 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 SANI-CLOTH AF3 Germicidal 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 subject information.  
 
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 first 4 hours of the study: 
1) capillary blood glucose falls to < 40 mg/dl at any time point, 2) capillary blood glucose 
exceeds 400 mg/dl on two occasions (120 min or more apart within a 4 hour window), 3) 
capillary blood glucose exceeds 400 mg/dl on two occasions more than 120 minutes apart but 
outside of the 4 hour window and during that time, the capillary blood glucose has not fallen 
below 250 mg/dl, 4) serum ketones are above 1.5 mM at any time, 5) seizure or unconsciousness 
associated with hypoglycemia, or 6) persistent nausea and vomiting thought to be related to 
glucagon.  
 
Statistical methods 
 
Primary endpoint 
The primary study endpoint is percent of time with glucose sensor < 70 mg/dl for the four hours 
after exercise. The hypothesis to be tested is the dual hormone closed-loop system with exercise 
detection is superior in reducing hypoglycemia as compared to the insulin only closed-loop 
system and as compared to the predictive low glucose suspend system.  Data will be analyzed 
using generalized estimating equations, which takes into account correlated data and repeated 
measures.  Data will be analyzed using an intention-to-treat analysis and missing sensed glucose 
values will be interpolated.   
    
Secondary endpoints 
Secondary endpoints will be analyzed using generalized estimating equations and using an 
intention-to-treat analysis.  Missing sensed glucose and missing CBG values will be interpolated.  
A Bonferroni-Holmes correction for multiple comparisons will be applied only to the secondary 
endpoint analyses.    
 
 
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 issue alerts and will be remote monitored 
during each visit with unserviced alerts being pushed to the study coordinator and investigator. If 
sensed glucose goes below 70 mg/dl or above 300 mg/dl, a capillary blood glucose check will be 
required. A study investigator will be on call at all times.  


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
Risks from exercise include falls, sprains, bruises, very low risk of bone fractures and head 
trauma. The likelihood of significant harm is quite low.  
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. 
 
XeriSol™ glucagon may cause blood sugars to go too high, which is also unlikely in the low 
doses that will be given. Rarely, there can be allergic responses to glucagon, such as skin 
redness, hives, itching of the skin, swelling of the mouth, or breathing difficulties. A few people 
may experience rapid heartbeat for a short while. There is a potential risk for developing anti-
glucagon antibodies from exposure to glucagon. These reactions are considered very unlikely. 
After glucagon injection, nausea, headache, dizziness and vomiting may occur occasionally. 
Users may feel a stinging sensation or moderate pain when the medication is injected and 
redness at the infusion site. Risks and side effects related to the injection of glucagon medicine 
include: 
 
Likely 
(10 or more subjects out of 100) 
Not Serious                                      Serious 
Dizziness 
Headache 
Nausea 
Vomiting 
None 
Less Likely 
(Between 3-9 subjects out of 100) 
Not Serious                                      Serious 
Weakness 
Fainting 
Heart Racing 
Sweating 
Thirst 
Vasodilation (widening of the 
blood vessels) 
None 
Rare 
(2 or less subjects out of 100) 
Not Serious                                      Serious 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
Rash 
Itchiness 
Back pain 
Nervousness 
Sore throat 
Loss of sense of taste 
Dry mouth 
Abdominal pain 
Confusion 
Diarrhea 
Indigestion 
Pain 
Fainting 
 
 
Benefits: The subject may not directly benefit from being in this study; however, their 
participation may help to advance automated insulin and glucagon delivery technology. 
 
COSTS:   
Subjects will receive $600 for completion of all study visits.  If subjects withdraw early from the 
study, compensation will be given as follows: $60 for visit 2 and $180 each for visits 3, 4, and 5. 
There is no compensation for the screening visit. If a subject is asked to repeat a study due to 
technical problems, he/she will receive an additional $180.   
 
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 
study. Drs. Jessica Castle, Peter Jacobs and Joseph El Youssef are inventors on patents regarding 
the algorithms. 
 
Data Collection: 
Subject privacy will be protected by using a three-digit identifying number to code study 
documents. Study staff will record data required by the protocol onto the Case Report Forms 
(CRF). Only a subject demographics/enrollment log case report form will be entered into 
REDCAP, a clinical research electronic data application designed to support traditional case 
report form data capture for research studies housed at Oregon Health Science University and 
administered by the Oregon Clinical and Translation Research Institute (OCTRI). The rest of the 
CRFs will be collected on paper or entered into Vision9 software through Prelude Dynamics. 
Investigators and research coordinator will verify that the procedures are conducted according to 
the approved protocol. 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 Android Nexus 5 phone will 
subsequently be entered into the authorized electronic REDCAP Cloud database.  
 
Recording of Data: 
Investigators and staff will record data collected during the clinical trial on the CRF’s. The CRFs 
will include: 
1. Screening form 
2. Dexcom Training Visit 
3. APC training 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
4. Companion training 
5. Day 1 Inpatient Dual-hormone Closed-loop Study Visit  
6. Day 1 Inpatient Insulin Only Closed-loop Study Visit 
7. Day 1 Inpatient Predictive low glucose suspend Study visit 
8. Day 4 Dual-hormone Closed-loop Study Visit  
9. Day 4 Insulin Only Closed-loop Study Visit 
10. Day 4 Predictive low glucose suspend Study visit 
11. Phone Update Form 
12. Adverse Event form 
13. Serious Adverse Event form 
14. 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.  If it is possible, we will 
attempt to recontact participants who already signed a consent and authorization without the 
repository information to get their permission to use their data for future research. However, if 
they cannot be reached for re-consent and it is not possible to re-consent them, we will still use 
their data for future research as outlined in the HIPAA waiver of authorization form. The data to 
be collected includes: 1) glucose sensor data, 2) blood glucose data, 3) insulin and glucagon data, 
4) physical activity data, and 5) food and exercise data. All data, except for blood glucose, is 
aggregated by the APC 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 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
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 subject. 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 subject experiencing the adverse event, 
a careful assessment of whether the adverse event is related or possibly related to the subject’s 
participation in the study. 
 
Triggers for reporting unanticipated problems are seizure, hospitalization, death or any other 
occurrence considered serious by the PI. If ongoing monitoring of the closed-loop studies reveals 
studies repeatedly being terminated because of unresponsive hyperglycemia or repeated serious 
hypoglycemia (resulting in altered mental status, loss of consciousness, or seizure) believed not 
amenable to revisions in control system parameter tuning, then the study will be discontinued 
immediately. If studies in two subjects are stopped for severe hypoglycemia or severe 
hyperglycemia, then the entire study will be halted. Severe hypoglycemia is defined as an event 
requiring the assistance of another person to administer carbohydrate, glucagon or resuscitative 
actions. Severe hyperglycemia is defined as 1) capillary blood glucose exceeds 400 mg/dl on two 
occasions (120 min or more apart within a 4 hour window), 2) capillary blood glucose exceeds 
400 mg/dl on two occasions more than 120 minutes apart but outside of the 4 hour window and 
during that time, the capillary blood glucose has not fallen below 250 mg/dl, or 3) serum ketones 
are above 1.5 mM at any time. 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. 
 
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 subject 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 subjects or others or serious or continuing noncompliance that might impact the criteria for 
IRB approval. The report will be submitted to the IRB by the principal investigator or study 
coordinator. A summary of all UP's and adverse events, including those that do not meet the 
requirement for RNI, will be submitted with the continuing review. 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 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
(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. 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.   
 
 
Appendix A: Physical Activity Readiness Questionnaire 
 
 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
 
Appendix B: Devices 
Insulet Omnipod insulin management system which includes PDM and Omnipod 
 
 
Dexcom G5 OR G6 Continuous Glucose Monitoring System which includes Sensor and 
Sensor Transmitter 
 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
      
 
 
 
Google Nexus 5 Smart phone 
 
 
 
 
 
 
Contour Next Blood Glucose Meter 
Abbott Precision Xtra Meter 
 
 
 
  
 
  
 
 
 
 
 
 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
 
Zephyrlife BioPatchBiopatch Heart Rate and Accelerometry Monitoring Device 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix C: 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) 
 
 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
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) 
 
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 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
 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)


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
Appendix D: Alert Manager Specifications  
 
Alert 
# 
Activation criteria 
Clearing Criteria 
Notification to subject 
Re-fire 
Time (min) 
Refractory 
Period (min) 
Coordinator 
push 
Physician 
push 
Waiting 
period 
2 
CBG entered ≥ 
75mg/dl with ARD ≥ 
35% AND second 
CBG not entered OR 
CBG entered < 
75mg/dl with AD ≥ 30 
mg/dl AND second 
CBG not entered 
CBG entry for 
calibration. Auto clears 
at second Re-fire 
"Sensor may not be accurate. 
Please calibrate sensor now.” 
10 
0 
After 2st Re-fire 
- 
- 
4 
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. 
 "Blood glucose is below 40 
mg/dl. Please take 30 gm of 
rescue carbohydrates and 
recheck your blood glucose 
level in 15 minutes." 
5 
- 
Immediately 
Immediately 
Waiting 
Period 
ends when 
alarm 13 
is serviced 
OR Clear 
Criteria is 
met 
5 
CBG < 70 mg/dl AND 
alert 5 not active AND 
alert 4 not active 
CBG entry ≥70 clears 
alert. Once rescue Carb 
are entered the waiting 
period starts. 
Alert clears if activation 
of alert 4 is met 
"Blood glucose is below 70 
mg/dl. Please take 15 gm of 
rescue carbohydrates and 
recheck your blood glucose 
level in 15 minutes." 
15 
- 
After 1st Re-fire 
After 2nd Re-
fire 
Waiting 
Period 
ends when 
alarm 13 
is serviced 
OR Clear 
Criteria is 
met 
6 
Sensor glucose < 70 
(no exercise) OR < 85 
mg/dl (exercise) AND 
alert 4 AND alert 5 
AND alert 6 not active 
or refractory & no 
CBG within last 15 
minutes 
CBG check. 
OR sensor ≥85 with 
exercise, ≥70 without 
exercise. 
"Sensor glucose is below 70 
(85) mg/dl. Please perform a 
blood glucose check now." 
15 
60 
After 1st Re-fire 
After 2nd Re-
fire 
- 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
7 
CBG ≥ 300 mg/dl 
AND alert 27 not 
active or refractory 
AND alert 7 not active 
or refractory) 
Ketone check 
"Blood glucose is above 300 
mg/dl. Please check the insulin 
infusion set for leaking or 
detachment and check ketone 
levels now." 
30 
120 
After 1st Re-fire 
After 2nd Re-
fire 
- 
8 
Sensor glucose ≥ 300 
mg/dl for 30 minutes 
within the last 45 
minute period AND 
alert 8 AND alert 7 
AND alert 28 not 
active or refractory 
AND no CBG in last 
30 minutes 
CBG check. 
OR sensor < 300 
"Sensor glucose is over 300 
mg/dl. Please perform a blood 
glucose check now." 
30 
60 
After 1st Re-fire 
After 2nd Re-
fire 
- 
10 
Active SH/DH mode: 
More than 50% of 
meal bolus fails to 
deliver for 4 cycles. 
Pause or PLGS mode: 
if meal bolus fails to 
deliver for 4 cycles. 
Auto clears  
Insulin bolus failed to deliver, 
please contact the study 
physician.  
- 
- 
Immediately 
Immediately 
- 
12 
G6: Last sensor 
calibration > 24 hours 
ago 
G5: Last sensor 
calibration > 12 hours 
ago 
CBG check and 
calibration (auto) 
"Sensor calibration is due. 
Please perform a blood glucose 
check now." 
60 
720 
After 1st Re-fire 
After 2nd Re-
fire 
- 
13 
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 
- 
14 
No connection to the 
Internet or Data for 40 
minutes 
Phone connects to a Wifi 
network or regain cell 
service 
There is no connection of the 
phone to the internet. Please 
move back into cell phone or 
Wifi range.  
40 
- 
- 
- 
- 
17 
Sensor is out of date 
for > 20 minutes AND 
alert 17 AND alert 18 
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 
- 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
AND alert 20 not 
active or refractory 
18 
APC 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 transmitter is no longer 
functional. Please replace it 
immediately." 
- 
120 
- 
- 
- 
19 
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 check your 
sensor site for problems. 
Contact the study coordinator if 
needed." 
20 
- 
After 1st Re-fire 
After 2nd Re-
fire 
- 
20 
APC 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 
functioning. Please replace it 
immediately." 
- 
120 
- 
- 
- 
21 
Basal Insulin Fails to 
Deliver Correct 
amount for 60 minutes 
OR insulin suspend 
required and no 
connection to pump 
Successful Basal INS is 
Delivered  OR insulin is 
successfully suspended 
Insulin communication failure. 
Please move PDM and POD 
closer to Phone  
60 minutes 
If alert fires 
after 
10:59PM, 
refractory lasts 
until 6:59AM. 
No refractory 
other hours of 
the day. 
After 1st Re-fire 
After 2nd Re-
fire 
- 
22 
Glucagon fails to 
deliver for two 
consecutive cycles  
Auto clears , clears if 
glucagon pump starts 
delivering 
Glucagon failed to deliver. 
Please move PDM and POD 
closer to Phone. 
- 
10 
- 
- 
- 
25 
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 
- 
26 
Insulin Delivery ≥ 
35% TDIRadj In last 
hour 
Auto clears  
"Max Insulin Has been 
Exceeded" 
- 
60 
Immediately 
Immediately 
- 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
 
27 
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 
Immediately 
Immediately 
- 
28 
Ketones ≥ 0.6 mmol/L 
User acknowledgement 
“Ketone levels are high. If not 
already done, please change the 
insulin pod. Do not exercise.” 
- 
- 
Immediately 
Immediately 
- 
29 
Insulin 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 
deactivate your current pod, and 
activate a new Insulin pod. 
120 
- 
After 1st Re-fire 
After 2nd Re-
fire 
- 
30 
Glucagon Omnipod 
has less than 10% of 
fluid volume 
remaining 
Pod with greater than 
10% volume is 
connected (i.e. pod is 
changed) 
Your Glucagon Pod is low. 
Please deactivate your current 
pod, and activate a new 
Glucagon pod. 
120 
- 
After 1st Re-fire 
After 2nd Re-
fire 
- 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
Appendix E: Visual Analog Scale (VAS) for Injection Site Discomfort 
 
Investigative Site Instructions: The subject should complete the VAS for Injection Site 
Discomfort at discharge on Day 1 and after removal of the glucagon Omnipod on Day 4 for each 
study visit. The subject completes the VAS by drawing a single vertical line through the scale 
corresponding to the perceived intensity (severity) of discomfort according to the instructions 
below. The goal is for the subject to report the amount of discomfort, if any, remaining at each 
time point, as opposed to reporting the transient pain associated with needle insertion. 
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: Ignoring any pain from insertion of the Omnipod, please draw a single 
vertical line through the scale below that corresponds to the intensity (severity) of any discomfort 
you have felt at the glucagon Omnipod insertion site. 
Discomfort could include stinging, burning, tingling, throbbing or pain. The further to the right 
you make your vertical mark, indicates the more intense discomfort you are feeling. 
You should normally draw a straight line across the scale to indicate your current level of 
discomfort. However, if you are currently feeling 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 
 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
Injection Site Discomfort Description and Duration Questionnaire 
Study Personnel Instructions:  Question 1a should be should be completed by the subject at 
discharge on Day 1 and after removal of the glucagon Omnipod on Day 4. Any subject reporting 
discomfort other than “none,” should complete question 1b. Any subject reporting duration of 
discomfort of “at least 10 minutes” should complete follow-up question 1c at the end of the study 
visit (i.e., at 180±5 minutes post-injection). The goal is for the subject to report the qualitative 
nature and duration of discomfort, if any, associated with injection of study drug, ignoring any 
transient pain associated with needle insertion. 
Note: If a subject is unable to physically complete the questionnaire, the subject will provide 
verbal responses, which will be recorded on the questionnaire by study staff. Documentation will 
be provided on each completed questionnaire as to who completed the form. 
Subject Instructions: Please answer question 1a and, if applicable to you, questions 1b and 1c. In 
answering these questions, you should ignore any pain from insertion of the needle. 
1a. How would you describe any discomfort you have had at the glucagon Omnipod infusion site 
since it was inserted? (Check all that apply): 
______None (Please ignore question 1b.) 
______Pain (e.g., throbbing, soreness, muscle ache) 
______Itching 
______Tingling, twitching or numbness 
______Irritation (e.g., burning, stinging) 
 
Other or additional comments:_____________________________________________________ 
 
1b. About how long did the discomfort last each time? (Check one): 
_____Less than 1 minute 
_____1-2 minutes 
_____3-5 minutes 
_____6-9 minutes 
_____at least 10 minutes (Please complete question 1c.) 
1c. In total, how long did the discomfort last each time? (Please enter a number below): 
 
_____ Minutes 
 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
Appendix F: Draize Scale 
 
 Study Personnel Instructions:  The modified Draize Scale as shown in the table below 
will be used for physical examination/rating of abnormalities at the glucagon 
injection site. 
 The injection site should be examined for formation of both erythema and edema and 
results recorded in the Case Report Form. Evaluations of the injection site should be 
performed at the end of Day 4 upon removal of the glucagon Omnipod. 
Erythema Formation 
Edema Formation 
Description 
Score 
Description 
Score 
No erythema 
0 
No edema 
0 
Very slight erythema 
Barely perceptible 
1 
Very slight edema 
Barely perceptible 
1 
Well defined 
erythema 
2 
Well defined edema 
2 
Moderate erythema 
3 
Moderate edema 
Raised approx. 1 mm 
3 
Severe erythema 
Beet redness to slight 
eschar formation 
4 
Severe edema 
Raised more than 1 mm 
and beyond exposure area 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB 17225 Protocol v12  
 
Date: April 17, 2019 
 
 
 
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