A Randomized, Four-way, Cross-over Outpatient Study to Assess the Efficacy of a Dual-hormone Versus Insulin Alone Closed-loop System With Exercise Detection vs a Predictive Low Glucose Suspend System vs Current Care
Phase: NA
Conditions: Type 1 Diabetes
Sponsor: Oregon Health and Science University

 
 
 
 
 
 
 
PROTOCOL TITLE: A randomized, four-way, cross-over outpatient study to assess the 
efficacy of a dual-hormone versus insulin alone closed-loop system with exercise detection 
vs a predictive low glucose suspend system vs current care 
 
NCT:02862730 
Date: 2/1/17 

PROTOCOL TITLE: A randomized, four-way, cross-over outpatient study to assess the 
efficacy of a dual-hormone versus insulin alone closed-loop system with exercise detection 
vs a predictive low glucose suspend system vs current care 
 
 
STUDY SITE: 
Oregon Health & Science University 
3181 SW Sam Jackson Park Rd 
Portland, OR 97239 
 
FUNDING: 
National Institute of Health 
PRINCIPAL INVESTIGATORS: 
Jessica R. Castle MD; Peter Jacobs PhD 
CO-INVESTIGATORS: 
Joseph El Youssef MBBS 
Leah Wilson MD 
Kathy Hanavan RN MSN ANP-BC, BC-ADM 
Elena Varlamov MD 
 
Background: 
The risk of hypoglycemia in type 1 diabetes increases considerably during exercise. This risk 
stems from increased glucose utilization during exercise as well as increased insulin sensitivity 
both during and after exercise. As a result, hypoglycemia is a potential barrier to an active 
lifestyle for individuals with type 1 diabetes. 
 
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 (MiniMed 530G with Enlite®). Already, the benefit of improved glycemic 
control compared to current open-loop pump therapy has been demonstrated in several trials. Our 
group has shown that a dual-hormone system effectively manages blood glucose in a clinic 
setting with great progress using glucagon to reduce hypoglycemic episodes (1-3). Clinical home 
studies using insulin only closed-loop systems have demonstrated improved overall glucose 
control without increasing the risk of hypoglycemia when compared to standard open-loop 
therapy (4, 5). Haidar recently completed a clinical study comparing bi- and single-hormone 
closed-loop systems and standard open-loop therapy. Their group found no difference in the 
proportion of time spent in the target glucose range with single vs double hormone closed-loop 
systems, however the number of hypoglycemic events was reduced using a dual-hormone 
approach to manage blood glucose (6). Danne has shown that sensor-augmented pump therapy 
with low glucose suspend reduces the frequency of hypoglycemia without compromising safety 
(7). The purpose of this study will be to further delineate the most effective approach towards 
engineering closed-loop systems. 

Our most recent inpatient study, under review for publication, shows that adjusting insulin and 
glucagon delivery during closed-loop treatment after exercise announcement effectively reduces 
mean time glucose is below 70 mg/dl when compared to closed-loop control without 
adjustments. In order to prepare for a future home study, the ability to detect and grade physical 
activity to appropriately adjust system parameters is vital in helping to prevent exercise-induced 
hypoglycemia in the home setting. 
 
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. The 
first two of these modes use a Fading Memory Proportional Derivative (FMPD) model for dosing 
either insulin only or insulin and glucagon within an automated closed-loop system with insulin 
and glucagon delivery adjusting every 5 minutes based on sensor glucose data. The last         
mode delivers insulin using the subject’s own basal profile(s) with a predictive low glucose 
suspend feature. The FMPD closed-loop algorithms include an exercise detection component that 
includes a reduction in insulin delivery upon exercise detection, with the dual-hormone system 
also increasing glucagon delivery upon detection. 3-axis accelerometry data as well as heart rate 
data will be collected using the Zephyrlife BioPatch. This data will be used in both FMPD 
systems to detect exercise and automatically trigger algorithm adjustments to reduce exercise- 
related hypoglycemia during and after exercise in individuals with type 1 diabetes. A Zephyr 
BioPatch will transmit heart rate and accelerometry values to the APC for the purposes of 
exercise detection while in the predictive low glucose suspend mode, but exercise detection will 
not trigger any hormone delivery changes while in this mode. 
 
Specific Objectives: 
Primary Objectives: 
• To determine whether a dual hormone AP with an exercise detection algorithm out- 
peforms a single hormone AP using exercise detection, a low glucose suspend algorithm 
and current care as measured by frequency of hypoglycemia across all four arms in free- 
living conditions. 
• To determine whether a dual hormone AP with an exercise detection algorithm out- 
peforms a single hormone AP using exercise detection, a low glucose suspend algorithm 
and current care as measured by percent of time with sensed glucose between 70 – 180 
mg/dl across all four arms. 
 
Secondary Objective: 
• To determine whether a dual hormone AP with an exercise detection algorithm out- 
peforms a single hormone AP using exercise detection, a low glucose suspend algorithm 
and current care as measured by other glucose metrics across all four arms. 
 
 
Study Hypothesis: 

Our hypothesis is that use of a dual-hormone artificial pancreas that automatically detects 
exercise and adjusts dosing based on the exercise will reduce exercise-induced hypoglycemia 
compared with an insulin-only AP, a low-glucose suspend AP and current care. 
Endpoints 
Primary Endpoints: 
1. Percent of time in hypoglycemia (CGM <70 mg/dL): across four arms 
o Period: entire study 
o Period: start of exercise in clinic until next meal 
 
2. Percent of time in euglycemia (CGM 70-180 mg/dL): across four arms 
o Period: entire study 
o Period: start of exercise in clinic until next meal 
 
Secondary Endpoints: (Time duration: Entire study) 
1. Mean sensed glucose 
2. Number of carbohydrate treatments 
3. Percent of time with sensed glucose <50 mg/dl 
4. Percent of time with sensed glucose >180 mg/dl 
5. Number of events with capillary blood glucose (CBG) <70 mg/dl 
6. Number of events with capillary blood glucose (CBG) <50 mg/dl 
7. Total amount of insulin delivered (in units/kg) 
8. Total amount of glucagon delivered (in mcg/kg) 
 
 
Study Type 
This is a single center, randomized, four treatment, crossover trial designed to compare the 
glucose control resulting from the use of (1) a dual-hormone closed-loop system with an exercise 
detection algorithm that adjusts insulin and glucagon dosing, (2) a single-hormone closed-loop 
system with an exercise detection algorithm that adjusts insulin dosing, (3) a predictive low 
glucose suspend system and (4) current care using the subject’s own pump. 
Study Population 
Study population will be adults with type 1 diabetes, ages 21 – 45 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. Twenty one subjects 
will be recruited to participate in studies. 
 
Power Analysis 
We estimate that 21 subjects will allow us to detect an approximately 60% reduction from a 
mean of 11% of time in hypoglycemia during the four hours between onset of exercise and the 
next meal. We simulated data for three treatment conditions in two steps: First, we used a 

random draw from a binomial distribution for the probability of having any hypoglycemic event; 
then, given that the event occurred, we generated total time in hypoglycemia with uniform 
probability from a minimum of five to a maximum of 90 minutes in multiples of five, which 
mimics the continuous glucose monitoring measurements. These simulated numbers allowed us 
to model time in hypoglycemia as a proportion of the total four hours of observation using a 
generalized linear model with a normal distribution and log link to constrain the estimates 
between 0 and 1. We used generalized estimating equations (GEE) with an exchangeable 
correlation structure and robust variance estimators to model the repeated observations on the 
same individual; we did not specify a correlation in the data generating phase, but partially 
randomized the data to induce a mild positive correlation. The assumptions for probability of any 
hypoglycemic event, minutes in hypoglycemia, percent of time in hypoglycemia, and correlation 
between repeated observations were informed by our previous study as well as other published 
work(6, 8). We repeated this simulation 500 times. We found a significant reduction in 80% of 
simulations at the 0.05 level of significance. 
 
Protocol Summary: 
Subjects will undergo four approximately 84 hour studies. The first day of each study will be an 
approximately 12 hour inpatient visit to include activities of daily living and an exercise period 
with 2 days spent as an outpatient. The subject will come back to the research center on the 
fourth day to complete another approximately 12 hour inpatient visit to include activities of daily 
living and an exercise period followed by removal of all devices. In randomized order, subjects 
will have glucose controlled using the following systems: 1) dual-hormone closed-loop system, 
2) insulin only closed-loop system, 3) predictive low glucose suspend system and 4) a current 
care arm. Both of the closed-loop system algorithms have an exercise detection algorithm that 
uses inputs from a heart rate monitor and accelerometer, the Zephyrlife BioPatch. After exercise 
detection, insulin is turned off for the first 30 minutes, the total insulin infusion rate is adjusted 
by an exercise multiplier, and for the dual-hormone system, the target glucose for glucagon is 
increased along with the maximum dose of glucagon allowed. The predictive low glucose 
suspend system will utilize the patient’s optimized basal rates, correction factor, and carb ratio. 
The patient will bolus for meals and hyperglycemia as usual under PLGS, but will have the 
additional safety net of the pump suspending insulin when it predicts a hypoglycemic event. The 
Dexcom CGM system will be used for all four arms. The Tandem t:slim pumps will be used for 
three of the intervention visits, the dual and single hormone arms and the predictive low glucose 
suspend arm. For the current care arm, subjects will use their own insulin and insulin pump. 
 
Subjects will arrive at the CTRC at ~7am at the start of intervention visits. Subjects will eat 
breakfast, lunch and dinner in the research center. Subjects will eat breakfast at ~8:30am. After 
breakfast, subjects will complete activities of daily living (sitting on a chair, lying on a bed, 
washing dishes, sweeping the floor, etc.). Subjects will eat lunch at ~12pm. Subjects will 
exercise for ~45 minutes on a treadmill around 2pm. Subjects will eat dinner at ~6pm and be 
discharged. See Figure 1 below. The subject will then go home for Day 2 and Day 3 and return 
on Day 4 to complete another 12 hour inpatient visit with the schedule of activities identical to 
Day 1. 

Figure 1: Schematic of Inpatient Study Flow 
 
 
 
During each study, the subject will wear one subcutaneous DexcomTM G4 Share or G5 
continuous glucose monitoring (CGM) system. (For the current care visit, the subject will use a 
blinded Dexcom G4 Share receiver or G5). 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 from the Dexcom 
Share sensor receiver or G5 transmitter to the Nexus 5 master controller every five minutes. The 
controller for the dual and single hormone and predictive low glucose suspend modes is a 
Google Nexus 5 phone. The Dexcom Share sensor receiver or G5 transmitter and smart phone 
will communicate wirelessly via Bluetooth Low Energy (BTLE). The smart phone will 
wirelessly communicate via BTLE to either a single t:slim pump for insulin delivery or two 
t:slim pumps, one used for automated insulin delivery and one for automated glucagon delivery. 
 
A study investigator or nurse practitioner will be present for study start-up, be on campus and 
immediately available via page during both exercise periods completed at OHSU. At all other 
times, the study investigator will be on call. Other personnel on site during the inpatient portion 
of the intervention visits will be a registered nurse and a study coordinator. The study 
investigators also 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. 
 
Subject Criteria 
Inclusion Criteria: 
1. Diagnosis of type 1 diabetes mellitus for at least 1 year. 
2. Male or female subjects 21 to 45 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) 
4. Current use of an insulin pump. 
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 with subject. 

6. Lives within 20 miles of OHSU. 
7.  A1C<10% 
8. Willingness to follow all study procedures, including attending all clinic visits. 
9. 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 report 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 or equal to 34%. 
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 (included in Appendix). Subjects will be 
excluded for four or more R responses. 
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. Allergy to glucagon. 
20. Insulin resistance requiring more than 200 units per day. 

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). See Appendix B. 
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 the Juvenile Diabetes Research Foundation staff 
based in Portland and 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 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 21 subjects. Up to four 
subjects will be replaced if needed, with a total enrollment of up to 25 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 that is related to patient safety as judged by the investigator. 
4. Substantial and repeated non-compliance with trial procedures. 
5. Pregnancy. 
6. Intention of becoming pregnant. 
7. Persistent nausea and/or vomiting thought to be secondary to glucagon. 
8. Seizure or unconsciousness associated with hypoglycemia. 
 
Visit Procedures 
Screening (Visit 1) 
Screening will take place within 12 weeks prior to the 2 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. 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. 
Upon arrival and prior to any procedures, the consent form will be signed. A copy of the 
consent/authorization form will be given to the subject. 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. 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 
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 
performed. A study investigator will assess inclusion/exclusion criteria and review the subject’s 
medical record for clarification as needed. 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 be delayed 
by approximately 1 hour for CBG values of <80 mg/dL. 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. 
 
Two Week Run-in Period (Visit 2) 
The two week run-in period will take place within 6 weeks prior to the first 84 hour treatment 
visit (Visit 3). 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. This 
test must be negative before further participation is allowed. Subjects will receive training during 
this visit on the following: the t:slim pump and the Dexcom G4 or G5 CGM system. 
 
A certified t:slim pump trainer will instruct each subject on how to use the Tandem t:slim insulin 
pump, adjust their basal, give meal boluses and corrections and change out the cartridges and 
infusion sets. Subjects will also be shown how to connect the t:slim pump to the Nexus 5 smart 
phone via Bluetooth. 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 t:slim pump 
and changing out the infusion set. If the subject experiences difficulties using the t:slim pump 
during this two week run in period, study staff will be available to educate and support this 
transition by phone. Subjects will switch back to using his/her own insulin pump at the end of the 
two week run in period. Subjects may be asked to bring back devices after the two week run-in 
period is complete. 
 
Subjects will receive training on how to use and calibrate the Dexcom G4 Share or G5 CGM 
system including changing out the sensor every 7 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. The Dexcom G4 Share or G5 CGM system will be calibrated at home according to  
the manufacturer’s directions. Subjects will be clearly instructed to use capillary glucose levels, 
not sensed glucose values, for the purpose of managing their diabetes at home. Subjects will be 
given a Dexcom G4 Share receiver and transmitter or G5 transmitter and sensors 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 Share sensor receiver or G5. Subjects will be instructed 
to completely avoid acetaminophen for all periods when wearing the Dexcom CGM system. 
Additionally, subjects may be asked to wear an ActiGraph wGT3X-BT or ActiGraph GT9X 
activity watch. 
 
84 hour Treatment Visits (Visits 3-6) 
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 7 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. 
 
A capillary blood glucose (CBG) will be obtained and measured by a Contour Next glucose 
meter and recorded. A new meter will be used for each subject. 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 rescheduled 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, 3) the insulin only mode with 
predictive low glucose suspend or 4) current care using subject’s own insulin pump. The first 12 
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 the fourth day to one of these locations for 
the last 12 hours of the visit. A code cart is on site at all locations and a code team is available by 
page at all times. . 
 
Inpatient Visit on Day 1 (12 hours) 
IV placement for dual-hormone insulin and glucagon mode study visit only 
An 18-22 gauge IV catheter will be placed for the inpatient portion of one closed-loop 
intervention visit (dual-hormone closed-loop studies). The IV cathether will be placed at least 
one hour before noon. Starting at noon, blood samples for pharmacokinetic analysis of insulin 
and glucagon levels will be collected every 15 minutes until discharge from the unit at 7pm. 
Normal saline will be infused at a rate of ~25 ml/hr to keep the IV catheter patent. It is possible 
that the IV catheter will not remain patent for the entire 7 hours, it which case another will be 
placed. In a blood-sparing technique, venous blood will be withdrawn from the IV catheter using 
a double stop-cock method. One side of the stop-cock is used to pull ~ 5 mL of saline-blood 
admixture. The other side of the stop-cock is used to pull approximately 2 ml for collection with 
the saline-blood admixture re-infused after collection. Heat will be applied to an IV catheter site 
as needed to facilitate blood withdrawal. There will be up to 28 samples drawn during the course 
of the study with approximately 2 mL per draw, for a total of ~56 ml of blood per study. The 
visit requiring an IV will occur at the OCTRI inpatient research unit. 
 
A t:slim infusion pump (Tandem® Diabetes Care) will be filled with aspart insulin for three of 
the four studies (excluding the current care arm), but the dual-hormone study will also have a 
t:slim pump filled with glucagon. The subjects will be instructed to remove his/her own infusion 
set/pump once study insulin is being delivered. Each pump will be labeled with a sticker 
indicating either "insulin" or "glucagon" for clear identification. A glucagon hypokit (GlucaGen, 
Novo-Nordisk) will be reconstituted with sterile water to a concentration of 1.0 mg/mL. The 
pumps will be primed and infusion sets inserted into the skin of the subject’s abdomen or flank 
as directed by the manufacturer. Glucagon will be replaced every 24 hours. 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 may be asked to wear an ActiGraph wGT3X-BT or ActiGraph GT9X activity watch. 
The ActiGraph will be used in addition to the Zephyr to collect heart rate and activity data. The 
Actigraph will not be connected to the APC system. See Figure 2 below for a diagram of the 
system design. 
 
 
Figure 2: Closed-loop Study Design 
 
 
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 an 
ample supply of Contour Next BG strips as well as supplies to change the insulin and/or 
glucagon reservoir. The study investigator will then depart the subject’s room at the research 
center but remain on call. 
 
During the 12 hour inpatient visit, study staff will complete a training with each subject and 
his/her companion on using the Zephyr BioPatch heart rate and accelerometer and how to use the 
Nexus 5 controller user interface which includes: entering meals, carb treatments, blood glucose 
values and ketone levels, addressing alarms, troubleshooting the devices connection to the phone 
via Bluetooth, and pausing the study. The subject will need to demonstrate competency in 
operating the system as well as having emergency contact numbers available before study staff 
leave the room. Subjects will also complete training on the proper reconstitution of the GlucaGen 
hypokit. 

 
A study coordinator will be available at all times for the dual and single hormone and predictive 
low glucose suspend visits with the ability to monitor the APC remotely via a cloud system via 
the web in the event of any issues. The APC will generate alarms on the smartphone as required. 
If the subject does not appropriately respond to the alarm in the alotted timeframe, the 
coordinator will be alerted (see Appendix D). At that time, the coordinator will pull up the web- 
based monitoring system. An investigator will be assigned to serve as a back-up to the 
coordinator, and will also be available on call at all times during these three visits. 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. 
 
During the dual and single hormone and predictive low glucose suspend visits, sensed glucose 
data will be wirelessly transmitted via BTLE from the Dexcom Share sensor receiver or G5 
transmitter to the Google Nexus 5 phone every five minutes. The algorithm will run on the 
Google Nexus 5 phone (predictive low glucose suspend, insulin only closed-loop or insulin and 
glucagon closed-loop). The smart phone will wirelessly communicate via BTLE to a t:slim pump 
to drive insulin delivery, and in the case of the dual-hormone closed-loop system, will also 
communicate with a second t:slim pump for automated glucagon delivery. 
 
During normal operation, the sensor will be calibrated approximately every 12 hours.  If at any 
time that 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. 
 
In order to ensure safety and to assess sensor accuracy, the subject will be asked to check their 
blood glucose four times during the day (typically before meals and at bedtime). The subject will 
be able to check his/her capillary blood glucose more than 4 times a day if they feel they need to. 
Subjects will also be asked to check capillary blood glucose immediately before exercise and 
when exercise is completed. If the subject’s blood glucose is < 70 mg/dl or is experiencing 
symptoms of hypoglycemia, he/she will be instructed to treat with 15-20 grams of carbohydrates 
and repeatedly check blood glucose every 15 minutes until greater than 70 mg/dl. Fruit juice 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. 
 
All alarms, including if sensor glucose is <70 mg/dL without exercise detection, will be populated 
on the smartphone. If the subject does not appropriately respond to the alarm in the alotted 
timeframe, the coordinator will be alerted (see Appendix D). At that time, the coordinator        
will pull up the web-based monitoring system. A study coordinator will be available at all times 
for the entire duration the subject is on the closed-loop system. An investigator will be assigned 
to serve as a back-up to the coordinator, and will also be available on call at all times during the 
closed-loop intervention visits. The study investigator and technician may intervene with a 
telephone call or a personal visit at any time. 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 every 10 minutes. 
Cloud coordinates will be pushed with a known, fixed offset to allow for scrambling. 
 
Subjects will eat a normal breakfast at ~8:30am after admission. Subjects will complete activities 
of daily living. These activities may include: 
1) sitting on a chair or lying on a bed, 
2) washing dishes or folding laundry, 
3) sweeping the floor or vacuuming, 
4) organizing a room or adjusting furniture in a room, 
5) scrubbing the carpet or the walls and/or 
6) going up and down flights of stairs. 
 
Each activity will be performed between 5-15 minutes. Subjects will perform the activities in the 
OCTRI inpatient unit, Harold Schnitzer Diabetes Health Center or Medicine Specialities clinic or 
at the Point of Care Lab in the Biomedical Engineering department at the CHH. 
 
Subjects will eat lunch at ~12pm. Subjects will warm-up for 5 minutes then exercise for 
approximately 45 minutes on a treadmill at ~2pm. Subjects will exercise at the CTRC. A code 
cart is 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. 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. 

 
Subjects will eat dinner at around 6pm. After dinner, the subject will be discharged from the 
inpatient unit to continue the study at home. 
 
During normal operation, the sensor will be calibrated approximately every 12 hours. The sensor 
will also be recalibrated 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 is greater 
than or equal to 75 mg/dl or (2) when a sensor is more than 30 mg/dl different than a CBG when 
the CBG is less than 75 mg/dl. Subjects will be advised not to calibrate if his/her glucose is  
rising or falling rapidly (greater than 2 mg/dl/min) or after administering oral carbohydrates. 
Additional calibrations may be ordered at the discretion of the investigator on call. 
 
For subject safety, if a sensor value is not available or communication with the insulin pump is 
lost for more than 20 minutes, the insulin t:slim pump will begin insulin delivery according to a 
pre-set basal profile(s) inputted for the subject at study start. 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 suspension time is 2 
hours. Prediction of sensor glucose is based on linear regression of the prior ten minutes of 
sensor glucose data. When communication with the pump or sensor is restored, system will 
automatically resume, updating the IOB accordingly. 
 
We are aware that there is a risk of true hypoglycemia occurring in the periods of time between 
blood glucose checks. For this reason, if the sensed glucose values fall below 70 mg/dl, the 
system will prompt the subject to obtain a capillary blood glucose sample. Daytime glucose 
target is 115 mg/dl (nominal) with nighttime target increased to 140 mg/dl (nominal) to account 
for sensor drift. 
 
Meals will be announced to the controller. For each meal during the inpatient study, 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 approximately 60% (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 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. 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 
(9)  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. 
 
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. 
 
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. 
 
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 excercising. If the participant acknowledges 
this and says “Yes”, the AP will adjust the dosing. If the participant says “No”, this is 
considered a false alarm because the algorithm has detected exercise, but the participant was not 
actually exercising. Because these false alarms 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 alarm 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. 
 
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 
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 when the participants’ glucose levels are in the range 
of 70-140 mg/dl and if sensor glucose is predicted to fall below 90 mg/dl within thirty minutes. 
The predictive suspend feature will deactivate within the range of 70-140 mg/dl if sensor glucose 
is predicted to rise above 120 mg/dl within thirty minutes. If sensor glucose falls below 70 mg/dl, 
insulin delivery will remain suspended. 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 hours of 7am-11pm 

(daytime), maximum time of suspension is 120 minutes within any 150 minute window. During 
the hours of 11pm-7am (nighttime), a maximum of 180 minutes of suspension time is allowed. 
During the predictive 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 the four arms. 
 
The algorithm will push data up to a cloud server for that can be monitored remotely every 5 
minutes for three visits, dual and single hormone and predictive low glucose suspend. 
 
Current Care Arm Visit (1 Visit) 
The study procedures for this visit are exactly the same as stated in the above protocol with the 
following exceptions: 1) the closed-loop system will not be used to manage blood glucose, 2) 
subjects will use their own insulin pump and insulin, 3) subjects will use his/her own sensor, if 
they typically use one, 4) subjects will wear a Dexcom G4 Share provided by the study with a 
blinded receiver or G5 with blinded glucose values, and 5) studies will not be remote monitored. 
The subject will continue to sample capillary blood glucose as stated above, but they will be able 
to check at other times if they feel they need to. The subject’s blood glucose will be managed 
using insulin pump therapy on the subject’s own insulin pump, contacting his/her provider with 
any questions or concerns. Subjects will wear the Zephyr Biopatch heart rate monitor for the 
duration of the study which will be transmitting data to the Nexus 5 smart phone controller. The 
subject’s insulin pump will be downloaded after the current care arm visit. Subjects will be given 
a glucose and hypoglycemia reporting diary to complete during the visit. For subjects randomized 
to complete the current care arm as his/her last visit, the subject will be asked to                     
come in to the Diabetes Health center for one additional visit in order to download the full data 
set from his/her pump. 
 
Discharge from inpatient unit 
At the completion of the inpatient visit, subjects will be discharged from the unit. Capillary   
blood glucose will be measured with two consecutive blood glucose measurements at least 15 
minutes apart prior to discharge. Subjects will be given enough supplies to continue running the 
study while at home for 2 days. All IV catheters will be removed before discharge. Subjects will 
be given an exercise diary to record the specifics of his/her exercise on Day 3 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 Day 4. 
 
We are aware that there is a risk of severe hypoglycemia while the subjects are at home. The 
system will alarm 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 20 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 tslim pump 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 tslim insulin pump while in pause mode. When the error is resolved, the 
participant can exit pause mode and the closed loop system can be resumed. For subject safety, 
when the system resumes normal insulin delivery after being in pause mode, the system will not 
allow any boluses to be entered into the phone controller for 15 minutes so the APC can get the 
bolus history from the t:slim insulin pump. 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 
infusion sets/cartridges for 2 days of closed-loop treatment at home as well as back up supplies. 
Subjects will continue to change out the glucagon every 24 hours. Whenever possible, subjects 
will be asked to have a second person verify the identity of the insulin or glucagon pump before 
changing out the cartridge/infusion set. 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 system 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. 
 
Inpatient Visit on Day 4 (12 hours) 
On the fourth day, subjects will return to the OCTRI inpatient clinic, the Harold Schnitzer 
Diabetes Health Center or the Medicine Specialties clinic at 7am. The procedures for the second 
inpatient visit on Day 4 are exactly the same as those on Day 1 with two exceptions: 1) the 
closed loop system will already be in progress, and 2) there will not be an IV placed during the 
dual-hormone closed loop study. 
 
After completion of the visit, the single or dual-hormone closed-loop, predictive low glucose 
suspend system 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, infusion sets and Dexcom sensor will be removed from 
the subject. The infusion sites and 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 
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. 
 
If multiple subjects have inpatient visits on the same day, the times for admission, meals, 
exercise, daily activities and discharge will be moved ahead approximately one hour for the 
second subject. The timing of all procedures will remain consistent for all four visits for each 
subject. 
 
Hypoglycemia Treatment Guidelines 
• 
CBG < 70 mg/dl 
o Give 15 grams of oral carbohydrate. 
o Verify that insulin pump is turned off. 
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 pump is turned off. 
o Further management per bedside 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 insulin pump for malfunction. This would include checking for insulin leaks, 
making sure infusion site is securely adhered to skin, and for closed-loop studies, making sure 
there are no error messages on the phone running the algorithm. 
 
If either the sensor or 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 for 
two hours, the on call study investigator will instruct the subject to administer a correction 
insulin dosage by injection. 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. 
 
Cleaning and Disinfecting 
All devices will be cleaned and disinfected between subjects. The smart phone, Dexcom G4 
Share receiver and transmitter or G5 transmitter, heart rate monitors and t:slim pumps 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. 
Technicians will dispose of gloves as biohazard waste and wash their hands immediately after 
completing disinfection. After disinfection, when the units are completely dry, they will be 
placed in a sealed bag labeled with the cleaning method, date and initials of technician that 
performed the disinfection. 

 
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 (60 min or more apart within a 4 hour window), 3) capillary 
blood glucose exceeds 400 mg/dl on two occasions more than 60 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 4) serum ketones are above 1.5 mM at any time. 
 
 
Statistical methods 
Primary endpoint 
The primary study endpoints are percent of time with sensed glucose < 70 mg/dl and percent of 
time with glucose sensor in target range of 70-180 mg/dl. The hypothesis to be tested is the dual- 
hormone closed-loop system with exercise detection reduces hypoglycemia and increases time 
spent in target range as compared to an insulin only closed-loop system, a predictive low glucose 
suspend system or current care. Data will be analyzed using generalized estimating equations, 
which takes into account correlated data and repeated measures. 
 
Secondary endpoints 
Secondary endpoints will be analyzed using generalized estimating equations. 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 The single and dual-hormone mode 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 for 
these studies, a capillary blood glucose check will be required A study investigator will be on 
call at all times. Though glucagon has been shown to be effective in avoiding hypoglycemia, it 
can sometimes cause nausea or vomiting when given in high doses, but is unlikely in the low 
doses that will be delivered under this protocol. 
 
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 or glucagon, 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 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 $900 for completion of all study visits. If subjects withdraw early from the 
study, compensation will be given as follows: $60 for visit 2 and $210 each for visits 3, 4, 5 and 
6. There is no compensation for the screening visit. If a subject is asked to repeat a study due to 
technical problems, yhe/she will receive an additional $210. 
 
Monitoring Entity: 
This investigation will be monitored by the principal investigators, Jessica Castle, MD and Peter 
Jacobs, PhD. Drs. Jacobs and Castle have no commercial interest in any of the companies which 
manufacture any of the devices used in this study. Dr. Castle is an inventor 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). Case report forms (CRF) for this study 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). 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. Original, completed 
CRF’s will be kept with the PI in a designated repository. All data from CRF’s will subsequently 
be entered into the authorized electronic REDCAP database. 
 
Recording of Data: 
Investigators and staff will record data collected during the clinical trial on the CRF’s. Case 
report forms (CRF) for this study will be entered into REDCAP, a clinical research electronic 
data repository housed at Oregon Health Science University and administered by the Oregon 
Clinical and Translation Research Institute (OCTRI). The REDCAP CRFs will include: 
Screening form 
Two Hour Run-in and Training Visit 
APC Verification form 

Day 1 Inpatient Dual-hormone Closed-loop Study Visit 
Day 1 Inpatient Insulin Only Closed-loop Study Visit 
Day 1 Inpatient Predictive low glucose suspend Study visit 
Day 1 Inpatient Current Care Visit 
Notes on Outpatient Visits 
Day 4 Inpatient Dual-hormone Closed-loop Study Visit 
Day 4 Inpatient Insulin Only Closed-loop Study Visit 
Day 4 Inpatient Predictive low glucose suspend Study visit 
Day 4 Inpatient Current Care Visit 
Phone Update Form 
Adverse Event form  
Serious Adverse Event form 
Concomitant Medications 
 
The Principal Investigators may authorize other personnel to make entries in the CRF. 
 
Monitoring Procedures: 
 
This protocol is written in accordance with the principles established by the 18th World Medical 
Assembly General Assembly (Helsinki, 1964) and amendments and clarifications adopted by the 
29th (Tokyo, 1975), 35th (Venice, 1983), 41st (Hong Kong, 1989), 48th (Somerset West, South 
Africa, 1996), 52nd (Edinburgh, 2000), 53rd (Washington, 2002), 55th (Tokyo, 2004), 59th 
(Seoul, 2008), and 64th (Brazil, 2013) General Assemblies. The investigator will ensure that the 
study described in this protocol is conducted in full conformance with those principles, the 
protocol, current FDA regulations, ICH Good Clinical Practices (GCP) guidelines, Good 
Laboratory Practices (GLP) guidelines, local ethical and regulatory requirements, including the 
Federal Food, Drug and Cosmetic Act, U.S. applicable Code of Federal Regulations (title 21), 
any IEC requirements relative to clinical studies. 
 
Should a conflict arise, the investigator will follow whichever law or guideline affords the  
greater protection to the individual 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. 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 
(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 with regard to these procedures. Upon 
enrollment, subjects will be assigned with a three-digit code that will be used instead of their 
name, medical record number or other personally identifying information. The key associating 
the code and the subjects personnal identifying information will be restricted to the PI and study 
staff. The key will be kept secure on a restricted OHSU network drive in a limited access folder. 
 
Electronic files for data analysis will contain only the subject code. Access to data or blood 
samples is restricted to study personnel and requires OHSU ID/password authentication. Paper 
files will be stored in locked filing cabinets in restricted access offices at OHSU. Electronic data 
is stored on restricted drives on the OHSU network or stored on encrypted computers as well as 
on the web-accessible REDCap database housed on an OHSU secure server. User passwords will 
be changed every 3 months and a firewall will be enabled at all times. 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 artificial 
pancreas/decision support device or discontinuance of pursuit of marketing approval. At the end 
of the study, an electronic copy of the database will be provided on a CD for long-term storage 
under lock. 

Appendix A: Physical Activity Readiness Questionnaire 
 
 

Appendix B: Devices 
Tandem t:slim pump 
 
 
 
 
 
 
 
 
 
 
Dexcom Share Continuous Glucose Monitoring System which includes Sensor, Sensor 
Receiver and Sensor Transmitter 
 
 
 
 
 
 
Dexcom G5 Continuous Glucose Monitoring System 
 
 
 

 
Google Nexus 5 Smart phone 
 
 
 
 
 
 
 
Custom Engineered Phone/Sensor Receiver Case 
 
 
 

Contour Next EZ Blood Glucose Meter 
Abbott Precision Xtra Meter 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
 
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 
  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) 

 
Appendix D: Alarm Manager Specifications 
 
If an alarm is pushed to a study investigator, it is repeated every 5 minutes until acknowledged. 
 
Alarm 
# 
Description of 
Alarm 
When Alarm is 
Considered 
Serviced 
Instructions for 
Subject 
Alarm 
Refractory 
Period 
(minutes) 
Alarm pushed to 
Study 
Coordinator 
Alarm pushed to 
Study Investigator 
2 
ARD ≥ 35% for BG 
≥ 75 
Calibration 
detected 
Sensor inaccuracy has 
been detected, please 
calibrate sensors with 
most recent blood 
glucose value. 
30 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
3 
Relative difference 
≥ 30 mg/dl if CBG 
entered is below 75 
mg/dl 
Calibration 
detected 
Sensor inaccuracy has 
been detected, please 
calibrate sensors with 
most recent blood 
glucose value. 
30 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
4 
CBG ≤ 40 mg/dl 
NA 
CBG is low. 
Please treat with 30 g 
of carbs and recheck 
CBG in 15 minutes. 
NA 
instantly 
instantly 
5 
CBG < 70 mg/dl 
and Alert 4 is not 
active 
Rescue carb 
treatment 
identified 
Blood glucose less 
than 70 mg/dL, treat 
with 15 g of carbs and 
recheck in 15 min. 
30 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
6 
Sensor < 70 mg/dl 
without exercise 
detection and <85 
mg/dl with exercise 
detection and no BG 
given within 15 
Blood glucose 
value is entered 
Sensor is less than 70 
mg/dL. 
Please check blood 
glucose. 
30 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 

 
minutes and alert 5 
inactive 
7 
CBG >300 mg/dl 
NA 
CBG is greater than 
300 mg/dl. Please 
change the insulin 
infusion and check 
your ketones. 
NA 
instantly 
instantly 
8 
Sensor glucose ≥ 
300 mg/dl and no 
BG given within 30 
minutes and alert 7 
inactive 
Blood glucose 
value is entered 
Sensor is greater than 
300 mg/dl, please 
check and enter blood 
glucose, and check 
insulin pump for 
malfunctions 
30 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
9 
Insulin basal failure 
Autoservices if 
pump 
communication is 
restored 
Insulin pump 
communication issue, 
please check pump 
and contact study 
physician 
20 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
10 
Insulin meal bolus 
failure 
Clears itself either 
after the meal flag 
is older than 
backlog of 15 
minutes or there is 
not a backlog of 
insulin to deliver 
Insulin meal bolus 
failed to deliver, 
please contact the 
study physician. 
20 
If refractory 
period expires 
Coordinator will call 
subject and 
determine issue and 
consult with 
investigator to 
determine if subject 
should give bolus 
open loop. 
11 
Glucagon delivery 
failure 
Autoservices if 
pump 
communication is 
restored 
Glucagon pump 
communication issue, 
please check pump 
and contact study 
physician 
10 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 

 
12 
Sensor calibration 
due 
Calibration 
detected 
Sensor calibration due 
now, please check 
blood glucose and 
calibrate your 
receivers. 
60 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
13 
If Alert 4 or 5 was 
activated, and no 
BG given in recent 
20 minutes 
Blood glucose 
value is entered 
Blood glucose check 
due now. 
20 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
14 
Cloud is not 
updating 
Cloud connection 
restored 
There is no connection 
of the phone to the 
internet. Please move 
back into cell phone or 
Wifi range. 
60 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
15 
User has sent a 
bolus command to 
pump when not in 
"Pause Mode" 
NA 
We have detected that 
you have entered a 
bolus using the pump. 
Please only do this 
when in "Pause 
Mode". 
Do not use the pump 
directly when the AP 
is running. 
NA 
Instantly- 
coordinator will 
call subject and 
determine reason 
for override and 
consult with 
investigator to 
determine if 
safety is a 
concern. 
17 
Sensor out for > 20 
minutes 
Autoservices if 
sensor 
communication is 
restored 
Sensor has not been 
acquired in 20 
minutes, please check 
transmitter. 
20 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
18 
Replace Transmitter 
Once fires, 
disables all sensor 
alarms for 120 
minutes. 
Replace transmitter 
NA 
NA 
NA 

 
19 
Sensor Value is 
Invalid 
Autoservices if 
sensor 
communication is 
restored 
Sensor value is not 
reporting correctly. 
Please check sensor. 
20 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
20 
Replace Sensor 
Once fires, 
disables all sensor 
alarms for 120 
minutes. 
Replace sensor 
NA 
NA 
NA 
21 
Basal insulin 
delivery failure 
Autoservices if a 
successful bolus is 
given 
Insulin basal delivery 
Failure, please contact 
the study physician 
20 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
22 
Glucagon delivery 
failure 
Autoservices if a 
successful bolus is 
given 
Glucagon failed to 
deliver, please contact 
the study physician 
20 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
23 
Insulin change due 
every 72 hours 
User must press 
button to service- 
every 72 hours 
Replace Insulin Fluid 
120 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 
24 
Glucagon change 
due every 24 hours 
User must press 
button to service- 
every 24 hours 
Replace Glucagon 
Fluid 
120 
If refractory 
period expires 
If refractory period 
expires two or more 
times in a row 

 
 
 
References 
 
1. Castle JR, Engle JM, El Youssef J, Massoud RG, Yuen KC, Kagan R, Ward WK. Novel use 
of glucagon in a closed-loop system for prevention of hypoglycemia in type 1 diabetes. 
Diabetes Care 2010 Jun;33(6):1282-1287 
 
2. Jacobs PG, El Youssef J, Castle J, Bakhtiani P, Branigan D, Breen M, Bauer D, Preiser N, 
Leonard G, Stonex T, Ward WK. Automated control of an adaptive bihormonal, dual-sensor 
artificial pancreas and evaluation during inpatient studies. IEEE Trans Biomed Eng 2014 
Oct;61(10):2569-2581 
 
3. Jacobs PG, El Youssef J, Castle JR, Engle JM, Branigan DL, Johnson P, Massoud R, Kamath 
A, Ward WK. Development of a fully automated closed loop artificial pancreas control 
system with dual pump delivery of insulin and glucagon. Conf Proc IEEE Eng Med Biol 
Soc 2011;2011:397-400 
 
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Dunger DB, Heller SR, Amiel SA, Evans ML, Hovorka R. Home use of closed-loop insulin 
delivery for overnight glucose control in adults with type 1 diabetes: A 4-week, multicentre, 
randomised crossover study. Lancet Diabetes Endocrinol 2014 Sep;2(9):701-709 
 
6. Haidar A, Legault L, Messier V, Mitre TM, Leroux C, Rabasa-Lhoret R. Comparison of dual- 
hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin 
pump therapy for glycaemic control in patients with type 1 diabetes: An open-label 
randomised controlled crossover trial. Lancet Diabetes Endocrinol 2015 Jan;3(1):17-26 
 
7. Danne T, Kordonouri O, Holder M, Haberland H, Golembowski S, Remus K, Blasig S, 
Wadien T, Zierow S, Hartmann R, Thomas A. Prevention of hypoglycemia by using low 
glucose suspend function in sensor-augmented pump therapy. Diabetes Technol Ther 2011 
Nov;13(11):1129-1134 
 
8. Diabetes Research in Children Network (DirecNet) Study Group, Tsalikian E, Kollman C, 
Tamborlane WB, Beck RW, Fiallo-Scharer R, Fox L, Janz KF, Ruedy KJ, Wilson D, Xing 
D, Weinzimer SA. Prevention of hypoglycemia during exercise in children with type 1 
diabetes by suspending basal insulin. Diabetes Care 2006 Oct;29(10):2200-2204 

9. Jacobs PG, Resalat N, El Youssef J, Reddy R, Branigan D, Preiser N, Condon J, Castle J. 
Incorporating an exercise detection, grading, and hormone dosing algorithm into the 
artificial pancreas using accelerometry and heart rate. J Diabetes Sci Technol 2015 Oct 
5;9(6):1175-1184