Evaluation of Physician-based Decision Support in Patients With Type 1 Diabetes on Multiple Daily Injection Therapy
Phase: NA
Conditions: Type 1 Diabetes Mellitus, MDI, CGM, Exercise
Sponsor: Oregon Health and Science University

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PROTOCOL TITLE: Evaluation of physician-based decision support in patients with type 
1 diabetes on multiple daily injection therapy 
 
  
STUDY SITE: 
Oregon Health Science University 
3181 SW Sam Jackson Park Rd 
Portland, OR 97639 
 
FUNDING: 
Dexcom 
 
PRINCIPAL INVESTIGATORS: 
Jessica R. Castle MD; Peter Jacobs PhD  
 
CO-INVESTIGATORS:  
Joseph El Youssef MBBS 
Leah Wilson MD 
Roula Zahr MD 
 
Background: 
 
The team at OHSU is developing a smartphone based application to provide decision support for 
patients with type 1 diabetes taking multiple daily injections and using continuous glucose 
monitoring (CGM). This smartphone application, DailyDose, will recommend changes to insulin 
doses to the user, such as adjusting the patient’s insulin to carbohydrate ratio. The goals of this 
study are: 1) to assess the impact of physician-driven insulin setting changes. Data gathered from 
this study will inform how much improvement in time in range can be expected over a 7 day 
period after an appropriate insulin dose change. This information will be used to power a future 
study assessing DailyDose (a decision support tool that incorporates diabetes management 
strategies to minimize hypoglycemia and hyperglycemia, especially after exercise including 
hypoglycemia the night following exercise) and 2) the collection of paired multiple daily 
injection data and CGM data in the context of everyday life and with structured exercise 
sessions. Creation of such a dataset will be extremely valuable for the ongoing development of 
the recommendation algorithms that function within DailyDose.  
 
The recent commercialization of Inpen, which captures short-acting insulin doses, and the 
availablility of GoCaps and Clipsulin, FDA-cleared devices, which capture multiple types of 
insulin doses including from a Lantus Solostar pen, has enabled the conduct of this type of study. 
The availability of devices such as a FitBit or Apple Watch allows for tracking of activity level. 
As a component of this study, subjects will wear the FDA-approved Dexcom G5 or G6 CGM 
system. The CGM values will be accessible via the Dexcom Clarity portal, which will allow 
study investigators to make insulin dose recommendations. Subjects will also wear an 
investigational Dexcom G6 sensor that includes a temperature logger that has been developed by 
Dexcom with the goal of assessing if sensor accuracy can be improved by correcting for changes 
in temperature. (See Appendix D for letter referencing IDE).  
 
 
 
 

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Primary Objective 
 The primary objective is to assess if weekly insulin dose changes by the physician 
increases time in range (Dexcom G5 or G6 CGM 70-180 mg/dL) and decreases time in 
hypoglycemia (Dexcom G5 or G6 CGM <70 mg/dL).  
 
Study Hypothesis: 
 The study hypothesis is that weekly insulin dose changes by the physician will increase 
time in range and decrease time in hypoglycemia.  
 
Endpoints 
Because the main purpose of the study is to refine methods and inform a formal trial, we are 
interested in point estimates (as an indication of feasibility) and within- and between-subjects 
variability in the endpoints listed below.  
 
Primary Endpoints:  
 Time in range (70-180 mg/dl): measured on Days 1-7 as compared to Days 22-28 based 
on the Dexcom G5 or G6 CGM data.  
 Time in hypoglycemia (<70 mg/dl): measured on Days 1-7 as compared to Days 22-28 
based on the Dexcom G5 or G6 CGM data. 
*Note that data from Day 1 and Day 28 will not contain 24 hrs of data. The hours will be 
matched such that if for example if data on Day 1 is available starting at 10 am, data from 
Day 22 will be taken starting at 10 am. Similarly, if data from Day 28 ends at 5 pm, the data 
from Day 7 after 5 pm will be excluded to allow for an equal comparison.  
 
Secondary Endpoints:  
 
Time in significant hypoglycemia (<54 mg/dl): measured on Days 1-7 as compared to 
Days 22-28 based on the Dexcom G5 or G6 CGM data. 
 
Mean glucose measured on Days 1-7 as compared to Days 22-28 based on the Dexcom 
G5 or G6 CGM data. 
 
Standard deviation of glucose measured on Days 1-7 as compared to Days 22-28 based 
on the Dexcom G5 or G6 CGM data. 
 
Additional within-subject time effects in glucose control measures (time in range and 
time in hypoglycemia): daily variation over the 28 days of study; means for work 
compared to non-work days; means for days 15-21 vs 1-7; and in the four hours after 
initiation of exercise.  
 
Sensor accuracy of the investigational Dexcom G6 sensor: mean absolute difference 
when reference capillary blood glucose is ≤75 mg/dL and mean absolute relative 
difference when reference capillary blood glucose is >75 mg/dL. 
 
Completeness of the investigational Dexcom G6 sensor data: Number, length, and timing 
of intervals of missing data. 
 
Sequence effect: Evaluate for a trend in the intervention effect from the first to last 
subject.  
 
 
 
 

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Study Type  
This is a single center randomized prospective study comparing time in range and time in 
hypoglycemia before insulin dosing changes as compared to after three weekly dose adjustments 
made by the study investigator.  
 
Study Population 
Study population will be adults with type 1 diabetes, ages 18 – 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 and efficacy first in the adult population. Twenty 
four subjects will be recruited to participate in studies.   
 
Power Analysis 
A formal power analysis was not conducted. The purpose of this study is to enable an accurate 
power analysis for a subsequent study using DailyDose.  
 
Protocol Summary: 
Subjects will be on study for 28 days.  Sensor glucose, exercise, insulin and meal data will be 
collected during this time. Subjects will wear the Dexcom G5 or G6 and G6 with temperature 
logger CGM systems and a FitBit Ionic (or similar FitBit) or Apple Watch physical activity 
monitor for the entire 28 days. The Dexcom G6 with temperature logger CGM is an 
investigational device (See Appendix D for letter referencing IDE) and will be inserted on Days 
1 and 14. Insulin data will be collected using the InPen for aspart insulin and GoCaps or 
Clipsulin for the long acting insulin. Subjects will complete 2 exercise visits in-clinic, on Days 9 
(window of days 9-14) and 16 (window of days 16-20). Subjects will be asked to exercise an 
additional 4 times while an outpatient: 1) Days 2 or 3, 2) Days 4 or 5, 3) Days 23 or 24 and 4) 
Days 25 or 26.  Subjects will use the T1 DEXI mobile app created by OHSU to capture photos of 
meals and document all hypoglycemia treatments over the 28 day period. These images may be 
fed in later to Bitesnap, an application for food analysis. Subjects will be randomized to aerobic, 
anaerobic or high intensity interval exercise sessions for 30 minutes each. During the in-clinic 
exercise visits, subjects will check capillary blood glucose (CBG) before exercise, every 10 
minutes during exercise, at the end of exercise and every 15 min for an additional 30 min at the 
end of exercise. While at home, subjects will check CBG two times daily and before and after 
exercise, for symptoms of hypoglycemia, and for Dexcom G5 or G6 alarms for sensor <70 
mg/dL and >300 mg/dL. Subjects will use the Inpen dose calculator using Dexcom G5/G6 or 
CBG values to determine aspart insulin doses for meals and correction of hyperglycemia. 
Physicians will review CGM and insulin data every 7 days and make insulin dose 
recommendations that the subject will adjust in the Inpen dose calculator. See Figure 1 below 
for a diagram of the study flow.  
 
 
 
 
 
 
A physician or nurse practitioner will be on campus for all in-clinic exercise sessions. 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.    
 
 
 
 

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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 18 to 50 years of age.  
3. Physically willing and able to perform 30 min of exercise (as determined by the 
investigator after reviewing the subject’s activity level).  
4. Use of multiple daily insulin injections (MDI).   
5. A1C ≥7.0% at the time of screening. 
6. Willingness to follow all study procedures, including attending all clinic visits.  
7. 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. 

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2. Any cardiovascular disease, defined as a clinically significant EKG abnormality at the 
time of screening or any history of: stroke, heart failure, myocardial infarction, angina 
pectoris, or coronary arterial bypass graft or angioplasty. Diagnosis of 2nd or 3rd degree 
heart block or any non-physiological arrhythmia judged by the investigator to be 
exclusionary. 
3. Renal insufficiency (GFR < 60 ml/min, using the MDRD equation as reported by the 
OHSU laboratory). 
4. Liver failure, cirrhosis, or any other liver disease that compromises liver function as 
determined by the investigator.   
5. Hematocrit of less than 36% for men, less than 32% for women. 
6. History of severe hypoglycemia during the past 12 months prior to screening visit or 
hypoglycemia unawareness as judged by the investigator. Subjects will complete a 
hypoglycemia awareness questionnaire.  Subjects will be excluded for four or more R 
responses.  
7. Adrenal insufficiency. 
8. Any active infection. 
9. Known or suspected abuse of alcohol, narcotics, or illicit drugs.  
10. Seizure disorder. 
11. Active foot ulceration. 
12. Peripheral arterial disease. 
13. Major surgical operation within 30 days prior to screening. 
14. Use of an investigational drug within 30 days prior to screening. 
15. Chronic usage of any immunosuppressive medication (such as cyclosporine, 
azathioprine, sirolimus, or tacrolimus). 
16. Bleeding disorder or platelet count below 50,000. 
17. Allergy to aspart or glargine insulin. 
18. Need for uninterrupted treatment of acetaminophen. 
19. Current administration of oral or parenteral corticosteroids. 
20. Any life threatening disease, including malignant neoplasms and medical history of 
malignant neoplasms within the past 5 years prior to screening (except basal and 
squamous cell skin cancer).  
21. Beta blockers or non-dihydropyridine calcium channel blockers. 
22. Current use of any medication intended to lower glucose other than insulin (ex. use of 
liraglutide). 
23. 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).  
24. Any chest discomfort with physical activity, including pain or pressure, or other types of 
discomfort.  
25. Any clinically significant disease or disorder which in the opinion of the Investigator 
may jeopardize the subject’s safety or compliance with the protocol.  

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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, Tuality, Kaiser and 
Legacy to pass along to patients/participants who show interest in the study. Records from 
OHSU Schnitzer Diabetes Clinic patients may be screened to find potential 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 24 subjects.  Up to four 
subjects will be replaced if needed, with a total enrollment of up to 28 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 Day 1 investigational Dexcom G6 sensor 
insertion/exercise visit (Visit 2).  All screening visits will take place at OHSU’s Oregon Clinical 
Translational Research Institute (OCTRI) outpatient clinic, the Biomedical Engineering Point of 
Care (BME POC) Laboratory or at the Harold Schnitzer Diabetes Health Center. 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 at the clinic 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 subject voices understanding of the informed consent 
and study requirements. To minimize the possibility of coercion and to ensure that subject is 
signing the appropriate version of 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.  
 

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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 
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.  If subjects have had any of the aforementioned labs performed within the 3 
months prior to the screening visit and we can access the results, a venous blood sample will not 
be taken for that test. An EKG will be completed. 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 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. The VO2max test can be completed at a separate visit after the initial 
screening visit but before the Dexcom G6 sensor insertion if needed to accommodate the 
subject’s schedule.  This visit will take approximately 2.5 hours.  
 
Dexcom G6 Sensor Insertion Visits: 
Dexcom G6 sensor insertion visits will be on Days 1 and 14. After arrival at the OHSU OCTRI 
outpatient clinic, the Biomedical Engineering Point of Care (BME POC) Laboratory or Harold 
Schnitzer Diabetes Health Center clinic, women of childbearing potential will receive a urine 
pregnancy test if the last pregnancy test performed was more than 7 days prior.  This test must be 
negative before further participation is allowed. This visit will take approximately 30 minutes.  
 
Subjects will have two glucose sensors inserted at this visit, a commercial G5 or G6 glucose 
sensor and an investigational G6 with temperature logger sensor. Subjects will receive training 
on how to insert the commercial Dexcom G5 or G6 system according to the manufacturer’s 
directions. Subjects will be instructed how to connect the transmitter to the Dexcom app on an 

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iPhone that will be returned at the end of the study. Subjects will be instructed how to calibrate 
and change out the sensor according to the manufacturer’s directions. If subjects are given a 
Dexcom G5, they will be asked to calibrate the sensor every 12 hours and the change out the 
sensor at home every 7 days.  If subjects are given a Dexcom G6, they will only enter two start-
up calibrations and change out every 10 days while at home. Subjects will be asked to replace the 
commercial sensors if they fail or become dislodged. Trained study personnel or a Dexcom 
representative will insert the G6 with temperature logger after appropriate preparation of the 
abdominal skin as per the manufacturer’s directions. An adhesive overlay may be placed over G5 
and/or G6 sensors to prevent dislodgement. The subjects will not be able to view the Dexcom G6 
with temperature logger sensor values. The wire glucose sensors are sterile and will be used for 
single use only as directed by the manufacturer.    
 
The G5/G6 CGM alerts will be set at 70 mg/dL and 300 mg/dL. Subjects will be given a Contour 
Next meter for measuring their capillary blood glucose in order to calibrate the Dexcom CGM 
system. Subjects will be instructed to check a CBG for symptoms of hypoglycemia and for CGM 
alarms indicating sensed glucose is less than 70 mg/dL. Subjects will be instructed to discontinue 
the use of acetaminophen for all periods when wearing the Dexcom G5 sensor. Subjects will be 
asked to collect the time, date and location of all G6 sensor insertions while at home.  
 
For the first sensor insertion visit on Day 1, subjects will be given a FitBit or Apple Watch to 
wear. Subjects will also be provided with Novolog cartridges for use in the Inpen and Lantus 
Solostar or Tresiba insulin pens for Days 1-28. Subjects will use the Inpen smartphone 
application to calculate insulin doses based on their usual insulin carbohydrate and correction 
factor ratios. These ratios will be entered in to the Inpen application by the study investigator at 
the time of the first study visit. If a subject was using Humalog or Apidra insulin prior to the 
study, the insulin doses will generally be kept the same given these short-acting insulin 
formulations are equivalent to Novolog. The investigator will review the patient’s current long 
acting insulin and their medical history to determine if the subject should use Tresiba or Lantus 
during the study. Subjects will use GoCaps or Clipsulin to track their long acting insulin dose. If 
subjects are switching their long-acting insulin, the investigator will review the insulin dose with 
the subject and determine an appropriate dose of Lantus or Tresiba.  
 
Subjects will be instructed on the use of these devices along with the mobile app T1 DEXI. 
Meals and exercise can be scheduled for specific times each week within the app. The app will 
alert the user with pre- and post meal reminders on the day of and the day after exercise. Subjects 
will be instructed to take a picture of their meals using the T1 DEXI app every day for the 28 
days and to record all carbohydrate treatments for hypoglycemia. A dietician or dietetic student 
will review the meal photos to determine meal content. Study staff may contact subjects by 
phone, text, or email for clarification if the meal photo is difficult to interpret. User Guides for all 
devices will be sent home with subjects, including for the T1 DEXI app. Subjects will be able to 
contact study staff for any issues with the devices. This instruction on Day 1 should take an 
additional 30 minutes.  
 
For the second sensor insertion visit on Day 14, study staff can insert the new G6 with 
temperature logger sensor before staff removes the previous G6 sensor to facilitate a quicker 
discharge. The sensor site will be inspected for signs of irritation or infection. In addition, the 

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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. 
 
Data Collection 
In this study, we will be collecting de-identified physiologic data from people with type 1 
diabetes.  The following data will be collected from participants in this study: 
 Glucose sensor data (Dexcom G5/G6) 
 Short-acting insulin injected into the body with an InPen wireless smart insulin pen. 
 Long-acting insulin injected into the body with a GoCaps or Clipsulin wireless smart 
insulin pen. 
 Physical activity data collected with a FitBit Ionic or Apple Watch watch.  This fitness 
data will include the following: 
o Heart rate 
o Step count 
o Metabolic expenditure 
o Sleep 
o Activity types (e.g. running, jogging, etc). 
 Self-report food and exercise data logged by the participant 
To collect the data, each participant in the study will be given an Apple iPhone.  The iPhone will 
have the following apps that will be used to collect data.   
 A Dexcom commercial app will collect data from the Dexcom G5/G6 glucose sensor.   
 A Companion InPen commercial app will collect data from the short-acting insulin 
InPen.   
 A GoCaps commercial app will collect data from the GoCaps long-acting insulin pen.   
 A Clipsulin commercial app will collect data from the Clipsulin insulin pen.  
 The FitBit commercial app will collect data from the FitBit Ionic.   
 The Apple Watch will collect data from Apple HealthKit. 
 A custom app developed by OHSU called T1-Dexi will also be installed on the 
iPhone.  The T1-Dexi app has undergone a security review by OHSU IT and the results 
of this can be provided upon request.   
 
The T1-Dexi app will serve as the ‘data aggregator’ on the phone and will perform the following 
functions: 
 T1-Dexi app will collect self-report meals and exercise data from the participants both as 
text / categorical selections and also as food photographs collected from the camera on 
the phone. 
 T1-Dexi app will aggregate all of the data collected from the glucose sensor, insulin pens, 
activity tracker, and self-logged food and exercise data to be stored as de-identified data 
within the iCloud storage area of the phone.  The data stored within iCloud is de-
identified and does not contain any information from the 18 HIPAA designations of 
personally identifiable information.  ITG has granted an Exception approval for using and 
storing data on the iCloud.  Data stored on the iCloud will be deleted once the study is 
complete.   

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We plan to install the OHSU AirWatch Agent / Container on the iPhones.  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 encrypted and kept secure on a restricted OHSU network drive in a limited access folder. 
The iPhones will be registered to the study participants’ unique study ID number and all of the 
data stored on the iPhone will be associated with this ID.   
Two In-Clinic Exercise Visits: 
The in-clinic exercise visits will be conducted in the Harold Schnitzer Diabetes Health Center, 
the Biomedical Engineering Point of Care (BME POC) Laboratory or the OCTRI outpatient 
research unit. After arrival at the clinic, women of childbearing potential will receive a urine 
pregnancy test if the last pregnancy test performed was more than 7 days prior.  This test must be 
negative before further participation is allowed. A code cart is on site at all locations and a code 
team is available by page at all times. The exercise visits will be on Days 9 (window of days 9-
14) and 16 (window of days 16-20). 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).   
 
Subjects will be randomized to either aerobic, anaerobic or high intensity interval exercise 
sessions. Exercise sessions will be approximately 2 hours. A 30 minute exercise video will be 
provided for the subjects to follow along with. A list of exercises to be performed is provided in 
Appendix E. Subjects will be given a Polar heart rate strap to wear during the in-clinic exercise. 
A capillary blood glucose (CBG) will be obtained and measured by the Contour Next glucose 
meter given to the subject.  For subject safety, CBG must be 80 mg/dl or higher to begin 
exercise. Subjects will be given 15 grams of carbohydate (such as 4 oz of juice) for values <120 
mg/dL at the start of exercise or for values of <70 mg/dL at any point after the start of exercise. 
For subjects who require carbohydrate treatment for values < 70 mg/dl, a CBG will be repeated 
in 15 minutes and exercise will be resumed once CBG is 70 mg/dL or higher. A study 
investigator will be contacted if CBG >250 mg/dL to determine if the subject requires a dose of 
short-acting insulin and serum ketones will be checked by the Precision Xtra blood ketone meter. 
The exercise visit will be cancelled  if ketones are greater than 0.6 mmol/L. The subject will be 
discharged with a bottle of water along with instructions from the investigator for checking 
glucose at home. Subjects will be taken to the emergency room for ketone levels > 3.0 mmol/L. 
The PEAK recommendations, guidelines from a collaboration of researchers through the 
Juvenile Diabetes Research Foundation (JDRF) for exercising with Type 1 diabetes, specify that 
it is safe to exercise if ketones are below this threshold [1]. Oral temperature will be taken with a 
thermometer just before and at the end of exercise and recorded. During exercise visits, for 
comparison with the CGM readings, CBG will be checked before exercise, every 10 minutes 
during exercise, at the end of exercise and every 15 minutes for an additional 30 minutes at the 
end of exercise.  
 
During the exercise period, there will be defined rules for stopping exercise, including: 
1) If the subject feels unwell, 

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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) For patient preference. 
 
At-home Study Exercise Sessions: 
Subjects will be asked to complete four at-home exercise sessions consistent with the assigned 
type of exercise, on Days 2 or 3, Days 4 or 5, Days 23 or 24 and Days 25 or 26.  Instructions for 
the exercise will be provided via video links and will be the same set as instructions for the in-
clinic visits (see Appendix E). Subjects will be instructed to check a CBG before initiating 
exercise to ensure safety. Subjects will be instructed to consume a snack if glucose is <120 
mg/dL and delay exercise until glucose is >80 mg/dL. Also, if glucose is >250 mg/dL, subjects 
will be instructed to use the InPen app to calculate if a correction dose is needed and delay 
exercise until glucose is <250 mg/dL. Subjects will enter information about exercise into the T1 
DEXI app. Subjects will receive reminders via phone or text to complete their exercise and to 
monitor adherence to protocol. Participants may also receive reminders to enter activity 
information through the T1DEXI app. Subjects will also be instructed to check a CBG after 
exercise and consume a snack if needed. 
 
 
Study Investigator review of CGM data: 
The study investigator will review the subject’s insulin and CGM data online approximately 
every 7 days (Days 7, 14, and 21) and  make insulin dose recommendations by phone. Subjects 
will confirm the settings were changed appropriately by taking a screen shot of the change and 
sending the picture to a study phone. The study investigator will make a note of why any changes 
were made.   
 
Day 28 Study Completion visit: 
At this visit, the insulin pens and other devices will be turned in for download. The subject’s 
weight will be collected at this visit. The study investigator will consult with the subject 
regarding appropriate insulin dosing for the remainder of the day. The FitBit or Apple Watch and 
Dexcom sensor(s) will be removed from the subject. The sensor site will be inspected for signs 
of irritation or infection. In addition, the sensor will be inspected for the possibility of breakage 
or fracture. If there is any evidence of sensor breakage, it will be recorded. If an area of 
inflammation of 1 cm or greater exists around the point of insertion, a de-identified photograph 
will be taken of the area and the 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 instructed to give an 
injection of aspart insulin if deemed appropriate by the study investigator for values above 150 
mg/dl.  
 

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If a study visit is stopped prematurely 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. 
 
Cleaning and Disinfecting  
All devices will be cleaned and disinfected between subjects. The smart phone, Dexcom G5 and 
G6 transmitters and FitBit or Apple Watch will be 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.  
 
Statistical methods 
 
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 for up to 20 min segments.   
    
Confidentiality and Protection of Human Subjects 
RISKS and BENEFITS 
Risks: The risks of the protocol procedures are considered minor. Subjects will be managing 
their own blood glucose as they normally would with recommendations for insulin dosing from 
the study investigator. A study investigator will be on campus during all exercise visits.  
 
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. 
 
Benefits: The subject may not directly benefit from being in this study; however, their 
participation may help to advance automated insulin decision support software. 
 
COSTS:   
Subjects will receive $700 for completion of all study visits.  If subjects withdraw early from the 
study, compensation will be given as follows: $175 per 7 study days in the study. If the subject 
completes a partial week, the subject will also receive $175 for the partial week. There is no 
compensation for the screening visit. If a subject is asked to repeat an in-clinic exercise study 
visit due to technical problems, he/she will receive an additional $75.   
 
Monitoring Entity: 

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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.  
 
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: 
1. Screening form 
2. G6 and Device Training visit 
3. G6 Sensor Insertion visit 
4. Exercise Visit 
5. Physician Follow-up 
6. Study Completion visit 
7. Adverse Event form 
8. Serious Adverse Event form 
9. Concomitant Medications 
 
The Principal Investigators may authorize other personnel to make entries in the CRF.  
 
The de-identified data collected during this study will be used for analysis of the primary and 
secondary endpoints listed in this protocol. This data will also be stored in the OregonAPC 
repository according to IRB protocol 19858.  During screening, participants may sign the 
consent form to store their study data in the data repository.  The data to be collected includes: 1) 
glucose sensor data, 2) blood glucose data, 3) insulin and data, 4) physical activity data, and 5) 
food and exercise data. All data, except for blood glucose, is aggregated by the DEXI 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. 
 
 

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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.  
 

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Confidentiality Procedures: 
To protect confidentiality, standard institutional practices will be followed as described in the 
OHSU Information Security and Research Data Resource Guide 
(http://ozone.ohsu.edu/cc/sec/isg/res_sec.pdf) to maintain the confidentiality and security of data 
collected in this study. Study staff will be trained regarding these procedures. See IRB protocol 
19858 for a complete description of the confidentiality and security of the study data collected 
during this study to be stored in the OregonAPC repository. Paper files will be stored in locked 
filing cabinets in restricted access offices at OHSU. After the study, source documents will be 
maintained at the participating clinical center (or offsite record storage facilities) 2 years after a 
marketing application is approved for our group's decision support device or discontinuance of 
pursuit of marketing approval.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix A: Physical Activity Readiness Questionnaire 
 
 
 

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Appendix B: Devices 
FitBit 
 
 
Apple Watch 
 
 
Dexcom G6 Continuous Glucose Monitoring System which includes Sensor and Sensor 
Transmitter 
 
      
 
 
 
iPhone Smart phone with T1 DEXI app 
 

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Contour Next Blood Glucose Meter 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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) 

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 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) 
 
 
 
 

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Appendix D: Letter of Authorization Dexcom  
 
 
 

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Appendix E: Exercise Video Outlines  
 
 
Aerobic Exercise Video Outline 
Segment 
Segment Time 
Activities  
Warm-Up Intro 
(2 min) 
0:00 – 2:00 
0:00: Welcome!  
0:15: Side to Side kick Back 
0:30: Side to Side Kick Back Pull Back 
0:45: Side to Side Reach Out 
1:00:  Side to Side Reach Up 
1:15: Side to Side Reach Out 
1:30: Side to Side Pull Back 
1:45: Side to Side Kick Back 
Active Exercise 
(30 min) 
Each activity is performed 
for 45 seconds, followed by 
a 15 second instructional 
transition to the next 
activity 
1. Low Kick 
2. Step back 
3. Heal Step  
4. Knee Raise 
5. Half Squat to Reach  
6. Side to Side Knee Raise Left (crunch) 
7. Side to Side Knee Raise Right (crunch) 
8. Knee to Elbow alternate 
9. Left Jab (left foot forward) 
10. Right Jab (left foot forward) Foundation  
11.  Left Right Left Right Jab Side Roll Right 
(left foot forward) variation 1 
12. Left Right Left Right Jab Squat Squat (left 
foot forward) variation 2 
13. Left Right Left Right Jab Knee Knee (left 
foot forward) variation 3 
14. Left Right Left Right Jab Roll Knee (left 
foot forward) variation 4  
15. Right Left Right Left Jab (right foot 
forward) foundation 
16. Right Left Right Left Jab   Roll Left (right 
foot forward) variation 1 
17. Right Left Right Left Jab Squat Squat 
(right foot forward) variation 2 
18. Right Left Right Left Jab Knee (right foot 
forward) variation 3 

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19. Right Left Right Left Jab Roll Knee (right 
foot forward) variation 4 
20. Hook, Hook, Upper Cut Upper Cut (left 
foot forward) 
21. Hook, Hook, Upper Cut Upper Cut (right 
foot forward)  
22. Squat to Upper Cut (left foot forward) 
23. Squat to Upper Cut (right foot forward) 
24. Left Right Left Right Knee Kick (left foot 
forward) 
25. Right Left Right Left Knee Kick (right foot 
forward) 
26. Forward Step Jab and Cross Step Back 
(left foot forward) 
27. Forward Step Jab and Cross Step Back 
(right foot forward) 
28. Horse Stance Overhead Reach Side Bend/ 
Standing Alternating Side Bend  
29. Cool Down (side to side kick back/pull back 
etc.) 
30. Cool Down (side to side kick back/reach up 
etc.) 
 
 
 
Intermittent High-Intensity Interval Exercise Video Outline 
 
Segment 
Segment Time 
Activities  
Warm-Up Intro (2 min) 
0:00 – 2:00 
0:00: Welcome!  
0:15: Side to Side Kick Back 
0:30: Side to Side Kick Back Pull Back 
0:45: Side to Side Reach Out 
1:00:  Side to Side Reach Up 
1:15: Side to Side Reach Out 
1:30: Side to Side Pull Back 
1:45: Side to Side Kick Back 

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Active Exercise (30 min) 
Each activity is performed 
for 40 seconds, followed by 
a 80 second cool down 
1. Jumping Jacks – 40 secs high intensity 
2. Jogging in place and then side-to-side 
kickbacks followed by pullbacks all at a 
light intensity -80 seconds 
3. Forward Jumping Jacks – 40 sec high 
intensity 
4. Jogging in place and then side-to-side 
kickbacks followed by pullbacks all at a 
light intensity -80 seconds 
5. Squat to Upper Cut Fast – 40 sec high 
intensity 
6. Jogging in place and then side-to-side 
kickbacks followed by pullbacks all at a 
light intensity -80 seconds 
7. Power Jumping Jacks – 40 seconds high 
intensity  
8. Jogging in place and then side-to-side 
kickbacks followed by pullbacks all at a 
light intensity- 80 seconds 
9. Inchworm– 40 seconds 
10. high intensity Jogging in place and then 
side-to-side kickbacks followed by 
pullbacks all at a light intensity- 80 seconds 
11. High Knee Sprint – 40 seconds high 
intensity 
12. Jogging in place and then side-to-side 
kickbacks followed by pullbacks all at a 
light intensity- 80 seconds 
13. Quick Feet – 40 seconds high intensity 
14. Jogging in place and then kick back/pull 
backs-all at a light intensity- 80 seconds 
15. Mountain Climbers- 40 seconds high 
intensity 
16. Stand up jog out and then kick back/pull 
backs all at a light intensity- 80 seconds 
17. Bicycle Kicks – 40 seconds high intensity 
Jogging in place and then kick back/pull 
backs all at a light intensity -80 seconds 
18. Push Ups – 40 seconds high intensity 
19. Stand up jog out and then kick back/pull 
backs all at a light intensity- -80 seconds 
20. Final cool down (2 min) 
 
 
 

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Resistance Exercise Video Outline  
Segment 
Segment Time 
Activities  
Warm-Up Intro (2 min) 
0:00 – 2:00 
0:00: Welcome!  
0:15: Marching 
0:30: Marching arm circles 
0:45: Marching reach out 
1:00: Side to side reach out 
1:15: Butt kick reach out 
1:30: Heel dig 
1:45: Chest squeeze 
Active Exercise (28 min) 
Each activity is performed 
at a controlled pace in 
good form. Aiming for 
about 2 seconds to pull the 
weight the entire range, 
holding for 1 second, then 
controlling the return of 
the movement in about 
another 1 seconds. 
Set 1: (approximately 8 min) Upper Body 
Resistance band bicep curl 3 x 8 
Resistance band high row 3 x 8 
Resistance band bent over row 3 x 8 
Resistance band side lateral shoulder raise 3 x 
8 
 
Set 2: (approximately 10 min) Lower Body 
Resistance band calf raise 3 x 8 
Resistance band reverse lunge 3 x 8 
Resistance band squat 3 x 8 
Resistance band deadlift 3 x 8 
 
Set 3: (approximately 10 min) Total Body and 
Abs 
Resistance band side lunge to single arm side 
lateral raise 3 x 8/side 
Resistance band standing abdominal (ab) twist 
3 x 8/side 
Resistance band bird dog 3 x 8  
Resistance band reverse crunch 3 x 8 
 
 
 
 
 
 
 

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References 
 
1. Riddell MC, Gallen IW, Smart CE, Taplin CE, Adolfsson P, Lumb AN, Kowalski A, Rabasa-Lhoret R, 
McCrimmon RJ, Hume C, Annan F. Exercise management in type 1 diabetes: a consensus statement. 
The lancet Diabetes & endocrinology. 2017 May 1;5(5):377-90.