Feasibility of a Decision Support System to Reduce Glucose Variability in Subject With T1DM
Phase: NA
Conditions: Type 1 Diabetes Mellitus
Sponsor: Daniel Chernavvsky, MD

School of Medicine 
Center for Diabetes Technology 
Feasibility of a Decision Support System 
To Reduce Glucose Variability  
In Subjects with T1DM  
NCT02558491
Version Date: 10-14-2016

CLINICAL PROTOCOL 
Version Date:  10/14/16 
Page 2
A. Purpose/Objectives
The purpose of this study is to demonstrate the safety and feasibility of a decision support
system aimed at reducing glucose variability in T1DM patients using continuous
subcutaneous insulin infusion (CSII) or multiple daily injections (MDI). The system will be
deployed on our portable medical application platform (DiAs) and will include the following
elements:
1. An insulin pump or MDI treatment parameters optimization routine, using a month of
collected CGM/insulin/meal data
2. An exercise risk warning system, capable of predicting hypoglycemia at the onset of
physical activity and advising on mitigating treatments such as insulin adjustment or
carbohydrate consumption
3. A smart bolus calculator based on CGM glucose measurements and insulin sensitivity
estimation.
Primary Specific Aim: 
To demonstrate feasibility and safety of a glucose variability-reducing decision support 
system, measured by non-inferiority of use of the system compared to standard SMBG-
informed CSII or MDI therapy in terms of occurrence of hypoglycemia and percent time 
spent between 70 and 180 mg/dl as measured by blinded CGM. 
Secondary Specific Aims: 
To assess the effect size of using the GV advisory system compared to standard CSII or MDI 
therapy in terms of: 

Occurrence of hypoglycemia during and immediately after exercise

Glycemic excursion post meals
B. Study Design Overview
Subjects: The study is intended to complete up to 20 subjects with Type 1 Diabetes
Mellitus who use continuous subcutaneous insulin infusion (CSII) and up to 20 subjects
with Type 1 Diabetes Mellitus who use multiple daily injections (MDI). The study will be a
randomized cross-over design with a Control and Experimental admission. The order of the
admissions will be randomized.  It is estimated that there will be a higher than normal rate
of screen failures, dropouts, or withdrawals, thus we intend to set a recruiting target of 70
subjects.

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 3 
 
Procedure: Data collected during an approximately 28 day data collection period will be 
analyzed and will be used to optimize insulin parameters. These new parameters are the basis 
for the treatment optimization, requiring a minimum of 14 valid days during the 28 days of 
collection to advise the system. The collected basal rates or basal insulin dose, insulin 
sensitivity factor (ISF), and carbohydrate ratio data will be used to optimize the subject’s insulin 
parameters (basal rates or basal insulin dose, insulin sensitivity factors and carbohydrate 
ratios). Subjects on MDI therapy will record this data into ‘MySugr’, an app that helps keep 
track of blood sugar levels, insulin dosages, meals, activities, mood and other information.  The 
subject may also use a novel Bluetooth connected insulin pen, called inPen, for prandial dosing 
(Companion Medical, San Diego CA). The optimized parameters will be approved, modified or 
rejected by the study MD. CGMs will be blinded during the trial.  
This system will only implement a retrospective optimization of the subject’s insulin therapy, 
with defined limits in how much it can deviate from the original (See Appendix A-3 for details). 
This optimization is then reviewed by the study physician prior to the Experimental admission. 
The study physician is at liberty to accept, modify, or reject the advised optimal settings. A 
record of these decisions will be maintained. If a change in the basal insulin dose is 
recommended and accepted by the physician for an MDI user, the subject will be instructed to 
use the new basal dose(s) for  approximately 5 days prior to the Experimental admission. Upon 
basal dose change, subject will be instructed to maintaina minimum of 7 SMBG per day, and 
clinical team will check back with the subject within 72h of dose change. Considering the limit 
of basal dose change, and the review by the study physician, such a procedure is well within the 
standards of care for T1D using MDI. 
The CGM is only blinded to the subject. The clinical and technical teams have access to this 
information via remote monitoring (password protected on DiAs) during the study 
admissions. The CGM is blinded to the study participant to avoid CGM-induced glucose 
variability reduction, as it would cloud the analysis of the impact of the system. 
Subjects will use their own insulin parameters, including basal rate or basal insulin dose insulin 
sensitivity factor and carbohydrate ratio, and determine their own insulin usage during the 
Control admission.  
MDI subjects will be provided with an insulin pen (NovoPen Junior, NovoPen Echo, or 
Companion Medical inPen Smart Pen) with short-acting insulin for treatment during the 
Experimental admission. These pens are capable of delivering insulin in 0.5 unit increments and 
are FDA approved but for the Smart Pen which is under 510(k) review (see letter of 
Authorization). If this option is selected, the Companion Medical pen, known as the InPen, will 
be used in the trial. This insulin pen contains computer chip technology built into the base and 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 4 
has Bluetooth LE wireless capability. It will collect the subject’s data and then transmits it to an 
app that contains a dose calculator and also calculates real-time insulin on board (IOB). The 
insulin pen has remote monitoring, permitting the subject to inform the study team of their 
insulin dose, BG and carbohydrates. An inPen User Guide will be available to all MDI subjects if 
this smart pen is used in the trial. If this pen is not available at the time of the trial, a pen that 
can deliver in 0.5 unit increments will be used, such as the Lilly Luxura insulin pen. 
The study is also designed to test the capacity of our exercise advisory system to avoid or limit 
exercise-induced hypoglycemia, by challenging the subject with two 3x15min exercise bouts. 
 
Study Diagram  
Visit 1: Screening Visit. All subjects will be consented and receive a history and physical. Study 
eligibility will be reviewed.  After a subject completes the screening criteria, the subject will be 
randomized to the Experimental or Control admission first. 
Visit 2: CGM Placement & Training. All subjects will receive training on the use of the 
continuous glucose monitor (CGM) and study glucometer prior to the Experimental admission. 
Approximately 28 days of blinded CGM data will be collected with a total of 14 valid days 
needed to participate in the research house/hotel admission. Visit 1 and 2 can be done on the 
same day.   
Visit 3: Data Collection Period. Blinded CGM data will be collected prior to the Experimental 
admission and analyzed by the study team to determine the optimal insulin therapy parameters 
that will be used during the Experimental admission. For CSII users, the insulin pump and CGM 
downloads will be reviewed approximately 72 hours before the Experimental admission by the 
study team to ensure proper collection procedures. For MDI users, data entered into the 
MySugr app and CGM downloads will be similarly reviewed. Subjects will also wear a ‘Fitbit’ to 
collect information activity, exercise, heart rate, and sleep. An anonymous Gmail account will 
be established for each subject. An app will be placed on the subject’s smartphone or subject’s 
personal laptop to facilitate weekly downloading of the Fitbit data. Additional Data Collection 
Periods may be requested to ensure proper data collection.  
Visit 4 and 5: Research House/Hotel Admission. The Experimental and Control admission will 
be separated by approximately 4 weeks, 8 weeks or 12 weeks. The order of these two visits will 
be randomly selected. Subjects will be admitted to the research house/hotel at ~16:00-17:00 
and will be discharged after approximately 48 hours.  

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 5 
 
Figure 1: Study Design 
C. Sample Size and Investigational Sites 
This study will be conducted at the University of Virginia Center for Diabetes Technology (CDT). 
Twenty subjects (N=20) with Type 1 Diabetes Mellitus who use CSII and twenty subjects (N=20) 
with Type 1 Diabetes Mellitus who use MDI to treat their diabetes will be needed to complete 
the protocol. The studies will be conducted at the CDT Research House as noted below. The 
study may also occur at a local hotel. Vulnerable populations (i.e. pregnant women, prisoners, 
etc.) will be excluded from participation. Based on our experience with similar studies, we 
estimate an higher than normal screen failures, dropouts, or withdrawals due to the data 
collection requirements and admission time restrictions; thus we intend to set a recruiting 
target of 70 subjects.  
As a safety/feasibility investigation, this study is not powered to a specific outcome. 
Nonetheless, based on prior work and computer simulations we estimate the likely effect size 
to be large (around 0.7); we therefore have chosen a sample size of 15-20 subjects for each 
group (CSII and MDI). Using a power analysis with a fixed sample size, significance and 0.8 
power, this would allow us to detect an effect size larger than 0.67. In prior studies, 15 subjects 
have also been considered by regulatory bodies as an appropriate sample size to demonstrate 
safety in transitional settings for CGM based insulin dosing.  

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 6 
Investigational Site 
The University of Virginia has granted the Center for Diabetes Technology the use of a facility 
designated Research House to perform outpatient studies related to the Artificial Pancreas 
Project. The facility is located 2.2 miles from the University of Virginia Emergency 
Department. It is a 4 bedroom/4 bath home with sleeping quarters on the first and second 
floors. The study team may test up to 3-5 study participants at the same time in the research 
house.   
 
Minimal Staffing Requirements 
At all times, a minimum of one registered nurse, trained in the execution of the protocol as 
well as in the management of hypo- and hyperglycemia, and a technician, trained in the use 
and maintenance of the DiAs system will be present during the entire trial. In addition, one of 
the study physicians and one senior engineer will be on call during the entire admission, with 
backup MDs and engineers available if the primary contact is unable to be reached. During 
exercise, there will be a minimum of one nurse per two subjects and one technician per two 
subjects on site.  In the event of five study subjects tested during a single admission, two 
medically trained personnel will be available during the trial.  
D. Study Duration 
The duration of the study for each patient is intended to be up to 10 weeks. Subjects will be 
permitted up to a two month delay if unable to attend their second research house/hotel visit 
as initially scheduled. However, if more than 100 days elapse between the Control and 
Experimental admissions, the subject will be discontinued and replaced by another subject. 
Admissions to the research house may be repeated if the admission or the data collection is 
suspended or inadequate. Screening or re-screening labs can be done either at the UVA CRU or 
at a LabCorp that is convenient to the subject. Lab values collected from a prior medical 
appointment may be used if dated within 4 weeks of the screening appointment.  
E. Inclusion and Exclusion Criteria 
Inclusion Criteria: To be eligible for the study, a subject must meet the following criteria: 
1. Clinical diagnosis based on investigator assessment, of type 1 diabetes for at least one year 
and either using insulin pump therapy for at least 6 months or MDI therapy for at least 6 
months; 1-2 basal insulin injections per day, consistent in amount and timing (administering 
at approximately the same time each day). The following MDI therapy will be permitted: 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 7 
 Subjects using Glargine (100 U/mL) once or twice daily. 
 Subjects using Detemir (100 U/mL) twice daily. 
 Subjects using Degludec (100 U/mL) once daily  
 
A. Historical criteria for documented hyperglycemia (at least 1 must be met): 
i. 
Fasting glucose ≥126 mg/dL. 
ii. 
Two-hour OGTT glucose ≥200 mg/dL. 
iii. 
Hemoglobin A1c ≥6.5% documented. 
iv. 
Random glucose ≥200 mg/dL with symptoms. 
v. 
No data at diagnosis is available but the participant has a convincing history of 
hyperglycemia consistent with diabetes. 
B. Historical criteria for requiring insulin at diagnosis (1 must be met): 
i. 
Participant required insulin at diagnosis and continually thereafter. 
ii. 
Participant did not start insulin at diagnosis but upon investigator review likely 
needed insulin (significant hyperglycemia that did not respond to oral agents) and 
did require insulin eventually and used continually. 
iii. 
Participant did not start insulin at diagnosis but continued to be hyperglycemic, had 
positive islet cell antibodies – consistent with latent autoimmune diabetes in adults 
(LADA) and did require insulin eventually and used continually. 
2. Age 15– 65 years old. 
3. Females, not currently known to be pregnant. If female and sexually active, must agree to 
use a form of contraception to prevent pregnancy while participating in the study. A 
negative urine/blood pregnancy test will be required for all premenopausal women who are 
not surgically sterile. Subjects who become pregnant will be discontinued from the study. 
4. Demonstration of proper mental status and cognition for the study 
5. CSII subjects must currently be using the bolus calculator function of the current insulin 
pump with pre-defined parameters for glucose goal, carbohydrate ratio, and insulin 
sensitivity factor. 
6. MDI users must currently be using Intensive Insulin Therapy including carbohydrate 
counting and use of pre-defined parameters for glucose goal, carbohydrate ratio, and 
insulin sensitivity factor.    

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 8 
7. Willing to use Humalog (lispro) or Novolog (aspart) insulin during the study procedures for 
MDI subjects. 
8. CSII subjects must be willing to use the current bolus calculator pump parameters and enter 
all carbohydrate intake into the pump during the 28 day data collection period. 
9. MDI users must be willing to use their carbohydrate counting parameters for all meal dosing 
and enter the information into the MySugr app. 
10. Ability to access the Internet to provide data to the clinical team or to travel to the research 
center so that the study equipment and personal pump can be downloaded.  
11. An understanding of and willingness to follow the protocol and sign the informed consent. 
 
Exclusion Criteria: The presence of any of the following is an exclusion for the study: 
1. Diabetic ketoacidosis (DKA) in the 6 months prior to enrollment. 
2. Severe hypoglycemia resulting in seizure or loss of consciousness in the 6 months prior to 
enrollment. 
3. Current treatment of a seizure disorder. 
4. Coronary artery disease or heart failure, unless written clearance is received from a 
cardiologist. 
5. Atrial or ventricular arrhythmias (benign premature atrial contractions [PACs] and 
premature ventricular contractions [PVCs] allowed) 
6. Cystic fibrosis. 
7. Pregnancy, breast-feeding, or intention of becoming pregnant over time of study 
procedures. 
8. A known medical condition that in the judgment of the investigator might interfere with the 
completion of the protocol such as the following examples: 
i. 
Inpatient psychiatric treatment in the past 6 months  
ii. 
Presence of a known adrenal disorder 
iii. 
Abnormal liver function test results (Transaminase >2 times the upper limit of 
normal); testing required for subjects taking medications known to affect liver 
function or with diseases known to affect liver function 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 9 
iv. 
Abnormal renal function test results (calculated GFR <60 mL/min/1.73m2); testing 
required for subjects with diabetes duration of greater than 5 years post onset of 
puberty  
v. 
Active gastroparesis 
vi. 
If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, lack of 
stability on the medication for the past 2 months prior to enrollment in the study 
vii. 
Uncontrolled thyroid disease (TSH undetectable or >10 mlU/L); testing required 
within three months prior to admission for subjects with a goiter, positive 
antibodies, or who are on thyroid hormone replacement, and within one year 
otherwise 
viii. 
Abuse of alcohol or recreational drugs 
ix. 
Infectious process not anticipated to be resolved prior to study procedures (e.g. 
meningitis, pneumonia, osteomyelitis, deep tissue infection).  
x. 
Uncontrolled arterial hypertension (Resting diastolic blood pressure >100 mmHg 
and/or systolic blood pressure >180 mmHg). 
xi. 
Oral steroids 
xii. 
Uncontrolled microvascular complications such as current active proliferative 
diabetic retinopathy defined as proliferative retinopathy requiring treatment (e.g. 
laser therapy) in the past 12 months. 
9. A recent injury to body or limb, muscular disorder, use of any medication, any carcinogenic 
disease, or other significant medical disorder if that injury, medication or disease in the 
judgment of the investigator will affect the completion of the protocol. 
10. Basal Rates <0.01 units/hour for CSII subjects. 
11. Allergy for or intolerance of both Novolog (aspart) and Humalog (lispro) insulin for MDI 
subjects. 
12. Diagnosed food allergies. 
13.  Current use of the following drugs and supplements:   
i. 
Regular acetaminophen user, or not willing to suspend acetaminophen 24 hours 
before and during the entire length of the trial  
ii. 
Any other medication that the investigator believes is a contraindication to the 
subject’s participation 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 10 
14. Any reason for which the study MD considers the subject not properly fitted for the trial 
(i.e. insulin pump that does not record what is needed for the trial). 
15. Current enrollment in another clinical trial. 
F. STUDY TIMELINE 
a. Visit 1: Screening / Enrollment Visit 
At the Screening Visit, the following procedures will be performed / criteria will be checked and 
documented: 
1. Signed and dated informed consent 
2. Inclusion and exclusion criteria 
3. Demographics (date of birth, gender, race and ethnicity) 
4. Medical history 
5. Details of the diabetic history: duration of disease (number of years), diagnosis details, 
current treatment (including basal rates or basal insulin dose(s), carbohydrate ratios, insulin 
sensitivity factors, target glucose, average total daily insulin, history of DKA, history of 
severe hypoglycemia, and self-monitoring blood glucose values) 
6. Surgical history 
7. Menstrual history (females) and Sexual Activity/Contraception (females) 
8. Allergies 
9. Medications and supplements 
10. Social history including drinking, smoking, and drug habits 
11. Physical examination 
12. Weight and height 
13. Vital signs  
14. EKG 
15. Blood and Urine testing for screening labs: 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 11 
 Hemoglobin A1c  
 Comprehensive chemistry panel 
 Pregnancy test: either urine or qualitative serum HCG in women with 
childbearing potential. If not performed, document reason (surgically sterile, 
postmenopausal) 
 Thyroid stimulating hormone (TSH) 
If a study subject has had a recent physical exam (less than 6 months) and blood work done 
(less than one month), the study physician will have the discretion to repeat any test as needed. 
Once all results of the screening evaluations are available, a decision will be made to determine 
the subject’s eligibility for the study or if one or more parts of the screening will have to be 
repeated. If at the first screening or repeat screening an exclusionary condition is identified, the 
study subject will be excluded from participation and referred to their primary care physician as 
needed. If the study subject is pregnant, the study physician will discuss the results of the blood 
test with the subject and the subject will be asked to seek confirmation of the test and the 
appropriate medical care. If the study subject has an abnormal initial blood pressure, the 
subject will be allowed to relax for >10 minutes and have the blood pressure reassessed. 
Subjects may be re-screened at a later date if their clinical situation changes as determined by 
the study physician. 
The total amount of blood to be withdrawn during the screening visit is ~22 cc. The screening 
visit will last approximately 2 hours. If the subject cannot schedule Visit 2 within 16 weeks of 
screening, screening labs, vital signs, and recent medical illness/medications will be re-
evaluated. The study physician will have the discretion to repeat any test as needed. 
If a subject meets all the study criteria, he/she will be enrolled in the trial and randomized to 
begin the Experimental or Control admit first. Visit 2 may be completed at the conclusion of 
Visit 1 if all eligibility requirements are met and the subject is randomized first to the 
Experimental admission.  
All subjects will also be given instructions to avoid acetaminophen prior to their study 
intervention or to reschedule their study intervention if they require acetaminophen, as there is 
potential for interference with glucose oxidase systems for measuring glucose such as the CGM. 
These instructions will also advise the subject to contact the study team in the event of a febrile 
illness within 24 hours of the study intervention, so that the study outpatient admission can be 
rescheduled. All subjects will be given instructions to bring all of their current medications and 
CSII or MDI supplies with them for use during or after the admissions. 
Ideally, the admissions will be 4 weeks apart. If the subject cannot schedule the second 
admission in 4 weeks, he/she may complete the admission 4, 8, or 12 weeks after the initial 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 12 
admission (Visit 4). If the second admission has not been completed within 12 weeks after Visit 
4, the subject will be discontinued from the trial. 
 
Visit 2: CGM Placement & Training Visit  
Continuous Glucose Monitor Training 
1. An outpatient visit will be scheduled for training on the blinded CGM. Subjects that are 
currently using a CGM at home may use the study CGM in the unblinded mode during data 
collection. 
2. Female subjects of childbearing potential will perform a urine pregnancy test, unless Visit 2 
follows immediately after Visit 1. If the test is positive, the subject will discontinue study 
participation. The subject will be asked to seek confirmation of the test and the appropriate 
medical care.  
3. The subject’s insulin pump, CGM receiver, and the study glucometer will be set using atomic 
clocks as a reference. 
4. The subject will be supervised during the initial CGM sensor placement. A CGM sensor will 
be inserted into fatty tissue under the skin and will stay attached 7 days and replaced per 
manufacturer directions.  
5. If the CGM device experiences a sensor failure while at home, the subject will replace the 
sensor. The study team will be available for questions or will provide any necessary 
guidance.  
6. The subject will be taught how to calibrate the CGM per manufacturer’s guidelines. The 
subject will be asked to perform all required calibrations with fingerstick glucose 
measurements via the study glucometer. 
7. The subject will be taught to look for skin irritation after sensor removal. 
8. The subject will be reminded to avoid products containing acetaminophen 24 hours prior to 
wearing the CGM and while the CGM is in use. 
9. If the subject requires an MRI, the sensor will be removed from the patient and the reason 
for removal will be noted. This will not be an adverse event. The visit may be rescheduled. 
10. The outpatient visit will last approximately 2 hours depending on prior knowledge of the 
equipment. 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 13 
11. The subject will be given an instruction sheet with 24-hour contact information of the 
research team to address any problems or questions. 
12. Unlimited additional appointments and telephone calls to the study team and study 
physician will be available. 
 
Study Glucometer Training 
1. The study glucometer will be the same through all phases of the study (Visit 2-5) and will be 
used for glucose measurements, safety/data and calibration of the CGM.  
2. Quality control testing will be performed on the study glucometer as recommended in the 
manufacturer guidelines. A tested glucometer will not be used in a study if it does not read 
within the target range at each concentration per manufacturer labeling.  
3. The subject will be trained on the use of the study glucometer and will demonstrate 
proficiency with a fingerstick test. The subject will be instructed that all fingersticks should 
be preceded by hand washing with warm water and a dry towel. The subject will be 
instructed to obtain fingerstick, avoiding alternative sites, when obtaining blood glucose 
(BG) values. The first drop will be discarded. The second hanging drop will be used to 
measure the glucose level. 
4. The subject will be informed that all treatment decisions should be based on fingerstick 
values and not on CGM values. 
5. The subject will be asked to obtain at least four BG fingerstick readings per day to comply 
with the study requirements. Two of these measurements must be upon the subject’s 
waking up and at bedtime. Any additional BG tests normally done by the participant should 
continue without interruption.  
 
Visit 3:  Data Collection Period Prior to Experimental Admission 
Special emphasis will be noted to the study subject that all meal information (i.e. 
carbohydrate quantity, insulin and SMBG) must be recorded in their insulin pump or in the 
MySugr app during the Data Collection Phase. 
1. Data will be collected for approximately 28 days.  
2. The subject will be instructed on how to download the equipment (i.e. personal insulin 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 14 
pump, glucometer, CGM). The subject will be asked to provide downloaded data 
periodically during the month (approximately 3-5 times) using a web-based diabetes 
management system (e.g. Diasend, Carelink Pro, etc.) and local diabetes device 
management software (e.g. Dexcom Studio). The study team will review subject data to 
ensure proper data collection. Study team will review quantity and quality of the data. 
Additional download request may occur depending upon the quality of the data collected.  
3. Subject will be advised to consistently use the bolus calculator (or “wizard”) of their insulin 
pump if on CSII or their carb counting parameters to calculate meal insulin if on MDI. 
4. Optional: Subjects will be asked to wear a Fitbit during the data collection phase, 
removing prior to bathing and participating in water activities.  
5. The subject may be asked to repeat up to 4 weeks of the Data Collection Period. 
6. If the subject is unable to provide the downloaded data from home, the subject will be 
asked to return to the office so the study team can assist them. 
7. The subject may return to the office at any time for additional support.  
8. If a change in the basal insulin dose is recommended and accepted by the physician for an 
MDI user, the subject will be instructed to use the new basal dose(s) for  approximately 5 
days prior to the Experimental admission. The subject will be instructed to maintain a 
minimum of 7 SMBG per day, and the study clinical team will contact the subject within 72h 
of the dose change to monitor safety. 
9. Visit 5 admission may be delayed no greater than 100 days. 
 
Visit 4: Research House/Hotel Admission (Randomized) 
Pre-Admission Procedures 
1. The subject will insert new CGM sensor ~24-36 hours prior to the start of the research 
house/hotel admission.  
2. Subjects will be asked to maintain their regular exercise pattern on the day prior to each 
research house/hotel admission.  
3. The subject will meet the study team and check in to the research house/hotel at 
approximately 16:00-17:00. 
4. The subject will be asked to perform a fingerstick using the study glucometer and ketone 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 15 
meter shortly after arrival. If glucose is <80 mg/dL or >300 mg/dL or β-Ketone test is >0.6 
mmol/L, the study physician will suggest appropriate treatment per the Glycemic Treatment 
Guidelines. The study subject may continue participation in the trial when blood glucose 
levels are between 80-300 mg/dL and ketone values are below 0.3 mmol/L.  
5. The study team will confirm that the subject brought his/her insulin, insulin pump or MDI 
supplies, and regular medications. The study team will also confirm the absence of a febrile 
illness and absence of acetaminophen use while wearing the CGM sensor. The subject may 
be rescheduled if these criteria are not met. 
6. Female subjects of childbearing potential will perform a urine pregnancy test. If positive, 
the subject will discontinue study participation. The subject will be asked to seek 
confirmation of the test and the appropriate medical care. 
 
Admission Procedures 
Day 1 
1. General Information: During both admissions, the subject will wear a blinded Dexcom CGM 
connected to DiAs for remote monitoring capabilities. The staff will remotely monitor the 
subject using the remote monitoring website. DiAs will be programmed with the home 
insulin dosing parameters during the Control admission and with the optimized insulin 
dosing parameters during the Experimental condition. DiAs will be used for meal insulin 
dosing advice for both admissions and for pre-exercise advice during the Experimental 
admission. DiAs will be informed of any BG values, meals, carb treatments, correction 
doses, or snacks during the admission. The DiAs system will be initiated prior to dinner.  
a. Experimental Admission – The DiAs will be programmed with the new optimized 
basal rates or basal insulin dose (entered as a basal rate U/hr = Lantus, Tresiba, 
Levemir dose/24hr), insulin sensitivity factor(s), and carbohydrate ratio(s). These 
new parameters will be used for insulin dosing advice during the entire admission. 
MDI users will use the study insulin pen for meal insulin dosing and the home insulin 
pen or syringe for Lantus (glargine), Tresiba [degludec], or Levemir [Detemir] dosing. 
Pump users will use the home pump for both meal insulin dosing and basal insulin 
administration during the admission.  
b. Control Admission –The study subject will use the home basal/bolus MDI or CSII 
insulin regimen via the home insulin pens or pump and determine the amount of 
insulin to give for the entire admission per the subject’s home carb counting 
parameters and as calculated by the DiAs meal screen.  

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 16 
2. Dinner: A dinner meal will be provided between 18:00-19:00. The subject will define the 
amount of carbohydrates at the dinner meal. The amount of carbs designated by the 
subject will be consistent between the Control and Experimental admission. 
a. Experimental Admission – The subject will inform DiAs of the dinner meal 
carbohydrates and current blood glucose level by activating the meal screen of the 
system. Insulin will be administered based on the new therapy regimen (basal 
profile, correction factor and carbohydrate ratio profiles) and according to the 
subject’s estimate of the carbohydrate content of the meal. The subject will self-
administer the DiAs-calculated meal bolus under study staff supervison.   
b. Control Admission – The subject will inform DiAs of the dinner meal carbohydrates 
and current blood glucose level by activating the meal screen of the system. Insulin 
will be administered based on the subject’s regular therapy regimen (basal profile, 
correction factor and carbohydrate ratio profiles) and according to the subject’s 
estimate of the carbohydrate content of the meal. The subject will self-administer the 
DiAs-calculated meal bolus under study staff supervison.   
3. Optional Snack: The subject may eat a snack in the evening with optional insulin coverage 
per their usual care. If chosen, this snack must be replicated at both admissions. The subject 
will inform DiAs of the carbohydrates in the snack and current blood glucose level by 
activating the meal screen of the system if insulin will be given with the snack. Otherwise 
the snack carbohydrates will be entered in DiAs using the hypoglycemia treatment screen. 
DiAs will advise an insulin dose using the usual patient carb ratio during the Control 
admission and using the optimized ratio during Experimental admission. The DiAs-advised 
insulin dose will be self-administered by the subject and supervised by the study staff. 
4. At approximately 23:00, lights will be turned out, and the subject will be encouraged to 
sleep. 
 
Day 2 
1. The subject will be awakened approximately between 7:00-8:00 AM and allowed time for 
routine hygiene. 
2. A BG fingerstick value will be obtained upon waking while the subject is still fasting.  
3. Breakfast: A breakfast meal will be served at approximately 8:00-9:00 AM. The subject will 
define the amount of carbohydrates in the breakfast meal. The subject will be informed of 
the planned exercise and may choose to underestimate the carbs in the breakfast meal. The 
amount of carbs designated by the subject will be consistent between the Control and 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 17 
Experimental admission.  
a. Experimental Admission – The subject will inform DiAs of the breakfast meal 
carbohydrates and current blood glucose level by activating the meal screen of the 
system. Insulin will be administered based on the new therapy regimen (basal 
profile, correction factor and carbohydrate ratio profiles) and according to the 
subject’s estimate of the carbohydrate content of the meal. The subject will self-
administer the DiAs-calculated meal bolus under study staff supervison.   
b. Control Admission – The subject will inform DiAs of the breakfast meal 
carbohydrates and current blood glucose level by activating the meal screen of the 
system. Insulin will be administered based on the subject’s regular therapy regimen 
(basal profile, correction factor and carbohydrate ratio profiles) and according to the 
subject’s estimate of the carbohydrate content of the meal. The subject will self-
administer the DiAs-calculated meal bolus under study staff supervison. The subject 
may use a temporary basal rate in preparation for exercise per the subject’s usual 
routine.   
4. Exercise Session: The subject will perform a controlled exercise activity designed to 
maintain (HR) at ~140 bpm and starting at approximately 11:00 AM. The exercise will 
consist of 45 minutes of cardiovascular activities that are divided into consecutive 15 
minute periods. Fingerstick BG will be performed before and after each 15 minute exercise 
bout and entered into DiAs via the BG entry screen. Blood glucose value must be ≥80 mg/dL 
to initiate each 15 minute exercise bout. Immediately prior and during exercise, fingerstick 
BG <100 mg/dL will be treated according to the Hypoglycemia Treatment Guidelines. 
Subjects will wear a heart rate monitor during this exercise session. 
a. Experimental Admission – The subject or study staff will inform DiAs of the 
impending exercise session by pressing the exercise advice button.  The exercise 
advice given by DiAs will be followed and may consist of the following: 
i. If no risk of hypoglycemia is detected, no intervention will be 
recommended.  
ii. If a mild-moderate risk of hypoglycemia is detected, DiAs will 
recommend a 0% temp basal rate x 1 hour for CSII users and a 12-16 
gram snack for MDI users.  
iii. If a high risk of hypoglycemia is detected, DiAs will recommend a 0% 
temp basal rate x 1 hour plus a 12-16 gram snack for CSII users and a 
24-32 gram snack for MDI users. 
After this initial advice, any carbs consumed during exercise will be per the 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 18 
Hypoglycemia Treatment Guidelines. Carbs advised by the system may replace 
additional hypoglycemia treatment if the amount is appropriate (no double 
treatments) 
b. Control Admission – Any carbs consumed during exercise will be per the 
Hypoglycemia Treatment Guidelines.  
Lunch: A lunch meal will be served at approximately 12:00-1:00 PM. The subject will 
estimate the amount of carbohydrates in the lunch meal. The amount of carbs designated 
by the subject will be consistent between the Control and Experimental admission.  
a. Experimental Admission – The subject will inform DiAs of the lunch meal 
carbohydrates and current blood glucose level by activating the meal screen of the 
system. Insulin will be administered based on the new therapy regimen (basal 
profile, correction factor and carbohydrate ratio profiles) and according to the 
subject’s estimate of the carbohydrate content of the meal. The subject will self-
administer the DiAs-calculated meal bolus under study staff supervison.   
b. Control Admission – The subject will inform DiAs of the dinner meal carbohydrates 
and current blood glucose level by activating the meal screen of the system. Insulin 
will be administered based on the subject’s regular therapy regimen (basal profile, 
correction factor and carbohydrate ratio profiles) and according to the subject’s 
estimate of the carbohydrate content of the meal. The subject will self-administer 
the DiAs-calculated meal bolus under study staff supervison.   
Quiet activities will be conducted during the afternoon and evening hours.  
5. Dinner: A dinner meal will be provided between 18:00-19:00. The subject will define the 
amount of carbohydrates at the dinner meal. The amount of carbs designated by the 
subject will be consistent between the Control and Experimental admission. 
a. Experimental Admission – The subject will inform DiAs of the dinner meal 
carbohydrates and current blood glucose level by activating the meal screen of the 
system. Insulin will be administered based on the new therapy regimen (basal 
profile, correction factor and carbohydrate ratio profiles) and according to the 
subject’s estimate of the carbohydrate content of the meal. The subject will self-
administer the DiAs-calculated meal bolus under study staff supervison.   

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 19 
b. Control Admission – The subject will inform DiAs of the dinner meal carbohydrates 
and current blood glucose level by activating the meal screen of the system. Insulin 
will be administered based on the subject’s regular therapy regimen (basal profile, 
correction factor and carbohydrate ratio profiles) and according to the subject’s 
estimate of the carbohydrate content of the meal. The subject will self-administer 
the DiAs-calculated meal bolus under study staff supervison.   
6. Optional Snack: The subject may eat a snack in the evening with optional insulin coverage 
per their usual care. If chosen, this snack must be replicated at both admissions. The subject 
will inform DiAs of the carbohydrates in the snack and current blood glucose level by 
activating the meal screen of the system if insulin will be given with the snack. Otherwise 
the snack carbohydrates will be entered in DiAs using the hypoglycemia treatment screen. 
DiAs will advise an insulin dose using the usual patient carb ratio during the Control 
admission and using the optimized ratio during Experimental admission. The DiAs-advised 
insulin dose will be self-administered by the subject and supervised by the study staff. 
7. At approximately 23:00, lights will be turned out, and the subject will be encouraged to 
sleep. 
 
Day 3 
1. The subject will be awakened approximately between 7:00-8:00 AM and allowed time for 
routine hygiene. 
2. A fingerstick value will be obtained upon waking while the subject is still fasting.  
3. Breakfast: A breakfast meal will be served at approximately 8:00-9:00 AM. The subject will 
define the amount of carbohydrates in the breakfast meal. The subject will be informed of 
the planned exercise and may choose to underestimate the carbs in the breakfast meal. The 
amount of carbs designated by the subject will be consistent between the Control and 
Experimental admission.  
a. Experimental Admission – The subject will inform DiAs of the breakfast meal 
carbohydrates and current blood glucose level by activating the meal screen of the 
system. Insulin will be administered based on the new therapy regimen (basal 
profile, correction factor and carbohydrate ratio profiles) and according to the 
subject’s estimate of the carbohydrate content of the meal. The subject will self-
administer the DiAs-calculated meal bolus under study staff supervison.   

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 20 
b. Control Admission – The subject will inform DiAs of the breakfast meal 
carbohydrates and current blood glucose level by activating the meal screen of the 
system. Insulin will be administered based on the subject’s regular therapy regimen 
(basal profile, correction factor and carbohydrate ratio profiles) and according to the 
subject’s estimate of the carbohydrate content of the meal. The subject will self-
administer the DiAs-calculated meal bolus under study staff supervison. The subject 
may use a temporary basal rate in preparation for exercise per the subject’s usual 
routine.   
4. Exercise Session: The subject will perform a controlled exercise activity designed to 
maintain (HR) at ~140 bpm and starting at approximately 10:00 AM. The exercise will 
consist of 45 minutes of cardiovascular activities that are divided into consecutive 15 
minute periods. Fingerstick BG will be performed before and after each 15 minute exercise 
bout and entered into DiAs via the BG entry screen. Blood glucose value must be ≥80 mg/dL 
to initiate each 15 minute exercise bout. Once exercise is started, fingerstick BG <100 mg/dL 
will be treated according to the Hypoglycemia Treatment Guidelines. Subjects will wear a 
heart rate monitor during this exercise session. 
a. Experimental Admission – The subject or study staff will inform DiAs of the 
impending exercise session by pressing the exercise advice button.  The exercise 
advice given by DiAs will be followed and may consist of the following: 
i. If no risk of hypoglycemia is detected, no intervention will be 
recommended.  
ii. If a mild-moderate risk of hypoglycemia is detected, DiAs will 
recommend a 0% temp basal rate x 1 hour for CSII users and a 12-16 
gram snack for MDI users.  
iii. If a high risk of hypoglycemia is detected, DiAs will recommend a 0% 
temp basal rate x 1 hour plus a 12-16 gram snack for CSII users and a 
24-32 gram snack for MDI users. 
After this initial advice, any carbs consumed during exercise will be per the Hypoglycemia 
Treatment Guidelines. Carbs advised by the system may replace additional hypoglycemia 
treatment if the amount is appropriate (no double treatments) 
b. Control Admission – Any carbs consumed during exercise will be per the 
Hypoglycemia Treatment Guidelines.  
5. Lunch: A lunch meal will be served at approximately 12:00-1:00 PM. The subject will 
estimate the amount of carbohydrates in lunch meal. The amount of carbs designated by 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 21 
the subject will be consistent between the Control and Experimental admission.  
a. Experimental Admission – The subject will inform DiAs of the lunch meal 
carbohydrates and current blood glucose level by activating the meal screen of the 
system. Insulin will be administered based on the new therapy regimen (basal 
profile, correction factor and carbohydrate ratio profiles) and according to the 
subject’s estimate of the carbohydrate content of the meal. The subject will self-
administer the DiAs-calculated meal bolus under study staff supervison.   
b. Control Admission – The subject will inform DiAs of the dinner meal carbohydrates 
and current blood glucose level by activating the meal screen of the system. Insulin 
will be administered based on the subject’s regular therapy regimen (basal profile, 
correction factor and carbohydrate ratio profiles) and according to the subject’s 
estimate of the carbohydrate content of the meal. The subject will self-administer 
the DiAs-calculated meal bolus under study staff supervison.   
6. Quiet activities will be conducted during the afternoon and evening hours.  
 
G. Procedures Related to Discharge  
1. At approximately 16:00, DiAs will be stopped and study equipment will be removed. 
2. The subject will resume his/her normal home CSII or MDI insulin therapy. 
3. The subject will be discharged if the fingerstick value is 80-300 mg/dL and ketone <0.6 
mmol/L. Staff will also review to ensure that the glucose trend is stable. 
4. If the subject’s glucose is out of the specified parameters, the Glycemic Treatment 
Guidelines (Appendix A-6) will be followed until the subject is in the specified range. 
5. The subject will be offered a meal prior to discharge. 
6. Subjects will be asked to check BG before dinner, at bedtime, and upon awakening the 
following day and to monitor for possible symptoms of hypoglycemia since discharge.  
7. Study staff will contact the subject within 24-48 hours after discharge to enquire about AEs 
or BG <50 or >400 mg/dL. 
8. If the first admission was the Control admission, the subject will participate in Visit 3 
approximately 30 days prior to the Experimental admission. Appropriate study supplies will 
be provided.  

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 22 
Meals 
1. Distribution of meals will be determined by the parameters defined by the subject’s weight 
(Rounded to the nearest 10 kgs.) and multiplied by the carbohydrate/fat/protein ratio as 
described in Figure 2. Meals will be a wide variety of carbohydrate/fat/protein to fully test 
the optimization capabilities of the bolus calculator.  
2. Meals will be replicated during each admission.  
3. The subject or study staff will enter the amount of carbohydrates into the DiAs meal screen 
for each meal. Carbohydrate amounts may be underestimated prior to exercise if that is the 
usual home routine. 
4. Snacks will only be permitted if advised by DiAs prior to exercise and per the usual routine 
prior to bedtime. Snacking between meals will not be permitted. 
Meal 
Carb 
Fat 
Protein 
Carb 
(g/kg) 
Fat 
(g/kg) 
Protein 
(g/kg) 
Day 1 
Dinner 
High 
Low 
Moderate 
1 
0.2 
0.27 
Day 2 
Breakfast 
Low 
Low 
Moderate 
0.5 
0.14 
0.27 
Lunch 
Moderate 
High 
Moderate 
0.75 
0.46 
0.27 
Dinner 
High 
High 
Moderate 
1 
0.53 
0.27 
Day 3 
Breakfast 
Low 
Low 
Moderate 
0.5 
0.14 
0.27 
Lunch 
Moderate 
Low 
Moderate 
0.75 
0.17 
0.27 
Figure 2:  Meal Composition  
Equipment Specifications 
1. All study equipment including the DiAs cell phone, computers, insulin pump (for CSII 
subjects), and CGM receivers will be set to the same time using an atomic clock as a 
reference. 
2. The study team will train the subject on the DiAs interface until all questions are answered. 
However, study staff will supervise all interactions with the DiAs, including entering 
information for meal dosing, FSBG results, hypoglycemia treatments and temporary basal 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 23 
rates. 
3. The CGM tracing will be blinded on the DiAs and on the CGM receiver.  
4. Subjects will wear a heart rate monitor during each exercise session. 
Blood Glucose Measurements  
 The subject will be instructed that all fingersticks should be preceded by hand washing with 
warm water and a dry towel. The subject will be instructed to obtain fingerstick, avoiding 
alternative sites, when obtaining blood values. The first drop of blood will be discarded. The 
second hanging drop will be used to measure the glucose level. 
• The subject will be reminded that all treatment decisions should be based on fingerstick 
values and not on CGM values. 
• Once a fingerstick is obtained for any reason during the admissions, the Glycemic Treatment 
Guidelines (Appendix A-6) will be followed to determine timing of subsequent fingersticks.  
• Scheduled times: prior to meals and snacks, before and after each 15 minute exercise bout, 
and at bedtime (23:00).  
• Prior to calibration of CGM and/or if calibration is requested by CGM. 
• The subject may request any additional fingersticks as desired. 
• Study personnel may also request additional fingersticks at their discretion. 
• BG treatments will be based on Glycemic Treatment Guidelines (Appendix A-6) although 
hypoglycemic treatments can occur at any time per the subject’s request.   
• If CGM <80 mg/dL, SMBG will be performed every 15 minutes. If SMBG <100 mg/dL, the 
Glycemic Treatment Guidelines (Appendix A-6) will be applied. 
• If CGM >300 mg/dL, SMBG will be performed every 60 minutes. If SMBG >300 mg/dL, the 
Glycemic Treatment Guidelines (Appendix A-6) will be applied. 
• In case of remote monitoring unavailability or in case of CGM failure (an alert will sound on 
the DiAs and on the remote monitoring), SMBG will be collected at bedtime, 3am and 7am 
until the issue is resolved.  
• Calibrations of the CGM will be per manufacturer guidelines. Hypoglycemia treatment (e.g. 
glucose tablets, glucose gel/liquid, and a glucagon emergency kit) will be available for 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 24 
treatment at all times.  
• The subject will have access to ad lib glucose-free beverages. 
• A study MD will be available for any clinical concerns. 
• The Senior DiAs Engineer with remote monitoring capability will be available if needed to 
view the study from another location. A DiAs trained technician will be on site for any 
system issues. 
• The subject will be accompanied by a medically qualified staff member and a technician 
during the admissions. 
SAFETY MONITORING / RISK ANALYSIS 
 
Monitoring Procedures by Staff 
1. CGM values are updated onto DiAs every 5 minutes.  
2. Study staff will be constantly monitoring the CGM and subject-entered SMBG values from 
the remote monitoring website and alert nursing and physician staff when the CGM is <80 
or >300 mg/dL.  
3. If CGM < 80 mg/dL, SMBG will be performed every 15 minutes. If SMBG >80 mg/dL, the 
Glycemic Treatment Guidelines (Appendix A-6) will be applied during both the Experimental 
and Control admissions.   
4. If CGM >300 mg/dL, SMBG will be performed every 60 minutes. If SMBG >300 mg/dL, the 
Glycemic Treatment Guidelines (Appendix A-6) will be applied Experimental and Control 
Admissions.  
5. The DiAs trained technician will monitor the system for the first floor of the research 
house/hotel during the entire admission.  
6. Medical personnel and emergency supplies are on the first floor of the research 
house/hotel but the study staff periodically round subjects’ rooms on both floors during the 
overnight hours.  
 
Glucose Monitoring Risk:  
Bayer CONTOUR NEXT glucometer is a FDA approved 510K Class II Medical Device (510K number 
K121087).  
 
Hypoglycemic/Hyperglycemic Risk:  

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 25 
The Glycemic Treatment Guidelines will be followed during Visit 4 and Visit 5. The treatment 
guidelines are attached in Appendix A-6. 
 
Calibration of CGM Risk:  
The CGM will be calibrated using fingerstick values before meals, bedtime, and as requested by 
the device during both the Experimental and Control Admissions. The study team may recommend 
calibrations as needed.  
 
Sterilization Risk:  
Study equipment cannot be sterilized in an autoclave. Cleaning instructions for study 
equipment provided to study the subject are provided below. 
 
Device Reuse Risk: 
The Dexcom Continuous Glucose Monitors are labeled for single use only. The sensor, the 
component of the system that enters the skin, will be single use only. The transmitter and 
receiver will be reused after cleaning as described below. The transmitter is attached to the 
sensor but does not enter the skin and the receiver is a hand held device. The transmitter and 
receiver will be cleaned adhering to hospital protocol as described below. The subject will be 
informed that the FDA has approved these devices for single use and that by using them among 
multiple patients, bloodborne pathogens (i.e. Hepatitis B) may be spread through the use of 
multiple users.  
Cleaning Procedure: Equipment that touches intact skin will be cleaned with ethyl or isopropyl 
alcohol (70-90%), quaternary ammonium germicidal detergent (i.e. CaviCide) or household 
bleach. The contact time on the surface depends on the method used to clean the equipment. 
CaviCide requires three minutes on the surface. Clorox Germicidal Bleach Wipes require two 
minutes on the equipment. The surface should remain wet (i.e. slightly damp) with the 
disinfectant to be considered effective though not wet enough to leave drops of liquid. 
Equipment will be stored in a clean zipped bag. 
The study glucometers are single use devices. 
The insulin pens are single use devices.  
Hb1Ac Risk: The University of Virginia central labs have College of American Pathologist (CAP) 
and the Clinical Laboratory Improvement Amendments (CLIA) certifications. While the central 
lab is not NGSP certified, the calibrators for the HbA1c assay are traceable to NGSP. The 
equipment (Tosoh G7) is NGSP certified. 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 26 
 
Misuse Risk: 
CGM Training: 
The subject will be introduced to the blinded CGM by a qualified member of the study team. 
The subject will be instructed how the device is inserted, calibrated and removed. The subject 
will be trained how to upload the CGM data. The subject will verbalize understanding of how 
the device is used, how to insert the device, how to calibrate the device and how to remove the 
device. The subject, with the guidance of the study team, will then insert the sensor and begin 
wearing the CGM. The study team will teach the subject how to calibrate the device as needed. 
The study team will confirm that all questions have been answered and that the subject has 
understood the training. The subject will be given a contact sheet containing phone numbers 
for the study team to call with any questions 24 hours per day. 
Study Glucometer Training: 
The Bayer CONTOUR NEXT Blood Glucose Monitoring System will be used during visit 2-5 as the 
study glucometer. The subject will be trained on proper use of the meter as described in the 
user manual. The subject will then be required to demonstrate proficiency on the use of the 
device. The subject will be instructed to wash their skin with warm water and a clean towel 
prior to obtaining fingerstick values. The subject will be instructed to obtain a fingerstick, 
avoiding alternative sites, when obtaining blood values. The first drop will be discarded. The 
second hanging drop will be used to measure the glucose level. QC will be completed prior to 
the subject receiving the study glucometer. The study team will confirm that all questions have 
been answered and that the subject has understood the training. 
DiAs Training: 
During the Control and Experimental admissions, a brief introduction to the DiAs UI will occur 
with a qualified clinical member of the study team. DiAs will be used as an insulin-dosing 
calculator for both admissions and the advice recommended by DiAs will be instituted using the 
home insulin pump for CSII users or the study insulin pen (Experimental admission) or home 
insulin pen (Control admission) for MDI users.  For the Control admission, DiAs will be pre-
programmed by the study team with the subject’s home insulin parameters. For the 
Experimental admission, DiAs will be pre-programmed with the optimized insulin parameters 
per the decision support system and that have been approved by the study physician. To 
minimize risk associated with the use of DiAs: 
1. The study team will confirm the home pump parameters entered in DiAs during 
the Control admission and the physician-approved optimized parameters during 
the Experimental admission.  

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 27 
2. DiAs CGM tracing will be remotely monitored at all times and monitored by a 
qualified study technician. Nursing and physician staff will be informed when the 
CGM is <80 or >300 mg/dL.  
3. Qualified study staff will supervise the subject during all interactions with the DiAs 
UI and during all administration of insulin. 
Risks of blood sampling collection, contamination from sampling techniques 
Hand washing with either soap & water or waterless hand sanitizer will be used prior to caring 
for the study subject. Gloves will be worn during blood sample collection and processing. 
Medical personnel will continue to practice hygiene for the patient's protection (i.e. hand 
washing, changing gloves frequently, disposing needles properly). Gloves will be removed and 
hands washed prior to leaving and upon return to the subject’s room. Soiled linen will be 
changed to minimize the transfer of pathogenic organisms. 
Study personnel with direct subject contact are required to complete Bloodborne Pathogens 
and Infection Control training annually. 
MEDICAL PERSONNEL TRAINING  
All study nurses will be currently licensed RNs or Nurse Practitioners. Emergency Medical 
Technicians or nursing students currently enrolled in accredited nursing program will be 
supervised by licensed nursing personnel. All medical personnel who will have direct contact 
with the study subject have current certification in CITI Training, Basic Life Support including 
CPR and AED. Medical personnel are oriented to the study protocol.  
In addition, liquid fast-acting rescue carbohydrates, glucagon injection, automated external 
defibrillator (AED) and Ambu-bag for ventilation will be available during the study procedures.  
STOPPING RULES 
Entire study 
The study will be stopped if two similar AE’s occur that result in stopping the study for 
individual study subjects or if there are system communication failures, which may trigger 
revision of the system software. The Principal Investigator and Senior DiAs Engineer will 
evaluate this data and make recommendations concerning continuation, modification, or 
termination of the trial. Additionally, the Principal Investigator or the IRB-HSR may decide to 
stop the trial or part of the trial at any time. In this case, the Principal Investigator will promptly 
inform the subjects and assure appropriate therapy and follow-up. Additionally the Principal 
Investigator will notify the IRB if the study is temporarily stopped. The pertinent regulatory 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 28 
authorities will be informed according to national regulations. 
Early study stop will be documented and following information will be collected: 
1. Date and cause of the ending 
2. Description of any serious adverse event leading to the study ending 
3. In the case of an unanticipated adverse device effects (UADE), the overall study 
may be suspended while the problem is diagnosed and the Principal Investigator 
investigates the UADE. If the Principal Investigator determines that the UADE 
poses an unreasonable risk to subjects, the study should be suspended until this 
UADE can be resolved. If it cannot be resolved, the study should be terminated. 
Termination should occur no later than 5 working days after Principal Investigator 
makes the decision to end the trial. The result of the investigation and the 
Principal Investigator’s decision to terminate the study shall be reported the site 
IRB, and the FDA per 21CFR 812.46(b) (2). The Principal Investigator must 
determine if the UADE presents an unreasonable risk to subjects. If so, all 
investigations, or parts of investigations presenting that risk, are terminated or 
halted as soon as possible but no later than 5 working days after making this 
determination and no later than 15 working days after first receipt notice of the 
UADE. 
4. The study may resume if the underlying problem can be corrected by a protocol or 
system modification that will not invalidate the results obtained prior to 
suspension. The IRB will be notified if the study is stopped, and permission to 
resume will be obtained from the FDA and IRB prior to restarting. 
Criteria for stopping study an individual subject 
1. The subject may request to be withdrawn (withdrawal of informed consent) from 
the study at any time for any/no reason. The Principal Investigator, IRB-HSR, or 
Senior DiAs Engineer may decide to stop the trial or part of the trial at any time. In 
this case, the Principal Investigator will promptly inform the subject and assure 
appropriate therapy and follow-up, if needed. The pertinent regulatory authorities 
will be informed according to national regulations.  
2. The subject will be stopped if time between Visit 4 and Visit 5 exceeds 100 days.  
3. A subject who does not complete the protocol may be replaced or rescheduled. 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 29 
4. If the subject has a positive pregnancy test, she will be stopped.  
5. If the subject has a serious adverse event, he/she will be stopped.   
Study procedures other than those required for subject safety would be stopped during 
the admissions if: 
a. The subject has a positive pregnancy test. 
b. The subject had a serious adverse event deemed related to study. 
c. Glucagon is required to treat hypoglycemia. 
d. The subject experiences a seizure. 
e. The subject experiences loss of consciousness. 
f. The subject becomes unable to eat or drink. 
g. The subject develops ketones >3.0 mmol/L. 
h. The subject develops abdominal pain, vomiting illness, fever ≥101.5ºF, clinical need 
for acetaminophen, significant illness, or need to use epinephrine or glucocorticoids. 
i. Subjects who were not able to complete the study for reasons other than a serious 
adverse event (i.e. hypoglycemic seizure, etc.) will be permitted to repeat the 
session. 
The subject may resume the study after the following problems are resolved: 
1. Correction of a malfunction of the system or controller once the problem is clearly 
identified and the system has been repaired  
2. Correction of ketones ≥0.6 mmol/L or BG ≥300 for 2 hours or more:  Study may be 
resumed when ketones are <0.6 mmol/L and the meter glucose is between 80-250 
mg/dL.   
3. Loss of sensor data acquisition for more than three hours  
4. If remote monitoring cannot be restored within 180 minutes, the CGM receiver 
will be unblinded and study staff will monitor it at least hourly. Values will remain 
blinded to the subject by covering the display.  

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 30 
Reason Study Stopped 
Repeat Session? 
Equipment Failure or similarly related 
issues that invalidate study data 
Can repeat session 
Hyperglycemic Events that did not result in 
Serious Adverse Event 
Can repeat session 
Hypoglycemic Events that did not result in 
Serious Adverse Event 
Can repeat session 
PI initiated discontinuation of study due to 
patient or equipment concerns 
Can repeat session 
Serious or Unanticipated Adverse Event 
deemed related to the study 
Unable to repeat session 
Table 1:  Repeat Session Table 
SAFETY MONITORING  
Adverse Events, Unanticipated Problems, Protocol Violations and Data Breaches 
Reporting of events are noted below:    
 
Type of Event 
To whom will it 
be reported: 
Time Frame for 
Reporting 
How reported? 
Any internal event resulting in 
death that is deemed DEFINITELY 
related to (caused by) study 
participation 
(Note:  An internal event is one that 
occurs in a subject enrolled in a 
UVa protocol.) 
IRB-HSR 
Within 24 hours 
IRB Online and phone call 
 
www.irb.virginia.edu/ 
 
Internal, Serious, Unexpected 
adverse event  
 
 
IRB-HSR 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event. 
Timeline includes 
submission of signed 
hardcopy of AE form. 
IRB Online 
 
www.irb.virginia.edu/ 
 
For Device Studies:  Unanticipated 
adverse device effects (internal) 
IRB-HSR 
Within 10 day 
calendar days of the 
study team receiving 
knowledge of the 
event 
 
IRB Online 
 
www.irb.virginia.edu/ 
 
Unanticipated Problems that are 
not adverse events or protocol 
violations  
This would include a Data Breach.   
IRB-HSR 
Within 10 day 
calendar days of the 
study team receiving 
knowledge of the 
event 
IRB Online 
 
www.irb.virginia.edu/ 
 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 31 
Protocol Violations/Noncompliance  
The IRB-HSR only requires that 
MAJOR violation be reported, 
unless otherwise required by the 
sponsor 
 
OR  
Enrollment Exceptions 
IRB-HSR 
 
 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event.  
Unanticipated Problem report 
form.  
 
http://www.virginia.edu/vprgs/
irb/HSR_docs/Forms/Reporting
_Requirements-
Unanticipated_Problems.doc ) 
Data Breach  
IRB-HSR 
 
 
Within 7 calendar 
days from the time 
the study team 
received knowledge 
of the event.  
 
Protocol Violation, 
Noncompliance and Enrollment 
Exception Reporting Form 
 
 
http://www.virginia.edu/vprgs/
irb/hsr_forms.html 
Go to 3rd bullet from the 
bottom 
Data Breach 
The UVa 
Corporate 
Compliance and 
Privacy Office, a 
 
 
ITC:  if breach 
involves  
electronic data-  
 
 
 
Police if breach 
includes items 
that are stolen: 
 
Stolen on UVA 
Grounds 
 
OR  
 
Stolen off UVa 
Grounds- 
contact police 
department of 
jurisdiction of 
last known 
location of PHI 
As soon as possible 
and no later than 24 
hours from the time 
the incident is 
identified. 
 
As soon as possible 
and no later than 24 
hours from the time 
the incident is 
identified. 
 
IMMEDIATELY.  
 
 
UVa Corporate Compliance and 
Privacy Office- Phone 924-9741 
 
 
 
 
ITC:  Information Security 
Incident Reporting procedure,  
http://www.itc.virginia.edu/sec
urity/reporting.html 
 
 
 
 
 
 
UVa Police- Phone-  
(434) 924-7166 
UVa PI HELD IDE 
Life-threatening and/or fatal 
unexpected events related or 
possibly related to the use of the 
investigational agent. 
FDA 
Within 7 calendar 
days of the study 
team learning of the 
event 
Form FDA 3500A (MedWatch) 
or narrative 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 32 
Serious, unexpected and related or 
possibly related adverse events 
FDA 
Within 15 calendar 
days after the study 
team receives 
knowledge of the 
event 
Form FDA 3500A (MedWatch) 
or narrative 
Unanticipated adverse device 
effects (internal or external) 
FDA 
Within 10 working 
days of the study 
team receiving 
knowledge of the 
event 
 
Form FDA 3500A (MedWatch) 
or narrative 
All adverse events 
FDA 
Annually 
IDE annual report 
 
Table 2:  Adverse Events, Unanticipated Problems, Protocol Violations and Data Breaches 
 
Definition of Adverse Event: A reportable adverse event is any untoward medical occurrence 
or any unexpected medical occurrence in a study subject.     
Hypoglycemic events are recorded as Adverse Events if the event required assistance of 
another person due to altered consciousness to actively administer carbohydrate, glucagon, 
or other resuscitative actions.  This means that the subject was impaired cognitively to the 
point that he/she was unable to treat him or herself, was unable to verbalize his or her 
needs, was incoherent, disoriented, and/or combative, or experienced seizure or coma.  
These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma.  
If plasma glucose measurements are not available during such an event, neurological 
recovery attributable to the restoration of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration.   
 
Hyperglycemic events are recorded as Adverse Events if evaluation or treatment was 
obtained from a health care provider or if the event involved diabetic ketoacidosis (DKA), as 
defined by the Diabetes Control and Complications Trial (DCCT), and had all of the following:  
 
Symptoms such as polyuria, polydipsia, nausea, or vomiting;  
 
Serum ketones or large/moderate urine ketones;  
 
Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
 
Treatment provided in a health care facility 
 
Recording of Adverse Events: Throughout the course of the study, all efforts will be made to 
remain alert to possible adverse events or untoward findings.  The first concern will be the 
safety of the subject, and appropriate medical intervention will be made. 
The investigator will elicit reports of adverse events from the subject at each visit and 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 33 
complete all adverse event forms.  
The investigator will assess the relationship of any adverse event to be related or unrelated 
by determining if there is a reasonable possibility that the adverse event may have been 
caused by the study device or study procedures.    
The intensity of adverse events will be rated on a three-point scale: (1) mild, (2) moderate, or 
(3) severe.  It is emphasized that the term severe is a measure of intensity: thus a severe 
adverse event is not necessarily serious.  For example, itching for several days may be rated 
as severe, but may not be clinically serious.   
Adverse events that continue after the participant’s discontinuation or completion of the 
study will be followed until their medical outcome is determined or until no further change in 
the condition is expected.   
Adverse events will be coded using the MedDRA dictionary.  
Definitions of relationship and intensity are listed on the data entry form.   
 
Reporting Serious or Unexpected Adverse Events 
A serious adverse event is any untoward occurrence that: 
 results in death, 
 is life-threatening (a non-life-threatening event which, had it been more severe, might have 
become life-threatening, is not necessarily considered a serious adverse event), 
 requires inpatient hospitalization or prolongation of existing hospitalization, 
 results in significant disability/incapacity, or  
 is a congenital anomaly/birth defect 
 
An Unanticipated Adverse Device Event (UADE) is defined as an adverse event caused by, or 
associated with, a device, if that effect or problem was not previously identified in nature, 
severity, or degree of incidence. 
All anticipated Adverse Events will be reported in details to both the IRB and FDA with the 
results of the study within 3 months of the completion of the trial. 
UADE will be thoroughly investigated and as required by 21 CFR 812.46, they will be reported 
to FDA and IRB no later than 10 working days after the sponsor first receives notice of the 
effect. 
The CGM (Dexcom Share AP) malfunctions which are not related to the modifications of the 
interface to include them as components of the AP device will be reported to its respective 
manufacturers as a complaint per MDR requirements (Dexcom for the Share AP CGM). 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 34 
Malfunctions related to the interfaces of the CGM with the DiAs platform will also be 
reported to their respective manufacturers within 10 days. 
The principal investigator/s is responsible for informing the UVA IRB of serious study-related 
adverse events and abiding by any other reporting requirements specific to their IRB 
Definition of an unanticipated problem  
An unanticipated problem is any event, experience that meets ALL 3 criteria below: 
 not anticipated or foreseen (e.g., not described in the consent form); 
 involves risk or harm to a research participant or others; and 
 probably, definitely related to, or caused by, the research. 
Definition of a protocol violation 
A protocol violation is defined as an accidental or unintentional change to the IRB approved 
protocol that harmed participants or others or that indicates participants or others may be at 
increased risk of harm. 
Definition of a Protocol Enrollment Exception 
No enrollment exceptions will be permitted in this trial. 
Definition of a Data Breach 
A data breach is defined in the HITECH Act (43 USC 17932) as an unauthorized acquisition, 
access, or use of protected health information (PHI) that compromises the security or privacy of 
such information. 
Data Collection 
Endpoint data be collected/recorded in the form of source documents and will be stored on a 
database on a Health Systems Computing Services (HS/CS) managed server that is configured to 
store data regulated by HIPAA.  
At UVa, safety data oversight will be completed by a member the UVa Clinical Trials Office. An 
example of the Monitoring Form is presented in Appendix A-10. 
The PI will conduct an aggregate review of the following data: 
 All adverse events 
 Unanticipated Problems 
 Protocol violations 
 Audit results 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 35 
 Early withdrawals 
 Data processing review 
IRB-HSR will be updated annually on the IRB-HSR continuation status form. This annual report 
will address: 
 Brief summary of research progress 
 Whether adverse event rates are consistent with pre-study assumptions 
 Enrollment status 
 Reason for dropouts from the study 
 Whether continuation of the study is justified 
 Conditions whereby the study might be terminated prematurely 
The relevant device regulation for reporting adverse events to the FDA will also be followed. 
Data from each subject will be reviewed by the PI after completion of participation to 
determine whether the DiAs system was working properly and whether there were safety 
concerns. 
Adverse Events / Unanticipated Problems 
Recording, Reporting, and Grading 
Only adverse events that are deemed related AND serious will be recorded, reported, and 
graded. The principal investigator will be responsible for the overall safety monitoring of the 
study. The principal investigator, along with the sub-investigators, will review the individual 
adverse events as they occur.  Any event that merits adverse event reporting will be collected 
and recorded in the IRB database by completing the IRB Adverse Event Reporting form online.  
The principal investigator can then use this database to produce a report of all adverse events 
reported on the study to do an aggregate review.  If the AE is unexpected and serious, a signed 
hard copy of the IRB Adverse Event Reporting form will be submitted to the IRB within 7 
calendar days. 
Grading of Adverse Events 
 Mild/Moderate/Severe 
 Serious/Not serious 
 
The PI will determine the relationship of adverse events to the study using the following 
scale: 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 36 
 Related:  AE is clearly related to the intervention 
 Possibly related:  AE may be related to the intervention 
 Unrelated:  AE is clearly not related to intervention 
 
Reporting/recording of adverse events/unanticipated problems will begin after the subject 
begins study drug/device placement/intervention/study-related procedure/specimen 
collection. 
Reporting/recording of adverse events/unanticipated problems will end at the end of study 
drug/device/ intervention/participation. 
CATASTROPHIC EVENT PLAN 
The Outpatient Emergency Plan will go into effect should a catastrophic event occur during the 
study admissions. A catastrophic event is defined as any event that requires emergency 
treatment by medical professionals that exceed the expected parameters of the protocol. A 
copy of this plan will be located at the monitoring desk. Staff will be aware of its location at all 
times. 
In the unlikely event of a disruption in 911 phone service, the sites will contact their local non-
emergency number (e.g. Charlottesville-UVA-Albemarle Emergency Communications Center can 
be reached via their non-emergency number 434-977-9041). This number feeds into their main 
call area where 911 dispatchers are available 24/7. 
 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 37 
Event 
RN Response 
Tech Response 
Respiratory Arrest 
1) Tell Tech to call 911 
2) Begin Basic Life Support 
Refer to Study Physician 
Cardiac Arrest 
1) Tell Tech to call 911 
2) Begin Basic Life Support 
Refer to Study Physician  
Severe Hypoglycemic Event as 
defined by hypoglycemia 
accompanied by unconsciousness 
or seizure 
1) Tell Tech to call 911 
2) Administer glucagon IM 
(described in Glycemic Treatment 
Guidelines Appendix A-6) 
3) Remove study pump 
Refer to Study Physician  
Severe Hyperglycemic Event as 
defined by β-ketone level ≥3.0 
mmol/L 
 
1) Discuss correction dose of insulin 
to administer s.c. via syringe with 
study M.D. 
Refer to Study Physician  
2) Encourage P.O. water intake 
3) Remove study pump and start 
home insulin pump 
4) Go to nearest medical facility for 
evaluation and treatment. 
Table 3: Outpatient Emergency Plan 
ENDPOINTS 
We assess the risk to the subject by computing the two classical hypo and hyperglycemia risk 
indices LBGI and HBGI, based of the blinded CGM data, retrofitted to the SMBG point (see 
DelFavero et al. JDST 2015). Gaps of less than 3h will be filled using spline based interpolation. 
LBGI is the primary endpoint. 
LBGI and HBGI are measures of glycemic risk that were developed by our groups in the late 
1990s and have been shown to be predictive of increased frequency of severe hypoglycemia 
and increased HbA1c. Detailed formula can be found in Kovatchev et al. Diabetes Care 1998. 
In addition we will capture: 
 Quality of glycemic control using the percent time spent between 70mg/dl and 
180mg/dl. 
 Meal insulin coverage will be assessed using Area Under the glucose Curve in the 
postprandial state. 

CLINICAL PROTOCOL 
 
 
Version Date:  10/14/16 
Page 38 
 Glucose variability will be assessed using the Risk Index (sum of LBGI and HBGI). 
SUCCESS CRITERIA / GOAL 
As a general rule, a session will be considered useful for data analysis if the subject completes 
more than 80% of the active study protocol. Subjects completing less than 80% of the protocol 
may be rescheduled.   
Safety and feasibility will mean that using our system, subjects will not increase either their risk 
of hypoglycemia as measured by LBGI (non-inferiority claim) 
STATISTICAL ANALYSIS PLAN 
All variables are continuous and though bounded by 0 unlikely to be close to their lower bound, 
therefore we will compare the control and experimental admissions using a paired Student t-
test for equality of mean. Nonetheless, LBGI may be very low in some subjects during the 
control admission. If such effect is observed in more than 5 subjects, LBGI will studied using the 
Wilcoxon signed rank test.