USS Virginia Closed-Loop Versus SAP Therapy for Hypoglycemia Reduction in T1D

The purpose of this study is to evaluate the effectiveness of the control system in reducing
hypoglycemia by comparing, in a randomized study, 24 hour control with USS Virginia versus
sensor augmented pump (SAP) therapy in subjects with type 1 diabetes and hypoglycemia
unawareness and/or risk for hypoglycemia. We will also evaluate the effectiveness of the
control system to improve hypoglycemia counterregulation, hypoglycemia awareness, and overall
glycemic control. To achieve this goal, we will conduct pre- and post-intervention inpatient
assessments of hypoglycemia counterregulation and symptom awareness. Subjects randomized to
USS Virginia will participate in two training visits at a monitored outpatient setting for
the step-wise deployment of the cell phone based Artificial Pancreas (AP) System at home. The
first training visit includes training on the study pump and AP System followed by 1 week use
of AP System at home in Pump mode. The second training visit includes additional training on
USS Virginia+AP System and confirmation of independent use by the subject followed by 4 week
use of the AP System at home in Closed Loop mode. Subjects randomized to sensor-augmented
pump therapy will complete 5 weeks of CGM with the home pump.

Inclusion Criteria:

Clinical diagnosis of type 1 diabetes for at least 1 year. For an individual to be enrolled
at least one criterion from each list must be met:

Criteria for documented hyperglycemia (at least 1 must be met):

1. Fasting glucose ≥126 mg/dL (confirmed)

2. Two-hour oral glucose tolerance test (OGTT) glucose ≥200 mg/dL (confirmed)

3. HbA1c ≥6.5% (confirmed)

4. Random glucose ≥200 mg/dL with symptoms

5. No data at diagnosis is available but the participant has a convincing history of
hyperglycemia consistent with diabetes or in the opinion of the investigator
participant has history consistent with type 1 diabetes.

Criteria for requiring insulin at diagnosis (at least 1 must be met):

1. Participant required insulin at diagnosis and continually thereafter

2. 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

3. Participant required 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 thereafter

- Use of insulin for the last 12 months or more

- Use of an insulin infusion pump for the last 6 months or longer

- Age 12-70 years old

- HbA1c <10.0% as measured with DCA2000 or equivalent device; if HbA1c <6.0% then
total daily insulin must be ≥0.5 U/kg

- Risk of hypoglycemia or hypoglycemia unawareness as defined by any of the
following:

- Clarke Hypoglycemia Perception Awareness questionnaire score of ≥4.

- Average Daily Risk Range (ADRR) >40 as assessed from Self-Monitoring Blood
Glucose (SMBG) readings from the prior month. Subject must have a glucometer that
can be downloaded for this assessment. The subjects may alternatively provide a
spreadsheet of their past 30 days of blood glucose values.

- Low Blood Glucose Index (LBGI) >2.5 as assessed from SMBG from the prior month or
LBGI >1.1 as assessed from 1 week of CGM readings from the prior three weeks.
Subject must have a glucometer or CGM that can be downloaded for this assessment.
For the glucometer data, the subjects may alternatively provide a spreadsheet of
their past 30 days of blood glucose values.

- Subject reports no recognition of hypoglycemia until the glucose is <60 mg/dL and
no adrenergic symptoms at glucose of 60 mg/dL (shakiness, palpitations,
diaphoresis).

- Able to speak and read English and use basic technology such as a cell phone.

- Currently using an insulin-to-carbohydrate ratio to calculate meal bolus sizes.

- Access to Internet or cell phone service in the subject's local environment.

- Willingness to maintain uninterrupted availability via personal cell phone at all
times during the study.

- Willingness to perform SMBG testing 4-6 times daily (before meals, about 2 hours
after meals and at bedtime, before driving, before exercise, and as indicated)
during the interventional phases of the study.

- Living with a diabetes care partner ≥18 years old who meets the following
inclusion criteria:

- Committed to potentially (if randomized to DiAs) participating in all training
activities involving DiAs components and emergency procedures,

- Knowledgeable at all times of the participant's location during the day when
closed loop is in use,

- Committed to maintaining uninterrupted availability via personal cell phone,

- Being present and available to provide assistance when the closed loop system is
being used at night,

- Able to speak and read English and use basic technology such as a cell phone, and

- Absence of known medical condition that in the judgment of the investigator might
interfere with the completion of the protocol such as the following examples:

- Inpatient psychiatric treatment in the past 6 months,

- Current or recent abuse of alcohol or recreational drugs by history

- 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.

Exclusion Criteria:

The presence of any of the following is an exclusion for the study:

1. Admission for diabetic ketoacidosis in the 12 months prior to enrollment.

2. Severe hypoglycemia resulting in seizure or loss of consciousness in the 3 months
prior to enrollment.

3. Hematocrit less that the lower limit of normal for the assay.

4. Pregnancy, breast-feeding, or intention of becoming pregnant over time of study
procedures; If female and sexually active, must agree to use a form of contraception
to prevent pregnancy while a participant in the study. A negative urine pregnancy test
will be required for all premenopausal women who are not surgically sterile. Subjects
who become pregnant will be discontinued from the study.

5. Conditions which may increase the risk of induced hypoglycemia such as: known coronary
artery disease, congestive heart failure, history of any cardiac arrhythmia (benign
premature atrial contractions and premature ventricular contractions allowed), history
of seizure disorder, history of cerebrovascular event or transient ischemic attack,
hypoglycemia-induced migraine within the last 6 months, or neurological disease.

6. Cystic fibrosis

7. A known medical condition that in the judgment of the investigator might interfere
with the completion of the protocol such as the following examples:

8. Inpatient psychiatric treatment in the past 6 months for either the subject or the
subject's diabetes care partner

9. Presence of a known adrenal disorder

10. Abnormal liver function tests (transaminase >3 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

11. Abnormal renal function test results (estimated Glomerular filtration rate (GFR) <60
mL/min/1.73m2); testing required for subjects with diabetes duration of greater than 5
years post onset of puberty

12. Active gastroparesis

13. 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

14. Uncontrolled thyroid disease (TSH undetectable or >10 mIU/L); testing required within
3 months prior to admission for subjects with a goiter, positive antibodies, or who
are on thyroid hormone replacement, and within one year otherwise

15. Current or recent abuse of alcohol or recreational drugs by patient history

16. Infectious process not anticipated to resolve prior to study procedures (e.g.
meningitis, pneumonia, osteomyelitis)

17. Any skin condition in the area of insertion that prevents safe sensor or pump
placement (e.g. bad sunburn, pre-existing dermatitis, intertrigo, psoriasis, extensive
scarring, cellulitis)

18. Diagnosed with celiac disease and not currently following a gluten free diet

- 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

- Current use of any of the following drugs and supplements:

19. Any medication being taken to lower blood glucose, such as Pramlintide, Metformin,
Glucagon-like peptide-1 (GLP-1) Analogs such as Liraglutide, and nutraceuticals
intended to lower blood glucose

20. Beta blockers

21. Oral glucocorticoids

22. Pseudoephedrine

23. Any other medication that the investigator believes is a contraindications to the
subject's participation