USS Virginia Closed-Loop for Overnight Control in Type 1 Diabetes

Unified Safety System (USS) Virginia Closed-Loop Versus Sensor Augmented Pump Therapy for Overnight Control in Type 1 Diabetes

The purpose of this study is to use the USS Virginia Closed-Loop system for overnight insulin delivery in adults with Type 1 Diabetes (T1DM) in an outpatient setting to evaluate the system's ability to significantly improve blood glucose levels. This protocol will test the feasibility of "bedside" closed-loop control - an approach comprised of standard sensor-augmented pump therapy during the day using off-the-shelf devices and overnight closed-loop control using experimental devices in an outpatient setting. The rationale for this study is as follows: we anticipate that closed-loop control may ultimately be adopted by patients with T1DM in a selective manner. Patient may choose to start using these systems for overnight control only, e.g. to alleviate the well documented fear of hypoglycemia while asleep. To test this paradigm of "bedside" closed-loop control, subjects will be studied with continuous glucose monitoring (CGM)-augmented usual pump therapy during the day followed by overnight use of USS Virginia Closed Loop Control.

The subject will participate in both the Experimental and the Control Admissions. The order of the two admissions will be randomized. During the Control Admission at home, the subject will use the study insulin pump along with a continuous glucose monitor receiver. During the Experimental Admission, the subject will be the research house/hotel where the subject will be in control of the DiAs. Participation in this study will require 5 study visits over 11-14 weeks.

Inclusion Criteria:

1. Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one year and using insulin for at least 1 year and an insulin pump for at least 6 months

   - Criteria for documented hyperglycemia (at least 1 must be met): i. Fasting glucose ≥126 mg/dL ii. Two-hour Oral Glucose Tolerance Test (OGTT) glucose ≥200 mg/dL iii. HbA1c ≥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.

   - 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 ≥21 to <65 years

3. HbA1c <10.0%

4. For females, not currently known to be pregnant 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. Demonstration of proper mental status and cognition for the study

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

7. Ability to access the Internet and upload CGM data via the DexCom company software during the data collection period.

8. Willingness to remain within approximately 30 miles radius of study site during the day time hours of Visit 4.

9. An understanding of and willingness to follow the protocol and sign the informed consent

Additional Inclusion Criteria for UVA subjects only who participate in the 5 days at-home portion

• Availability of a significant other or family member committed to participating in all training activities, knowledgeable at all times of the participant's location, and being present and available to provide assistance when system is being used at night
• Commitment to maintaining uninterrupted availability via cell phone and avoiding any overnight travel for the duration of the period of time using the closed-loop system at home.
• Access to internet and cell phone service at home

Exclusion Criteria:

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

2. Severe hypoglycemia resulting in seizure or loss of consciousness in the 12 months prior to enrollment

3. History of a seizure disorder (except hypoglycemic seizure), unless written clearance is received from a neurologist

4. Coronary artery disease or heart failure, unless written clearance is received from a cardiologist

5. Cystic fibrosis

6. A 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
   • Presence of a known adrenal disorder
   • 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
   • 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
   • Active gastroparesis
   • 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
   • 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
   • Abuse of alcohol or recreational drugs
   • Infectious process not anticipated to resolve prior to study procedures (e.g. meningitis, pneumonia, osteomyelitis).
   • Uncontrolled arterial hypertension (Resting diastolic blood pressure >90 mmHg and/or systolic blood pressure >160 mmHg).
   • Oral steroids
   • 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.

7. 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

8. Basal Rates <0.01 units/hour.

9. Current use of the following drugs and supplements:

   • Acetaminophen
   • Any medication being taken to lower blood glucose, such as Pramlintide, Metformin, glucagon-like peptide (GLP)-1 Analogs such as Liraglutide, and nutraceuticals intended to lower blood glucose
   • Beta blockers
   • Any other medication that the investigator believes is a contraindication to the subject's participation