Feasibility Study of Closed Loop Control in Type 1 Diabetes Using Heart Rate Monitoring as an Exercise Marker

The combination of the Control to Range system and the cell phone is called the "Artificial
Pancreas (AP) Platform". The purpose of this study is to see if this investigational
technology can help control blood sugar in people with type 1 diabetes mellitus on insulin
pump therapy can be successfully used and supervised in a hospital setting. This study is
also being done to see if giving information about heart rate to the Closed-to-Range System
can reduce hypoglycemia as it relates to exercise. Subjects will exercise on an exercise
bike in the clinical research unit. During one exercise testing session, the Control to
Range System will receive information about your heart rate (Experimental Condition). During
the other exercise testing session, the Control to Range System will not receive information
about your heart rate (Control Condition). This part of the study is being done to see
whether heart rate information helps the Control to Range System reduce the occurrences of
exercise-related hypoglycemia.

The Control to Range system has two parts (modules) that can work together or separately.

A. The Safety Supervision Module helps to prevent low blood sugars. It can reduce the amount
of basal insulin that the pump is delivering and alert you if carbohydrates are needed to
help prevent a low blood sugar. This module will be active at all times during the operation
of the Control to Range System.

B. The Hyperglycemia Mitigation Module helps to prevent high blood sugars. It can instruct
the insulin pump to deliver small boluses to help prevent high blood sugar. It can also help
warn you of a possible pump problem if the blood sugar level is not responding to the
insulin as it should.

The Control to Range System works with the insulin pump and continuous glucose monitor to
help keep the blood sugar in a desired range (80-180 mg/dL) during the day and help avoid
hypoglycemia during the night.

Inclusion Criteria

1. ≥21 and <65 years old with clinical diagnosis of Type 1 Diabetes Mellitus for at
least 1 year.

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

1. Fasting glucose ≥126 mg/dL - confirmed

2. Two-hour OGTT glucose ≥200 mg/dL - confirmed

3. HbA1c ≥6.5% documented - confirmed

4. Random glucose ≥200 mg/dL with symptoms

3. No data at diagnosis is available but the participant has a convincing history of
hyperglycemia consistent with diabetesCriteria for requiring insulin at diagnosis (at
least 1 criterion 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 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
continuallyCriteria for Type 1 Diabetes Mellitus (at least 1 criterion must be
met)

4. Documented low or absent C-peptide level.

5. Documented presence of ICA or GAD65 antibodies.

4. Use of an insulin pump to treat his/her diabetes for at least 6 months

5. Actively using a bolus calculator with the current insulin pump with pre-defined
parameters for carbohydrate [CHO] ratio, insulin sensitivity factor [ISF], and target
glucose

6. HbA1c between 5.0% and 10.5% as measured with DCA2000 or equivalent device

7. Not currently known to be pregnant, breast feeding, or intending to become pregnant
(females)

8. Demonstration of proper mental status and cognition for the study.

9. Willingness to avoid consumption of acetaminophen-containing products during the
study interventions involving DexCom use.

10. If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, have
stability on the medication for at least 2 months prior to enrollment in the study.

Exclusion Criteria

1. Clinical diagnosis of Type 2 Diabetes Mellitus

2. Diabetic ketoacidosis within the 6 months prior to enrollment

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

4. Pregnancy, breast feeding, or intention of becoming pregnant

5. Uncontrolled arterial hypertension (diastolic blood pressure >90 mmHg and/or systolic
blood pressure >160 mmHg)

6. Hematocrit <36% (females); <38% (males)

7. Uncontrolled thyroid disease or thyroid replacement as determined by a TSH out of the
UVa reference range.

8. Impaired hepatic function measured as alanine aminotransferase or aspartate
aminotransferase >2 times the upper limit of normal

9. Impaired renal function measured as Creatinine >1.5 mg/dL

10. Conditions which may increase the risk of hypoglycemia such as known coronary artery
disease (e.g. history of myocardial infarction, acute coronary syndrome, therapeutic
coronary intervention, coronary bypass or stenting procedure, stable or unstable
angina, episode of chest pain of cardiac etiology with documented EKG changes, or
positive stress test or catheterization with coronary blockages >50%), congestive
heart failure, history of cerebrovascular event, seizure disorder, syncope, adrenal
insufficiency, neurologic disease or atrial fibrillation

11. Additional conditions which may inhibit the ability to perform exercise on a
stationary bike (e.g. injury to or immobility of limbs, neuromuscular disease,
exercise-induced asthma requiring inhaler use within the last 12 months or clinically
impaired pulmonary function)

12. Use of a medication that significantly lowers heart rate (beta blockers, reserpine,
guanethidine, methyldopa, clonidine, cimetidine, digitalis, calcium channel blockers,
amiodarone, antiarrythmic drugs, or lithium)

13. History of a systemic or deep tissue infection with methicillin-resistant staph
aureus or Candida albicans

14. Use of a device that may pose electromagnetic compatibility issues and/or
radiofrequency interference with the DexCom CGM (implantable
cardioverter-defibrillator, electronic pacemaker, neurostimulator, intrathecal pump,
and cochlear implants)

15. Medical condition requiring use of an acetaminophen-containing medication that cannot
be withheld for the study admissions.

16. Psychiatric disorders that would interfere with study tasks (e.g. inpatient
psychiatric treatment within 6 months prior to enrollment, uncontrolled anxiety or
panic disorder)

17. Mental incapacity, unwillingness or language barriers precluding adequate
understanding or cooperation

18. Current or recent alcohol or drug abuse by patient history

19. Medical conditions that would make operating a CGM, cell phone or insulin pump
difficult (e.g. blindness, severe arthritis, immobility)

20. Any skin condition that prevents sensor or pump placement on the abdomen or arm (e.g.
bad sunburn, pre-existing dermatitis, intertrigo, psoriasis, extensive scarring,
cellulitis)

21. Known microvascular (diabetic) complications (other than diabetic non-proliferative
retinopathy), such as history of laser coagulation, proliferative diabetic
retinopathy, known diabetic nephropathy (other than microalbuminuria with normal
creatinine) or neuropathy requiring treatment

22. Active gastroparesis requiring current medical therapy

23. 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

24. Known bleeding diathesis or dyscrasia

25. Known allergy to medical adhesives, components of the insulin pump insertion set or
continuous glucose monitor sensor

26. Anticoagulant therapy other than aspirin

27. Oral steroids

28. Active enrollment in another clinical trial

29. Unwillingness to avoid acetaminophen while the continuous glucose monitor is in use.

30. Unwillingness to withhold dietary supplements two weeks prior to admission and for
the duration of the study participation.

31. Subjects with basal rates less than 0.05.

Restrictions on use of other drugs or treatments

1. Pramlintide, liraglutide and exenatide will be held for the duration of the study
intervention.

2. Oral steroids are excluded

3. Anticoagulant therapy other than aspirin is excluded

4. Acetaminophen will not be allowed while the continuous glucose monitor is in use

5. Dietary supplements will be withheld two weeks prior to admission and for the
duration of study participation

6. Beta blockers, reserpine, guanethidine, methyldopa, clonidine, cimetidine, digitalis,
calcium channel blockers, amiodarone, antiarrythmic drugs, and lithium are excluded