Outpatient Control-to-Range: System and Monitoring Testing

Automated closed-loop control (CLC) of blood glucose, known as "artificial pancreas" (AP)
can have tremendous impact on the health and lives of people with type 1 diabetes (T1DM).
Our inter-institutional and international research team has been on the forefront of CLC
developments since the beginning of the JDRF Artificial Pancreas initiative in 2006. Thus
far, we have conducted three closed-loop control clinical trials (totaling 60 subjects with
T1DM), which demonstrated significantly more time in an acceptable "target" blood glucose
range during CLC, and significantly fewer hypoglycemic events during CLC compared to open
loop. Our overall objective is to sequentially test, validate, obtain regulatory approval
for, and deploy at home, a closed-loop Control-to-Range (CTR) system comprised of two
algorithmic components: a Safety Supervision Module (SSM) and a Hypoglycemia Mitigation
Module (HMM). The SSM will monitor the safety of the subject's continuous subcutaneous
insulin infusion pump (CSII) to prevent hypoglycemia and will also monitor the integrity of
continuous glucose monitor (CGM) data for signal sensor deviations or loss of sensitivity.
The HMM will be responsible for the optimal regulation of postprandial hyperglycemic
excursions through correction boluses.

This study will test the ability of AP Platform to (1) run CTR in an outpatient setting, and
(2) be remotely monitored. Specifically, this study involves studying adults with T1DM who
are experienced insulin pump users. Subjects will spend two nights (~42 hours) in a local
hotel, during which the AP Platform will be remotely monitored in an adjacent hotel room for
validation that remote system monitoring can successfully occur. During the study, study
subject will be responsible for operating the CTR system with nursing and technicians
available for additional support. A study physician and senior engineer will be on call.

INCLUSION CRITERIA

1. ≥21 and <65 years old

2. Clinical diagnosis of type 1 diabetes mellitus:

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

- Fasting glucose ≥126 mg/dL - confirmed

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

- HbA1c ≥6.5% documented by history - confirmed

- Random glucose ≥200 mg/dL with symptoms

- No data at diagnosis is available but the participant has a convincing
history of hyperglycemia consistent with diabetes

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

- Participant required insulin at diagnosis and continually thereafter

- 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

- 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

3. Use of an insulin pump to treat his/her diabetes for at least 1 year

4. Actively using an insulin pump with bolus calculator feature including predefined
parameters for carbohydrate ratio, insulin sensitivity factor, target BG and active
insulin.

5. HbA1c between 6.0% - 9.0% as measured with DCA2000 or equivalent device

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

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

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

9. 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. Diabetic ketoacidosis within the 6 months prior to enrollment

2. Severe hypoglycemia resulting in seizure, loss of consciousness, or 3rd party
assistance in the 12 months prior to enrollment

3. Subject reports that he/she has hypoglycemia unawareness with severe low blood sugars
(e.g. <50 mg/dL without symptoms)

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. Conditions which may increase the risk of hypoglycemia such as any cardiac
disorder/arrhythmia, uncontrolled coronary artery disease during the previous year
(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

7. Hematocrit <40% (males) and <35% (females)

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

9. 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)

10. Anticoagulant therapy other than aspirin

11. Oral steroids

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

13. Psychiatric disorders that would interfere with study tasks (e.g. inpatient
psychiatric treatment within 6 months prior to enrollment)

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

15. Known current or recent alcohol or drug abuse

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

17. 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)

18. Impaired hepatic function measured as alanine aminotransferase or aspartate
aminotransferase ≥three times the upper reference limit

19. Impaired renal function measured as creatinine >1.2 times above the upper limit of
normal

20. Uncontrolled microvascular (diabetic) complications (other than diabetic
non-proliferative retinopathy), such as current proliferative diabetic retinopathy,
known diabetic nephropathy (other than microalbuminuria with normal creatinine) or
neuropathy requiring treatment

21. Active gastroparesis requiring current medical therapy

22. If taking 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

23. Uncontrolled thyroid disease

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. Active enrollment in another clinical trial

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

28. Use of anti-diabetic agents other than CSII including long-acting insulin,
intermediate-acting insulin, metformin, sulfonylureas, meglitinides,
thiazolidinediones, DPP-IV inhibitors, glucagon-like peptide 1 agonists, and
alpha-glucosidase inhibitors

29. Subjects with basal rates less than 0.05.

RESTRICTIONS ON USE OF OTHER DRUGS OR TREATMENTS.

1. Use of anti-diabetic agents other than CSII including long-acting insulin,
intermediate-acting insulin, metformin, sulfonylureas, meglitinides,
thiazolidinediones, DPP-IV inhibitors, glucagon-like peptide 1 agonists, and
alpha-glucosidase inhibitors.

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. Medications that block symptoms of hypoglycemia, including but not limited to beta
blockers