Early Feasibility Study of Adaptive Advisory/Automated (AAA) Control of Type 1 Diabetes

Early Feasibility Study of Adaptive Advisory/Automated (AAA) Control of Type 1 Diabetes

The purpose of this study is to use an Advisory/Automated Adaptive (AAA) or Closed-Loop Control (CLC) system for 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. A component of this study evaluated AAA or CLC Control overnight only in 5 consecutive overnights in a cross-over trial with sensor-augmented pump therapy occurring prior to or following CLC overnight. Another component of this study planned evaluating if the AAA Control system run on the Diabetes Assistant (DiAs) system can prevent hypoglycemia during and following exercise more efficiently during a 40 hour trial this part of the trial was not conducted due to a preference for overnight only configuration in pilot testing. This protocol represents a culmination of prior clinical trials in development of this AAA system and benefits from the synthesis of those components.

The primary goal of this study is to test an Advisory/Automated Adaptive (AAA) or CLC Control system, which includes three interacting control modules:

• Module 1 - Automated Safety Supervision (SSM) responsible for prevention of hypoglycemia, which can be adapted (individualized) with prior data for each subject;
• Module 2 - Advisory Module (AM) responsible for pre-meal boluses and postprandial corrections, which can be adapted (individualized) with prior data for each subject;
• Module 3 -- Automated Basal Rate Module (BRM) responsible for augmentation of basal rate to compensate for changes in insulin sensitivity, particularly overnight (e.g. dawn phenomenon), which can be adapted with prior data for each subject.

Daytime control (40hour studies) includes all 3 modules (n=36 were not recruited). Overnight only closed loop control (5 consecutive overnights) includes Module 1 and 3 (n=5-7).

Inclusion Criteria:

1. ≥21 and <65 years old.

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

   o Criteria for documented hyperglycemia (at least 1 must be met): i. Fasting glucose ≥126 mg/dL - confirmed ii. Two-hour Oral Glucose Tolerance Test glucose ≥200 mg/dL - confirmed iii. Hemoglobin A1C (HbA1c) ≥6.5% documented - confirmed 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

   o 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

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

4. Familiarity with a bolus calculator with the current insulin pump with pre-defined parameters for carbohydrate ratio, insulin sensitivity factor (ISF), target glucose and active insulin.

5. HbA1c <9% 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 24 hours prior to and during CGM use.

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

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. Severe hypoglycemia resulting in seizure, loss of consciousness, or diabetic ketoacidosis within the 12 months prior to enrollment.

2. Pregnancy; breast feeding, or intention of becoming pregnant.

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

4. Conditions which may increase the risks associated with possible hypoglycemia, such as any active 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, uncontrolled adrenal insufficiency, neurologic disease or atrial fibrillation.

5. Self-reported hypoglycemia unawareness.

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

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

8. Anticoagulant therapy other than aspirin.

9. Oral steroids.

10. Subjects currently taking Amylin.

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

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

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

14. Known current or recent alcohol or drug abuse.

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

16. 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, and cellulitis).

17. In adherence with the One Touch Ultra 2 User Guide that may be used in the experimental session and overnight during substudy, subjects with hematocrit levels less than 30% and above 55% will be excluded.

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, such as current proliferative diabetic retinopathy or macular edema, known diabetic nephropathy (other than microalbuminuria with normal creatinine) or neuropathy requiring treatment.

21. Active gastroparesis requiring current medical therapy.

22. 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.

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 treatment clinical trial. Observational trials may be permitted at the discretion of the study physician.

27. Use of anti-diabetic agents other than continuous subcutaneous insulin infusion (CSII) including long-acting insulin, intermediate-acting insulin, metformin, sulfonylureas, meglitinides, thiazolidinediones, Dipeptidyl peptidase-4 inhibitors, glucagon- like peptide 1 agonists, and alpha-glucosidase inhibitors

28. Unwillingness to use an approved form of birth control during this study by a sexually active female participant.

29. Subjects with basal rates less than 0.01U/hr.

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, Dipeptidyl peptidase-4 inhibitors, glucagon- like peptide 1 agonists, and alpha-glucosidase inhibitors.
2. Acetaminophen will be restricted starting 24 hours prior to CGM use.
3. Medications that block symptoms of hypoglycemia, including but not limited to beta blockers.