Optimizing Closed-Loop Control of Type 1 Diabetes Mellitus in Adolescents

The purpose of this study is to use a closed-loop Control-to-Range (CTR) system in
adolescents with type 1 diabetes in an outpatient setting, and to evaluate the CTR system's
ability to significantly improve blood glucose levels when an insulin bolus is omitted for a
30 gram carbohydrate snack and when insulin bolus is insufficient for the amount of
carbohydrates consumed for a meal. The CTR system is comprised of two algorithmic layers:
(i) A Safety Supervision Module (SSM) which contains a predictive insulin request dampener
(or brakes); (ii) a Range Correction Module (RCM), consisting in (a) a Hyperglycemia
Mitigation System, and (b) Insulin on Board controller. Both modules will receive continuous
glucose monitoring (CGM) and historical insulin delivery data. The SSM will monitor the
safety of the subject's continuous subcutaneous insulin infusion pump (CSII) to prevent
hypoglycemia. The RCM will be responsible for optimizing blood glucose (BG) control and
mitigating postprandial hyperglycemic excursions through a mix of increased basal rate and,
potentially, isolated insulin boluses. To run CTR, we will use our wearable artificial
pancreas platform, known as DiAs (Diabetes Assistant) which consists of a smart phone
running CTR and connected to standard insulin delivery and CGM devices.

Inclusion Criteria:

1. ≥13 and ≤18 years old

2. Clinical diagnosis of type 1 diabetes mellitus for at least 2 years as noted by the
following:

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

- Fasting glucose ≥126 mg/dL - confirmed

- Two-hour Oral Glucose Tolerance Test (OGTT) ≥200 mg/dL - confirmed

- Hemoglobin A1c (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 6 months

4. Actively using a carbohydrate (CHO) /insulin ratio for insulin bolus adjustments in
order to keep blood glucose in a predefined range

5. Tanner stage II or greater based on physician exam

6. HbA1c between <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 visits involving DexCom use

10. Self-reported behavior of snacking without insulin coverage or under bolus for meals

11. Willingness to consume a 30 grams snack without insulin coverage and willingness to
bolus 75 % of usual treatment for an 80 grams lunch during both admissions

12. Willingness to remove home CGM for admissions if the subject typically wears a CGM

13. Medication stability in the preceding two months if taking antihypertensive, thyroid,
anti-depressant or lipid lowering medication

14. Reported history of missed or inaccurate bolus treatments at meal time

Exclusion Criteria:

1. Diabetic ketoacidosis (DKA) within the 6 months prior to enrollment

2. In adherence with the One Touch Ultra 2 User Guide, subjects with hematocrit levels
below 30% or above 55% will be excluded. Severe hypoglycemia resulting in seizure or
loss of consciousness in the 12 months prior to enrollment

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

4. Uncontrolled arterial hypertension (based on resting blood pressure > 95 percentile
as listed according to age and height percentile in the Harriet Lane Handbook of
Pediatrics)

5. Conditions which may increase the risk of hypoglycemia such as 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 electrocardiogram (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

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

7. History of arrythmia

8. 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)

9. Anticoagulant therapy other than aspirin

10. Oral steroids

11. Medical condition requiring use of an acetaminophen-containing medication that cannot
be withheld for for 24 hours before CGM insertions until the end of each the study
admissions.

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 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,
cellulitis)

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

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

19. Uncontrolled 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

20. Active gastroparesis requiring current medical therapy

21. Uncontrolled thyroid disease

22. Known bleeding diathesis or dyscrasia

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

24. Active enrollment in another clinical trial

25. 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 (DPP-4)
inhibitors, glucagon-like peptide 1 agonists and alpha-glucosidase inhibitors

26. Subjects with basal rates less than 0.01 units/hour

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-4, inhibitors, glucagon-like peptide 1 agonists, and
alpha-glucosidase inhibitors.

2. Acetaminophen will be restricted 24 hours before the insertion of not be allowed
while the continuous glucose monitor is in use.

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

4. Subjects on amylin analogs will be asked to withhold the medication during the
outpatient admissions.