Phase 2 Study of Adaptive Insulin Meal Supervisor (AIMS) in Adults With Type 1 Diabetes Mellitus

The current study will probe the concept that if a Model Predictive Control insulin delivery
strategy for closed-loop glucose control supervised by a safety system is coupled with a
standard amylin replacement therapy in patients with type 1 diabetes the resulting combined
treatment will unify the benefits of both individual therapies. In order to reduce post-meal
blood glucose excursions in patients with type 1 diabetes mellitus, pramlintide (an analog
of the human β-cell hormone, amylin) has been utilized, thus dealing with the problem or
meal hyperglycemia more effectively than insulin infusion alone. Pramlintide has been
successful in maintaining more normal blood glucose concentrations by significantly
improving the postprandial glucose excursions in these patients when added to their mealtime
insulin to mimic more closely the diurnal β-cell secretory pattern seen in normal
physiology. However, pramlintide treatment can result in post-prandial hypoglycemia
primarily due to overbolusing with insulin. Closed-loop systems have shown potential for
significantly reducing hypoglycemia. A combined closed-loop insulin + pramlintide therapy
could provide advantages over each of the individual therapies, and may also provide certain
benefits with respect to weight control and improvement in sense of well being while
decreasing glucose variability. A potentially important secondary benefit of combining the
pramlintide treatment with a precise insulin delivery by the closed-loop system is that,
based upon animal studies performed by the research team, a moderate inhibition of glucagon,
as is usually achieved with pramlintide treatment, is anticipated to potentially improve the
safety of insulin treatment as well by enhancing the glucagon response to hypoglycemia,
which are usually impaired in type 1 diabetes, if it should occur in the early postprandial
period.

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 (OGTT) glucose ≥200
mg/dL - confirmed iii. 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 (CHO) ratio, insulin sensitivity factor (ISF), target
glucose and active insulin.

5. HbA1c 6.5-9% 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 during the
study interventions involving CGM use.

9. Willingness to refrain from strenuous exercise for 2 days prior to admission.
Non-strenuous walks of less than 15 minutes around the guest house will be permitted
during the study.

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.

11. Normal renal function (determined utilizing the comprehensive metabolic panel at
screening with the Modification of Diet in Renal Disease (MDRD) formula and defined
by estimated Glomerular Filtration Rate (eGFR) ≥60 ml/min/1.73 m2.

EXCLUSION CRITERIA

1. Known hypersensitivity to pramlintide or any of its components, including metacresol.

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

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

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

5. 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
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. Self-reported hypoglycemia unawareness.

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

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

9. Anticoagulant therapy other than aspirin.

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

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

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

13. Known current or recent alcohol or drug abuse.

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

15. 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).

16. In adherence with the One Touch Ultra 2 User Guide, subjects with hematocrit levels
less than 30% and above 55% will be excluded.

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

18. Abnormal liver function (Transaminase >2 times the upper limit of normal).

19. 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 drug treatment.

20. Active gastroparesis requiring current medical therapy.

21. Uncontrolled adrenal disorder.

22. Uncontrolled thyroid disease.

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

27. Subjects who are sexually active and able to become pregnant and not using an
acceptable method of birth control.

RESTRICTIONS ON USE OF OTHER DRUGS OR TREATMENTS

1. 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, colesevelam, quick release
bromocriptine, sodium-glucose linked transporter (SGLT-2) inhibitors and
alpha-glucosidase inhibitors.

2. Acetaminophen will 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. Oral steroids or other medications, which in the judgment of the investigator would
be a contraindication to participation in the study.

5. Use of drugs that stimulate gastrointestinal motility (e.g. metoclopramide).

6. Orally administered medications (prescription and non-prescription) which require
rapid onset as a critical determinant of effectiveness must be given at least 1 hour
prior to or 2 hours after the Pramlintide injection and that subjects who require
such medications be excluded if the medication must be given less than 1 hour prior
to or 2 hours after the pramlintide dose.

7. Medications known to interfere with hypoglycemic symptoms including but not limited
to beta- blockers, clonidine, reserpine, and guanethidine.