Phase 2 Study of Adaptive Insulin Meal Supervisor (AIMS) in Adults With Type 1 Diabetes Mellitus
Phase 2 Study of Adaptive Insulin Meal Supervisor (AIMS) in Adults With Type 1 Diabetes Mellitus
In this study, a closed-loop Adaptive Insulin Meal Supervisor system (AIMS) utilizing
 continuous glucose monitoring (CGM), a subcutaneous insulin pump and standard pramlintide
 therapy will be applied in individuals with type 1 diabetes. Pramlintide, a drug well
 recognized to help control hyperglycemia with meals, will be evaluated in both closed loop
 and open loop control. It is expected that the closed loop control condition with pramlintide
 will improve glycemia, thus combining better control with enhanced safety. In a recent pilot
 study, the investigators started testing this concept and collected data showing that in
 order to be successful such strategy must have a controller equipped with the ability to
 optimize the configuration and timing of meal boluses with concomitant administration of
 pramlintide. Our preliminary data and review of previously unavailable individual data from a
 German study indicate a large individual variability in the timing of the appearance of meal
 insulin needs. Thus, for both adequate safety and efficacy of meal insulin on pramlintide,
 the investigators have developed a new closed-loop controller that accounts for the
 variability in the individual responses to a meal and meal delays, the Adaptive Insulin Meal
 Supervisor system (AIMS). In this study, the performance of a combination between the AIMS
 system and a standard pramlintide treatment will be tested versus the standard pramlintide
 treatment alone.
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.