Pramlintide Combined With Model Predictive Control Algorithm

The objective of this study is to test whether standard pramlintide treatment plus a
closed-loop insulin therapy is more efficacious in controlling glycemia than either of the
individual therapies. The control algorithm is in effect an insulin dose calculator for
mimicry of basal insulin secretion by estimating requirements for basal rates of insulin
pump infusion based on current and past glucose levels estimated from the Continuous Glucose
Monitor (CGM) device and prior insulin infusions. The closed-loop system-recommended insulin
will replace for 24 hours (in a clinical setting) the basal rate insulin that the patient
would normally use. The patients' meal insulin needs will be estimated using an
insulin-to-carbohydrate ratio as per standard clinical practice and will be optimized prior
to admission to the General Clinical Research Center [GCRC].

The primary goal of this feasibility study is to test the hypothesis that the combination of
a closed loop system (Open-Loop Informed with a Model Predicted Control [MPC] algorithm plus
a safety system module [SSM]) with pramlintide (a synthetic analog of the hormone amylin
which in health is released by the β-cells along with insulin) treatment will improve
glucose control versus each of the individual therapies. Because pramlintide reduces
hyperglycemia extremes generated at meals and closed loop control markedly reduces the risk
of hypoglycemia, thus representing potentially important complementary actions to reduced
variability — the investigators expect to find decreased hyperglycemia while simultaneously
decreasing hypoglycemia risks.

Secondary goals are to explore factors associated with achieving safer and/or more effective
closed loop control. For example, based upon our work in animal models, one secondary goal
is to explore whether moderate inhibition of α-cell glucagon, known to occur with
pramlintide administration in the early postprandial period, has the potential to repair
inadequate glucagon counterregulation.

Inclusion Criteria:

- Clinical diagnosis of type 1 diabetes for at least one year and using an insulin pump
for at least six months (the diagnosis of type 1 diabetes is based on the
investigator's judgment; C peptide level and antibody determination are not needed).

- Age 21 to 65 years

- For females, not currently known to be pregnant

- An understanding of the protocol and a willingness to follow it

- HbA1c between 7 and 9%

- 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) of ≥60 ml/min/1.73 m2.

- Hematocrit >36 (females); >38 (males)

Exclusion Criteria:

- Known hypersensitivity to SYMLIN or any of its components, including metacresol

- Poor compliance with current insulin regimen

- Poor compliance with prescribed self-blood glucose monitoring

- HbA1c <7 or >9%

- Severe hypoglycemia resulting in seizure or loss of consciousness in the 2 weeks
prior to enrollment

- Active infection

- Current use of dietary supplements (subjects may be enrolled if they stop taking
dietary supplements two weeks prior to admission and for the duration of their
participation)

- Active gastroparesis

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

- Diabetic ketoacidosis in the past 3 months

- Current treatment for a seizure disorder

- Cystic fibrosis

- Asthma requiring hospitalization or treatment with oral steroids within the past year

- Presence of a uncontrolled adrenal disorder

- A known medical condition that in the judgment of the investigator might interfere
with the completion of the protocol such as the following examples:

- Inpatient psychiatric treatment in the past 6 months

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

- Heart failure

- Coronary artery disease

- Arrhythmia

- Seizure disorder

- Any carcinogenic disease

- Creatinine concentration above the upper limit of normal for age and sex

- Active coronary artery disease

- Uncontrolled thyroid disease

- Use or abuse of alcohol

- Active kidney dialysis

- 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

- Note: adequately treated thyroid disease and celiac disease do not exclude
subjects from enrollment

- Addison's disease

- Current use of a beta blocker medication

- Hematocrit < 36 (female), <38 (male)

- Current use of oral glucocorticoids or other medications, which in the judgment of
the investigator would be a contraindication to participation in the study

- Allergy to the sensor or to one of its components

- Continued use of acetaminophen.