Improving Post-Prandial Blood Glucose Control With Afrezza During Closed-Loop Therapy

There are 2 primary study aims that this research will address. The first study aim will be
to determine whether use of Afrezza inhaled insulin with ultra-fast kinetics will improve the
performance of a closed-loop (CL) system, both with respect to immediate post-prandial
hyperglycemia and the subsequent late post-prandial hypoglycemia as compared to hybrid CL
(HCL) with subcutaneous (SC) rapid-acting insulin (RAI) pre-meal bolus.

The second study aim will be to examine the efficiency and feasibility of Afrezza inhaled
insulin as a pre-meal bolus and a missed meal correction bolus on mitigating post-prandial
blood glucose control during outpatient CL therapy.

This study will test the hypothesis that Afrezza inhaled insulin given before a meal to mimic
physiologic first phase insulin release will limit the magnitude and rate of rise of glucose
levels following a meal and will achieve greater percent time spent within target blood
glucose range as compared to conventional hybrid CL therapy without inhaled insulin both in
the in-clinic research and outpatient real-life setting.

Inclusion Criteria:

- The age inclusion criterion is 18-29 years for phase I and 18-50y for phase II

- Previously diagnosed with Type 1 Diabetes Mellitus, as determined by the judgment of
the Principal Investigator, based on clinical presentation and as documented in the
clinic record (formal antibody or genetic testing will not be required).

- Diabetes duration at least 1 year.

- Willing to have an intravenous (IV) line inserted for frequent blood sampling and
infusion of glucose.

- Hemoglobin A1c (HbA1c) ≤10%

- Speak and understand English.

Exclusion Criteria:

- HbA1c >10.0% at the time of screening

- Insulin pump naïve subjects and subjects with unstable insulin dosing parameters
requiring daily adjustments in insulin sensitivity factor, insulin to carbohydrate
ratio and basal rates other than the established temporary rates that are determined
to manage specific conditions such as exercise.

- History of an episode of severe hypoglycemia or Diabetic Ketoacidosis (DKA) requiring
inpatient management within six months prior to the screening visit and/or subjects
with history of clinician diagnosed hypoglycemia unawareness.

- History of recurrent DKA defined as more than three episodes of admissions for DKA
during the past 12 months.

- Subjects requiring an insulin total daily dose <0.1u/kg/day and >3u/kg/day.

- History of physician diagnosis of asthma or any other clinically important pulmonary
disease, or use of any medications to treat such conditions within the last year

- Allergy or know hypersensitivity for Afrezza or to drugs with similar chemical
structure

- Any disease or exposure to any medication which, in the judgment of the principal
investigator, may impact glucose metabolism.

- FEV1 <70% of NHANES III; Forced vital capacity (FVC) < 70% of NHANES III predicted for
children ≥8 years of age.

- Positive urine pregnancy test for female patients of childbearing, breast feeding, or
intention to become pregnant.

- Smoking of tobacco or other substances.

- Subjects who discontinued smoking (including cigarettes, cigars, pipes) within the
past 6 months.

- History of abnormal spirometry or chest X-ray suggestive of lung disease.

- History of respiratory tract malignancy.

- Any condition or medication that may result in pulmonary toxicity (e.g. current or
previous chemotherapy or radiation therapy or history of or current use of
amiodarone).

- Inability to perform study procedures including pulmonary function testing and Afrezza
inhalation using the BluHale system.

- Patients who take acetaminophen containing medications on a regular basis or
anticipate taking during the study period and are unable and/or unwilling to
substitute with a non-acetaminophen containing medication.

- 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).

- Active gastroparesis requiring current medical therapy.

- Known bleeding diathesis or dyscrasia.