PURPOSE: The purpose of this study is to determine, in subjects with type 2 diabetes mellitus currently receiving a sulfonylurea and /or metformin as therapy (1) whether glycemic control can be improved, as measured by a decrease of at least 1% in the glycosylated hemoglobin, by the addition of a regimen of pre-meal inhaled insulin and (2) the toleration and safety of inhaled insulin therapy and its effects after 3 months, if any, on measures of pulmonary function. METHODS: In total, 60 subjects will participate in this trial, with approximately 6 being evaluated at this site. During this three-month comparative trial, half of the subjects will be randomized to receive an inhaled insulin regimen plus pre-study oral agent while the other half will continue pre-study oral agent. Patients who successfully complete this three-month trial will be eligible for a one-year, open-label protocol extension. Prior to study entry, subjects undergo a screening session, including a history and physical exam, EKG, CXR, and lab studies to verify that the patient is eligible for participation. This is followed by a 4 week baseline lead-in period, during which patients continue their pre-study oral agent. Subjects undergo pulmonary function tests (PFTs), dietary instruction, and home blood glucose monitoring instruction during this time. All patients are provided with a glucose meter and supplies and are required to perform blood glucose checks 4 times/day, to record doses and meter readings, and to document any hypoglycemic or adverse events which occur. At the end of the baseline period, subjects are admitted for a 2 day inpatient session, during which they are instructed in the use of the device and dosing with inhaled insulin. At the end of the admission, subjects are randomized to one of two treatment groups (premeal inhaled insulin plus oral hypoglycemic agent vs premeal inhaled placebo plus oral agent). Randomization is double-blinded and is stratified based on HbA1c. During the treatment period, patients are followed at weekly intervals. For the first 4 weeks of treatment, patients must return to the clinic for evaluation every week. After that, patients may return once every other week. Meal challenge studies will be performed at weeks 0,4,8, and 12, during which a patient will be asked to consume 16 oz of Sustacal beverage and timed blood draws measuring blood glucose and free insulin levels will be collected. Also at clinic visits, blood samples will be collected to evaluate HbA1c, fasting blood glucose, fructosamine, and lipids. Spirometry will be performed at week 6, and a full PFT battery will be repeated at week 12. In the optional one year extension, patients are required to return for monthly clinic visits. PFT's will be performed every 3 months. RESULTS AND CONCLUSIONS: The study is ongoing, and results are not available to date. SIGNIFICANCE: The Diabetes Control and Complications Trial (DCCT) demonstrated the long-term benefits of tight glycemic control. However, the clinical realization of the benefits of aggressive insulin therapy has been limited by the shortcomings of available SC delivery methods. In particular, multiple injection therapy has had poor patient acceptance. This study aims to determine whether the addition of a pre-meal inhaled insulin regimen can provide improved glycemic control to patients poorly controlled on oral agents. This system is designed to permit safe, non-invasive delivery of rapid-acting insulin in 1-2 inhalations per dose. If proven to be safe and effective, inhaled insulin, which is easy to administer and provides a predictable pattern of insulin action, may be more acceptable to patients requiring insulin therapy and may provide better overall glycemic control thereby possibly reducing the incidence of diabetic complications. Plans for phase III studies of inhaled insulin are currently underway by the study sponsor, Pfizer, Inc.
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