18-Week, Randomized, Double-blind, Placebo Controlled, Forced Titration Study of Patients With Type 2 Diabetes

A Randomized, Double-blind, Controlled, Stepwise Titration Study to Evaluate Dose Response to Prandial Administration of Inhaled Technosphere/Insulin or Technosphere in Patients With Type 2 Diabetes Mellitus Who Are Sub-optimally Treated

Designed to evaluate dose response of force-titrated prandial administration of TI as compared to placebo (TP) in subjects with Type 2 diabetes who were suboptimally controlled

Inclusion Criteria:

• Male and females patients from 18 to <80 years of age
• Clinical diagnosis of type 2 diabetes mellitus
• Duration of diabetes of >3 years and <20 years
• Glycemic control at upper end of acceptable level or sub-optimal in control (HbA1c between 7.0% and 12?0%)
• Confirmation of diagnosis of diabetes such as a history of 2 hour postprandial blood glucose >11.1 mmol/L (200 mg/dL) or following a glucose tolerance test
• A minimum of 2 months of treatment with a stable dose of one or more of the following anti-hyperglycemic agents: sulphonylureas, alpha glucosidase inhibitors, metformin, meglitinides, thiazolidinediones and/or Lantus basal insulin therapy
• FBG:>6 mmol/L (108 mg/dL)
• C-peptide: >0.5 nmol/L
• BMI <38 kg/m2
• Baseline DLco, FVC, FEV1 >75% of predicted normal
• Subjects who, in the opinion of the Investigator, will be able to complete this study
• Written informed consent

Exclusion Criteria:

• Severe complications of diabetes including history of: blindness from or grade III or IV diabetic retinopathy, renal failure requiring dialysis or transplantation, amputation of limbs or digits related to diabetic vasculopathy or foot ulcers
• Treatment with another investigational drug within 3 months prior to study entry and for the duration of the study
• History of drug or alcohol dependency
• Significant hepatic disease (as evidenced by ALT or AST >3 times the normal upper reference range or bilirubin >1.5 times the normal upper reference range)
• Significant renal disease (as evidenced by creatinine >1.5 mg/dL for males or >1.3 mg/dL for females) or proteinuria >1,000 mg/24 hours
• History of chronic obstructive pulmonary disease, or history of other known chronic pulmonary diseases, such as reactive airway disease, chronic bronchitis, emphysema, or asthma
• Heart disease graded as class III or class IV according to New York Heart Association criteria
• Prior treatment with , or participation in a clinical study involving an inhaled insulin product
• Smokers
• Current use of preprandial or prandially administered fast-acting or rapid acting insulin or insulin analogs
• Previous participation in a TI or TP clinical trial
• Allergy to insulin or to any drugs to be used as part of the clinical trial
• History of malignancy within 5 years of study entry (other than basal cell carcinoma)
• Anemia (hemoglobin level less than 11 g/dL for females or 12 g/dL for males at study entry)
• Diagnosis of Acquired Immunodeficiency Syndrome (AIDS) and Aids Related Complex A major psychiatric disorder that will preclude satisfactory participation in this study
• Subjects who have had a myocardial infarction or stroke within the preceding 6 months
• Prior diagnosis of systemic autoimmune or collagen vascular disease requiring previous or current treatment with systemic corticosteroids, cytotoxic drugs, or penicillamine
• History of severe or multiple allergies
• Progressive fatal disease
• Recent loss (within the past 2 months) of >5% of body weight
• Evidence of "moderate" or greater ketones in urine or history of ketoacidosis
• Use of medications known to modify glucose metabolism or the ability to recover from hypoglycemia such as oral, parenteral and inhaled steroids, or greater than 25 mg hydrochlorothiazide daily
• Women who are pregnant or lactating
• Women of childbearing potential practicing inadequate birth control (adequate birth control is defined as using oral contraceptives, condoms or diaphragms with spermicide, intrauterine devices, or surgical sterilization).