Efficacy and Safety in Subjects With Type 2 Diabetes Receiving Subcutaneous Basal Insulin and Prandial Inhalation of Technosphere/Insulin Versus Subcutaneous Premixed Insulin Therapy Over a 52-Week Treatment Period and a 4-Week Follow-up

Study Overview
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Brief Summary
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The purpose of this 13 month study (12 month treatment period and 1 month follow-up period) is to determine whether inhaled insulin is safe and effective in the treatment of type 2 diabetes.

Official Title
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A Prospective, Multi-Center, Open-Label, Randomized, Controlled Clinical Trial Comparing the Efficacy and Safety in Subjects With Type 2 Diabetes Receiving Subcutaneous Basal Insulin and Prandial Inhalation of Technosphere /Insulin Versus Subcutaneous Premixed Insulin Therapy Over a 52-Week Treatment Period and a 4-Week Follow-up

Conditions
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Diabetes Type 2

Intervention / Treatment
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* Drug: Technosphere® Insulin Inhalation Powder
* Drug: 70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women ≥ 18 and ≤ 80 years old Clinical diagnosis of type 2 diabetes mellitus HbA1c > 7.0% and ≤ 11.0% BMI ≤ 40 kg/m2 Negative smoking status and urine cotinine test Written informed consent Receiving sc insulin 2-3 times daily administered as any of the following 3 regimens: self-mix regimen, pre-mix regimen, or long-acting analogue and regular or rapid-acting insulin analogue not to exceed 3 daily injections. Subjects may also have received oral antidiabetic agents including metformin or thiazolidinediones. No dose adjustments for insulin and oral antidiabetic agents within the preceding 6 weeks. FEV1 ≥ 70% of NHANES III predicted; TLC) ≥ 80% of predicted (Intermountain Thoracic Society); DLCO uncorrected ≥ 70% of predicted Exclusion Criteria: Total daily dose of insulin ≥1.4 IU/kg body weight Treatment with any sulfonylureas and/or meglitinides and/or alpha-glucosidase inhibitors within the preceding 8 weeks Treatment with pramlintide acetate (Symlin®), and/or any incretins (e.g., exenatide [Byetta®]) within the preceding 8 weeks Unstable diabetes mellitus control, defined as 2 or more episodes of severe hypoglycemia (requiring third party intervention) and/or any hospitalization or emergency room visit due to poor diabetic control or hyperglycemia requiring hospitalization within the preceding 6 months Exposure to an inhaled insulin at any time, treatment with an investigational drug within the preceding 3 months, and/or current participation in another clinical trial Allergy to insulin or to any drugs to be used as part of the clinical trial, or history of hypersensitivity to the investigational drug or to drugs of similar chemical structures History of active viral and/or cirrhotic hepatic disease and/or abnormal liver enzymes as evidenced by serum aspartate aminotransferase (AST)and/or alanine aminotransferase (ALT) ≥ 3 x Upper Limit of Normal (ULN)(Includes active hepatitis A, positive hepatitis B and/or hepatitis C serology) Serum creatinine > 1.8 mg/dL in women and > 2.0 mg/dL in men History of chronic obstructive pulmonary disease (COPD), asthma (any history of bronchospasm or asthma after the age of 14), and/or any other clinically important pulmonary disease confirmed by documented history, pulmonary function testing, or radiologic findings Congestive heart disease graded as class III or class IV according to New York Heart Association criteria and subjects currently being treated pharmacologically for ventricular dysrhythmias using amiodarone History of myocardial infarction, cardiac surgery, coronary angioplasty, and/or stroke within the preceding 3 months Symptomatic coronary artery disease, including crescendo angina, unstable angina, and/or unstable or symptomatic cardiac arrhythmias Poorly controlled arterial hypertension despite pharmacologic treatment, defined as systolic blood pressure (BP) > 180 mm Hg and/or diastolic BP > 110 mm Hg at screening History of malignancy within the preceding 5 years (other than excised basal cell carcinoma of the skin), any history of lung neoplasm, and/or subjects with current or previous chemotherapy or radiation therapy that may result in pulmonary toxicity History of acquired immunodeficiency syndrome (AIDS), AIDS-related complex (ARC), or positive human immunodeficiency virus (HIV) serology Prior diagnosis of systemic autoimmune or collagen vascular disease requiring previous or current treatment with systemic corticosteroids, cytotoxic drugs, or penicillamine Visit 1/Screening (Week -3), but prior to Visit 1 PFTs and before Visit 3/Baseline (Week 0), subject will be scheduled for PFTs after 30 days from resolution of respiratory infection. An additional hemoglobin and urine β-HCG (for women of childbearing potential age only) will be required Women who are pregnant, lactating or planning to become pregnant Women of childbearing potential (defined as pre-menopausal and not surgically sterilized or postmenopausal for less than 2 years) not practicing adequate birth control. Adequate birth control is defined as using oral, percutaneous and/or transdermal contraceptives; condoms and diaphragms with a spermicide, or intrauterine devices Current drug and/or alcohol abuse Subjects who in the opinion of the Investigator will be unable to comply with the requirements of the protocol Severe complications of diabetes mellitus, in the opinion of the Investigator, including: symptomatic autonomic neuropathy, disabling peripheral neuropathy, active proliferative retinopathy; nephropathy with renal failure, renal transplant and/or dialysis; history of foot ulcers; nontraumatic amputations due to gangrene;and/or vascular claudication Any other concurrent medical or major psychiatric condition which, in the opinion of the Investigator, makes the subject unsuitable for the clinical trial, or could limit the validity of the ICF and/or impair the subject's ability to participate in the trial Inability to perform PFT maneuvers meeting recommended American Thoracic Society (ATS) acceptability and repeatability criteria.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TI + Insulin glargine<br>Technosphere® Insulin Inhalation Powder + insulin glargine | Drug: Technosphere® Insulin Inhalation Powder<br>* Inhalation, 15U/30U<br>|
| Active Comparator: BPR 70/30<br>70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin) | Drug: 70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)<br>* BPR 70/30, which is a premix of intermediate acting and rapid acting insulin given sc<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c to Week 52 |  | Baseline to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Weight to Week 52 |  | Baseline to Week 52 | 
| Change From Baseline in Fasting Plasma Glucose to Week 52 |  | Baseline to Week 52 | 
| Number of Subjects Achieving Week 52 HbA1c Levels Less Than or Equal to 7.0% |  | Week 52 | 
| Incidence of Total Hypoglycemia | Defined as hypoglycemic symptoms that are relieved with carbohydrate intake or blood glucose measurement <= 63 mg/dL, regardless of symptoms. | 52 Weeks | 
| Incidence of Severe Hypoglycemia | Severe hypoglycemia occurs when all 3 of the following occur simultaneously: Subject requires the assistance of another person; Subject exhibits at least 1 cognitive neurological symptom (memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, seizure, loss of consciousness); Measured BG is ≤ 49 mg/dL (2.7 mmol/L), or, in the absence of a BG measurement, clinical symptoms are reversed by oral carbohydrates, sc glucagon or intravenous glucose administration; OR, Measured BG is ≤ 36 mg/dL (2.0 mmol/L) with or without symptoms. | 52 Weeks | 
| Total Hypoglycemia Event Rate | Number of Hypoglycemic Events/Total Subject Exposure Time (in months) | 52 Weeks | 
| Severe Hypoglycemia Event Rate | Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months) | 52 Weeks |