Comparison of Technosphere® Insulin Versus Technosphere Powder (Placebo) in Insulin-Naive Subjects With Type 2 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
Insulin-naive subjects with Type 2 Diabetes Mellitus who are sub-optimally controlled on either maximum tolerated dose of metformin or maximum tolerated dose of metformin plus one or two other oral anti-diabetic medications will have either Prandial Technosphere® Insulin or Technosphere Powder (placebo) added to their oral antidiabetic drugs.

Official Title
-----------------
A Phase 3, Multicenter, Double-blind, Placebo-controlled, Randomized, Clinical Trial Evaluating the Efficacy and Safety of Prandial Technosphere® Insulin Inhalation Powder Versus Technosphere Inhalation Powder in Insulin Naïve Subjects With Type 2 Diabetes Mellitus Poorly Controlled With Oral Antidiabetic Agents Over a 24 Week Treatment Period

Conditions
-----------------
Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: Technosphere® Insulin
* Drug: Technosphere Powder


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HbA1c > or = to 7.5% and < or = to 10.0% Body mass index (BMI) < or = to 45 kg/m2 Non smoker for at least 6 months before Screening Clinical diagnosis of type 2 diabetes mellitus for more than 12 months Currently receiving as diabetes treatment only metformin or 2 or more OADs and on stable doses for at least 3 months before enrollment Subjects receiving metformin must be on at least 1.5gm daily, or up to the maximum tolerated dose Subjects treated with a sulfonylurea must be on at least 50% of the total maximum approved dose for a given agent Subjects receiving a DPP-4 inhibitor must receive the maximum approved dose specific for that agent Metiglinide and alpha-glucoside inhibitors must be taken at the highest tolerated dose within the approved dose range No previous or current treatment with insulin, except during an acute illness, gestational diabetes, or at time of initial diagnosis of diabetes Forced expiratory volume in one second (FEV1) > or = to 70% Third National Health and Nutrition Examination Survey (NHANES III) predicted Forced vital capacity (FVC) > or = to 70% NHANES III predicted Forced expiratory volume in one second as a percentage of forced vital capacity (FEV1/FVC) > or = to NHANES III lower limit of normal (LLN) Exclusion Criteria: History of chronic obstructive pulmonary disease (COPD), clinically proven asthma, or any other clinically important pulmonary disease (eg, pulmonary fibrosis) Any clinically significant radiological findings on screening chest x-ray Use of medications for asthma, COPD, or any other chronic respiratory conditions Evidence of serious complications of diabetes (proliferative retinopathy, autonomic neuropathy with symptoms of gastroparesis or cardiac arrhythmia; sensory neuropathy that makes manipulation of the Gen2C inhaler difficult) Renal disease or renal dysfunction Significant cardiovascular dysfunction or history thereof within 12 months of screening; serious arrhythmia, treatment with medications to control/treat arrhythmias; myocardial infarction; cardiac surgery; history of valvular heart disease Previous or current use of amiodarone Treatment with glucagon-like peptide-1 (GLP-1) analogs, thiazolidinediones (TZD), or weight loss drugs (eg, sibutramine, orlistat) within 3 months of screening History of pulmonary embolism or deep venous thrombosis in the 12 months before Screening History of recent blood transfusion (within previous 3 months) or diagnosis of hemoglobinopathies that may affect HbA1c measurements

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TI inhalation powder<br>Technosphere® Insulin powder administered via the Gen2 inhaler added to 2 or more stable OADs | Drug: Technosphere® Insulin<br>* Technosphere® Insulin Inhalation Powder<br>|
| Placebo Comparator: Technosphere powder<br>Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable OADs | Drug: Technosphere Powder<br>* Placebo Comparator<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 in HbA1c | Efficacy as measured by change in glycated hemoglobin (HbA1c) at Week 24 | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Responders Achieving HbA1c <= 7.0% | Efficacy as measured in proportion of subjects achieving HbA1c < or = to 7.0% | Week 24 | 
| Proportion of Responders Achieving HbA1c <= 6.5% | Efficacy as measured in proportion of subjects achieving HbA1c < or = to 6.5% at Week 24 | Week 24 | 
| FPG Change From Baseline to Week 24 | Efficacy as measured by mean change in fasting plasma glucose (FPG) | Baseline to Week 24 | 
| Proportion of Subjects Requiring Rescue Therapy |  | Baseline to Week 24 | 
| Time to Rescue | Time from Week 0 (baseline) to initiation of rescue therapy (up to a maximum of 24 weeks/end of treatment) for subjects not responding to treatment | Baseline to Week 24 | 
| FEV1 Change From Baseline to Week 24 | Forced Expiratory Volume in 1 second - change from baseline to week 24 | Baseline to Week 24 | 
| Incidence of Total Hypoglycemia | Hypoglycemia, defined as blood glucose <= 70 mg/dL or in absence of blood glucose, symptoms that are resolved by the administration of carbohydrates. | Baseline to Week 24 | 
| Incidence of Severe Hypoglycemia | Severe Hypoglycemia defined as: Requiring 3rd party assistance. | Baseline to Week 24 | 
| Total Hypoglycemia Event Rate | Number of Hypoglycemic Events/Total Subject Exposure Time (in months) | Baseline to Week 24 | 
| Severe Hypoglycemia Event Rate | Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months) | Baseline to Week 24 | 
| Mean 7-point Glucose Baseline Values | Mean 7-point self-monitored glucose at baseline | Baseline | 
| Mean 7-point Glucose Week 24 Values | Mean 7-point self-monitored blood glucose at Week 24 | Week 24 | 
| Change in Body Weight From Baseline to Week 24 | Change in body weight from Baseline to Week 24 | Baseline to Week 24 |