A Phase 3, 24-Week, Multi-Center, Open-Label, Randomized, Controlled Trial Comparing the Efficacy and Safety of Prandial Inhalation of Technosphere®/Insulin in Combination with Metformin or Technosphere®/Insulin Alone Versus 2 Oral Anti-Diabetic Agents (Metformin and a Secretagogue) in Subjects With Type 2 Diabetes Mellitus Sub-Optimally Controlled on Combination Metformin and a Secretagogue

INTERVENTION: Product Name: Technosphere®/Insulin Pharmaceutical Form: Inhalation powder, pre‐dispensed INN or Proposed INN: Insulin Human rDNA CAS Number: 11061‐68‐0 Concentration unit: IU/mg international unit(s)/milligram Concentration type: equal Concentration number: 3‐ Pharmaceutical form of the placebo: Inhalation powder, pre‐dispensed Route of administration of the placebo: Inhalation use Trade Name: The patient will enter the trial on whatever brand of Metformin they are prescribed at the time Product Name: Metformin Product Code: NA Pharmaceutical Form: Tablet INN or Proposed INN: Metformin HCL CAS Number: 1115‐70‐4 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 500‐1000 Trade Name: The patient will enter the trial on whatever brand of sulphonamide, urea derivative they are prescribed at the time Product Name: Sulphonamides, urea derivatives Product Code: NA Pharmaceutical Form: Tablet INN or Proposed INN: Tolbutamide CAS Number: 64‐77‐7 Concentration unit: IU/mg international unit(s)/milligram Concentration type: equal Concentration number: 500‐ INN or Proposed INN: Gliclazide CAS Number: 21187‐96‐4 Concentration unit: IU/mg international unit(s)/milligram Concentration type: equal Concentration number: 30‐ INN or Proposed INN: Glimepiride CAS Number: 93479‐97‐1 Concentration unit: IU/mg international unit(s)/milligram Concentration type: range Concentration number: 1‐6 INN or Proposed INN: Glibenclamide CAS Number: 10238‐21‐8 Concentration unit: IU/mg international unit(s)/milligram Concentration type: range Concentration number: 1.75‐3.5 Trade Name: The patient will enter the trial on whatever brand of meglitinide they are prescribed at the time Product Name: Meglitinide Pharmaceutical Form: Tablet INN or Proposed INN: Repaglinide CAS Number: 135062‐02‐1 Concentration unit: IU/mg international unit(s)/milligram Concentration type: equal Concentration number: 500‐ CONDITION: Diabetes mellitus type II ; MedDRA version: 8.1 Level: LLT Classification code 10012601 Term: Diabetes mellitus PRIMARY OUTCOME: Main Objective: The primary objective of this trial is to demonstrate the efficacy of inhaled prandial Technosphere®/Insulin (T/I) in combination with metformin versus combination metformin and a secretagogue (sulfonylurea or meglitinide) in subjects with sub‐optimally controlled type 2 diabetes mellitus. Primary end point(s): Primary Efficacy Endpoint: The primary efficacy endpoint is the change from Baseline to Week 12 in glycated hemoglobin (HbA1c) for prandial T/I in combination with metformin versus combination metformin and a secretagogue (sulfonylurea or meglitinide). Secondary Objective: The secondary objectives are to evaluate the:; • Efficacy of inhaled prandial T/I alone versus combination metformin and a secretagogue (sulfonylurea or meglitinide).; • Effect of inhaled prandial T/I on post‐prandial glucose (PPG) excursions following the ingestion of a standardized liquid meal (Meal Challenge).; • Effect of inhaled prandial T/I on the proportion of subjects achieving predefined targets of glycemic control.; • Effect of inhaled prandial T/I on Quality of Life (QoL) and treatment satisfaction.; • Safety of inhaled prandial T/I, expressed as the incidence of hypoglycemia, pulmonary and other adverse events (AEs) and changes in pulmonary function.; INCLUSION CRITERIA: Key inclusion criteria include: Non‐smoking male and female subjects = 18 and = 80 years of age with clinical diagnosis of type 2 diabetes mellitus for = 6 months. Stable regimen of metformin = 1000 mg/day (or maximum tolerated dose) and a secretagogue (sulfonylurea or meglitinide) = ½ the maximum manufacturer‐recommended daily dose (or maximum tolerated dose) without any dose adjustments within the preceding 6 weeks. Fixed dose combination products of metformin and sulfonylurea are acceptable as long as each individual dose meets inclusion criteria. HbA1c = 7.5% and = 11.0%. Body Mass Index (BMI) = 40 kg/m2. The following PFTs: FEV1 = 70 % National Health and Nutrition Examination Survey (NHANES) III Predicted, Total Lung Capacity (TLC) = 80% of Predicted (ITS) and single breath carbon monoxide diffusing capacity (DLco (unc)) = 80% of Predicted (Miller). Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐6