Safety and Efficacy of Technosphere® Insulin Inhalation Powder and Lantus® Compared to Humalog® and Lantus® Over 16-Weeks

A Phase3, Multi-Center, Open-Label, Randomized, Clinical Trial Evaluating the Efficacy and Safety of Technosphere® Insulin Inhalation Powder in Combination With Lantus® Versus Humalog® in Combination With Lantus® in Subjects With Type 1 Diabetes Mellitus Over a 16-Week Treatment Period

The objective of this study is to demonstrate that TI® Inhalation Powder combined with Lantus® is as effective as Humalog® combined with Lantus® on HbA1c.

Inclusion Criteria:

• Men or women ≥ 18 and ≤ 80 years old

• Clinical diagnosis of type 1 diabetes mellitus for more than 12 months

• Body mass index (BMI) ≤ 30 kg/m2

• Stable antidiabetic regimen of sc insulin therapy at a total daily dose ≤ 1.5 IU/kg/day

• HbA1c > 7.0% and ≤ 9.0%

• C-peptide level ≤ 0.30 pmol/mL

• Nonsmokers (includes cigarettes, cigars, pipes, and chewing tobacco) for at least the preceding 6 months

• Negative urine cotinine defined as ≤ 100 ng/mL

• Pulmonary function tests (PFTs):

  • Forced expiratory volume in 1 second (FEV1) ≥ 70% Third National Health and Nutrition Examination Survey (NHANES III) predicted
  • FEV1 as a percentage of FEV1/forced vital capacity (FVC) ≥ 70% (NHANES III) predicted
  • Total lung capacity (TLC) ≥ 80% predicted (Intermountain Thoracic Society [ITS])
  • Single breath carbon monoxide diffusing capacity of the lung, hemoglobin-corrected (DLco-Hb) (uncorrected) ≥ 70% predicted

• For the subset of subjects having Doppler echocardiograms: right ventricular systolic pressure (RVSP) ≤ 40 mm Hg at Visit 1

• Written informed consent

Exclusion Criteria:

• Treatment with any type of antidiabetic drugs, other than sc insulin, within the preceding 12 weeks

• Two or more severe hypoglycemic episodes within 6 months of screening or episode of severe hypoglycemia between Visit 1 and Visit 5

• Any hospitalization or emergency room visit due to poor diabetic control within 6 months of Visit 1, or hospitalization or emergency room visit due to poor diabetic control between Visit 1 and Visit 5

• Severe complications of diabetes, in the opinion of the PI, including symptomatic autonomic neuropathy; disabling peripheral neuropathy; active proliferative retinopathy; nephropathy with renal failure, renal transplant, or dialysis; history of foot ulcers; nontraumatic amputations due to gangrene; or vascular claudication

• Previous exposure to an inhaled insulin product within 3 months of Visit 1

• History of insulin pump use within 6 weeks of Visit 1

• Allergy or known hypersensitivity to insulin or to any of the drugs to be used in the trial, or a history of hypersensitivity to TI Inhalation Powder or to drugs with a similar chemical structure

• Significant improvement in pre- to postbronchodilator spirometry at Visit 1 (defined as an increase of 12% and 200 mL in either FEV1 or FVC)

• History of chronic obstructive pulmonary disease (COPD), clinically proven asthma, or any other clinically important pulmonary disease (eg, obstructive sleep apnea) confirmed by pulmonary function testing or radiologic findings

• Inability to perform spirometry maneuvers meeting recommended American Thoracic Society (ATS) standards of acceptability and repeatability criteria

• Active respiratory infection (subject could return after 30 days from resolution for rescreening); if respiratory infection manifested after Visit 1 but before Visit 1 PFTs, subject was to be scheduled for PFTs after 30 days from resolution of respiratory infection. An additional hemoglobin was to be required

• Major organ system diseases, including:

  • Seizure disorder
  • Significant cardiovascular dysfunction or history within 3 months of Visit 1, eg, congestive heart failure (New York Heart Association [NYHA] Class III or IV), or serious arrhythmia, myocardial infarction, cardiac surgery, recurrent syncope, transient ischemic attacks, or cerebrovascular accident
  • Uncontrolled hypertension with a systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg at Visit 1 despite pharmacologic treatment
  • Nephrotic syndrome; renal dysfunction or disease; serum creatinine > 2.0 mg/dL (0.11 mmol/L) in men and > 1.8 mg/dL (0.1 mmol/L) in women; or blood urea nitrogen (BUN) > 50 mg/dL (2.8 mmol/L)
  • Cancer (other than excised cutaneous basal cell carcinoma) within the past 5 years or any history of lung neoplasms
  • History of active viral or cirrhotic hepatic disease or abnormal liver enzymes as evidenced by serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal (ULN)
  • Active infection (eg, human immunodeficiency virus [HIV], hepatitis) or history of severe infection within 30 days of Visit 1
  • Anemia (hemoglobin ≤ 10.5 g/dL for women or ≤ 11.5 g/dL for men)
  • Diagnosis of systemic autoimmune or collagen vascular disease requiring previous or current treatment with systemic corticosteroids, cytotoxic drugs, or penicillamine
  • Any concurrent illness, other than diabetes mellitus, not controlled by a stable therapeutic regimen

• Current or previous chemotherapy or radiation therapy that might result in pulmonary toxicity

• Use of medications prescribed for weight loss (eg, sibutramine, orlistat) within 12 weeks of Visit 1

• Any history of or current use of amiodarone

• Clinically significant abnormalities on screening laboratory evaluation (unless discussed with and approved by the medical monitor)

• Women who were pregnant, lactating, or planning to become pregnant during the trial

• Women of childbearing potential (defined as premenopausal and not surgically sterilized or postmenopausal for fewer than 2 years) not practicing adequate birth control. Adequate birth control was defined as using oral, percutaneous, or transdermal contraceptives; condoms and diaphragms (double barrier) with a spermicide; or intrauterine devices. Postmenopausal for this trial included amenorrhea for 2 or more years or surgically sterile

• Current drug or alcohol abuse or a history of drug or alcohol abuse that, in the opinion of the PI, would make the subject an unsuitable candidate for participation in the trial

• Exposure to any investigational medications or devices within 30 days before trial entry, or participation in another clinical trial while participating in this trial

• Unable or unlikely to comprehend and follow the trial protocol (including SBGM and diabetes education)

• Unable or unlikely to comprehend how to use the MedTone Inhaler or inability to use the device

• Unable or unlikely to follow a meal plan that included at least 2 meals/day (with or without a third meal or additional snacks)

• Noncompliance with medication or procedures that, in the PI's opinion, might affect the trial data or subject safety and that precluded the subject from further participation in the trial

• Any other concurrent medical or major psychiatric condition that, in the opinion of the PI, made the subject unsuitable for the clinical trial or could limit the validity of the informed consent or impair the subject's ability to participate in the trial

• For the subset of subjects having Doppler echocardiograms:

  • Subjects with left ventricular ejection fraction (LVEF) ≤ 35% at Visit 1
  • Subjects with known history of sickle cell disease
  • Previous use of Redux® (dexfenfluramine) or Pondimin® (fenfluramine)
  • History of valvular heart disease, including mild or greater aortic insufficiency or moderate or greater mitral insufficiency
  • Significant cardiovascular dysfunction or history within 12 months of Visit 1 (eg, congestive heart failure [NYHA Class III or IV]) or serious arrhythmia, treatment with medications to control or treat arrhythmias, myocardial infarction, cardiac surgery, recurrent syncope, transient ischemic attacks, or cerebrovascular accident
  • History of pulmonary embolism or deep venous thrombosis in the 12 months before Screening