Safety and Efficacy of Technosphere® Insulin Inhalation Powder and Lantus® Compared to Humalog® and Lantus® Over 16-Weeks
Condition: Diabetes, Type 1
MeSH terms: Diabetes Mellitus, Type 1
Intervention: Technosphere Insulin; Insulin glargine; Insulin lispro
Intervention description: Technosphere Insulin Inhalation Powder 15U or 30U; Lantus-injectible supplied as 3mL (300 units) pens; Humalog autopen cartridges pre-filled with 3mL (300 units)
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin Lispro
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 130.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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