Diabetes Type 2
Conditions
Brief summary
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.
Interventions
Inhalation, 15U/30U
DRUG70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin)
BPR 70/30, which is a premix of intermediate acting and rapid acting insulin given sc
Sponsors
Mannkind Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in HbA1c to Week 52 | Baseline to Week 52 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 52 Weeks | Defined as hypoglycemic symptoms that are relieved with carbohydrate intake or blood glucose measurement \<= 63 mg/dL, regardless of symptoms. |
| Change From Baseline in Weight to Week 52 | Baseline to Week 52 | — |
| Total Hypoglycemia Event Rate | 52 Weeks | Number of Hypoglycemic Events/Total Subject Exposure Time (in months) |
| Severe Hypoglycemia Event Rate | 52 Weeks | Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months) |
| Incidence of Severe Hypoglycemia | 52 Weeks | 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. |
Countries
Argentina, Brazil, Canada, Chile, Mexico, Poland, Russia, Spain, United Kingdom, United States
Participant flow
Recruitment details
First subject enrolled Feb. 23, 2006 Multi-national trial conducted in US, Canada, Mexico, Brazil, Argentina, Chile, Spain, UK, Poland, Russia
Pre-assignment details
3 week Screening period prior to randomization - 2064 Screened / 673 Eligible . 677 subjects were randomized. ( 4 ineligible subjects were randomized in error) 1391 screen failures. 23 Subjects randomized but never dosed.
Participants by arm
| Arm | Count |
|---|---|
| TI + Insulin Glargine Technosphere® Insulin Inhalation Powder + Insulin glargine | 323 |
| BPR 70/30 70% insulin aspart protamine suspension and 30% insulin aspart injection (rDNA origin) | 331 |
| Total | 654 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 29 | 12 |
| Overall Study | Death | 4 | 1 |
| Overall Study | Lost to Follow-up | 6 | 22 |
| Overall Study | Physician Decision | 5 | 8 |
| Overall Study | Protocol Violation | 6 | 3 |
| Overall Study | Randomized but not dosed | 11 | 12 |
| Overall Study | Various | 7 | 7 |
| Overall Study | Withdrawal by Subject | 50 | 32 |
Baseline characteristics
| Characteristic | TI + Insulin Glargine | BPR 70/30 | Total |
|---|---|---|---|
| Age, Continuous | 55.9 years STANDARD_DEVIATION 10.68 | 55.9 years STANDARD_DEVIATION 9.91 | 55.9 years STANDARD_DEVIATION 10.29 |
| Fasting Plasma Glucose (FPG) | 171.8 milligrams per deciliter STANDARD_DEVIATION 68.53 | 176.2 milligrams per deciliter STANDARD_DEVIATION 67.15 | 174 milligrams per deciliter STANDARD_DEVIATION 67.82 |
| HbA1c | 8.7 percentage STANDARD_DEVIATION 1.14 | 8.7 percentage STANDARD_DEVIATION 1.1 | 8.7 percentage STANDARD_DEVIATION 1.12 |
| Sex: Female, Male Female | 160 Participants | 185 Participants | 345 Participants |
| Sex: Female, Male Male | 163 Participants | 146 Participants | 309 Participants |
| Weight | 88.1 kilogram STANDARD_DEVIATION 17.33 | 85.7 kilogram STANDARD_DEVIATION 18.07 | 86.9 kilogram STANDARD_DEVIATION 17.74 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 225 / 323 | 251 / 331 |
| serious Total, serious adverse events | 37 / 323 | 31 / 331 |
Outcome results
Primary
Change From Baseline in HbA1c to Week 52
Time frame: Baseline to Week 52
Population: Intention to treat (ITT) with Last Observation Carried Forward (LOCF); participants with available data at baseline and post-baseline.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TI + Insulin Glargine | Change From Baseline in HbA1c to Week 52 | -0.59 percent | Standard Error 0.063 |
| BPR 70/30 | Change From Baseline in HbA1c to Week 52 | -0.71 percent | Standard Error 0.061 |
95% CI: [-0.05, 0.29]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose to Week 52
Time frame: Baseline to Week 52
Population: Intention to treat (ITT) population; participants with available data at baseline and Week 52.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TI + Insulin Glargine | Change From Baseline in Fasting Plasma Glucose to Week 52 | -35.7 milligrams per deciliter | Standard Error 4.61 |
| BPR 70/30 | Change From Baseline in Fasting Plasma Glucose to Week 52 | -17.9 milligrams per deciliter | Standard Error 4.21 |
Comparison: ANCOVA model with terms of pooled site and treatment as fixed effects and baseline fasting plasma glucose as covariatep-value: 0.002995% CI: [-29.3, -6.1]ANCOVA
Secondary
Change From Baseline in Weight to Week 52
Time frame: Baseline to Week 52
Population: Intention to treat (ITT) population; participants with available data at baseline and Week 52.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TI + Insulin Glargine | Change From Baseline in Weight to Week 52 | 0.9 kilogram | Standard Error 0.32 |
| BPR 70/30 | Change From Baseline in Weight to Week 52 | 2.5 kilogram | Standard Error 0.29 |
Comparison: ANCOVA model with terms of pooled site and treatment as fixed effects and baseline weight as covariatep-value: 0.000295% CI: [-2.4, -0.7]ANCOVA
Secondary
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.
Time frame: 52 Weeks
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI + Insulin Glargine | Incidence of Severe Hypoglycemia | 4.33 percentage of participants |
| BPR 70/30 | Incidence of Severe Hypoglycemia | 9.97 percentage of participants |
p-value: 0.006695% CI: [0.215, 0.78]Regression, Logistic
Secondary
Incidence of Total Hypoglycemia
Defined as hypoglycemic symptoms that are relieved with carbohydrate intake or blood glucose measurement \<= 63 mg/dL, regardless of symptoms.
Time frame: 52 Weeks
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI + Insulin Glargine | Incidence of Total Hypoglycemia | 47.99 percentage of participants |
| BPR 70/30 | Incidence of Total Hypoglycemia | 68.58 percentage of participants |
p-value: <0.00195% CI: [0.307, 0.581]Regression, Logistic
Secondary
Number of Subjects Achieving Week 52 HbA1c Levels Less Than or Equal to 7.0%
Time frame: Week 52
Population: Intention to treat (ITT); participants with available data at baseline and Week 52.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI + Insulin Glargine | Number of Subjects Achieving Week 52 HbA1c Levels Less Than or Equal to 7.0% | 47 participants |
| BPR 70/30 | Number of Subjects Achieving Week 52 HbA1c Levels Less Than or Equal to 7.0% | 65 participants |
Comparison: logistic regression analysis with the terms of treatment and baseline HbA1c in the modelp-value: 0.279395% CI: [0.486, 1.231]Regression, Logistic
Secondary
Severe Hypoglycemia Event Rate
Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months)
Time frame: 52 Weeks
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI + Insulin Glargine | Severe Hypoglycemia Event Rate | 0.73 Number of events/100 subject-months |
| BPR 70/30 | Severe Hypoglycemia Event Rate | 2.20 Number of events/100 subject-months |
p-value: 0.0591Generalized Estimating Equation
Secondary
Total Hypoglycemia Event Rate
Number of Hypoglycemic Events/Total Subject Exposure Time (in months)
Time frame: 52 Weeks
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI + Insulin Glargine | Total Hypoglycemia Event Rate | 0.41 Number of events/subject-month |
| BPR 70/30 | Total Hypoglycemia Event Rate | 0.61 Number of events/subject-month |
p-value: 0.0027Generalized Estimation Equation