Diabetes, Type I
Conditions
Brief summary
To determine the safety and efficacy of inhaled insulin in the treatment of type 1 diabetes
Interventions
Inhalation, 15U/30U
DRUGActive comparator
sc injectable insulin
Sponsors
Mannkind Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* Clinical diagnosis of type 1 diabetes for at least 1 year * Nonsmokers for prior 6 months * BMI less than or equal to 35kg/m2 * HbA1c \> or = 7% and \< or = 11% * Serum creatinine \< or = 1.8 mg/dL in female subjects and \< or = 2.0 mg/dL in male subjects * FEV1 \> or = 70% of predicted, DLco \> or = 70% , TLC \> or = 80% predicted * Maintenance of a treatment regimen of insulin less than or equal to 1.4 iu/kg/day * Urine cotinine \< or = 100 ng/mL
Exclusion criteria
* History of chronic obstructive pulmonary disease, asthma, any other clinically significant pulmonary disease confirmed by documented history, pulmonary function testing or radiologic findings * Evidence of severe complications of diabetes * Aminotransferase and/or alanine aminotransferase \> than 3 times the upper limit of normal
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Compare the Mean Change From Baseline to Week 52 in HbA1c | Baseline to Week 52 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose to Week 52 | Baseline to Week 52 | Change from baseline in fasting plasma glucose at Week 52 |
| Number of Subjects Achieving Week 52 HbA1c Levels Less Than or Equal to 7.0% | Baseline to Week 52 | Number of subjects achieving week 52 HbA1c levels less than or equal to 7.0% |
| Incidence of Total Hypoglycemia | Baseline to Week 52 | 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 | Change from baseline in weight at Week 52 |
| Total Hypoglycemia Event Rate | Baseline to Week 52 | Number of Hypoglycemic Events/Total Subject Exposure Time (in months) |
| Severe Hypoglycemia Event Rate | Baseline to Week 52 | Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months) |
| Incidence of Severe Hypoglycemia | Baseline to Week 52 | 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 Patient enrolled Feb, 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 - 1420 Screened / 598 Eligible of which 589 were randomized - 822 screen failures 24 Subjects randomized but never dosed
Participants by arm
| Arm | Count |
|---|---|
| TI + Insulin Glargine TI + Insulin glargine | 293 |
| Insulin Aspart + Insulin Glargine Comparator | 272 |
| Total | 565 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 17 | 2 |
| Overall Study | Lost to Follow-up | 5 | 5 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Physician Decision | 15 | 7 |
| Overall Study | Protocol Violation | 3 | 14 |
| Overall Study | Randomized but not dosed | 8 | 16 |
| Overall Study | Various | 7 | 5 |
| Overall Study | Withdrawal by Subject | 47 | 19 |
Baseline characteristics
| Characteristic | TI + Insulin Glargine | Insulin Aspart + Insulin Glargine | Total |
|---|---|---|---|
| Age, Continuous | 37.9 years STANDARD_DEVIATION 13.06 | 38.1 years STANDARD_DEVIATION 13.18 | 38 years STANDARD_DEVIATION 13.11 |
| HbA1c | 8.4 percent STANDARD_DEVIATION 0.95 | 8.5 percent STANDARD_DEVIATION 0.97 | 8.5 percent STANDARD_DEVIATION 0.96 |
| Sex: Female, Male Female | 139 Participants | 132 Participants | 271 Participants |
| Sex: Female, Male Male | 154 Participants | 140 Participants | 294 Participants |
| Weight | 76.7 kilogram STANDARD_DEVIATION 15.64 | 76.8 kilogram STANDARD_DEVIATION 14.95 | 76.7 kilogram STANDARD_DEVIATION 15.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 265 / 293 | 257 / 272 |
| serious Total, serious adverse events | 52 / 293 | 47 / 272 |
Outcome results
Primary
Compare the Mean Change From Baseline to Week 52 in HbA1c
Time frame: Baseline to Week 52
Population: Intention to treat (ITT) with Last Observation Carried Forward (LOCF)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TI + Insulin Glargine | Compare the Mean Change From Baseline to Week 52 in HbA1c | -0.13 Percentage | Standard Error 0.058 |
| Insulin Aspart + Insulin Glargine | Compare the Mean Change From Baseline to Week 52 in HbA1c | -0.37 Percentage | Standard Error 0.059 |
95% CI: [0.08, 0.4]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose to Week 52
Change from baseline in fasting plasma glucose at Week 52
Time frame: Baseline to Week 52
Population: participants in ITT population with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TI + Insulin Glargine | Change From Baseline in Fasting Plasma Glucose to Week 52 | -46.5 mg/dl | Standard Error 5.61 |
| Insulin Aspart + Insulin Glargine | Change From Baseline in Fasting Plasma Glucose to Week 52 | -25.7 mg/dl | Standard Error 5.23 |
p-value: 0.005295% CI: [-35.4, -6.3]ANCOVA
Secondary
Change From Baseline in Weight to Week 52
Change from baseline in weight at Week 52
Time frame: Baseline to Week 52
Population: participants in ITT population with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TI + Insulin Glargine | Change From Baseline in Weight to Week 52 | -0.5 kilogram | Standard Error 0.32 |
| Insulin Aspart + Insulin Glargine | Change From Baseline in Weight to Week 52 | 1.4 kilogram | Standard Error 0.3 |
Comparison: ANCOVA model with terms of pooled site and treatment as fixed effects and baseline weight as covariatep-value: <0.000195% CI: [-2.7, -1]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: Baseline to Week 52
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI + Insulin Glargine | Incidence of Severe Hypoglycemia | 32.08 percentage of participants |
| Insulin Aspart + Insulin Glargine | Incidence of Severe Hypoglycemia | 36.40 percentage of participants |
p-value: 0.278695% CI: [0.582, 1.169]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: Baseline to Week 52
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI + Insulin Glargine | Incidence of Total Hypoglycemia | 85.67 percentage of participants |
| Insulin Aspart + Insulin Glargine | Incidence of Total Hypoglycemia | 92.28 percentage of participants |
p-value: 0.012495% CI: [0.278, 0.856]Regression, Logistic
Secondary
Number of Subjects Achieving Week 52 HbA1c Levels Less Than or Equal to 7.0%
Number of subjects achieving week 52 HbA1c levels less than or equal to 7.0%
Time frame: Baseline to Week 52
Population: participants in ITT population with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI + Insulin Glargine | Number of Subjects Achieving Week 52 HbA1c Levels Less Than or Equal to 7.0% | 33 Participants |
| Insulin Aspart + Insulin Glargine | Number of Subjects Achieving Week 52 HbA1c Levels Less Than or Equal to 7.0% | 35 Participants |
Comparison: logistic regression analysis with the terms of treatment and baseline HbA1c in the modelp-value: 0.831195% CI: [0.536, 1.652]Regression, Logistic
Secondary
Severe Hypoglycemia Event Rate
Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months)
Time frame: Baseline to Week 52
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI + Insulin Glargine | Severe Hypoglycemia Event Rate | 0.08 Number of events/subject-month |
| Insulin Aspart + Insulin Glargine | Severe Hypoglycemia Event Rate | 0.10 Number of events/subject-month |
p-value: 0.2131Generalized Estimating Equation
Secondary
Total Hypoglycemia Event Rate
Number of Hypoglycemic Events/Total Subject Exposure Time (in months)
Time frame: Baseline to Week 52
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI + Insulin Glargine | Total Hypoglycemia Event Rate | 1.81 Number of events/subject-month |
| Insulin Aspart + Insulin Glargine | Total Hypoglycemia Event Rate | 1.86 Number of events/subject-month |
p-value: 0.1193Generalized Estimation Equation