Diabetes, Type 1, Diabetes, Type 2
Conditions
Brief summary
Pulmonary Safety in Diabetics with T/I
Interventions
Inhalation, 15U/30U
DRUGUsual Care
Subjects will receive antidiabetes treatment at the discretion of their physicians
Sponsors
Mannkind Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* For All Subjects: * Nonsmoking * Body mass index \<42 kg/m2 * FEV1 greater than or equal to 70% of predicted , DLco and TLC greater than or equal to 80% of predicted at screening, * No abnormalities in screening pulmonary radiology * For Subjects with diabetes mellitus: * Type 1 or type 2 diabetes for at least 2 years * HbA1c greater than or equal to 6.6 % and less than or equal to 12.0 % * For Subjects without abnormalities in glucose control: * No history of diabetes * Normal results from a formal glucose tolerance test
Exclusion criteria
* History of chronic obstructive pulmonary disease, asthma, or other significant pulmonary disease * Significant renal, hepatic, or cardiac disease * Women who are pregnant, lactating, or planning on becoming pregnant * Subjects who have participated in studies of other investigational drugs within the previous 3 months * Evidence of severe complications of diabetes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Month 24 in Forced Expiratory Volume in 1 Second (FEV1) by MMRM for TI vs Usual Care | Baseline to Month 24 | Change from Baseline to End of Study in FEV1 by MMRM |
| FEV1 Decrease of ≥ 15% From Baseline Value at Last Measurement for TI vs Usual Care | Baseline to Month 24 | FEV1 decrease of ≥ 15% from Baseline value at last measurement |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Month 24 in Total Lung Capacity (TLC) by MMRM | Baseline to Month 24 | Change from baseline to Month 24 in TLC by MMRM |
| Change From Baseline to Month 24 in Hemoglobin Corrected DLco by MMRM | Baseline to Month 24 | Change from baseline to Month 24 in hemoglobin-corrected DLco by MMRM |
| Forced Vital Capacity (FVC) Decrease of ≥ 15% From Baseline Value at Last Measurement | Baseline to Month 24 | FVC Decrease of ≥15% from Baseline Value at Last Measurement |
| Total Lung Capacity (TLC) Decrease of ≥ 15% From Baseline Value at Last Measurement | Baseline to Month 24 | TLC Decrease of ≥ 15% from Baseline Value at Last Measurement |
| Change From Baseline to Last Measurement in FEV1 for TI vs Usual Care | Baseline to Month 24 | Change from Baseline to last measurement(Month 24) in FEV1 |
| Hemoglobin-Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLco) Decrease of >3 ml/Min/mmHg From Baseline Value at Last Measurement | Baseline to Month 24 | Hemoglobin-corrected DLco decrease of \>3 ml/min/mmHg from baseline value at last measurement |
| Change From Baseline in Glycated Hemoglobin A1c (HbA1c) at Last Measurement for TI vs Usual Care | Baseline to Month 24 | Change from baseline in HbA1c at last measurement |
| Change in Weight From Baseline at Month 24 | Baseline to Month 24 | Change from baseline in weight at Month 24 |
| Hemoglobin-Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLco) Decrease of ≥ 15% From Baseline Value at Last Measurement | Baseline to Month 24 | Hemoglobin-corrected DLco decrease of ≥ 15% from baseline value at last measurement |
| Change From Baseline to Month 24 in Forced Vital Capacity (FVC) by MMRM | Baseline to Month 24 | Change from Baseline to Month 24 in FVC by MMRM |
Countries
Canada, Czechia, Poland, Russia, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
First subject enrolled July 25, 2005 Multi-national trial conducted in Canada, Czech Republic, Poland, Russia, Spain, Ukraine, UK, and US
Pre-assignment details
Subjects were required to meet all inclusion/exclusion criteria 3741 screened/2053 eligible of which all were randomized, including 164 non-diabetics - 1688 screen failures 17 diabetics randomized but not dosed 1 non-diabetic elected not to participate
Participants by arm
| Arm | Count |
|---|---|
| Technosphere® Insulin Technosphere Insulin | 923 |
| Usual Care Usual care | 949 |
| Non-diabetes Subjects without abnormalities in glucose control | 163 |
| Total | 2,035 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 104 | 9 | 0 |
| Overall Study | Death | 4 | 3 | 0 |
| Overall Study | Lost to Follow-up | 56 | 80 | 5 |
| Overall Study | Physician Decision | 15 | 2 | 1 |
| Overall Study | Protocol Violation | 34 | 9 | 5 |
| Overall Study | Various | 32 | 20 | 8 |
| Overall Study | Withdrawal by Subject | 218 | 166 | 18 |
Baseline characteristics
| Characteristic | Technosphere® Insulin | Usual Care | Non-diabetes | Total |
|---|---|---|---|---|
| Age, Continuous | 50.8 years STANDARD_DEVIATION 11.55 | 50.4 years STANDARD_DEVIATION 11.62 | 38.2 years STANDARD_DEVIATION 12.59 | 49.6 years STANDARD_DEVIATION 12.15 |
| Body mass index | 29.87 kilograms per meter squared STANDARD_DEVIATION 5.366 | 29.76 kilograms per meter squared STANDARD_DEVIATION 5.035 | 25.27 kilograms per meter squared STANDARD_DEVIATION 4.494 | 29.5 kilograms per meter squared STANDARD_DEVIATION 5.29 |
| HbA1c | 8.7 percentage STANDARD_DEVIATION 1.39 | 8.7 percentage STANDARD_DEVIATION 1.38 | 0 percentage STANDARD_DEVIATION 0 | 8.4 percentage STANDARD_DEVIATION 1.61 |
| Sex: Female, Male Female | 366 Participants | 371 Participants | 92 Participants | 829 Participants |
| Sex: Female, Male Male | 557 Participants | 578 Participants | 71 Participants | 1206 Participants |
| Weight | 87.69 kilograms STANDARD_DEVIATION 18.628 | 87.53 kilograms STANDARD_DEVIATION 17.638 | 74.35 kilograms STANDARD_DEVIATION 16.204 | 86.6 kilograms STANDARD_DEVIATION 18.33 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 559 / 923 | 472 / 949 | 47 / 163 |
| serious Total, serious adverse events | 92 / 923 | 91 / 949 | 5 / 163 |
Outcome results
Primary
Change From Baseline to Month 24 in Forced Expiratory Volume in 1 Second (FEV1) by MMRM for TI vs Usual Care
Change from Baseline to End of Study in FEV1 by MMRM
Time frame: Baseline to Month 24
Population: Intention to Treat (ITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere® Insulin | Change From Baseline to Month 24 in Forced Expiratory Volume in 1 Second (FEV1) by MMRM for TI vs Usual Care | -0.16 liters | Standard Deviation 0.208 |
| Usual Care | Change From Baseline to Month 24 in Forced Expiratory Volume in 1 Second (FEV1) by MMRM for TI vs Usual Care | -0.12 liters | Standard Deviation 0.211 |
Comparison: Mixed model repeated measures with fixed effects diabetes type, visit, pooled site and treatment and baseline FEV1 as a covariate95% CI: [0.014, 0.06]Mixed Models Analysis
Primary
FEV1 Decrease of ≥ 15% From Baseline Value at Last Measurement for TI vs Usual Care
FEV1 decrease of ≥ 15% from Baseline value at last measurement
Time frame: Baseline to Month 24
Population: Intention to Treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Technosphere® Insulin | FEV1 Decrease of ≥ 15% From Baseline Value at Last Measurement for TI vs Usual Care | 42 Participants |
| Usual Care | FEV1 Decrease of ≥ 15% From Baseline Value at Last Measurement for TI vs Usual Care | 27 Participants |
Comparison: Logistic regression excluding non-diabetics95% CI: [-4.5578, -0.3956]Regression, Logistic
Secondary
Change From Baseline in Glycated Hemoglobin A1c (HbA1c) at Last Measurement for TI vs Usual Care
Change from baseline in HbA1c at last measurement
Time frame: Baseline to Month 24
Population: Intention to treat (ITT) with last observation carried forward (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere® Insulin | Change From Baseline in Glycated Hemoglobin A1c (HbA1c) at Last Measurement for TI vs Usual Care | -0.42 percentage | Standard Deviation 1.41 |
| Usual Care | Change From Baseline in Glycated Hemoglobin A1c (HbA1c) at Last Measurement for TI vs Usual Care | -0.49 percentage | Standard Deviation 1.37 |
Secondary
Change From Baseline to Last Measurement in FEV1 for TI vs Usual Care
Change from Baseline to last measurement(Month 24) in FEV1
Time frame: Baseline to Month 24
Population: Intention to Treat (ITT) with Last Observation Carried Forward (LOCF)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Technosphere® Insulin | Change From Baseline to Last Measurement in FEV1 for TI vs Usual Care | -0.128 liters |
| Usual Care | Change From Baseline to Last Measurement in FEV1 for TI vs Usual Care | -0.092 liters |
Comparison: ANCOVA model with treatment site, diabetes type, and baseline FEV195% CI: [0.016, 0.057]ANCOVA
Secondary
Change From Baseline to Month 24 in Forced Vital Capacity (FVC) by MMRM
Change from Baseline to Month 24 in FVC by MMRM
Time frame: Baseline to Month 24
Population: Intention to Treat (ITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere® Insulin | Change From Baseline to Month 24 in Forced Vital Capacity (FVC) by MMRM | -0.14 liters | Standard Deviation 0.242 |
| Usual Care | Change From Baseline to Month 24 in Forced Vital Capacity (FVC) by MMRM | -0.11 liters | Standard Deviation 0.262 |
| Non-diabetes | Change From Baseline to Month 24 in Forced Vital Capacity (FVC) by MMRM | -0.09 liters | Standard Deviation 0.21 |
Comparison: Mixed model repeated measures with fixed effects diabetes type, visit, pooled site and treatment and baseline FVC as a covariate95% CI: [0.008, 0.061]Mixed Models Analysis
Secondary
Change From Baseline to Month 24 in Hemoglobin Corrected DLco by MMRM
Change from baseline to Month 24 in hemoglobin-corrected DLco by MMRM
Time frame: Baseline to Month 24
Population: participants in ITT population with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere® Insulin | Change From Baseline to Month 24 in Hemoglobin Corrected DLco by MMRM | -1.60 mL/min/mmHg | Standard Deviation 2.83 |
| Usual Care | Change From Baseline to Month 24 in Hemoglobin Corrected DLco by MMRM | -1.36 mL/min/mmHg | Standard Deviation 2.862 |
| Non-diabetes | Change From Baseline to Month 24 in Hemoglobin Corrected DLco by MMRM | -1.33 mL/min/mmHg | Standard Deviation 3.203 |
Comparison: Mixed model repeated measures with fixed effects diabetes type, visit, pooled site, and treatment and baseline TLC as a covariate95% CI: [-0.037, 0.574]Mixed Models Analysis
Secondary
Change From Baseline to Month 24 in Total Lung Capacity (TLC) by MMRM
Change from baseline to Month 24 in TLC by MMRM
Time frame: Baseline to Month 24
Population: participants in ITT population with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere® Insulin | Change From Baseline to Month 24 in Total Lung Capacity (TLC) by MMRM | -0.05 liters | Standard Deviation 0.321 |
| Usual Care | Change From Baseline to Month 24 in Total Lung Capacity (TLC) by MMRM | -0.07 liters | Standard Deviation 0.322 |
| Non-diabetes | Change From Baseline to Month 24 in Total Lung Capacity (TLC) by MMRM | -0.02 liters | Standard Deviation 0.297 |
Comparison: Mixed model repeated measures with fixed effects diabetes type, visit, pooled site, and treatment and baseline TLC as a covariate95% CI: [-0.042, 0.031]Mixed Models Analysis
Secondary
Change in Weight From Baseline at Month 24
Change from baseline in weight at Month 24
Time frame: Baseline to Month 24
Population: Safety population at Month 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere® Insulin | Change in Weight From Baseline at Month 24 | 1.0 kilograms | Standard Deviation 6.653 |
| Usual Care | Change in Weight From Baseline at Month 24 | 1.64 kilograms | Standard Deviation 5.066 |
| Non-diabetes | Change in Weight From Baseline at Month 24 | 1.19 kilograms | Standard Deviation 4.457 |
Comparison: Two sample t-testp-value: 0.112t-test, 2 sided
Secondary
Forced Vital Capacity (FVC) Decrease of ≥ 15% From Baseline Value at Last Measurement
FVC Decrease of ≥15% from Baseline Value at Last Measurement
Time frame: Baseline to Month 24
Population: participants in ITT population with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Technosphere® Insulin | Forced Vital Capacity (FVC) Decrease of ≥ 15% From Baseline Value at Last Measurement | 23 participants |
| Usual Care | Forced Vital Capacity (FVC) Decrease of ≥ 15% From Baseline Value at Last Measurement | 17 participants |
| Non-diabetes | Forced Vital Capacity (FVC) Decrease of ≥ 15% From Baseline Value at Last Measurement | 2 participants |
Comparison: Logistic regression excluding non-diabetics95% CI: [0.3432, 1.2219]Regression, Logistic
Secondary
Hemoglobin-Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLco) Decrease of ≥ 15% From Baseline Value at Last Measurement
Hemoglobin-corrected DLco decrease of ≥ 15% from baseline value at last measurement
Time frame: Baseline to Month 24
Population: participants in ITT population with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Technosphere® Insulin | Hemoglobin-Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLco) Decrease of ≥ 15% From Baseline Value at Last Measurement | 105 Participants |
| Usual Care | Hemoglobin-Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLco) Decrease of ≥ 15% From Baseline Value at Last Measurement | 108 Participants |
| Non-diabetes | Hemoglobin-Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLco) Decrease of ≥ 15% From Baseline Value at Last Measurement | 20 Participants |
Comparison: Logistic regression excluding non-diabetics95% CI: [0.6703, 1.1958]Regression, Logistic
Secondary
Hemoglobin-Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLco) Decrease of >3 ml/Min/mmHg From Baseline Value at Last Measurement
Hemoglobin-corrected DLco decrease of \>3 ml/min/mmHg from baseline value at last measurement
Time frame: Baseline to Month 24
Population: participants in ITT population with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Technosphere® Insulin | Hemoglobin-Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLco) Decrease of >3 ml/Min/mmHg From Baseline Value at Last Measurement | 181 Participants |
| Usual Care | Hemoglobin-Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLco) Decrease of >3 ml/Min/mmHg From Baseline Value at Last Measurement | 181 Participants |
| Non-diabetes | Hemoglobin-Corrected Diffusing Capacity of the Lung for Carbon Monoxide (DLco) Decrease of >3 ml/Min/mmHg From Baseline Value at Last Measurement | 40 Participants |
Comparison: Logistic regression excluding non-diabetics95% CI: [0.6722, 1.077]Regression, Logistic
Secondary
Total Lung Capacity (TLC) Decrease of ≥ 15% From Baseline Value at Last Measurement
TLC Decrease of ≥ 15% from Baseline Value at Last Measurement
Time frame: Baseline to Month 24
Population: participants in ITT population with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Technosphere® Insulin | Total Lung Capacity (TLC) Decrease of ≥ 15% From Baseline Value at Last Measurement | 7 Participants |
| Usual Care | Total Lung Capacity (TLC) Decrease of ≥ 15% From Baseline Value at Last Measurement | 6 Participants |
| Non-diabetes | Total Lung Capacity (TLC) Decrease of ≥ 15% From Baseline Value at Last Measurement | 1 Participants |
Comparison: Logistic regression excluding non-diabetics95% CI: [0.251, 2.2431]Regression, Logistic