Type 2 Diabetes
Conditions
Brief summary
Insulin-naive subjects with Type 2 Diabetes Mellitus who are sub-optimally controlled on either maximum tolerated dose of metformin or maximum tolerated dose of metformin plus one or two other oral anti-diabetic medications will have either Prandial Technosphere® Insulin or Technosphere Powder (placebo) added to their oral antidiabetic drugs.
Interventions
Technosphere® Insulin Inhalation Powder
DRUGTechnosphere Powder
Placebo Comparator
Sponsors
Mannkind Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HbA1c \> or = to 7.5% and \< or = to 10.0% * Body mass index (BMI) \< or = to 45 kg/m2 * Non smoker for at least 6 months before Screening * Clinical diagnosis of type 2 diabetes mellitus for more than 12 months * Currently receiving as diabetes treatment only metformin or 2 or more OADs and on stable doses for at least 3 months before enrollment * Subjects receiving metformin must be on at least 1.5gm daily, or up to the maximum tolerated dose * Subjects treated with a sulfonylurea must be on at least 50% of the total maximum approved dose for a given agent * Subjects receiving a DPP-4 inhibitor must receive the maximum approved dose specific for that agent * Metiglinide and alpha-glucoside inhibitors must be taken at the highest tolerated dose within the approved dose range * No previous or current treatment with insulin, except during an acute illness, gestational diabetes, or at time of initial diagnosis of diabetes * Forced expiratory volume in one second (FEV1) \> or = to 70% Third National Health and Nutrition Examination Survey (NHANES III) predicted * Forced vital capacity (FVC) \> or = to 70% NHANES III predicted * Forced expiratory volume in one second as a percentage of forced vital capacity (FEV1/FVC) \> or = to NHANES III lower limit of normal (LLN)
Exclusion criteria
* History of chronic obstructive pulmonary disease (COPD), clinically proven asthma, or any other clinically important pulmonary disease (eg, pulmonary fibrosis) * Any clinically significant radiological findings on screening chest x-ray * Use of medications for asthma, COPD, or any other chronic respiratory conditions * Evidence of serious complications of diabetes (proliferative retinopathy, autonomic neuropathy with symptoms of gastroparesis or cardiac arrhythmia; sensory neuropathy that makes manipulation of the Gen2C inhaler difficult) * Renal disease or renal dysfunction * Significant cardiovascular dysfunction or history thereof within 12 months of screening; serious arrhythmia, treatment with medications to control/treat arrhythmias; myocardial infarction; cardiac surgery; history of valvular heart disease * Previous or current use of amiodarone * Treatment with glucagon-like peptide-1 (GLP-1) analogs, thiazolidinediones (TZD), or weight loss drugs (eg, sibutramine, orlistat) within 3 months of screening * History of pulmonary embolism or deep venous thrombosis in the 12 months before Screening * History of recent blood transfusion (within previous 3 months) or diagnosis of hemoglobinopathies that may affect HbA1c measurements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 24 in HbA1c | Baseline to Week 24 | Efficacy as measured by change in glycated hemoglobin (HbA1c) at Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Responders Achieving HbA1c <= 6.5% | Week 24 | Efficacy as measured in proportion of subjects achieving HbA1c \< or = to 6.5% at Week 24 |
| FPG Change From Baseline to Week 24 | Baseline to Week 24 | Efficacy as measured by mean change in fasting plasma glucose (FPG) |
| Proportion of Subjects Requiring Rescue Therapy | Baseline to Week 24 | — |
| Time to Rescue | Baseline to Week 24 | Time from Week 0 (baseline) to initiation of rescue therapy (up to a maximum of 24 weeks/end of treatment) for subjects not responding to treatment |
| FEV1 Change From Baseline to Week 24 | Baseline to Week 24 | Forced Expiratory Volume in 1 second - change from baseline to week 24 |
| Incidence of Total Hypoglycemia | Baseline to Week 24 | Hypoglycemia, defined as blood glucose \<= 70 mg/dL or in absence of blood glucose, symptoms that are resolved by the administration of carbohydrates. |
| Proportion of Responders Achieving HbA1c <= 7.0% | Week 24 | Efficacy as measured in proportion of subjects achieving HbA1c \< or = to 7.0% |
| Total Hypoglycemia Event Rate | Baseline to Week 24 | Number of Hypoglycemic Events/Total Subject Exposure Time (in months) |
| Severe Hypoglycemia Event Rate | Baseline to Week 24 | Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months) |
| Mean 7-point Glucose Baseline Values | Baseline | Mean 7-point self-monitored glucose at baseline |
| Mean 7-point Glucose Week 24 Values | Week 24 | Mean 7-point self-monitored blood glucose at Week 24 |
| Change in Body Weight From Baseline to Week 24 | Baseline to Week 24 | Change in body weight from Baseline to Week 24 |
| Incidence of Severe Hypoglycemia | Baseline to Week 24 | Severe Hypoglycemia defined as: Requiring 3rd party assistance. |
Countries
Brazil, Russia, Ukraine, United States
Participant flow
Recruitment details
First Patient enrolled November 2011. Multi-national trial conducted in US, Russia, Ukraine and Brazil
Pre-assignment details
6 week Screening Period prior to OAD run-in period. 1379 Screened /539 Eligible of which 535 entered the run-in period. 439 met randomization criteria at end of run-in of which 353 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| TI Inhalation Powder + OADs Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient | 177 |
| Technosphere Powder Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient | 176 |
| Total | 353 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 9 |
| Overall Study | Adverse Event + Elevated Fasting Glucose | 0 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 6 | 4 |
| Overall Study | Moved out of country | 0 | 1 |
| Overall Study | Non-compliance with protocol | 1 | 1 |
| Overall Study | Non-compliance with study drug | 1 | 3 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Withdrawal by Subject | 10 | 14 |
Baseline characteristics
| Characteristic | TI Inhalation Powder + OADs | Technosphere Powder | Total |
|---|---|---|---|
| Age, Customized 18-30 years | 1 participants | 0 participants | 1 participants |
| Age, Customized 31-49 years | 37 participants | 33 participants | 70 participants |
| Age, Customized 50-64 years | 102 participants | 110 participants | 212 participants |
| Age, Customized >=65 years | 37 participants | 33 participants | 70 participants |
| BMI | 31.8 kg/m^2 | 32.4 kg/m^2 | 32.1 kg/m^2 |
| Duration of Diabetes | 9.7 years | 9.2 years | 9.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 43 Participants | 41 Participants | 84 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 134 Participants | 135 Participants | 269 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Fasting Plasma Glucose (FPG) | 179.1 mg/dL | 177.2 mg/dL | 178.2 mg/dL |
| HbA1c | 8.26 Percent of hemoglobin | 8.35 Percent of hemoglobin | 8.31 Percent of hemoglobin |
| Oral Anti-Diabetic Drug (OAD) Type 2 or more OADs (not including Metformin) | 3 participants | 3 participants | 6 participants |
| Oral Anti-Diabetic Drug (OAD) Type Metformin + 1 or more OADs not specified above | 9 participants | 9 participants | 18 participants |
| Oral Anti-Diabetic Drug (OAD) Type Metformin + DPP-4 Inhibitor | 9 participants | 9 participants | 18 participants |
| Oral Anti-Diabetic Drug (OAD) Type Metformin Only | 42 participants | 40 participants | 82 participants |
| Oral Anti-Diabetic Drug (OAD) Type Metformin + Sulfonylurea | 114 participants | 115 participants | 229 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants | 17 Participants | 38 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 151 Participants | 155 Participants | 306 Participants |
| Region of Enrollment Brazil | 15 participants | 14 participants | 29 participants |
| Region of Enrollment Russian Federation | 55 participants | 56 participants | 111 participants |
| Region of Enrollment Ukraine | 19 participants | 19 participants | 38 participants |
| Region of Enrollment United States | 88 participants | 87 participants | 175 participants |
| Sex: Female, Male Female | 95 Participants | 102 Participants | 197 Participants |
| Sex: Female, Male Male | 82 Participants | 74 Participants | 156 Participants |
| Weight | 90.2 kg | 90.8 kg | 90.5 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 108 / 177 | 82 / 176 |
| serious Total, serious adverse events | 5 / 177 | 9 / 176 |
Outcome results
Primary
Change From Baseline to Week 24 in HbA1c
Efficacy as measured by change in glycated hemoglobin (HbA1c) at Week 24
Time frame: Baseline to Week 24
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TI Inhalation Powder + OADs | Change From Baseline to Week 24 in HbA1c | -0.82 percentage of hemoglobin | Standard Error 0.061 |
| Technosphere Powder | Change From Baseline to Week 24 in HbA1c | -0.42 percentage of hemoglobin | Standard Error 0.062 |
p-value: <0.000195% CI: [-0.57, -0.23]Mixed Models Analysis
Secondary
Change in Body Weight From Baseline to Week 24
Change in body weight from Baseline to Week 24
Time frame: Baseline to Week 24
Population: Full analysis set for patients with data at both Baseline and at Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TI Inhalation Powder + OADs | Change in Body Weight From Baseline to Week 24 | 0.49 kg | Standard Error 0.333 |
| Technosphere Powder | Change in Body Weight From Baseline to Week 24 | -1.13 kg | Standard Error 0.347 |
p-value: <0.000195% CI: [0.9, 2.34]ANCOVA
Secondary
FEV1 Change From Baseline to Week 24
Forced Expiratory Volume in 1 second - change from baseline to week 24
Time frame: Baseline to Week 24
Population: Full analysis set for patients with data at both Baseline and at Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TI Inhalation Powder + OADs | FEV1 Change From Baseline to Week 24 | -0.13 Liters | Standard Deviation 0.175 |
| Technosphere Powder | FEV1 Change From Baseline to Week 24 | -0.04 Liters | Standard Deviation 0.147 |
95% CI: [-0.12, -0.05]Mixed Models Analysis
Secondary
FPG Change From Baseline to Week 24
Efficacy as measured by mean change in fasting plasma glucose (FPG)
Time frame: Baseline to Week 24
Population: Full analysis set for subjects with data at both Baseline and at Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TI Inhalation Powder + OADs | FPG Change From Baseline to Week 24 | -11.20 mg/dL | Standard Error 3.776 |
| Technosphere Powder | FPG Change From Baseline to Week 24 | -3.78 mg/dL | Standard Error 3.864 |
p-value: 0.169895% CI: [-18.03, 3.18]Mixed Models Analysis
Secondary
Incidence of Severe Hypoglycemia
Severe Hypoglycemia defined as: Requiring 3rd party assistance.
Time frame: Baseline to Week 24
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI Inhalation Powder + OADs | Incidence of Severe Hypoglycemia | 5.1 percentage of participants |
| Technosphere Powder | Incidence of Severe Hypoglycemia | 1.7 percentage of participants |
Secondary
Incidence of Total Hypoglycemia
Hypoglycemia, defined as blood glucose \<= 70 mg/dL or in absence of blood glucose, symptoms that are resolved by the administration of carbohydrates.
Time frame: Baseline to Week 24
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI Inhalation Powder + OADs | Incidence of Total Hypoglycemia | 67.8 percentage of participants |
| Technosphere Powder | Incidence of Total Hypoglycemia | 30.7 percentage of participants |
Secondary
Mean 7-point Glucose Baseline Values
Mean 7-point self-monitored glucose at baseline
Time frame: Baseline
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TI Inhalation Powder + OADs | Mean 7-point Glucose Baseline Values | Before Lunch | 176.7 mg/dL | Standard Deviation 49.58 |
| TI Inhalation Powder + OADs | Mean 7-point Glucose Baseline Values | Before Dinner | 176.8 mg/dL | Standard Deviation 41.81 |
| TI Inhalation Powder + OADs | Mean 7-point Glucose Baseline Values | After Breakfast | 212.8 mg/dL | Standard Deviation 51.01 |
| TI Inhalation Powder + OADs | Mean 7-point Glucose Baseline Values | After Dinner | 205.2 mg/dL | Standard Deviation 48.72 |
| TI Inhalation Powder + OADs | Mean 7-point Glucose Baseline Values | After Lunch | 197.0 mg/dL | Standard Deviation 46.94 |
| TI Inhalation Powder + OADs | Mean 7-point Glucose Baseline Values | Bedtime | 203.3 mg/dL | Standard Deviation 50.55 |
| TI Inhalation Powder + OADs | Mean 7-point Glucose Baseline Values | Before Breakfast | 178.5 mg/dL | Standard Deviation 37.58 |
| Technosphere Powder | Mean 7-point Glucose Baseline Values | Bedtime | 203.8 mg/dL | Standard Deviation 46.52 |
| Technosphere Powder | Mean 7-point Glucose Baseline Values | Before Breakfast | 182.2 mg/dL | Standard Deviation 40.5 |
| Technosphere Powder | Mean 7-point Glucose Baseline Values | After Breakfast | 219.9 mg/dL | Standard Deviation 51.77 |
| Technosphere Powder | Mean 7-point Glucose Baseline Values | Before Lunch | 183.6 mg/dL | Standard Deviation 53.76 |
| Technosphere Powder | Mean 7-point Glucose Baseline Values | After Lunch | 209.1 mg/dL | Standard Deviation 44.37 |
| Technosphere Powder | Mean 7-point Glucose Baseline Values | Before Dinner | 187.6 mg/dL | Standard Deviation 50.04 |
| Technosphere Powder | Mean 7-point Glucose Baseline Values | After Dinner | 211.2 mg/dL | Standard Deviation 50.44 |
Secondary
Mean 7-point Glucose Week 24 Values
Mean 7-point self-monitored blood glucose at Week 24
Time frame: Week 24
Population: Full analysis set for patients with data at Week 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TI Inhalation Powder + OADs | Mean 7-point Glucose Week 24 Values | Before Lunch | 152.4 mg/dL | Standard Deviation 48.13 |
| TI Inhalation Powder + OADs | Mean 7-point Glucose Week 24 Values | Before Dinner | 157.4 mg/dL | Standard Deviation 49.34 |
| TI Inhalation Powder + OADs | Mean 7-point Glucose Week 24 Values | After Breakfast | 170.3 mg/dL | Standard Deviation 44.23 |
| TI Inhalation Powder + OADs | Mean 7-point Glucose Week 24 Values | After Dinner | 164.3 mg/dL | Standard Deviation 44.84 |
| TI Inhalation Powder + OADs | Mean 7-point Glucose Week 24 Values | After Lunch | 158.0 mg/dL | Standard Deviation 42.79 |
| TI Inhalation Powder + OADs | Mean 7-point Glucose Week 24 Values | Bedtime | 163.0 mg/dL | Standard Deviation 42.66 |
| TI Inhalation Powder + OADs | Mean 7-point Glucose Week 24 Values | Before Breakfast | 156.6 mg/dL | Standard Deviation 30.8 |
| Technosphere Powder | Mean 7-point Glucose Week 24 Values | Bedtime | 178.7 mg/dL | Standard Deviation 44.5 |
| Technosphere Powder | Mean 7-point Glucose Week 24 Values | Before Breakfast | 160.9 mg/dL | Standard Deviation 36.7 |
| Technosphere Powder | Mean 7-point Glucose Week 24 Values | After Breakfast | 194.7 mg/dL | Standard Deviation 50.02 |
| Technosphere Powder | Mean 7-point Glucose Week 24 Values | Before Lunch | 163.4 mg/dL | Standard Deviation 49.8 |
| Technosphere Powder | Mean 7-point Glucose Week 24 Values | After Lunch | 183.8 mg/dL | Standard Deviation 47.73 |
| Technosphere Powder | Mean 7-point Glucose Week 24 Values | Before Dinner | 164.7 mg/dL | Standard Deviation 40.6 |
| Technosphere Powder | Mean 7-point Glucose Week 24 Values | After Dinner | 188.5 mg/dL | Standard Deviation 43.93 |
Secondary
Proportion of Responders Achieving HbA1c <= 6.5%
Efficacy as measured in proportion of subjects achieving HbA1c \< or = to 6.5% at Week 24
Time frame: Week 24
Population: Full analysis set for subjects with available data at Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI Inhalation Powder + OADs | Proportion of Responders Achieving HbA1c <= 6.5% | 15.9 percentage of participants |
| Technosphere Powder | Proportion of Responders Achieving HbA1c <= 6.5% | 4.2 percentage of participants |
p-value: 0.002195% CI: [1.7, 11.17]Regression, Logistic
Secondary
Proportion of Responders Achieving HbA1c <= 7.0%
Efficacy as measured in proportion of subjects achieving HbA1c \< or = to 7.0%
Time frame: Week 24
Population: Full analysis set for subjects with available data at Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI Inhalation Powder + OADs | Proportion of Responders Achieving HbA1c <= 7.0% | 37.7 percentage of participants |
| Technosphere Powder | Proportion of Responders Achieving HbA1c <= 7.0% | 19.0 percentage of participants |
p-value: 0.000595% CI: [1.55, 4.8]Regression, Logistic
Secondary
Proportion of Subjects Requiring Rescue Therapy
Time frame: Baseline to Week 24
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI Inhalation Powder + OADs | Proportion of Subjects Requiring Rescue Therapy | 6.8 percentage of participants |
| Technosphere Powder | Proportion of Subjects Requiring Rescue Therapy | 9.7 percentage of participants |
Secondary
Severe Hypoglycemia Event Rate
Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months)
Time frame: Baseline to Week 24
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI Inhalation Powder + OADs | Severe Hypoglycemia Event Rate | 2.37 Events/100 Subject-Month |
| Technosphere Powder | Severe Hypoglycemia Event Rate | 0.60 Events/100 Subject-Month |
p-value: 0.2024Negative Binomial Regression
Secondary
Time to Rescue
Time from Week 0 (baseline) to initiation of rescue therapy (up to a maximum of 24 weeks/end of treatment) for subjects not responding to treatment
Time frame: Baseline to Week 24
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TI Inhalation Powder + OADs | Time to Rescue | 95 Days |
| Technosphere Powder | Time to Rescue | 85 Days |
Secondary
Total Hypoglycemia Event Rate
Number of Hypoglycemic Events/Total Subject Exposure Time (in months)
Time frame: Baseline to Week 24
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TI Inhalation Powder + OADs | Total Hypoglycemia Event Rate | 1.16 Events/Subject-Month |
| Technosphere Powder | Total Hypoglycemia Event Rate | 0.50 Events/Subject-Month |
p-value: <0.0001Negative binomial regression