Type 2 Diabetes
Conditions
Brief summary
This is an open-label, randomized, forced-titration clinical trial evaluating the efficacy and safety of Technosphere Insulin (TI) Inhalation Powder in combination with insulin glargine versus insulin aspart in combination with insulin glargine in subjects with type 2 diabetes.
Detailed description
Phase 3 clinical trial is designed to examine the efficacy and safety of inhaled prandial TI Inhalation Powder in combination with basal insulin verses insulin aspart in combination with basal insulin in subjects with type 2 diabetes who are suboptimally controlled with their current insulin regimens.This trial will employ a variety of methods to intensively manage these subjects.
Interventions
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
No
Inclusion criteria
* Men and women ≥ 18 and ≤ 80 years of age * Clinical diagnosis of type 2 diabetes mellitus for more than 12 months * Body mass index (BMI) ≤ 45 kg/m2 * Glycated Hemoglobin (HbA1c) \> 6.5% and ≤ 10.0% * Treatment with 1 to 3 Oral Antidiabetic Drugs (OADs) and basal insulin for a minimum of 3 months before screening. Doses of OADs must have been stable for 3 months before study entry * Nonsmokers (includes cigarettes, cigars, pipes, and chewing tobacco) for the preceding ≥ 6 months * Office spirometry at the investigator site * Forced expiratory volume in 1 second (FEV1) ≥ 65% Third National Health and Nutrition Examination Survey (NHANES III) predicted * Forced vital capacity (FVC) ≥ 65% NHANES III predicted * Forced expiratory volume in 1 second as a percentage of forced vital capacity (FEV1/FVC) ≥ lower limit of normal (LLN)
Exclusion criteria
* Current or prior treatment with prandial or PreMix (70/30) insulin * History of insulin pump use within 6 weeks of Visit 1 * Treatment with Glucagon-like Peptide (GLP-1) analog drugs within the preceding 12 weeks of Visit 1 * History of chronic obstructive pulmonary disease (COPD), 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 (eg, symptomatic autonomic neuropathy) * Significant cardiovascular dysfunction or history within 3 months of Visit 1 (eg, congestive heart failure \[New York Heart Association {NYHA} Class III or IV\]) * Serious arrhythmia, myocardial infarction, cardiac surgery, recurrent syncope, transient ischemic attacks, or any cerebrovascular accident * History of pulmonary embolism or deep venous thrombosis in the 12 months before Screening (Visit 1)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c (%) From Baseline to Week 16 | Baseline to Week 16 | Change from Baseline in glycated hemoglobin at Week 16 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Fasting Plasma Glucose (FPG) Levels at Randomization and Throughout the Study | Change from baseline to 16 weeks | Not analyzed due to early termination of the trial. |
| Comparison of Post-prandial Glucose (PPG) Levels at Randomization and Throughout the Study | Change from baseline to 16 weeks | Not analyzed due to early termination of the trial. |
| Glycomark and Fructosamine Levels Measured Throughout the Study | Change from baseline to 16 weeks | Not analyzed due to early termination of the trial. |
| Seven-point Glucose at Randomization and Throughout the Study | Change from baseline to 16 weeks | Not analyzed due to early termination of the trial. |
| Glycemic Excursions and Variability as Assessed Through Continuous Glucose Monitoring (CGM) | Change from baseline to 16 weeks | Not analyzed due to early termination of the trial. |
| Changes in Body Weight at 16 Weeks | Change from baseline to 16 weeks | Not analyzed due to early termination of the trial. |
| Treatment Satisfaction as Assessed by Subject Treatment and Health Outcomes Questionnaires | Change from baseline to 16 weeks | Not analyzed due to early termination of the trial. |
| Total Number of Cough Episodes | Baseline to Week 16 | Total number of times patients coughed once, intermittently or continuously (inclusive) |
| Severe Hypoglycemic Event Rate | Baseline to Week 16 | Severe hypoglycemic event rate, ie, total number of events divided by subject-months of observation Severe hypoglycemia is defined as a subject who requires the assistance of another individual (not merely requested) and either: * SMBG levels ≤ 36 mg/dL OR * There is a prompt response to the administration of carbohydrate, glucagon, or other resuscitative measures |
| Mild or Moderate Hypoglycemic Event Rate | Baseline to Week 16 | Mild or moderate hypoglycemic event rate, ie, total number of events divided by subject-months of observation Nonsevere hypoglycemia is defined as a subject: * SMBG levels \< 70 mg/dL AND/OR * Symptoms that are relieved by the self-administration of carbohydrates |
| Number of Subjects Reporting Cough Episodes | Baseline to Week 16 | Number of Subjects Reporting Cough Episodes |
| Number of Subjects Reporting Intermittent Coughing Episodes | Baseline to Week 16 | Number of subjects reporting Intermittent Coughing Episodes |
| To Evaluate the Effect of Each Treatment on HbA1c | Change from baseline to 16 weeks | Not analyzed due to early termination of the trial. |
| Number of Cough Episodes Occuring Within 10 Minutes of Drug Inhalation | Baseline to Week 16 | — |
| Baseline Forced Expiratory Volume in 1 Second (FEV1) | Baseline | Baseline FEV1 |
| Week 16 Forced Expiratory Volume in 1 Second | Week 16 | Week 16 FEV1 |
| Week 16 Change From Baseline in Forced Expiratory Volume in 1 Second | Baseline to Week 16 | Week 16 Change from Baseline in FEV1 |
| Week 20 (Follow-up) Forced Expiratory Volume in 1 Second | Week 20 (Follow-up) | Week 20 (Follow-up) FEV1, 4 weeks after discontinuation of study treatment |
| Week 20 (Follow-up) Change From Baseline in Forced Expiratory Volume in 1 Second | Baseline to Week 20 | Week 20 (Follow-up, 4 weeks after discontinuation of study treatment) Change from Baseline in FEV1 |
| Baseline Forced Vital Capacity (FVC) | Baseline | Baseline FVC |
| Week 16 Forced Vital Capacity | Week 16 | Week 16 FVC |
| Week 16 Change From Baseline Forced Vital Capacity | Baseline to Week 16 | Week 16 Change from Baseline FVC |
| Week 20 (Follow-up) Forced Vital Capacity | Week 20 | Week 20 (Follow-up, 4 weeks after discontinuation of study treatment) FVC |
| Week 20 (Follow-up) Change From Baseline in Forced Vital Capacity | Baseline to Week 20 | Week 20 (Follow-up, 4 weeks after discontinuation of study treatment) Change from Baseline in FVC |
| Number of Single Coughing Episodes | Baseline to Week 16 | Total number of times patients coughed only once |
Countries
United States
Participant flow
Recruitment details
The FIrst Patient First Visit (FPFV) was September 21, 2010, and Last Patient Last Visit (LPLV) was August 25, 2011. Trial conducted in US. The study was terminated before completion of full enrollment for business reasons. Subjects already enrolled were allowed to complete the study to assess the safety of the titration algorithms.
Pre-assignment details
After a 1 week to 5 week run-in period, subjects were randomized to receive either TI Inhalation Powder in combination with insulin glargine, or insulin aspart in combination with insulin glargine. 105 Screened/46 Eligible. 39 subjects were randomized; 59 screen failures and 7 were screened but not randomized.
Participants by arm
| Arm | Count |
|---|---|
| Technosphere Insulin + Insulin Glargine Technosphere Insulin Inhalation Powder (administered prior to each meal) in combination with insulin glargine (once or twice daily); doses individualized for each patient | 19 |
| Insulin Aspart + Insulin Glargine Insulin Aspart (prior to each meal) and Insulin Glargine (once or twice daily) ; doses individualized for each patient | 18 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Various | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Total | Technosphere Insulin + Insulin Glargine | Insulin Aspart + Insulin Glargine |
|---|---|---|---|
| Age, Continuous | 59.4 years | 60.6 years FULL_RANGE 7.95 | 58.1 years FULL_RANGE 10.67 |
| Body Mass Index | 33.2 kg/m2 | 33.2 kg/m2 FULL_RANGE 5.78 | 33.3 kg/m2 FULL_RANGE 5.51 |
| Body Weight | 100.9 kg | 100.9 kg FULL_RANGE 21.84 | 100.8 kg FULL_RANGE 20.3 |
| Duration of Diabetes | 15.1 years | 14.6 years FULL_RANGE 7.95 | 15.6 years FULL_RANGE 10.67 |
| HbA1c | 7.85 % | 7.76 % FULL_RANGE 1.097 | 7.94 % FULL_RANGE 1.098 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 15 Participants | 11 Participants |
| Region of Enrollment United States | 37 participants | 19 participants | 18 participants |
| Sex: Female, Male Female | 12 Participants | 8 Participants | 4 Participants |
| Sex: Female, Male Male | 25 Participants | 11 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 19 | 11 / 18 |
| serious Total, serious adverse events | 1 / 19 | 1 / 18 |
Outcome results
Primary
Change in HbA1c (%) From Baseline to Week 16
Change from Baseline in glycated hemoglobin at Week 16
Time frame: Baseline to Week 16
Population: Safety Population, participants with data available at Baseline and Week 16
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Technosphere Insulin + Insulin Glargine | Change in HbA1c (%) From Baseline to Week 16 | -1.2179 Percentage of total hemoglobin | Standard Deviation 0.1468 |
| Insulin Aspart + Insulin Glargine | Change in HbA1c (%) From Baseline to Week 16 | -1.2652 Percentage of total hemoglobin | Standard Deviation 0.1571 |
Comparison: ANCOVA model with terms of treatment as a fixed effect and baseline HbA1c as covariatep-value: 0.828395% CI: [-0.4901, 0.3956]ANCOVA
Secondary
Baseline Forced Expiratory Volume in 1 Second (FEV1)
Baseline FEV1
Time frame: Baseline
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere Insulin + Insulin Glargine | Baseline Forced Expiratory Volume in 1 Second (FEV1) | 2.97 L | Standard Deviation 0.63 |
| Insulin Aspart + Insulin Glargine | Baseline Forced Expiratory Volume in 1 Second (FEV1) | 2.83 L | Standard Deviation 0.75 |
Secondary
Baseline Forced Vital Capacity (FVC)
Baseline FVC
Time frame: Baseline
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere Insulin + Insulin Glargine | Baseline Forced Vital Capacity (FVC) | 3.63 L | Standard Deviation 0.78 |
| Insulin Aspart + Insulin Glargine | Baseline Forced Vital Capacity (FVC) | 3.48 L | Standard Deviation 1.02 |
Secondary
Changes in Body Weight at 16 Weeks
Not analyzed due to early termination of the trial.
Time frame: Change from baseline to 16 weeks
Secondary
Comparison of Fasting Plasma Glucose (FPG) Levels at Randomization and Throughout the Study
Not analyzed due to early termination of the trial.
Time frame: Change from baseline to 16 weeks
Secondary
Comparison of Post-prandial Glucose (PPG) Levels at Randomization and Throughout the Study
Not analyzed due to early termination of the trial.
Time frame: Change from baseline to 16 weeks
Secondary
Glycemic Excursions and Variability as Assessed Through Continuous Glucose Monitoring (CGM)
Not analyzed due to early termination of the trial.
Time frame: Change from baseline to 16 weeks
Secondary
Glycomark and Fructosamine Levels Measured Throughout the Study
Not analyzed due to early termination of the trial.
Time frame: Change from baseline to 16 weeks
Secondary
Mild or Moderate Hypoglycemic Event Rate
Mild or moderate hypoglycemic event rate, ie, total number of events divided by subject-months of observation Nonsevere hypoglycemia is defined as a subject: * SMBG levels \< 70 mg/dL AND/OR * Symptoms that are relieved by the self-administration of carbohydrates
Time frame: Baseline to Week 16
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Technosphere Insulin + Insulin Glargine | Mild or Moderate Hypoglycemic Event Rate | 4.47 Events / subject-month |
| Insulin Aspart + Insulin Glargine | Mild or Moderate Hypoglycemic Event Rate | 4.41 Events / subject-month |
Secondary
Number of Cough Episodes Occuring Within 10 Minutes of Drug Inhalation
Time frame: Baseline to Week 16
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Technosphere Insulin + Insulin Glargine | Number of Cough Episodes Occuring Within 10 Minutes of Drug Inhalation | 5 Cough episodes |
| Insulin Aspart + Insulin Glargine | Number of Cough Episodes Occuring Within 10 Minutes of Drug Inhalation | 0 Cough episodes |
Secondary
Number of Single Coughing Episodes
Total number of times patients coughed only once
Time frame: Baseline to Week 16
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Technosphere Insulin + Insulin Glargine | Number of Single Coughing Episodes | 1 Cough episodes |
| Insulin Aspart + Insulin Glargine | Number of Single Coughing Episodes | 0 Cough episodes |
Secondary
Number of Subjects Reporting Cough Episodes
Number of Subjects Reporting Cough Episodes
Time frame: Baseline to Week 16
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Technosphere Insulin + Insulin Glargine | Number of Subjects Reporting Cough Episodes | 4 Number of participants |
| Insulin Aspart + Insulin Glargine | Number of Subjects Reporting Cough Episodes | 0 Number of participants |
Secondary
Number of Subjects Reporting Intermittent Coughing Episodes
Number of subjects reporting Intermittent Coughing Episodes
Time frame: Baseline to Week 16
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Technosphere Insulin + Insulin Glargine | Number of Subjects Reporting Intermittent Coughing Episodes | 4 Number of participants |
| Insulin Aspart + Insulin Glargine | Number of Subjects Reporting Intermittent Coughing Episodes | 0 Number of participants |
Secondary
Seven-point Glucose at Randomization and Throughout the Study
Not analyzed due to early termination of the trial.
Time frame: Change from baseline to 16 weeks
Secondary
Severe Hypoglycemic Event Rate
Severe hypoglycemic event rate, ie, total number of events divided by subject-months of observation Severe hypoglycemia is defined as a subject who requires the assistance of another individual (not merely requested) and either: * SMBG levels ≤ 36 mg/dL OR * There is a prompt response to the administration of carbohydrate, glucagon, or other resuscitative measures
Time frame: Baseline to Week 16
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Technosphere Insulin + Insulin Glargine | Severe Hypoglycemic Event Rate | 0.01 Events / subject-month |
| Insulin Aspart + Insulin Glargine | Severe Hypoglycemic Event Rate | 0.34 Events / subject-month |
Secondary
To Evaluate the Effect of Each Treatment on HbA1c
Not analyzed due to early termination of the trial.
Time frame: Change from baseline to 16 weeks
Secondary
Total Number of Cough Episodes
Total number of times patients coughed once, intermittently or continuously (inclusive)
Time frame: Baseline to Week 16
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Technosphere Insulin + Insulin Glargine | Total Number of Cough Episodes | 5 Cough episodes |
| Insulin Aspart + Insulin Glargine | Total Number of Cough Episodes | 0 Cough episodes |
Secondary
Treatment Satisfaction as Assessed by Subject Treatment and Health Outcomes Questionnaires
Not analyzed due to early termination of the trial.
Time frame: Change from baseline to 16 weeks
Secondary
Week 16 Change From Baseline Forced Vital Capacity
Week 16 Change from Baseline FVC
Time frame: Baseline to Week 16
Population: Safety Population, with data available at Week 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere Insulin + Insulin Glargine | Week 16 Change From Baseline Forced Vital Capacity | -0.13 L | Standard Deviation 0.34 |
| Insulin Aspart + Insulin Glargine | Week 16 Change From Baseline Forced Vital Capacity | -0.07 L | Standard Deviation 0.36 |
Secondary
Week 16 Change From Baseline in Forced Expiratory Volume in 1 Second
Week 16 Change from Baseline in FEV1
Time frame: Baseline to Week 16
Population: Safety Population, with data available at Week 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere Insulin + Insulin Glargine | Week 16 Change From Baseline in Forced Expiratory Volume in 1 Second | -0.14 L | Standard Deviation 0.32 |
| Insulin Aspart + Insulin Glargine | Week 16 Change From Baseline in Forced Expiratory Volume in 1 Second | -0.07 L | Standard Deviation 0.27 |
Secondary
Week 16 Forced Expiratory Volume in 1 Second
Week 16 FEV1
Time frame: Week 16
Population: Safety Population, with data available at Week 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere Insulin + Insulin Glargine | Week 16 Forced Expiratory Volume in 1 Second | 2.91 L | Standard Deviation 0.57 |
| Insulin Aspart + Insulin Glargine | Week 16 Forced Expiratory Volume in 1 Second | 2.66 L | Standard Deviation 0.7 |
Secondary
Week 16 Forced Vital Capacity
Week 16 FVC
Time frame: Week 16
Population: Safety Population, with data available at Week 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere Insulin + Insulin Glargine | Week 16 Forced Vital Capacity | 3.61 L | Standard Deviation 0.72 |
| Insulin Aspart + Insulin Glargine | Week 16 Forced Vital Capacity | 3.33 L | Standard Deviation 0.98 |
Secondary
Week 20 (Follow-up) Change From Baseline in Forced Expiratory Volume in 1 Second
Week 20 (Follow-up, 4 weeks after discontinuation of study treatment) Change from Baseline in FEV1
Time frame: Baseline to Week 20
Population: Safety Population, with data available at Week 20
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere Insulin + Insulin Glargine | Week 20 (Follow-up) Change From Baseline in Forced Expiratory Volume in 1 Second | -0.07 L | Standard Deviation 0.29 |
| Insulin Aspart + Insulin Glargine | Week 20 (Follow-up) Change From Baseline in Forced Expiratory Volume in 1 Second | -0.05 L | Standard Deviation 0.28 |
Secondary
Week 20 (Follow-up) Change From Baseline in Forced Vital Capacity
Week 20 (Follow-up, 4 weeks after discontinuation of study treatment) Change from Baseline in FVC
Time frame: Baseline to Week 20
Population: Safety Population, with data available at Week 20
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere Insulin + Insulin Glargine | Week 20 (Follow-up) Change From Baseline in Forced Vital Capacity | -0.05 L | Standard Deviation 0.35 |
| Insulin Aspart + Insulin Glargine | Week 20 (Follow-up) Change From Baseline in Forced Vital Capacity | -0.06 L | Standard Deviation 0.38 |
Secondary
Week 20 (Follow-up) Forced Expiratory Volume in 1 Second
Week 20 (Follow-up) FEV1, 4 weeks after discontinuation of study treatment
Time frame: Week 20 (Follow-up)
Population: Safety Population, with data available at Week 20
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere Insulin + Insulin Glargine | Week 20 (Follow-up) Forced Expiratory Volume in 1 Second | 3.07 L | Standard Deviation 0.55 |
| Insulin Aspart + Insulin Glargine | Week 20 (Follow-up) Forced Expiratory Volume in 1 Second | 2.86 L | Standard Deviation 0.7 |
Secondary
Week 20 (Follow-up) Forced Vital Capacity
Week 20 (Follow-up, 4 weeks after discontinuation of study treatment) FVC
Time frame: Week 20
Population: Safety Population, with data available at Week 20
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Technosphere Insulin + Insulin Glargine | Week 20 (Follow-up) Forced Vital Capacity | 3.77 L | Standard Deviation 0.73 |
| Insulin Aspart + Insulin Glargine | Week 20 (Follow-up) Forced Vital Capacity | 3.57 L | Standard Deviation 0.96 |