Diabetes Mellitus, Type 2
Conditions
Keywords
Inhaled Insulin
Brief summary
The original protocol was a randomized, open-label, 3-way cross-over study with 9 scheduled visits. The visits comprised an initial screening visit, 3 treatment visits for the meal challenge followed by a 2-6-week blood-loss recovery period, an interim safety visit, 3 sequential visits for the glucose clamp, and a final close-out visit. Protocol Amendment 1 was a randomized, open-label, 2-way cross-over study with 7 visits for each completed subject. The visits comprise an initial screening visit, 2 treatment visits for the meal challenge followed by a 2-6-week blood-loss recovery period, an interim safety visit, 2 sequential visits for the glucose clamp, and a final close-out visit. For both the original protocol and Protocol Amendment 1, subjects were hospitalized in the clinical unit for all procedures.
Detailed description
The original protocol was a randomized, open-label, 3-way cross-over study with 9 scheduled visits. The visits comprised an initial screening visit, 3 treatment visits for the meal challenge followed by a 2-6-week blood-loss recovery period, an interim safety visit, 3 sequential visits for the glucose clamp, and a final close-out visit. After review of the meal challenge data from the Original Protocol design, it became apparent that the TI Inhalation Powder, insulin lispro, and Exubera doses were not well matched, and resulted in significantly higher insulin exposure following insulin lispro than the two inhaled treatments. All meal challenge visits were completed for the 18 subjects enrolled. However, the glucose clamp visits were discontinued since it was discovered that a direct comparison between the treatments was not possible. The protocol was amended (Amendment 1) to ensure that the insulin exposures between TI Inhalation Powder and insulin lispro were more suited (increased the TI Inhalation Powder doses and decreased the insulin lispro dose). An Exubera arm was not included in Amendment 1 due to the market removal of this product. Protocol Amendment 1 was a randomized, open-label, 2-way cross-over study with 7 visits for each completed subject. The visits comprise an initial screening visit, 2 treatment visits for the meal challenge followed by a 2-6-week blood-loss recovery period, an interim safety visit, 2 sequential visits for the glucose clamp, and a final close-out visit. For both the original protocol and Protocol Amendment 1, subjects were hospitalized in the clinical unit for all procedures.
Interventions
Inhalation 15U/30U
Sponsors
Mannkind Corporation
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Receiving diabetes treatment with insulin for a minimum of 3 months * Body Mass Index (BMI) of ≤ 34 kg/m2 and ≥ 25 kg/m2 * HbA1c ≤ 8.5% based upon results from a central laboratory * Non-smoking Males and females ≥ 18 and ≤ 70 years of age * A clinical diagnosis of type 2 diabetes mellitus for ≥ 12 months
Exclusion criteria
* Total daily insulin requirement of ≥ 1.2 U/kg body weight * Use of Symlin® (pramlintide acetate) and/or Byetta® (exenatide) within the preceding 8 weeks * Two or more severe hypoglycemic episodes within 6 months of screening * Any hospitalization or emergency room visit due to poor diabetic control within 6 months of Screening * Severe complications of diabetes * Previous exposure to any inhaled insulin product * Currently using an insulin delivery pump * Allergy or known hypersensitivity to insulin or to any of the drugs to be used in the trial * Any clinically important pulmonary disease, confirmed by documented history, pulmonary function testing, or radiologic findings * Chronic use of systemic steroids * Inability to perform PFT maneuvers to meet the recommended American Thoracic Society (ATS) standards of acceptability and repeatability * Significant improvement in spirometry following bronchodilation * Active respiratory infection * Seizure disorder * Significant cardiovascular dysfunction and/or history within 3 months of Screening * Uncontrolled hypertension with a systolic blood pressure of \>160 mm Hg and/or diastolic blood pressure \> 95 mm Hg at screening, despite pharmacologic treatment * Clinical nephrotic syndrome or renal dysfunction or disease * Cancer (other than an excised cutaneous basal cell carcinoma) within the past 5 years or any history of lung neoplasms * History of active viral and/or cirrhotic hepatic disease and/or abnormal liver enzymes * Active infection eg, Human Immunodeficiency Virus (HIV), Hepatitis, or history of severe infection within 30 days of Screening * Anemia * A previous diagnosis of systemic autoimmune or collagen vascular disease requiring prior or current treatment with systemic corticosteroids, cytotoxic drugs or penicillamine * Any concurrent illness, other than diabetes mellitus not controlled by a stable therapeutic regime * Current or previous chemotherapy or radiation therapy that may result in pulmonary toxicity * Clinically significant abnormalities on screening laboratory evaluation * Female subjects who are pregnant, lactating or planning to become pregnant during the clinical trial period * Female subjects of childbearing potential (defined as pre-menopausal and not surgically sterilized or post-menopausal for less than 2 years) not practicing adequate birth control. * Current drug or alcohol abuse, or a history of drug or alcohol abuse, that, in the opinion of the PI, would not make the subject a suitable candidate for participation in the clinical trial * Exposure to any investigational medications or devices within the previous 30 days prior to trial entry or participation in another clinical trial during this trial * Unable and/or unlikely to comprehend and/or follow the trial protocol * Concurrent medical or major psychiatric condition which, in the opinion of the PI, makes the subject unsuitable for the clinical trial, or could limit the validity of the informed consent and/or impair the subject's ability to participate in the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Minimum Endogenous Glucose Production (EGP) - Meal Challenge | 0-480 minutes | Time to minimum EGP post dose |
| Minimum EGP - Meal Challenge | 0-480 minutes | Minimum calculated EGP per subject as change from baseline |
| EGP AOC0-480 - Meal Challenge | 0-480 minutes | EGP area over the curve from 0 to 480 minutes postdose |
Countries
Germany
Participant flow
Recruitment details
This single-center study was conducted at: Profil Institut fur Stoffwechselforschung GmbH Hellersbergstrasse 9 D-41460 Neuss, Germany Principal Investigator: Dr. Klaus Rave First subjects first visit: 20 September 2007 Last subject last visit: 30 January 2009
Pre-assignment details
This randomized, open-label crossover study was conducted in 2 phases: original protocol (TI 45 U, Exubera 4mg and Lispro 12 U) and amendment 1 (TI 60U or TI 90 U, and Lispro 10 U). Both original protocol and amendment 1 had screening visits, meal challenge and glucose clamp visits (with a blood-loss recovery period between them) and final visits.
Participants by arm
| Arm | Count |
|---|---|
| Amendment 1 2-way crossover study of 60 U or 90 U of Technosphere Insulin Inhalation Powder crossed with 10 U of subcutaneous insulin lispro | 12 |
| Original Protocol 3-way crossover study of 45 U of Technosphere Insulin Inhalation Powder, 4 mg of Exubera, and 12 U of subcutaneous insulin lispro | 18 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Washout 3 (7-21 Days) - Orig Protocol | Sponsor Decision | 0 | 0 | 0 | 0 | 3 | 3 | 2 | 3 | 2 | 3 |
| Washout 4 (7-21 Days) - Orig Protocol | Sponsor Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Washout 5 (7-21 Days) - Orig Protocol | Sponsor Decision | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Original Protocol | Amendment 1 | Total |
|---|---|---|---|
| Age, Continuous | 54.9 years STANDARD_DEVIATION 6.9 | 55.3 years STANDARD_DEVIATION 7.6 | 55.1 years STANDARD_DEVIATION 7.2 |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 15 Participants | 9 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 6 | 4 / 6 | 1 / 12 | 5 / 18 | 1 / 18 | 7 / 18 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 12 | 0 / 18 | 0 / 18 | 0 / 18 |
Outcome results
Primary
EGP AOC0-480 - Meal Challenge
EGP area over the curve from 0 to 480 minutes postdose
Time frame: 0-480 minutes
Population: Amendment 1: Subjects with type 2 diabetes. All subjects crossed over to lispro treatment. Original protocol:Subjects with type 2 diabetes; all subjects received all doses; AOC could not be calculated for 1 subject for Exubera and 2 subjects for the other treatments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amendment 1 - TI Inhalation Powder 90 U | EGP AOC0-480 - Meal Challenge | 2272.8 µmol/kg | Standard Deviation 266.2 |
| Amendment 1 - TI Inhalation Powder 60U | EGP AOC0-480 - Meal Challenge | 2108.7 µmol/kg | Standard Deviation 498.3 |
| Amendment 1 - Insulin Lispro 10 U | EGP AOC0-480 - Meal Challenge | 2190.9 µmol/kg | Standard Deviation 674.5 |
| Original Protocol - TI Inhalation Powder 45 U | EGP AOC0-480 - Meal Challenge | 2129.4 µmol/kg | Standard Deviation 764.4 |
| Original Protocol - Exubera 4 mg | EGP AOC0-480 - Meal Challenge | 2488.3 µmol/kg | Standard Deviation 845.1 |
| Original Protocol - Insulin Lispro 12 U | EGP AOC0-480 - Meal Challenge | 1985.9 µmol/kg | Standard Deviation 623.5 |
Primary
Minimum EGP - Meal Challenge
Minimum calculated EGP per subject as change from baseline
Time frame: 0-480 minutes
Population: Amendment 1: Subjects with type 2 diabetes; all received TI and were crossed over to lispro; 3 subjects in the 90 U TI group had insufficient data. Original protocol:Subjects with type 2 diabetes; all subjects received all doses; EGPmin could not be calculated for 1 subject for Exubera and 2 subjects for the other treatments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amendment 1 - TI Inhalation Powder 90 U | Minimum EGP - Meal Challenge | -10.29 µmol/kg/min | Standard Deviation 4.394 |
| Amendment 1 - TI Inhalation Powder 60U | Minimum EGP - Meal Challenge | -6.92 µmol/kg/min | Standard Deviation 1.584 |
| Amendment 1 - Insulin Lispro 10 U | Minimum EGP - Meal Challenge | -7.11 µmol/kg/min | Standard Deviation 2.018 |
| Original Protocol - TI Inhalation Powder 45 U | Minimum EGP - Meal Challenge | -7.59 µmol/kg/min | Standard Deviation 3.015 |
| Original Protocol - Exubera 4 mg | Minimum EGP - Meal Challenge | -7.86 µmol/kg/min | Standard Deviation 2.962 |
| Original Protocol - Insulin Lispro 12 U | Minimum EGP - Meal Challenge | -7.63 µmol/kg/min | Standard Deviation 2.709 |
Primary
Time to Minimum Endogenous Glucose Production (EGP) - Meal Challenge
Time to minimum EGP post dose
Time frame: 0-480 minutes
Population: Amendment 1: Subjects with type 2 diabetes; all received TI and were crossed over to lispro; 3 subjects in the 90 U TI group had insufficient data. Original protocol:Subjects with type 2 diabetes; all subjects received all doses; EGPmin could not be calculated for 1 subject for Exubera and 2 subjects for the other treatments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Amendment 1 - TI Inhalation Powder 90 U | Time to Minimum Endogenous Glucose Production (EGP) - Meal Challenge | 75.0 Minutes |
| Amendment 1 - TI Inhalation Powder 60U | Time to Minimum Endogenous Glucose Production (EGP) - Meal Challenge | 75.0 Minutes |
| Amendment 1 - Insulin Lispro 10 U | Time to Minimum Endogenous Glucose Production (EGP) - Meal Challenge | 125.0 Minutes |
| Original Protocol - TI Inhalation Powder 45 U | Time to Minimum Endogenous Glucose Production (EGP) - Meal Challenge | 60 Minutes |
| Original Protocol - Exubera 4 mg | Time to Minimum Endogenous Glucose Production (EGP) - Meal Challenge | 160 Minutes |
| Original Protocol - Insulin Lispro 12 U | Time to Minimum Endogenous Glucose Production (EGP) - Meal Challenge | 130 Minutes |