Diabetes Mellitus, Type 2
Conditions
Brief summary
to demonstrate the efficacy of inhaled Technosphere/Insulin in combination with metformin versus combination metformin and a secretagogue
Interventions
Inhalation, 15U/30U, prandial
DRUGMetformin & Secretagogues
Metformin tablets,Secretagogues supplied as any of the currently marketed brands and formulations.
DRUGTechnosphere Insulin & Metformin
Technosphere Insulin Inhalation Powder 15U/30U, Metformin tablets
Sponsors
Mannkind Corporation
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Non-smokers with clinical diagnosis of Type 2 diabetes mellitus for \>or= to 6 months * Stable regimen of metformin for \> or = to 1000mg/day or maximum tolerated dose) and a secretagogue \< or = 1/2 the maximum manufacturer-recommended daily dose without any dose adjustments within the preceding 6 wks. * Fixed dose combination products of metformin and sulfonylurea are acceptable as long as each individual dose meets inclusion criteria * HbA1c \>or= to 7.5% and \< or= to 11.0% * BMI \< or = to 40kg/m2. * FEV1\> or = to 70%, Total Lung capacity and \> or =80% DLco \> or= to 70%
Exclusion criteria
* Treatment with any type of anti-diabetic therapy, other than metformin & secretagogues within the preceding 12 weeks * Serum creatinine \> 1.4mg/dL in female subjects and \>1.5mg/dL in male subjects * History of chronic obstructive pulmonary disease, clinically proven asthma and/or any other clinically important pulmonary function testing and/or radiologic findings * Evidence of serious complications of diabetes (e.g. autonomic neuropathy)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Difference in Change From Baseline for HbA1c Between TI+ Metformin and Metformin+Secretagogue | Baseline to Week 12 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Change From Baseline for HbA1c Between TI Alone and Metformin+Secretagogue | Baseline to Week 12 | (Change from baseline within TI Alone) minus (change from baseline within metformin + secretagogue) |
| Change in HbA1c From Baseline to Week 24 (Subjects Who Stayed on Original Treatment) | Week 24 | — |
Countries
Argentina, Brazil, Canada, Chile, Czechia, Mexico, Poland, Russia, Spain, Ukraine, United States
Participant flow
Recruitment details
31 May 2006 (first subject enrolled) to 03 Mar 2008 (last subject completed. Multi-national trial conducted in Argentina, Brazil, Canada, Chile, Czech Republic, Mexico, Poland, Russian Federation, Spain, Ukraine, and USA.
Pre-assignment details
2 week screening period prior to randomization. 1512 patients screened with 528 patients randomized. 977 patients failed screening criteria, 9 subjects passed screening but were not randomized, 2 subjects failed screening but were randomized.
Participants by arm
| Arm | Count |
|---|---|
| TI Inhalation Powder Alone | 177 |
| Metformin & Secretagogues | 162 |
| TI Inhalation Powder + Metformin | 169 |
| Total | 508 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Initial Treatment Phase (Weeks 0 - 12) | Adverse Event | 8 | 2 | 6 |
| Initial Treatment Phase (Weeks 0 - 12) | Lost to Follow-up | 1 | 3 | 0 |
| Initial Treatment Phase (Weeks 0 - 12) | Physician Decision | 13 | 2 | 10 |
| Initial Treatment Phase (Weeks 0 - 12) | Protocol Violation | 3 | 1 | 0 |
| Initial Treatment Phase (Weeks 0 - 12) | Various | 4 | 0 | 20 |
| Initial Treatment Phase (Weeks 0 - 12) | Withdrawal by Subject | 21 | 10 | 20 |
| Transfer Treatment Phase (Weeks 12 - 24) | Adverse Event | 0 | 0 | 3 |
| Transfer Treatment Phase (Weeks 12 - 24) | Lost to Follow-up | 0 | 0 | 1 |
| Transfer Treatment Phase (Weeks 12 - 24) | Physician Decision | 0 | 0 | 3 |
| Transfer Treatment Phase (Weeks 12 - 24) | Protocol Violation | 0 | 0 | 1 |
| Transfer Treatment Phase (Weeks 12 - 24) | Various | 0 | 0 | 5 |
| Transfer Treatment Phase (Weeks 12 - 24) | Withdrawal by Subject | 2 | 2 | 8 |
Baseline characteristics
| Characteristic | TI Inhalation Powder Alone | Metformin & Secretagogues | TI Inhalation Powder + Metformin | Total |
|---|---|---|---|---|
| Age, Continuous | 57.3 years | 57.6 years | 56.8 years | 57.2 years |
| Body Weight | 86.1 kilograms STANDARD_DEVIATION 15.6 | 84.2 kilograms STANDARD_DEVIATION 16.2 | 83.9 kilograms STANDARD_DEVIATION 13.9 | 84.8 kilograms STANDARD_DEVIATION 15.27 |
| Fasting Plasma Glucose | 193.5 milligrams per deciliter STANDARD_DEVIATION 52.4 | 194.6 milligrams per deciliter STANDARD_DEVIATION 48.5 | 188.6 milligrams per deciliter STANDARD_DEVIATION 49.7 | 192.2 milligrams per deciliter STANDARD_DEVIATION 50.23 |
| HbA1c | 8.9 percentage STANDARD_DEVIATION 0.95 | 8.9 percentage STANDARD_DEVIATION 0.94 | 9.0 percentage STANDARD_DEVIATION 0.97 | 8.9 percentage STANDARD_DEVIATION 0.95 |
| Sex: Female, Male Female | 93 Participants | 88 Participants | 101 Participants | 282 Participants |
| Sex: Female, Male Male | 84 Participants | 74 Participants | 68 Participants | 226 Participants |
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 | 72 / 181 | 42 / 166 | 138 / 351 |
| serious Total, serious adverse events | 5 / 181 | 5 / 166 | 11 / 351 |
Outcome results
Primary
Difference in Change From Baseline for HbA1c Between TI+ Metformin and Metformin+Secretagogue
Time frame: Baseline to Week 12
Population: Intention to Treat (ITT) Population with Last Observation Carried Forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Metformin & Secretagogues | Difference in Change From Baseline for HbA1c Between TI+ Metformin and Metformin+Secretagogue | -0.78 Percentage of total hemoglobin | 95% Confidence Interval -0.78 |
| TI Inhalation Powder + Metformin | Difference in Change From Baseline for HbA1c Between TI+ Metformin and Metformin+Secretagogue | -0.70 Percentage of total hemoglobin | 95% Confidence Interval -0.7 |
Comparison: ANCOVA fitting model change from baseline in A1c with fixed effects for treatment and pooled site and baseline A1c as a covariatep-value: 0.4295% CI: [-0.11, 0.27]ANCOVA
Secondary
Change in HbA1c From Baseline to Week 24 (Subjects Who Stayed on Original Treatment)
Time frame: Week 24
Population: Intent to Treat: Subjects who stayed on original treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin & Secretagogues | Change in HbA1c From Baseline to Week 24 (Subjects Who Stayed on Original Treatment) | -1.82 percentage of total hemoglobin | Standard Deviation 1.114 |
| TI Inhalation Powder + Metformin | Change in HbA1c From Baseline to Week 24 (Subjects Who Stayed on Original Treatment) | -1.23 percentage of total hemoglobin | Standard Deviation 1.08 |
| TI Inhalation Powder + Metformin | Change in HbA1c From Baseline to Week 24 (Subjects Who Stayed on Original Treatment) | -1.68 percentage of total hemoglobin | Standard Deviation 1.014 |
Secondary
Difference in Change From Baseline for HbA1c Between TI Alone and Metformin+Secretagogue
(Change from baseline within TI Alone) minus (change from baseline within metformin + secretagogue)
Time frame: Baseline to Week 12
Population: Intention to Treat (ITT) Population for patients with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin & Secretagogues | Difference in Change From Baseline for HbA1c Between TI Alone and Metformin+Secretagogue | 0.12 Percentage of total hemoglobin | Standard Deviation 1.3 |
| TI Inhalation Powder + Metformin | Difference in Change From Baseline for HbA1c Between TI Alone and Metformin+Secretagogue | -0.76 Percentage of total hemoglobin | Standard Deviation 0.92 |
Comparison: ANCOVA fitting model change from baseline in A1c with fixed effects for treatment and pooled site and baseline A1c as a covariatep-value: <0.00195% CI: [0.69, 1.14]ANCOVA