Diabetes Mellitus, Type 2
Conditions
Brief summary
The purpose of this clinical research study is to learn whether Saxagliptin added to thiazolidinedione (TZD) therapy is more effective than TZD alone as a treatment for Type 2 diabetic subjects who are not sufficiently controlled with TZD alone
Detailed description
All subjects will participate in a lead-in period, and qualifying subjects will continue into a short-term randomized treatment period. Subjects who complete the short-term period will be eligible to enter the long term extension period. Also, subjects in the short-term period who have an elevated blood sugar that requires additional medication for blood sugar control will be eligible to enter the long-term treatment extension period where they will receive metformin (defined as rescue medication) added onto their blinded study medication
Interventions
DRUGrosiglitazone
Tablets, Oral, 4 mg, once daily or 8 mg, either as once or twice daily (6 months ST, 12 months LT)
DRUGSaxagliptin
Tablets, Oral, 2.5 mg, Once daily (6 months ST, 12 months LT)
DRUGPlacebo
Tablets, Oral, 0 mg, Once daily (6 months ST, 12 months LT)
DRUGpioglitazone
Tablets, Oral, 30 mg or 45 mg, once daily (6 months ST, 12 months LT)
DRUGmetformin
Tablets, Oral, 500-2500 mg, as needed (12 months LT)
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 77 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetics currently receiving a stable dose of TZD monotherapy (pioglitazone 30mg or 45mg, or rosiglitazone 4mg or 8mg) for at least 12 weeks prior to screening. * Hemoglobin A1c (HbA1c) \> = 7.0% and \< = 10.5% * Body mass index \< = 45kg/m2 * Fasting C-peptide \> = 1 ng/mL
Exclusion criteria
* Symptomatic poorly controlled diabetes * Recent cardiac or cerebrovascular event * Serum creatinine \> = 2.0 mg/dL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | Baseline, Week 24 | Mean change from baseline in A1C at Week 24, adjusted for baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Baseline, Week 24 | Mean change from baseline in FPG at Week 24, adjusted for baseline value. |
| Percentage of Participants Achieving A1c <7% at Week 24 | Week 24 | Percentage of participants achieving A1C \< 7%, the American Diabetic Association's defined goal for glycemia, at each dose of saxagliptin plus TZD versus placebo plus TZD at Week 24. |
| Changes From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Oral Glucose Tolerance Test (OGTT) at Week 24 | Baseline, Week 24 | Mean change from baseline for 0 to 180 minutes PPG AUC achieved at each dose of saxagliptin plus TZD versus placebo plus TZD at Week 24, adjusted for baseline value. |
Countries
Argentina, Canada, India, Mexico, Peru, Philippines, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Saxagliptin 2.5 mg Plus Open-label TZD The Saxagliptin 2.5 mg + Open-Label TZD group includes data from subjects randomized to receive coadministration of blinded Saxagliptin 2.5 mg plus open-label pioglitazone 30 mg or 45 mg once daily (QD), or open label rosiglitazone 4 mg QD, or 8 mg, either QD or in 2 divided doses of 4 mg. | 195 |
| Saxagliptin 5 mg Plus Open-label TZD The Saxagliptin 5 mg + Open-Label TZD group includes data from subjects randomized to receive coadministration of blinded Saxagliptin 5 mg plus pioglitazone 30 mg or 45 mg once daily (QD), or rosiglitazone 4 mg QD, or 8 mg, either QD or in 2 divided doses of 4 mg. | 186 |
| Placebo Plus Open-label TZD The placebo + open-label TZD group includes data from subjects randomized to receive coadministration of blinded placebo plus pioglitazone 30 mg or 45 mg once daily (QD), or rosiglitazone 4 mg QD, or 8 mg, either QD or in 2 divided doses of 4 mg. | 184 |
| Total | 565 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative reason by sponsor | 0 | 0 | 1 |
| Overall Study | Adverse Event | 9 | 17 | 9 |
| Overall Study | Death | 1 | 1 | 0 |
| Overall Study | Lack of Efficacy | 19 | 7 | 16 |
| Overall Study | Lost to Follow-up | 6 | 11 | 7 |
| Overall Study | Physician Decision | 9 | 10 | 8 |
| Overall Study | Poor/Noncompliance | 2 | 2 | 6 |
| Overall Study | Subject No Longer Meets Study Criteria | 0 | 3 | 3 |
| Overall Study | Withdrawal of consent by subject | 16 | 16 | 26 |
Baseline characteristics
| Characteristic | Saxagliptin 2.5 mg Plus Open-label TZD | Saxagliptin 5 mg Plus Open-label TZD | Placebo Plus Open-label TZD | Total |
|---|---|---|---|---|
| Age, Continuous | 54.85 years STANDARD_DEVIATION 9.73 | 53.22 years STANDARD_DEVIATION 10.56 | 54.01 years STANDARD_DEVIATION 10.08 | 54.04 years STANDARD_DEVIATION 10.13 |
| Sex: Female, Male Female | 89 Participants | 97 Participants | 99 Participants | 285 Participants |
| Sex: Female, Male Male | 106 Participants | 89 Participants | 85 Participants | 280 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 | 109 / 184 | 107 / 195 | 109 / 186 |
| serious Total, serious adverse events | 20 / 184 | 19 / 195 | 18 / 186 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (A1C) at Week 24
Mean change from baseline in A1C at Week 24, adjusted for baseline value.
Time frame: Baseline, Week 24
Population: Randomized participants who took at least 1 dose of double-blind treatment. To be included in analysis of change from baseline to Week 24 Last Observation Carried Forward (LOCF), participants must have had a baseline and at least 1 post-baseline measurement. If participant received rescue medication, measurement must have been taken before rescue.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 2.5 mg Plus Open-label TZD | Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | Week 24 Mean | 7.59 percent | Standard Error 0.098 |
| Saxagliptin 2.5 mg Plus Open-label TZD | Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | Baseline Mean | 8.25 percent | Standard Error 0.08 |
| Saxagliptin 2.5 mg Plus Open-label TZD | Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | Adjusted Mean Change from Baseline | -0.66 percent | Standard Error 0.074 |
| Saxagliptin 5 mg Plus Open-label TZD | Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | Week 24 Mean | 7.39 percent | Standard Error 0.086 |
| Saxagliptin 5 mg Plus Open-label TZD | Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | Baseline Mean | 8.35 percent | Standard Error 0.08 |
| Saxagliptin 5 mg Plus Open-label TZD | Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | Adjusted Mean Change from Baseline | -0.94 percent | Standard Error 0.075 |
| Placebo Plus Open-label TZD | Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | Baseline Mean | 8.19 percent | Standard Error 0.08 |
| Placebo Plus Open-label TZD | Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | Adjusted Mean Change from Baseline | -0.30 percent | Standard Error 0.076 |
| Placebo Plus Open-label TZD | Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | Week 24 Mean | 7.91 percent | Standard Error 0.1 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Mean change from baseline in FPG at Week 24, adjusted for baseline value.
Time frame: Baseline, Week 24
Population: Randomized participants who took at least 1 dose of double-blind treatment. To be included in analysis of change from baseline to Week 24 LOCF, participants must have had a baseline and at least 1 post-baseline measurement. If a participant received rescue medication, then that measurement must have been taken before rescue.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 2.5 mg Plus Open-label TZD | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Week 24 Mean | 148.2 mg/dL | Standard Error 3.36 |
| Saxagliptin 2.5 mg Plus Open-label TZD | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Baseline Mean | 163.0 mg/dL | Standard Error 3.54 |
| Saxagliptin 2.5 mg Plus Open-label TZD | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Adjusted Mean Change from Baseline | -14.3 mg/dL | Standard Error 2.87 |
| Saxagliptin 5 mg Plus Open-label TZD | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Week 24 Mean | 143.0 mg/dL | Standard Error 3.2 |
| Saxagliptin 5 mg Plus Open-label TZD | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Baseline Mean | 159.5 mg/dL | Standard Error 3.34 |
| Saxagliptin 5 mg Plus Open-label TZD | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Adjusted Mean Change from Baseline | -17.3 mg/dL | Standard Error 2.94 |
| Placebo Plus Open-label TZD | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Baseline Mean | 162.4 mg/dL | Standard Error 3.43 |
| Placebo Plus Open-label TZD | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Adjusted Mean Change from Baseline | -2.8 mg/dL | Standard Error 2.97 |
| Placebo Plus Open-label TZD | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Week 24 Mean | 159.3 mg/dL | Standard Error 4.29 |
Secondary
Changes From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Oral Glucose Tolerance Test (OGTT) at Week 24
Mean change from baseline for 0 to 180 minutes PPG AUC achieved at each dose of saxagliptin plus TZD versus placebo plus TZD at Week 24, adjusted for baseline value.
Time frame: Baseline, Week 24
Population: Randomized participants who took at least 1 dose of double-blind treatment. To be included in analysis of change from baseline to Week 24 LOCF, participants must have had a baseline and at least 1 post-baseline measurement. If a participant received rescue medication, then that measurement must have been taken before rescue.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 2.5 mg Plus Open-label TZD | Changes From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Oral Glucose Tolerance Test (OGTT) at Week 24 | Baseline Mean | 48301 mg*min/dL | Standard Error 968.5 |
| Saxagliptin 2.5 mg Plus Open-label TZD | Changes From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Oral Glucose Tolerance Test (OGTT) at Week 24 | Adjusted Mean Change from Baseline | -7849 mg*min/dL | Standard Error 740.6 |
| Saxagliptin 2.5 mg Plus Open-label TZD | Changes From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Oral Glucose Tolerance Test (OGTT) at Week 24 | Week 24 Mean | 40255 mg*min/dL | Standard Error 919.7 |
| Saxagliptin 5 mg Plus Open-label TZD | Changes From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Oral Glucose Tolerance Test (OGTT) at Week 24 | Baseline Mean | 47866 mg*min/dL | Standard Error 1048.9 |
| Saxagliptin 5 mg Plus Open-label TZD | Changes From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Oral Glucose Tolerance Test (OGTT) at Week 24 | Week 24 Mean | 38587 mg*min/dL | Standard Error 991.3 |
| Saxagliptin 5 mg Plus Open-label TZD | Changes From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Oral Glucose Tolerance Test (OGTT) at Week 24 | Adjusted Mean Change from Baseline | -9269 mg*min/dL | Standard Error 794.9 |
| Placebo Plus Open-label TZD | Changes From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Oral Glucose Tolerance Test (OGTT) at Week 24 | Baseline Mean | 47256 mg*min/dL | Standard Error 1057.4 |
| Placebo Plus Open-label TZD | Changes From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Oral Glucose Tolerance Test (OGTT) at Week 24 | Week 24 Mean | 44819 mg*min/dL | Standard Error 1023.4 |
| Placebo Plus Open-label TZD | Changes From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Oral Glucose Tolerance Test (OGTT) at Week 24 | Adjusted Mean Change from Baseline | -2690 mg*min/dL | Standard Error 820.6 |
Secondary
Percentage of Participants Achieving A1c <7% at Week 24
Percentage of participants achieving A1C \< 7%, the American Diabetic Association's defined goal for glycemia, at each dose of saxagliptin plus TZD versus placebo plus TZD at Week 24.
Time frame: Week 24
Population: Randomized participants who took at least 1 dose of double-blind treatment. To be included in the Week 24 LOCF analysis, subjects must have had at least 1 post-baseline measurement. If a participant received rescue medication, then that measurement must have been taken before rescue.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin 2.5 mg Plus Open-label TZD | Percentage of Participants Achieving A1c <7% at Week 24 | 42.2 Percentage of participants |
| Saxagliptin 5 mg Plus Open-label TZD | Percentage of Participants Achieving A1c <7% at Week 24 | 41.8 Percentage of participants |
| Placebo Plus Open-label TZD | Percentage of Participants Achieving A1c <7% at Week 24 | 25.6 Percentage of participants |