Type 2 Diabetes
Conditions
Keywords
DPP-4 inhibitors, HbA1c, Incretins
Brief summary
Saxagliptin is a new investigational medication being developed for treatment of type 2 diabetes. This study is designed to evaluate the efficacy and safety in adult patients who have inadequate glycaemic control when treated with metformin in addition to diet and exercise.
Interventions
DRUGSaxagliptin
Oral tablet, once daily for 24 weeks
DRUGPlacebo
oral tablet, once daily for 24 weeks
DRUGMetformin
oral tablet, once daily for 24 weeks
Sponsors
Bristol-Myers Squibb
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosed with Type 2 diabetes * Treatment with metformin at a stable dose \>1500 mg/day * HbA1c ≥ 7.0% and ≤10.0%
Exclusion criteria
* Insulin therapy within one year of enrolment (with the exception of insulin therapy during a hospitalization or use in gestational diabetes) * Type 1 diabetes, history of ketoacidosis, or hyperosmolar non-ketonic koma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline to Week 24 in Glycosylated Haemoglobin A1c (HbA1c) | Baseline , Week 24 | Adjusted\* mean change from baseline in HbA1c achieved with saxagliptin 5 mg + metformin versus placebo + metformin at week 24 (LOCF, Full Analysis set). HbA1c is a continuous measure, the change from baseline for each subject is calculated as the week 24 values minus the baseline value. \*Adjusted for baseline HbA1c. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Achieving a Therapeutic Glycemic Response | Baseline , Week 24 | Proportion of participants achieving a therapeutic glycemic response, defined as having HbA1c \< 7.0% for saxagliptin + metformin versus placebo + metformin at week 24 |
| Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mmol/L | Baseline , Week 24 | Adjusted\* mean change from baseline in fasting plasma glucose (FPG) achieved with saxagliptin 5 mg + metformin versus placebo + metformin at week 24 (Last Observation Carried Out (LOCF), Full Analysis set). FPG is a continuous measure, the change from baseline for each subject is calculated as the week 24 values minus the baseline value. \*Adjusted for baseline FPG. |
| Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mg/dL | Baseline , Week 24 | Adjusted\* mean change from baseline in fasting plasma glucose (FPG) achieved with saxagliptin 5 mg + metformin versus placebo + metformin at week 24 (LOCF, Full Analysis set). FPG is a continuous measure, the change from baseline for each subject is calculated as the week 24 values minus the baseline value. \*Adjusted for baseline FPG. |
| Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Baseline , Week 24 | Adjusted\* mean change from baseline in PPG AUC achieved with saxagliptin 5 mg + metformin versus placebo + metformin at week 24 (LOCF, Full Analysis set). Trapezoidal method was used to compute AUC under the 3 hour PPG curve. The change from baseline for each subject is calculated as the week 24 value minus the baseline value. \*Adjusted for baseline PPG AUC. |
Countries
China, India, South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Saxagliptin 5 mg + Metformin Saxagliptin 5 mg tablet, once daily (OD), added on to stable Metformin for 24 weeks | 283 |
| Placebo + Metformin Placebo tablet, OD, added on to stable Metformin for 24 weeks | 287 |
| Total | 570 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 4 |
| Overall Study | Incorrect enrollment | 2 | 0 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Metformin dose haven't decreasd to 2.5 g | 1 | 0 |
| Overall Study | Safety reasons | 1 | 0 |
| Overall Study | Severe non-compliance to protocol | 0 | 1 |
| Overall Study | Study specific discontinuation criteria | 4 | 11 |
| Overall Study | Withdrawal by Subject | 13 | 23 |
Baseline characteristics
| Characteristic | Saxagliptin 5 mg + Metformin | Placebo + Metformin | Total |
|---|---|---|---|
| Age Continuous | 53.75 Years STANDARD_DEVIATION 10.42 | 54.36 Years STANDARD_DEVIATION 10.06 | 54.05 Years STANDARD_DEVIATION 10.24 |
| Sex: Female, Male Female | 147 Participants | 148 Participants | 295 Participants |
| Sex: Female, Male Male | 136 Participants | 139 Participants | 275 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 283 | 13 / 287 |
| serious Total, serious adverse events | 8 / 283 | 3 / 287 |
Outcome results
Primary
Absolute Change From Baseline to Week 24 in Glycosylated Haemoglobin A1c (HbA1c)
Adjusted\* mean change from baseline in HbA1c achieved with saxagliptin 5 mg + metformin versus placebo + metformin at week 24 (LOCF, Full Analysis set). HbA1c is a continuous measure, the change from baseline for each subject is calculated as the week 24 values minus the baseline value. \*Adjusted for baseline HbA1c.
Time frame: Baseline , Week 24
Population: Randomized participants who took at least 1 dose of double-blind treatment. To be included in analysis: change from baseline to Wk 24 LOCF for efficacy, subjects must have had a baseline and at least 1 post baseline efficacy measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin | Absolute Change From Baseline to Week 24 in Glycosylated Haemoglobin A1c (HbA1c) | Baseline | 7.90 percent | Standard Error 0.049 |
| Saxagliptin 5 mg + Metformin | Absolute Change From Baseline to Week 24 in Glycosylated Haemoglobin A1c (HbA1c) | Week 24 | 7.10 percent | Standard Error 0.056 |
| Saxagliptin 5 mg + Metformin | Absolute Change From Baseline to Week 24 in Glycosylated Haemoglobin A1c (HbA1c) | adjusted baseline HbA1c | -0.78 percent | Standard Error 0.051 |
| Placebo + Metformin | Absolute Change From Baseline to Week 24 in Glycosylated Haemoglobin A1c (HbA1c) | Baseline | 7.94 percent | Standard Error 0.05 |
| Placebo + Metformin | Absolute Change From Baseline to Week 24 in Glycosylated Haemoglobin A1c (HbA1c) | Week 24 | 7.55 percent | Standard Error 0.062 |
| Placebo + Metformin | Absolute Change From Baseline to Week 24 in Glycosylated Haemoglobin A1c (HbA1c) | adjusted baseline HbA1c | -0.37 percent | Standard Error 0.05 |
p-value: <0.000195% CI: [-0.55, -0.29]ANCOVA
Secondary
Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mg/dL
Adjusted\* mean change from baseline in fasting plasma glucose (FPG) achieved with saxagliptin 5 mg + metformin versus placebo + metformin at week 24 (LOCF, Full Analysis set). FPG is a continuous measure, the change from baseline for each subject is calculated as the week 24 values minus the baseline value. \*Adjusted for baseline FPG.
Time frame: Baseline , Week 24
Population: Randomized participants who took at least 1 dose of double-blind treatment. To be included in analysis: change from baseline to Wk 24 LOCF for efficacy, subjects must have had a baseline and at least 1 post baseline efficacy measurement
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin | Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mg/dL | Baseline | 154.54 mg/dL | Standard Error 2.103 |
| Saxagliptin 5 mg + Metformin | Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mg/dL | Week 24 | 137.15 mg/dL | Standard Error 2.116 |
| Saxagliptin 5 mg + Metformin | Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mg/dL | Adjusted Change from Baseline | -20.52 mg/dL | Standard Error 2.051 |
| Placebo + Metformin | Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mg/dL | Baseline | 159.73 mg/dL | Standard Error 2.467 |
| Placebo + Metformin | Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mg/dL | Week 24 | 149.54 mg/dL | Standard Error 2.286 |
| Placebo + Metformin | Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mg/dL | Adjusted Change from Baseline | -10.42 mg/dL | Standard Error 2.004 |
p-value: <0.000295% CI: [-15.37, -4.83]ANCOVA
Secondary
Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mmol/L
Adjusted\* mean change from baseline in fasting plasma glucose (FPG) achieved with saxagliptin 5 mg + metformin versus placebo + metformin at week 24 (Last Observation Carried Out (LOCF), Full Analysis set). FPG is a continuous measure, the change from baseline for each subject is calculated as the week 24 values minus the baseline value. \*Adjusted for baseline FPG.
Time frame: Baseline , Week 24
Population: Randomized participants who took at least 1 dose of double-blind treatment. To be included in analysis: change from baseline to Wk 24 LOCF for efficacy, subjects must have had a baseline and at least 1 post baseline efficacy measurement
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin | Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mmol/L | Baseline | 8.57 mmol/L | Standard Error 0.117 |
| Saxagliptin 5 mg + Metformin | Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mmol/L | Week 24 | 7.61 mmol/L | Standard Error 0.117 |
| Saxagliptin 5 mg + Metformin | Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mmol/L | Adjusted Change from Baseline | -1.14 mmol/L | Standard Error 0.114 |
| Placebo + Metformin | Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mmol/L | Baseline | 8.87 mmol/L | Standard Error 0.137 |
| Placebo + Metformin | Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mmol/L | Week 24 | 8.30 mmol/L | Standard Error 0.127 |
| Placebo + Metformin | Absolute Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) mmol/L | Adjusted Change from Baseline | -0.58 mmol/L | Standard Error 0.111 |
p-value: <0.000295% CI: [-0.85, -0.26]ANCOVA
Secondary
Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup
Adjusted\* mean change from baseline in PPG AUC achieved with saxagliptin 5 mg + metformin versus placebo + metformin at week 24 (LOCF, Full Analysis set). Trapezoidal method was used to compute AUC under the 3 hour PPG curve. The change from baseline for each subject is calculated as the week 24 value minus the baseline value. \*Adjusted for baseline PPG AUC.
Time frame: Baseline , Week 24
Population: MMTT was measured on a subset of patients in China cohort only at baseline and Wk 24. Randomized participants who took at least 1 dose of double-blind treatment to be included in analysis: change from baseline to Wk 24 (LOCF), must have had a baseline and a post baseline data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin | Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Baseline | 2355 mmol*min/L | Standard Error 45.6 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Week 24 | 2058 mmol*min/L | Standard Error 44.4 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Adjusted Change from Baseline | -315 mmol*min/L | Standard Error 38.6 |
| Placebo + Metformin | Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Baseline | 2427 mmol*min/L | Standard Error 51.5 |
| Placebo + Metformin | Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Week 24 | 2249 mmol*min/L | Standard Error 46.9 |
| Placebo + Metformin | Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Adjusted Change from Baseline | -160 mmol*min/L | Standard Error 39 |
p-value: 0.005295% CI: [-264, -47]ANCOVA
Secondary
Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup
Adjusted\* mean change from baseline in PPG AUC achieved with saxagliptin 5 mg + metformin versus placebo+metformin at week 24 (LOCF, Full Analysis set). Trapezoidal method was used to compute AUC under the 3 hour PPG curve. The change from baseline for each subject is calculated as the week 24 value minus the baseline value. \*Adjusted for baseline PPG AUC.
Time frame: Baseline , Week 24
Population: MMTT was measured on a subset of patients in China cohort only at baseline and Wk 24. Randomized participants who took at least 1 dose of double-blind treatment to be included in analysis: change from baseline to Wk 24 (LOCF), must have had a baseline and a post baseline data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin | Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Baseline | 42423 mg*min/dL | Standard Error 821.9 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Week 24 | 37071 mg*min/dL | Standard Error 799.4 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Adjusted Change from Baseline | -5673 mg*min/dL | Standard Error 695.9 |
| Placebo + Metformin | Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Baseline | 43719 mg*min/dL | Standard Error 927.3 |
| Placebo + Metformin | Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Week 24 | 40521 mg*min/dL | Standard Error 845.7 |
| Placebo + Metformin | Change From Baseline in the Area Under the Curve (AUC) From 0 to 180 Minutes for Postprandial Glucose (PPG) During a Mixed Meal Tolerance Test (MMTT) in a Subgroup | Adjusted Change from Baseline | -2871 mg*min/dL | Standard Error 702.1 |
p-value: 0.005295% CI: [-4753, -852]ANCOVA
Secondary
Proportion of Patients Achieving a Therapeutic Glycemic Response
Proportion of participants achieving a therapeutic glycemic response, defined as having HbA1c \< 7.0% for saxagliptin + metformin versus placebo + metformin at week 24
Time frame: Baseline , Week 24
Population: Randomized participants who took at least 1 dose of double-blind treatment. To be included in analysis: change from baseline to Wk 24(LOCF) for efficacy, subjects must have had a baseline and at least 1 post baseline efficacy measurement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin 5 mg + Metformin | Proportion of Patients Achieving a Therapeutic Glycemic Response | 46.5 Percentage of participants |
| Placebo + Metformin | Proportion of Patients Achieving a Therapeutic Glycemic Response | 30.5 Percentage of participants |
p-value: <0.000195% CI: [8, 24]ANCOVA