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 assess the efficacy and tolerability of saxagliptin in addition to metformin and compare to sulphonylurea in addition with metformin.
Interventions
DRUGMetformin
open-label metformin
DRUGSulphonylurea
Glipizide 5-20 mg capsules (titrated to optimal effect or highest tolerable dose during 18 weeks)
DRUGSaxagliptin
Saxagliptin 5 mg tablets
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 alone on stable doses of 1500 mg or higher per day for at least 8 weeks prior to Visit 1, * HbA1c \>6.5% and ≤10.0%
Exclusion criteria
* Type 1 diabetes, * history of diabetic ketoacidosis or hyperosmolar non-ketonic coma, * Insulin therapy within one year of enrolment (with the exception of insulin therapy during a hospitalization or use in gestational diabetes)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hemoglobin A1c (HbA1c) Change From Baseline to Week 52 | Baseline to 52 Weeks | Adjusted mean change from baseline in HbA1c achieved with saxagliptin added on to metformin versus glipizide added on to metformin at Week 52 (Per Protocol Analysis Set). HbA1c is a continuous measure, the change from baseline for each participant is calculated as the Week 52 value minus the baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Reporting at Least One Episode of Any Hypoglycaemic Event Over 52 Weeks | From Baseline to Week 52 | Proportion of participants reporting at least one episode of any hypoglycaemic event for saxagliptin added on to metformin versus glipizide added on to metformin over 52 weeks (Safety Analysis Set) |
| Body Weight Change From Baseline to Week 52 | Baseline, Week 52 (Last Observation Carried Forward) | Adjusted mean change from baseline in Body Weight achieved with saxagliptin added on to metformin versus glipizide added on to metformin at Week 52 (Safety Analysis Set). Body Weight is a continuous measure, the change from baseline for each participant is calculated as the Week 52 (LOCF) value minus the baseline value. |
| Mean Slope of the Regressions of Change From Week 24 to Week 52 in HbA1c | Week 24 to Week 52 | Mean slopes of regression of change from Week 24 to Week 52 in HbA1c for saxagliptin added on to metformin versus glipizide added on to metformin (Per Protocol Analysis Set) achieved by fitting a mixed model with subject specific slopes for the time effect (weeks on randomized treatment was utilized). This analysis gives an assessment of the durability of the HbA1c effect. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Hemoglobin A1c (HbA1c) Change From Baseline to Week 104 | Baseline, Week 104 | Adjusted mean change from baseline in HbA1c achieved with saxagliptin added on to metformin versus glipizide added on to metformin at Week 104 (Full Analysis Set). HbA1c is a continuous measure, the change from baseline for each participant is calculated as the Week 104 value minus the baseline value. |
| Proportion of Participants Reporting at Least One Episode of Any Hypoglycaemic Event Over 104 Weeks | Baseline, Week 104 | Proportion of participants reporting at least one episode of any hypoglycaemic event for saxagliptin added on to metformin versus glipizide added on to metformin over 104 weeks (Safety Analysis Set) |
| Body Weight Change From Baseline to Week 104 | Baseline, Week 104 | Adjusted mean change from baseline in Body Weight achieved with saxagliptin added on to metformin versus glipizide added on to metformin at Week 104. Body Weight is a continuous measure, the change from baseline for each participant is calculated as the Week 104 value minus the baseline value. |
| Mean Slope of the Regressions of Change From Week 24 to Week 104 in HbA1c | Week 24 to Week 104 | Mean slopes of regression of change from Week 24 to Week 104 in HbA1c for saxagliptin added on to metformin versus glipizide added on to metformin (Full Analysis Set) achieved by fitting a mixed model with subject specific slopes for the time effect (weeks on randomized treatment was utilized). This analysis gives an assessment of the durability of the HbA1c effect. |
Countries
Finland, Germany, Hungary, India, Netherlands, Norway, Russia, Slovakia, South Korea, United Kingdom, Vietnam
Participant flow
Pre-assignment details
891 participants were enrolled in the study; 33 participants did not enter the treatment period; 858 participants were randomized and treated.
Participants by arm
| Arm | Count |
|---|---|
| Saxagliptin + Metformin Saxagliptin 5 mg tablets added on to open-label metformin | 428 |
| Glipizide + Metformin Glipizide 5-20 mg capsules (titrated to optimal effect or highest tolerable dose during 18 weeks) added on to open-label metformin | 430 |
| Total | 858 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 13 |
| Overall Study | Death | 4 | 2 |
| Overall Study | Elevated triglyceride | 1 | 0 |
| Overall Study | Impossible to determine HbA1c | 0 | 1 |
| Overall Study | Incorrect enrollment | 8 | 4 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Patient moved | 1 | 3 |
| Overall Study | Safety reasons | 2 | 1 |
| Overall Study | Severe non-compliance to protocol | 5 | 7 |
| Overall Study | Study specific discontinuation criteria | 203 | 218 |
| Overall Study | Withdrawal by Subject | 27 | 31 |
Baseline characteristics
| Characteristic | Saxagliptin + Metformin | Glipizide + Metformin | Total |
|---|---|---|---|
| Age Continuous | 57.50 years STANDARD_DEVIATION 10.26 | 57.59 years STANDARD_DEVIATION 10.37 | 57.55 years STANDARD_DEVIATION 10.31 |
| Sex: Female, Male Female | 216 Participants | 198 Participants | 414 Participants |
| Sex: Female, Male Male | 212 Participants | 232 Participants | 444 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 105 / 428 | 201 / 430 |
| serious Total, serious adverse events | 54 / 428 | 55 / 430 |
Outcome results
Primary
Hemoglobin A1c (HbA1c) Change From Baseline to Week 52
Adjusted mean change from baseline in HbA1c achieved with saxagliptin added on to metformin versus glipizide added on to metformin at Week 52 (Per Protocol Analysis Set). HbA1c is a continuous measure, the change from baseline for each participant is calculated as the Week 52 value minus the baseline value.
Time frame: Baseline to 52 Weeks
Population: Randomized participants who completed the 52 weeks of treatment had both baseline and week 52 HbA1c measurement and had no significant protocol deviations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin + Metformin | Hemoglobin A1c (HbA1c) Change From Baseline to Week 52 | Baseline | 7.46 Percent | Standard Error 0.045 |
| Saxagliptin + Metformin | Hemoglobin A1c (HbA1c) Change From Baseline to Week 52 | Week 52 | 6.74 Percent | Standard Error 0.042 |
| Saxagliptin + Metformin | Hemoglobin A1c (HbA1c) Change From Baseline to Week 52 | Adjusted Change from Baseline to Week 52 | -0.74 Percent | Standard Error 0.038 |
| Glipizide + Metformin | Hemoglobin A1c (HbA1c) Change From Baseline to Week 52 | Baseline | 7.53 Percent | Standard Error 0.045 |
| Glipizide + Metformin | Hemoglobin A1c (HbA1c) Change From Baseline to Week 52 | Week 52 | 6.71 Percent | Standard Error 0.042 |
| Glipizide + Metformin | Hemoglobin A1c (HbA1c) Change From Baseline to Week 52 | Adjusted Change from Baseline to Week 52 | -0.80 Percent | Standard Error 0.038 |
95% CI: [-0.05, 0.16]
Secondary
Body Weight Change From Baseline to Week 52
Adjusted mean change from baseline in Body Weight achieved with saxagliptin added on to metformin versus glipizide added on to metformin at Week 52 (Safety Analysis Set). Body Weight is a continuous measure, the change from baseline for each participant is calculated as the Week 52 (LOCF) value minus the baseline value.
Time frame: Baseline, Week 52 (Last Observation Carried Forward)
Population: Randomized participants who took at least 1 dose of double-blind treatment. To be included in the LOCF analysis, participants must have had a baseline and at least 1 post-baseline measurement
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin + Metformin | Body Weight Change From Baseline to Week 52 | Baseline | 88.7 kilogram | Standard Error 0.91 |
| Saxagliptin + Metformin | Body Weight Change From Baseline to Week 52 | Week 52 | 87.6 kilogram | Standard Error 0.9 |
| Saxagliptin + Metformin | Body Weight Change From Baseline to Week 52 | Adjusted Change from Baseline to Week 52 | -1.1 kilogram | Standard Error 0.17 |
| Glipizide + Metformin | Body Weight Change From Baseline to Week 52 | Baseline | 88.6 kilogram | Standard Error 0.95 |
| Glipizide + Metformin | Body Weight Change From Baseline to Week 52 | Week 52 | 89.7 kilogram | Standard Error 0.99 |
| Glipizide + Metformin | Body Weight Change From Baseline to Week 52 | Adjusted Change from Baseline to Week 52 | 1.1 kilogram | Standard Error 0.17 |
p-value: <0.000195% CI: [-2.7, -1.7]ANCOVA
Secondary
Mean Slope of the Regressions of Change From Week 24 to Week 52 in HbA1c
Mean slopes of regression of change from Week 24 to Week 52 in HbA1c for saxagliptin added on to metformin versus glipizide added on to metformin (Per Protocol Analysis Set) achieved by fitting a mixed model with subject specific slopes for the time effect (weeks on randomized treatment was utilized). This analysis gives an assessment of the durability of the HbA1c effect.
Time frame: Week 24 to Week 52
Population: Randomized participants who completed the 52 weeks of treatment had both baseline and week 52 HbA1c measurement and had no significant protocol deviations
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin + Metformin | Mean Slope of the Regressions of Change From Week 24 to Week 52 in HbA1c | 0.001 Percent | Standard Error 0.001 |
| Glipizide + Metformin | Mean Slope of the Regressions of Change From Week 24 to Week 52 in HbA1c | 0.004 Percent | Standard Error 0.001 |
p-value: 0.0495% CI: [-0.0046, -0.0001]Mixed Models Analysis
Secondary
Proportion of Participants Reporting at Least One Episode of Any Hypoglycaemic Event Over 52 Weeks
Proportion of participants reporting at least one episode of any hypoglycaemic event for saxagliptin added on to metformin versus glipizide added on to metformin over 52 weeks (Safety Analysis Set)
Time frame: From Baseline to Week 52
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin + Metformin | Proportion of Participants Reporting at Least One Episode of Any Hypoglycaemic Event Over 52 Weeks | 3 Percentage of Participants |
| Glipizide + Metformin | Proportion of Participants Reporting at Least One Episode of Any Hypoglycaemic Event Over 52 Weeks | 36.3 Percentage of Participants |
p-value: <0.000195% CI: [-38.1, -28.5]Fisher Exact
Other Pre-specified
Body Weight Change From Baseline to Week 104
Adjusted mean change from baseline in Body Weight achieved with saxagliptin added on to metformin versus glipizide added on to metformin at Week 104. Body Weight is a continuous measure, the change from baseline for each participant is calculated as the Week 104 value minus the baseline value.
Time frame: Baseline, Week 104
Population: Number of subjects with observed values at Week 104 was n=186 for saxagliptin + metformin and n=165 for glipizide + metformin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin + Metformin | Body Weight Change From Baseline to Week 104 | Baseline | 88.69 kilograms | Standard Error 0.905 |
| Saxagliptin + Metformin | Body Weight Change From Baseline to Week 104 | Week 104 | 87.47 kilograms | Standard Error 0.898 |
| Saxagliptin + Metformin | Body Weight Change From Baseline to Week 104 | Adjusted Change from Baseline to Week 104 | -1.47 kilograms | Standard Error 0.2 |
| Glipizide + Metformin | Body Weight Change From Baseline to Week 104 | Baseline | 88.57 kilograms | Standard Error 0.955 |
| Glipizide + Metformin | Body Weight Change From Baseline to Week 104 | Week 104 | 89.80 kilograms | Standard Error 0.987 |
| Glipizide + Metformin | Body Weight Change From Baseline to Week 104 | Adjusted Change from Baseline to Week 104 | 1.29 kilograms | Standard Error 0.205 |
95% CI: [-3.32, -2.2]Repeated Measures
Other Pre-specified
Hemoglobin A1c (HbA1c) Change From Baseline to Week 104
Adjusted mean change from baseline in HbA1c achieved with saxagliptin added on to metformin versus glipizide added on to metformin at Week 104 (Full Analysis Set). HbA1c is a continuous measure, the change from baseline for each participant is calculated as the Week 104 value minus the baseline value.
Time frame: Baseline, Week 104
Population: Number of subjects with observed values at Week 104 was n=184 for saxagliptin + metformin and n=160 for glipizide + metformin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin + Metformin | Hemoglobin A1c (HbA1c) Change From Baseline to Week 104 | Baseline | 7.65 Percent | Standard Error 0.044 |
| Saxagliptin + Metformin | Hemoglobin A1c (HbA1c) Change From Baseline to Week 104 | Week 104 | 7.27 Percent | Standard Error 0.05 |
| Saxagliptin + Metformin | Hemoglobin A1c (HbA1c) Change From Baseline to Week 104 | Adjusted Change from Baseline to Week 104 | -0.41 Percent | Standard Error 0.041 |
| Glipizide + Metformin | Hemoglobin A1c (HbA1c) Change From Baseline to Week 104 | Baseline | 7.65 Percent | Standard Error 0.041 |
| Glipizide + Metformin | Hemoglobin A1c (HbA1c) Change From Baseline to Week 104 | Week 104 | 7.27 Percent | Standard Error 0.046 |
| Glipizide + Metformin | Hemoglobin A1c (HbA1c) Change From Baseline to Week 104 | Adjusted Change from Baseline to Week 104 | -0.35 Percent | Standard Error 0.043 |
95% CI: [-0.17, 0.06]Repeated Measures
Other Pre-specified
Mean Slope of the Regressions of Change From Week 24 to Week 104 in HbA1c
Mean slopes of regression of change from Week 24 to Week 104 in HbA1c for saxagliptin added on to metformin versus glipizide added on to metformin (Full Analysis Set) achieved by fitting a mixed model with subject specific slopes for the time effect (weeks on randomized treatment was utilized). This analysis gives an assessment of the durability of the HbA1c effect.
Time frame: Week 24 to Week 104
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saxagliptin + Metformin | Mean Slope of the Regressions of Change From Week 24 to Week 104 in HbA1c | 0.0041 Percent | Standard Error 0.0005 |
| Glipizide + Metformin | Mean Slope of the Regressions of Change From Week 24 to Week 104 in HbA1c | 0.0076 Percent | Standard Error 0.0005 |
95% CI: [-0.0048, -0.0022]Mixed Models Analysis
Other Pre-specified
Proportion of Participants Reporting at Least One Episode of Any Hypoglycaemic Event Over 104 Weeks
Proportion of participants reporting at least one episode of any hypoglycaemic event for saxagliptin added on to metformin versus glipizide added on to metformin over 104 weeks (Safety Analysis Set)
Time frame: Baseline, Week 104
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin + Metformin | Proportion of Participants Reporting at Least One Episode of Any Hypoglycaemic Event Over 104 Weeks | 3.5 Percentage of Participants |
| Glipizide + Metformin | Proportion of Participants Reporting at Least One Episode of Any Hypoglycaemic Event Over 104 Weeks | 38.4 Percentage of Participants |
95% CI: [-39.8, -30]