Type 2 Diabetes
Conditions
Brief summary
The purpose of this study was to compare effect of Saxagliptin as add-on to Metformin on 24-hour mean weighted glucose (MWG) to the effect of uptitrating Metformin in subjects with T2DM inadequately controlled on metformin alone.
Interventions
DRUGSaxagliptin
Tablets, Oral, 5 mg, once daily, 4 weeks
DRUGMetformin XR
Tablets, Oral, 1500 mg, once daily, 4 weeks
DRUGPlacebo matching Metformin XR
Tablets, Oral, 0 mg, once daily, 4 weeks
Tablets, Oral, 0 mg, once daily, 4 weeks
Sponsors
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 78 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes * 18-78 years of age * Taking stable dose of metformin immediate release (IR) or XR ≥850 mg and ≤1500 mg as monotherapy for at least 8 weeks prior to screening * Glycosylated hemoglobin A1C (A1C) 7.5-11.5% at screening * Fasting C-peptide: ≥1.0 ng/mL * FPG≥126 mg/dl obtained at the Day -7 visit * Body mass index (BMI): ≤ 40kg/m² * A1C ≥ 7.0% and ≤ 11.0% obtained at the Day -7 visit for randomization
Exclusion criteria
* Women of childbearing potential unable or unwilling to use acceptable birth control * Women who are pregnant or breastfeeding * Significant cardiovascular history * Active liver disease * Renal impairment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Baseline, Week 4 | Adjusted mean change from baseline in MWG achieved with saxagliptin 5 mg plus metformin XR versus placebo plus metformin XR at Week 24. MWG was calculated as the area under the curve (AUC) for the full 24 hours expressed as average mg/dL. Glucose measurements were collected 30 minutes before and just prior to each meal (0 minutes) and 30, 60, 120, and 180 minutes after each meal (with 1 additional measurement at 240 minutes after the evening meal), midnight, 3 AM, and at end-of-domicile visit 24 hours after the first measurement. Mean change from baseline was adjusted for baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 4 in 2-hour Postprandial Glucose (PPG) (2 Hours After the Evening Meal) | Baseline, Week 4 | Adjusted mean change from baseline in 2-hour postprandial (after mealtime) plasma glucose two hours after start of the evening meal during 24-hour domicile visits evaluated both at pre-randomization (baseline) and at Week 4. Mean change from baseline was adjusted for baseline value. |
| Change From Baseline Fasting Plasma Glucose (FPG) at Week 4, Obtained Immediately Before the Morning Meal | Baseline, Week 4 | FPG measurements were done at baseline, day 14 and 28. At baseline and day 28, the FPG value=plasma glucose value collected 30 minutes prior to the morning meal during the domicile visit. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Participants With Confirmed Hypoglycemia Events During the Treatment Period | AEs: up to last treatment day (LTD) +1 day or last visit day (LVD), whichever came last ; SAEs: up to LTD +30 days or LVD + 30 days, whichever came last. Mean duration of exposure=27.7 days for Saxa 5 mg + Met XR 1500 mg, and 28.3 days for Met 2000 mg. | 'Confirmed' = recorded on the hypoglycemia AE case report form with a fingerstick for glucose \<= 50 mg/dL and associated symptoms. |
| Participants With Reported Hypoglycemic Adverse Events During Treatment Period | AEs: up to last treatment day (LTD) +1 day or last visit day (LVD), whichever came last ; SAEs: up to LTD +30 days or LVD + 30 days, whichever came last. Mean duration of exposure=27.7 days for Saxa 5 mg + Met XR 1500 mg, and 28.3 days for Met 2000 mg. | Hypoglycemic events are based upon the Saxagliptin Predefined List of Events, which includes hypoglycemia, blood glucose decreased, and hypoglycemic unconsciousness. The Hypoglycemic events occurred in less than 5% of the participants and hence do not appear in the adverse events module. |
Countries
Argentina, Israel, Mexico, United States
Participant flow
Pre-assignment details
219 participants were enrolled; 126 entered single-blind dietary/exercise/metformin extended release (XR) lead-in period (either 4- or 8-weeks long, based on pre-enrollment metformin dose). 33 participants did not enter treatment period (22 no longer met study criteria, 7 withdrew consent, 2 lost to follow-up, 1 adverse event, and 1 other reason).
Participants by arm
| Arm | Count |
|---|---|
| Saxagliptin 5 mg + Metformin XR 1500 mg saxagliptin 5 mg plus metformin XR 1500 plus matching metformin XR 500 mg placebo | 46 |
| Metformin 2000 mg metformin XR 500 mg plus metformin XR 1500 mg plus matching saxagliptin 5 mg placebo | 47 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Subject withdrew consent | 1 | 1 |
Baseline characteristics
| Characteristic | Metformin 2000 mg | Total | Saxagliptin 5 mg + Metformin XR 1500 mg |
|---|---|---|---|
| 120-minute postprandial glucose (PPG) | 283.3 mg/dL STANDARD_DEVIATION 66.14 | 282.3 mg/dL STANDARD_DEVIATION 59.08 | 281.3 mg/dL STANDARD_DEVIATION 51.59 |
| Age categorization Females Only <= 50 years | 9 participants | 14 participants | 5 participants |
| Age categorization Females Only > 50 years | 16 participants | 32 participants | 16 participants |
| Age, Continuous | 50.64 years STANDARD_DEVIATION 9.74 | 52.25 years STANDARD_DEVIATION 9.66 | 53.89 years STANDARD_DEVIATION 9.41 |
| Age, Customized <65 years | 45 participants | 85 participants | 40 participants |
| Age, Customized >=65 years | 2 participants | 8 participants | 6 participants |
| BMI Categorization < 30 kg/m^2 | 17 Participants | 33 Participants | 16 Participants |
| BMI Categorization >= 30 kg/m^2 | 30 Participants | 60 Participants | 30 Participants |
| Body Mass Index (BMI) | 31.06 kg/m^2 STANDARD_DEVIATION 4.28 | 31.75 kg/m^2 STANDARD_DEVIATION 4.72 | 32.45 kg/m^2 STANDARD_DEVIATION 5.08 |
| Fasting Plasma Glucose (FPG) | 164.2 mg/dL STANDARD_DEVIATION 36.21 | 163.8 mg/dL STANDARD_DEVIATION 34.16 | 163.5 mg/dL STANDARD_DEVIATION 32.32 |
| FPG Categorization < 126 mg/dL | 5 participants | 10 participants | 5 participants |
| FPG Categorization >= 126 mg/dL to < 150 mg/dL | 14 participants | 25 participants | 11 participants |
| FPG Categorization >= 150 mg/dL to < 220 mg/dL | 23 participants | 51 participants | 28 participants |
| FPG Categorization >= 220 mg/dL to < 300 mg/dL | 5 participants | 7 participants | 2 participants |
| Glycosylated Hemoglobin (A1C) | 8.4 percentage STANDARD_DEVIATION 0.9 | 8.5 percentage STANDARD_DEVIATION 0.9 | 8.6 percentage STANDARD_DEVIATION 0.9 |
| Race/Ethnicity, Customized Black/African American | 2 Participant | 5 Participant | 3 Participant |
| Race/Ethnicity, Customized Hispanic/Latino | 17 Participant | 33 Participant | 16 Participant |
| Race/Ethnicity, Customized Not Hispanic/ Not Latino | 8 Participant | 16 Participant | 8 Participant |
| Race/Ethnicity, Customized Not Reported | 22 Participant | 44 Participant | 22 Participant |
| Race/Ethnicity, Customized White | 45 Participant | 88 Participant | 43 Participant |
| Sex: Female, Male Female | 22 Participants | 47 Participants | 25 Participants |
| Sex: Female, Male Male | 25 Participants | 46 Participants | 21 Participants |
| Weight | 86.94 kg STANDARD_DEVIATION 15.24 | 89.09 kg STANDARD_DEVIATION 16.94 | 91.27 kg STANDARD_DEVIATION 18.43 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 47 | 3 / 46 |
| serious Total, serious adverse events | 0 / 47 | 1 / 46 |
Outcome results
Primary
Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4
Adjusted mean change from baseline in MWG achieved with saxagliptin 5 mg plus metformin XR versus placebo plus metformin XR at Week 24. MWG was calculated as the area under the curve (AUC) for the full 24 hours expressed as average mg/dL. Glucose measurements were collected 30 minutes before and just prior to each meal (0 minutes) and 30, 60, 120, and 180 minutes after each meal (with 1 additional measurement at 240 minutes after the evening meal), midnight, 3 AM, and at end-of-domicile visit 24 hours after the first measurement. Mean change from baseline was adjusted for baseline value.
Time frame: Baseline, Week 4
Population: Randomized participants who had both baseline and Week 4 assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin XR 1500 mg | Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Baseline Mean | 191.3 mg/dL | Standard Error 6.26 |
| Saxagliptin 5 mg + Metformin XR 1500 mg | Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Week 4 Mean | 173.2 mg/dL | Standard Error 5.85 |
| Saxagliptin 5 mg + Metformin XR 1500 mg | Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Adjusted Change from Baseline | -19.0 mg/dL | Standard Error 5.69 |
| Metformin 2000 mg | Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Baseline Mean | 192.0 mg/dL | Standard Error 6.14 |
| Metformin 2000 mg | Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Week 4 Mean | 184.2 mg/dL | Standard Error 6.52 |
| Metformin 2000 mg | Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Adjusted Change from Baseline | -8.2 mg/dL | Standard Error 5.96 |
Comparison: With at least 36 participants per treatment group (72 total), there is 90% power to detect a difference of 18 mg/dL between the two treatment groups. Assuming approximately 20% of participants will discontinue without any valid post-randomization assessment at Week 4, a total of 90 participants (45 participants per treatment group) needed to be randomized.p-value: 0.127895% CI: [-24.8, 3.2]ANCOVA
Secondary
Change From Baseline Fasting Plasma Glucose (FPG) at Week 4, Obtained Immediately Before the Morning Meal
FPG measurements were done at baseline, day 14 and 28. At baseline and day 28, the FPG value=plasma glucose value collected 30 minutes prior to the morning meal during the domicile visit.
Time frame: Baseline, Week 4
Population: Randomized participants who had both baseline and Week 4 assessments. Last Observation Carried Forward (LOCF).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin XR 1500 mg | Change From Baseline Fasting Plasma Glucose (FPG) at Week 4, Obtained Immediately Before the Morning Meal | Baseline mean | 162.9 mg/dL | Standard Error 4.84 |
| Saxagliptin 5 mg + Metformin XR 1500 mg | Change From Baseline Fasting Plasma Glucose (FPG) at Week 4, Obtained Immediately Before the Morning Meal | Week 4 LOCF mean | 155.2 mg/dL | Standard Error 6.49 |
| Saxagliptin 5 mg + Metformin XR 1500 mg | Change From Baseline Fasting Plasma Glucose (FPG) at Week 4, Obtained Immediately Before the Morning Meal | Adjusted mean change from baseline | -9.3 mg/dL | Standard Error 5.93 |
| Metformin 2000 mg | Change From Baseline Fasting Plasma Glucose (FPG) at Week 4, Obtained Immediately Before the Morning Meal | Baseline mean | 164.2 mg/dL | Standard Error 5.28 |
| Metformin 2000 mg | Change From Baseline Fasting Plasma Glucose (FPG) at Week 4, Obtained Immediately Before the Morning Meal | Week 4 LOCF mean | 161.8 mg/dL | Standard Error 5.23 |
| Metformin 2000 mg | Change From Baseline Fasting Plasma Glucose (FPG) at Week 4, Obtained Immediately Before the Morning Meal | Adjusted mean change from baseline | -3.6 mg/dL | Standard Error 6.17 |
95% CI: [-20, 8.5]ANCOVA
Secondary
Change From Baseline to Week 4 in 2-hour Postprandial Glucose (PPG) (2 Hours After the Evening Meal)
Adjusted mean change from baseline in 2-hour postprandial (after mealtime) plasma glucose two hours after start of the evening meal during 24-hour domicile visits evaluated both at pre-randomization (baseline) and at Week 4. Mean change from baseline was adjusted for baseline value.
Time frame: Baseline, Week 4
Population: Randomized participants who had both baseline and Week 4 assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin XR 1500 mg | Change From Baseline to Week 4 in 2-hour Postprandial Glucose (PPG) (2 Hours After the Evening Meal) | Baseline mean | 229.7 mg/dL | Standard Error 9.07 |
| Saxagliptin 5 mg + Metformin XR 1500 mg | Change From Baseline to Week 4 in 2-hour Postprandial Glucose (PPG) (2 Hours After the Evening Meal) | Week 4 mean | 195.3 mg/dL | Standard Error 7.99 |
| Saxagliptin 5 mg + Metformin XR 1500 mg | Change From Baseline to Week 4 in 2-hour Postprandial Glucose (PPG) (2 Hours After the Evening Meal) | Adjusted mean change from baseline | -31.4 mg/dL | Standard Error 9.69 |
| Metformin 2000 mg | Change From Baseline to Week 4 in 2-hour Postprandial Glucose (PPG) (2 Hours After the Evening Meal) | Baseline mean | 234.0 mg/dL | Standard Error 10.32 |
| Metformin 2000 mg | Change From Baseline to Week 4 in 2-hour Postprandial Glucose (PPG) (2 Hours After the Evening Meal) | Week 4 mean | 228.1 mg/dL | Standard Error 11.3 |
| Metformin 2000 mg | Change From Baseline to Week 4 in 2-hour Postprandial Glucose (PPG) (2 Hours After the Evening Meal) | Adjusted mean change from baseline | -0.2 mg/dL | Standard Error 10.09 |
95% CI: [-54.6, -7.7]ANCOVA
Other Pre-specified
Participants With Confirmed Hypoglycemia Events During the Treatment Period
'Confirmed' = recorded on the hypoglycemia AE case report form with a fingerstick for glucose \<= 50 mg/dL and associated symptoms.
Time frame: AEs: up to last treatment day (LTD) +1 day or last visit day (LVD), whichever came last ; SAEs: up to LTD +30 days or LVD + 30 days, whichever came last. Mean duration of exposure=27.7 days for Saxa 5 mg + Met XR 1500 mg, and 28.3 days for Met 2000 mg.
Population: Treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin 5 mg + Metformin XR 1500 mg | Participants With Confirmed Hypoglycemia Events During the Treatment Period | 0 participants |
| Metformin 2000 mg | Participants With Confirmed Hypoglycemia Events During the Treatment Period | 0 participants |
Other Pre-specified
Participants With Reported Hypoglycemic Adverse Events During Treatment Period
Hypoglycemic events are based upon the Saxagliptin Predefined List of Events, which includes hypoglycemia, blood glucose decreased, and hypoglycemic unconsciousness. The Hypoglycemic events occurred in less than 5% of the participants and hence do not appear in the adverse events module.
Time frame: AEs: up to last treatment day (LTD) +1 day or last visit day (LVD), whichever came last ; SAEs: up to LTD +30 days or LVD + 30 days, whichever came last. Mean duration of exposure=27.7 days for Saxa 5 mg + Met XR 1500 mg, and 28.3 days for Met 2000 mg.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saxagliptin 5 mg + Metformin XR 1500 mg | Participants With Reported Hypoglycemic Adverse Events During Treatment Period | 1 participants |
| Metformin 2000 mg | Participants With Reported Hypoglycemic Adverse Events During Treatment Period | 2 participants |