Type 2 Diabetes
Conditions
Brief summary
This protocol will compare 24 hour glucose control for subject taking saxagliptin and metformin extended release (XR) versus metformin XR alone
Interventions
DRUGSaxagliptin
Tablets, Oral, 5mg, once daily, 4 weeks
DRUGPlacebo
Tablets, Oral, 0 mg, once daily, 4 weeks
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
* ≥18- and ≤77-years-old * Type 2 diabetes * Taking metformin immediate release (IR) or XR ≥1500 mg for at least 8 weeks as monotherapy * Glycosylated hemoglobin (A1C) ≥7% and ≤10% * Body mass index (BMI) ≤40 kg/m2
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 in 4-Hour Mean Weighted Postprandial Plasma Glucose at Week 4 | Baseline, Week 4 | Adjusted mean change from baseline in 4-hour mean weighted postprandial (after mealtime) plasma glucose after 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 in 2-Hour Postprandial Plasma Glucose After the Evening Meal at Week 4 | Baseline, Week 4 | Adjusted mean change from baseline in 2-hour postprandial plasma glucose after 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 in Mean Daily Glucose at Week 4 | Baseline, Week 4 | Adjusted mean change from baseline in daily glucose at Week 4. Mean daily glucose was calculated based on finger stick glucose measurements collected by the subjects at home in a 3-day period, prior to collection of the 24-hour blood samples at baseline and Week 4. Mean change from baseline was adjusted for baseline value. |
| Change From Baseline in 2-Day Average Fasting Plasma Glucose (FPG) at Week 4 | Baseline, Week 4 | Adjusted mean change from baseline in 2-day average of FPG at baseline and Week 4. Baseline value=the average of the values at Day -2 and Day 1. Week 4 measurement=average of Day 26 and Day 28 value during the double blind period. At pre-randomization and Day 28 the FPG value was the plasma glucose value collected 30 minutes prior to the morning meal during domicile visits. Mean change from baseline was adjusted for baseline value. |
Countries
Argentina, Israel, Italy, Mexico, Philippines, Puerto Rico, Sweden, United States
Participant flow
Pre-assignment details
218 subjects were enrolled and 128 entered the 4-week dietary and exercise, and metformin extended release (XR) lead-in period. Thirty-five subjects did not enter treatment period (21 no longer met study criteria, 7 withdrew consent, 7 for poor protocol compliance).
Participants by arm
| Arm | Count |
|---|---|
| Saxagliptin 5 mg + Metformin Saxagliptin tablets, 5 mg, taken orally once daily for 4 weeks, plus metformin XR. | 46 |
| Placebo + Metformin Placebo tablets, taken orally once daily for 4 weeks, plus metformin XR. | 47 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Subject Withdrew Consent | 1 | 0 |
Baseline characteristics
| Characteristic | Saxagliptin 5 mg + Metformin | Placebo + Metformin | Total |
|---|---|---|---|
| Age, Continuous | 54.50 years STANDARD_DEVIATION 9.2 | 55.77 years STANDARD_DEVIATION 9.14 | 55.14 years STANDARD_DEVIATION 9.14 |
| Age, Customized <65 years | 40 participants | 38 participants | 78 participants |
| Age, Customized >= 65 years to <75 years | 6 participants | 8 participants | 14 participants |
| Age, Customized >= 75 years | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Black/African American | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 39 Participants | 43 Participants | 82 Participants |
| Sex: Female, Male Female | 20 Participants | 24 Participants | 44 Participants |
| Sex: Female, Male Male | 26 Participants | 23 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 47 | 1 / 46 |
| serious Total, serious adverse events | 0 / 47 | 0 / 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 took at least 1 dose of double-blind treatment. To be included in an analysis of change from baseline to Week 4 the subject must have had a baseline and a Week 4 measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin | Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Baseline Mean | 177.5 mg/dL | Standard Error 4.99 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Week 4 Mean | 163.8 mg/dL | Standard Error 5.09 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Adjusted Mean Change from Baseline | -13.8 mg/dL | Standard Error 2.99 |
| Placebo + Metformin | Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Baseline Mean | 181.2 mg/dL | Standard Error 6.3 |
| Placebo + Metformin | Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Week 4 Mean | 184.2 mg/dL | Standard Error 7.05 |
| Placebo + Metformin | Change From Baseline in 24-Hour Mean Weighted Glucose (MWG) at Week 4 | Adjusted Mean Change from Baseline | 3.0 mg/dL | Standard Error 2.89 |
Comparison: With 39 subjects per treatment group, there was a 93% power for the primary endpoint to detect a difference in 24-hour mean weighted glucose of 16 mg/dL between saxagliptin and placebo, assuming a standard deviation of 20 mg/dL. Assuming a dropout rate of 15%, a total of 92 subjects (46 subjects per treatment arm) needed to be randomized.p-value: 0.000195% CI: [-25.1, -8.5]ANCOVA
Secondary
Change From Baseline in 2-Day Average Fasting Plasma Glucose (FPG) at Week 4
Adjusted mean change from baseline in 2-day average of FPG at baseline and Week 4. Baseline value=the average of the values at Day -2 and Day 1. Week 4 measurement=average of Day 26 and Day 28 value during the double blind period. At pre-randomization and Day 28 the FPG value was the plasma glucose value collected 30 minutes prior to the morning meal during domicile visits. Mean change from baseline was adjusted for baseline value.
Time frame: Baseline, Week 4
Population: Randomized participants who took at least 1 dose of double-blind treatment. To be included in an analysis of change from baseline to Week 4 the subject must have had a baseline and a Week 4 measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin | Change From Baseline in 2-Day Average Fasting Plasma Glucose (FPG) at Week 4 | Baseline Mean | 152.2 mg/dL | Standard Error 4.14 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in 2-Day Average Fasting Plasma Glucose (FPG) at Week 4 | Week 4 Last Observation Carried Forward Mean | 141.9 mg/dL | Standard Error 3.99 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in 2-Day Average Fasting Plasma Glucose (FPG) at Week 4 | Adjusted Mean Change from Baseline | -10.8 mg/dL | Standard Error 2.84 |
| Placebo + Metformin | Change From Baseline in 2-Day Average Fasting Plasma Glucose (FPG) at Week 4 | Baseline Mean | 158.9 mg/dL | Standard Error 5.8 |
| Placebo + Metformin | Change From Baseline in 2-Day Average Fasting Plasma Glucose (FPG) at Week 4 | Week 4 Last Observation Carried Forward Mean | 162.9 mg/dL | Standard Error 6 |
| Placebo + Metformin | Change From Baseline in 2-Day Average Fasting Plasma Glucose (FPG) at Week 4 | Adjusted Mean Change from Baseline | 4.5 mg/dL | Standard Error 2.81 |
Comparison: With 39 subjects per treatment group, there was a 93% power for the primary endpoint to detect a difference in 24-hour mean weighted glucose of 16 mg/dL between saxagliptin and placebo, assuming a standard deviation of 20 mg/dL. Assuming a dropout rate of 15%, a total of 92 subjects (46 subjects per treatment arm) needed to be randomized.p-value: 0.000295% CI: [-23.3, -7.4]ANCOVA
Secondary
Change From Baseline in 2-Hour Postprandial Plasma Glucose After the Evening Meal at Week 4
Adjusted mean change from baseline in 2-hour postprandial plasma glucose after 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 took at least 1 dose of double-blind treatment. To be included in an analysis of change from baseline to Week 4 the subject must have had a baseline and a Week 4 measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin | Change From Baseline in 2-Hour Postprandial Plasma Glucose After the Evening Meal at Week 4 | Baseline Mean | 237.6 mg/dL | Standard Error 8.87 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in 2-Hour Postprandial Plasma Glucose After the Evening Meal at Week 4 | Week 4 Mean | 198.5 mg/dL | Standard Error 8.82 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in 2-Hour Postprandial Plasma Glucose After the Evening Meal at Week 4 | Adjusted Change from Baseline | -38.2 mg/dL | Standard Error 7.49 |
| Placebo + Metformin | Change From Baseline in 2-Hour Postprandial Plasma Glucose After the Evening Meal at Week 4 | Baseline Mean | 233.1 mg/dL | Standard Error 7.74 |
| Placebo + Metformin | Change From Baseline in 2-Hour Postprandial Plasma Glucose After the Evening Meal at Week 4 | Week 4 Mean | 231.1 mg/dL | Standard Error 9.22 |
| Placebo + Metformin | Change From Baseline in 2-Hour Postprandial Plasma Glucose After the Evening Meal at Week 4 | Adjusted Change from Baseline | -2.8 mg/dL | Standard Error 7.23 |
Comparison: With 39 subjects per treatment group, there was a 93% power for the primary endpoint to detect a difference in 24-hour mean weighted glucose of 16 mg/dL between saxagliptin and placebo, assuming a standard deviation of 20 mg/dL. Assuming a dropout rate of 15%, a total of 92 subjects (46 subjects per treatment arm) needed to be randomized.p-value: 0.00195% CI: [-56.2, -14.7]ANCOVA
Secondary
Change From Baseline in 4-Hour Mean Weighted Postprandial Plasma Glucose at Week 4
Adjusted mean change from baseline in 4-hour mean weighted postprandial (after mealtime) plasma glucose after 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 took at least 1 dose of double-blind treatment. To be included in an analysis of change from baseline to Week 4 the subject must have had a baseline and a Week 4 measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin | Change From Baseline in 4-Hour Mean Weighted Postprandial Plasma Glucose at Week 4 | Baseline Mean | 212.1 mg/dL | Standard Error 6.8 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in 4-Hour Mean Weighted Postprandial Plasma Glucose at Week 4 | Week 4 Mean | 181.4 mg/dL | Standard Error 6.79 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in 4-Hour Mean Weighted Postprandial Plasma Glucose at Week 4 | Adjusted Mean Change from Baseline | -30.7 mg/dL | Standard Error 5.14 |
| Placebo + Metformin | Change From Baseline in 4-Hour Mean Weighted Postprandial Plasma Glucose at Week 4 | Baseline Mean | 211.1 mg/dL | Standard Error 6.6 |
| Placebo + Metformin | Change From Baseline in 4-Hour Mean Weighted Postprandial Plasma Glucose at Week 4 | Week 4 Mean | 210.8 mg/dL | Standard Error 8.02 |
| Placebo + Metformin | Change From Baseline in 4-Hour Mean Weighted Postprandial Plasma Glucose at Week 4 | Adjusted Mean Change from Baseline | -0.4 mg/dL | Standard Error 4.9 |
Comparison: With 39 subjects per treatment group, there was a 93% power for the primary endpoint to detect a difference in 24-hour mean weighted glucose of 16 mg/dL between saxagliptin and placebo, assuming a standard deviation of 20 mg/dL. Assuming a dropout rate of 15%, a total of 92 subjects (46 subjects per treatment arm) needed to be randomized.p-value: <0.000195% CI: [-44.4, -16.1]ANCOVA
Secondary
Change From Baseline in Mean Daily Glucose at Week 4
Adjusted mean change from baseline in daily glucose at Week 4. Mean daily glucose was calculated based on finger stick glucose measurements collected by the subjects at home in a 3-day period, prior to collection of the 24-hour blood samples at baseline and Week 4. Mean change from baseline was adjusted for baseline value.
Time frame: Baseline, Week 4
Population: Randomized participants who took at least 1 dose of double-blind treatment. To be included in an analysis of change from baseline to Week 4 the subject must have had a baseline and a Week 4 measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saxagliptin 5 mg + Metformin | Change From Baseline in Mean Daily Glucose at Week 4 | Adjusted Change from Baseline | -11.7 mg/dL | Standard Error 3.02 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in Mean Daily Glucose at Week 4 | Baseline Mean | 179.0 mg/dL | Standard Error 5.76 |
| Saxagliptin 5 mg + Metformin | Change From Baseline in Mean Daily Glucose at Week 4 | Week 4 Mean | 167.5 mg/dL | Standard Error 4.87 |
| Placebo + Metformin | Change From Baseline in Mean Daily Glucose at Week 4 | Week 4 Mean | 191.8 mg/dL | Standard Error 8.41 |
| Placebo + Metformin | Change From Baseline in Mean Daily Glucose at Week 4 | Adjusted Change from Baseline | 7.0 mg/dL | Standard Error 2.94 |
| Placebo + Metformin | Change From Baseline in Mean Daily Glucose at Week 4 | Baseline Mean | 184.9 mg/dL | Standard Error 7.14 |
Comparison: With 39 subjects per treatment group, there was a 93% power for the primary endpoint to detect a difference in 24-hour mean weighted glucose of 16 mg/dL between saxagliptin and placebo, assuming a standard deviation of 20 mg/dL. Assuming a dropout rate of 15%, a total of 92 subjects (46 subjects per treatment arm) needed to be randomized.p-value: <0.000195% CI: [-27.1, -10.3]ANCOVA