Type 2 Diabetes
Conditions
Brief summary
The purpose of this study is to learn if a combination of BMS-477118 (Saxagliptin) and BMS -512148 (Dapagliflozin) added to Metformin can improve (decrease) Glycosylated Hemoglobin (Hemoglobin A1c) in patients with type 2 diabetes after 24 weeks of treatment. The safety of this treatment will also be studied.
Interventions
DRUGSaxagliptin
Tablets, Oral, 5mg , Once daily, 24 weeks
DRUGMetformin XR
Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks
DRUGDapagliflozin
Tablets, Oral, 10mg , Once daily, 24 weeks
Tablets, Oral, 0mg, Once daily, 24 weeks
Tablets, Oral, 0mg, Once daily, 24 weeks
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects with Type 2 diabetes mellitus (T2DM) with HbA1c ≥ 8.0% and ≤ 12.0% * Stable metformin therapy dose of ≥ 1500mg for at least 8 weeks prior to screening * Body mass index (BMI) ≤ 45.0kg/m2
Exclusion criteria
* Estimated glomerular filtration rate (eGFR) \< 60mL/min/1,73m2 and Serum Creatinine (Scr) ≥ 1.5 mg/dL in males or ≥ 1.4 mg/dL in females * Uncontrolled hypertension Systolic Blood Pressure (SBP) ≥ 160mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100mmHg * Hepatic disease * Cardiovascular disease within 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 | Baseline (Week 0) and at Week 24 | HbA1c was measured as percent of hemoglobin by a central laboratory. Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained at Week 24 in the double-blind period, including observations prior to rescue. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in 2-hour Post Prandial Glucose (PPG) From a Liquid Meal Tolerance Test (MTT) at Week 24 (Last Observation Carried Forward [LOCF]) | Baseline (Week 0) and at Week 24 | Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. PPG measurements were obtained at week 24 in the doubleblind period, including observations prior to rescue. |
| Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Baseline (Week 0) and at Week 24 | Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained at Week 24 in the doubleblind period, including observations prior to rescue. |
| Adjusted Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | At Week 24 | Therapeutic glycemic response is defined as HbA1c \<7.0%. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. |
| Adjusted Mean Change From Baseline in Body Weight at Week 24 | Baseline (Week 0) and at Week 24 | Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained at Week 24 in the doubleblind period, including observations prior to rescue. |
Countries
Canada, Mexico, Poland, Puerto Rico, Romania, South Africa, South Korea, United States
Participant flow
Pre-assignment details
Of 1282 participants enrolled subjects, 534 eligible subjects entered the randomized, double-blind treatment period. Of 534 randomized and treated subjects, 490 subjects completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Saxagliptin+Metformin XR+Placebo Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks | 176 |
| Arm 2: Dapagliflozin+Metformin XR+Placebo Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks | 179 |
| Arm 3: Saxagliptin+Dapagliflozin+Metformin XR Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 | 179 |
| Total | 534 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 |
| Overall Study | discontinue study treatment | 0 | 2 | 1 |
| Overall Study | Lost to Follow-up | 6 | 8 | 5 |
| Overall Study | Poor/Non-compliance | 1 | 0 | 0 |
| Overall Study | Pregnancy | 0 | 1 | 1 |
| Overall Study | Reason 'Other' in the protocol | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 6 | 1 |
Baseline characteristics
| Characteristic | Arm 1: Saxagliptin+Metformin XR+Placebo | Total | Arm 3: Saxagliptin+Dapagliflozin+Metformin XR | Arm 2: Dapagliflozin+Metformin XR+Placebo |
|---|---|---|---|---|
| Age, Continuous | 54.6 Years STANDARD_DEVIATION 9.6 | 53.8 Years STANDARD_DEVIATION 9.7 | 53.4 Years STANDARD_DEVIATION 9.8 | 53.5 Years STANDARD_DEVIATION 9.7 |
| Age, Customized <65 years | 148 participants | 466 participants | 160 participants | 158 participants |
| Age, Customized >=65 years | 28 participants | 68 participants | 19 participants | 21 participants |
| Body Mass Index (BMI) | 31.8 kg/m^2 STANDARD_DEVIATION 5.142 | 31.67 kg/m^2 STANDARD_DEVIATION 5.08 | 31.76 kg/m^2 STANDARD_DEVIATION 4.787 | 31.46 kg/m^2 STANDARD_DEVIATION 5.321 |
| HbA1c | 9.03 % STANDARD_DEVIATION 1.05 | 8.94 % STANDARD_DEVIATION 1.13 | 8.92 % STANDARD_DEVIATION 1.18 | 8.87 % STANDARD_DEVIATION 1.16 |
| Race/Ethnicity, Customized Asian | 11 participants | 33 participants | 12 participants | 10 participants |
| Race/Ethnicity, Customized Black african/american | 22 participants | 60 participants | 22 participants | 16 participants |
| Race/Ethnicity, Customized Other | 22 participants | 69 participants | 25 participants | 22 participants |
| Race/Ethnicity, Customized White | 121 participants | 372 participants | 120 participants | 131 participants |
| Sex: Female, Male Female | 82 Participants | 266 Participants | 94 Participants | 90 Participants |
| Sex: Female, Male Male | 94 Participants | 268 Participants | 85 Participants | 89 Participants |
| T2DM duration | 8.2 years STANDARD_DEVIATION 5.52 | 7.6 years STANDARD_DEVIATION 5.33 | 7.1 years STANDARD_DEVIATION 5.04 | 7.4 years STANDARD_DEVIATION 5.4 |
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 | 0 / 176 | 0 / 179 | 0 / 179 |
| serious Total, serious adverse events | 6 / 176 | 2 / 179 | 2 / 179 |
Outcome results
Primary
Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24
HbA1c was measured as percent of hemoglobin by a central laboratory. Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained at Week 24 in the double-blind period, including observations prior to rescue.
Time frame: Baseline (Week 0) and at Week 24
Population: All randomized participants who received study medication and had nonmissing HbA1c values at baseline and Week 24
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1: Saxagliptin+Metformin XR+Placebo | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 | -0.88 % HbA1c |
| Arm 2: Dapagliflozin+Metformin XR+Placebo | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 | -1.20 % HbA1c |
| Arm 3: Saxagliptin+Dapagliflozin+Metformin XR | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 | -1.47 % HbA1c |
p-value: <0.000195% CI: [-0.81, -0.37]Mixed Models Analysis
p-value: 0.016695% CI: [-0.48, -0.05]Mixed Models Analysis
Secondary
Adjusted Mean Change From Baseline in 2-hour Post Prandial Glucose (PPG) From a Liquid Meal Tolerance Test (MTT) at Week 24 (Last Observation Carried Forward [LOCF])
Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. PPG measurements were obtained at week 24 in the doubleblind period, including observations prior to rescue.
Time frame: Baseline (Week 0) and at Week 24
Population: All randomized participants who received study medication and had nonmissing PPG values at baseline and Week 24 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Saxagliptin+Metformin XR+Placebo | Adjusted Mean Change From Baseline in 2-hour Post Prandial Glucose (PPG) From a Liquid Meal Tolerance Test (MTT) at Week 24 (Last Observation Carried Forward [LOCF]) | -35.6 MG/DL PPG | 95% Confidence Interval 3.51 |
| Arm 2: Dapagliflozin+Metformin XR+Placebo | Adjusted Mean Change From Baseline in 2-hour Post Prandial Glucose (PPG) From a Liquid Meal Tolerance Test (MTT) at Week 24 (Last Observation Carried Forward [LOCF]) | -70.4 MG/DL PPG | 95% Confidence Interval 3.538 |
| Arm 3: Saxagliptin+Dapagliflozin+Metformin XR | Adjusted Mean Change From Baseline in 2-hour Post Prandial Glucose (PPG) From a Liquid Meal Tolerance Test (MTT) at Week 24 (Last Observation Carried Forward [LOCF]) | -79.6 MG/DL PPG | 95% Confidence Interval 3.426 |
Comparison: LOCFp-value: <0.000195% CI: [-53.7, -34.3]ANCOVA
Comparison: LOCFp-value: 0.063995% CI: [-18.8, 0.5]ANCOVA
Secondary
Adjusted Mean Change From Baseline in Body Weight at Week 24
Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained at Week 24 in the doubleblind period, including observations prior to rescue.
Time frame: Baseline (Week 0) and at Week 24
Population: All randomized participants who received study medication and had nonmissing body weight values at baseline and Week 24
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1: Saxagliptin+Metformin XR+Placebo | Adjusted Mean Change From Baseline in Body Weight at Week 24 | 0.00 Body weight Kg |
| Arm 2: Dapagliflozin+Metformin XR+Placebo | Adjusted Mean Change From Baseline in Body Weight at Week 24 | -2.39 Body weight Kg |
| Arm 3: Saxagliptin+Dapagliflozin+Metformin XR | Adjusted Mean Change From Baseline in Body Weight at Week 24 | -2.05 Body weight Kg |
95% CI: [-2.73, -1.37]
Secondary
Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained at Week 24 in the doubleblind period, including observations prior to rescue.
Time frame: Baseline (Week 0) and at Week 24
Population: All randomized participants who received study medication and had nonmissing PPG values at baseline and Week 24
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1: Saxagliptin+Metformin XR+Placebo | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -14.0 mg/dL |
| Arm 2: Dapagliflozin+Metformin XR+Placebo | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -31.7 mg/dL |
| Arm 3: Saxagliptin+Dapagliflozin+Metformin XR | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -37.8 mg/dL |
95% CI: [-31.6, -15.9]
95% CI: [-13.8, 1.7]
Secondary
Adjusted Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])
Therapeutic glycemic response is defined as HbA1c \<7.0%. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.
Time frame: At Week 24
Population: All randomized participants who received study medication and were not missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Saxagliptin+Metformin XR+Placebo | Adjusted Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 18.3 % of Participants |
| Arm 2: Dapagliflozin+Metformin XR+Placebo | Adjusted Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 22.2 % of Participants |
| Arm 3: Saxagliptin+Dapagliflozin+Metformin XR | Adjusted Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 41.4 % of Participants |
95% CI: [14.7, 31.5]
95% CI: [10.1, 28.1]