Type 2 Diabetes
Conditions
Brief summary
The purpose of this clinical research study is to learn if BMS-512148 (Dapagliflozin) can help reduce the blood sugar levels in Asian patients with Type 2 Diabetes who are not well controlled on metformin alone. The safety of this treatment will also be studied.
Interventions
DRUGDapagliflozin
Tablets, Oral, 5 mg, Once daily, 24 weeks
DRUGMetformin
Tablets, Oral, 1500-3000 mg, Twice daily, 24 weeks
Tablets, Oral, 0 mg, Once daily, 24 weeks
DRUGPioglitazone
Tablets, Oral, 15-45 mg (as needed for rescue based on protocol specific criteria), Up to 20 weeks
Sponsors
AstraZeneca, 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
* Males and females, 18 to 77 years old, with type 2 diabetes and with inadequate glycemic control * Drug naive or treated with anti-diabetic medication for \< 24 weeks * C-peptide ≥ 1.0 ng/mL * Body Mass Index ≤ 45.0 kg/m²
Exclusion criteria
* AST and/or ALT \> 3 times ULN * Serum total bilirubin \> 2 mg/dL * Serum creatinine ≥ 1.50 mg/dL for men or ≥ 1.40 mg/dL for women * Creatine kinase ≥ 3 times ULN * Symptoms of severely uncontrolled diabetes * Currently unstable or serious cardiovascular, renal, hepatic, hematological, oncological, endocrine, psychiatric, or rheumatic diseases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | From Baseline to Week 24 | HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, 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 during the qualification and lead-in periods and on Day 1 and Weeks 4, 8, 12, 16, 20, and 24 in the double-blind period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | From Baseline to Week 24 | Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Fasting plasma glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, 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 during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 8, 12, 16, 20, and 24 in the double-blind period. |
| Adjusted Mean Change From Baseline in 2-hour Post Meal Glucose (PMG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF]) | From Baseline to Week 24 | Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Post Meal Glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. PMG measurements were obtained on Day 1 and week 24 in the double-blind period. |
| Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | From Baseline to Week 24 | Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, 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 during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 8, 12, 16, 20, and 24 of the double-blind period. |
| Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | From Baseline to Week 24 | Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. 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. Percentage of participants were estimated by modified logistic regression model, adjusted for baseline HbA1c. |
Countries
China, India, South Korea
Participant flow
Recruitment details
Of 1484 patients enrolled, 554 completed a qualification period. Of these 554 patients, 444 were randomized and received treatment. Of these 444 participants, 409 completed the double-blind treatment period
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Metformin | 145 |
| Dapagliflozin 5 mg + Metformin | 147 |
| Dapagliflozin 10 mg + Metformin | 152 |
| Total | 444 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 3 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 2 | 0 |
| Overall Study | Non-compliance, not met criteria etc. | 7 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 6 | 1 |
Baseline characteristics
| Characteristic | Placebo + Metformin | Dapagliflozin 5 mg + Metformin | Dapagliflozin 10 mg + Metformin | Total |
|---|---|---|---|---|
| Age, Continuous | 53.5 Years STANDARD_DEVIATION 9.2 | 53.1 Years STANDARD_DEVIATION 9.09 | 54.6 Years STANDARD_DEVIATION 9.54 | 53.8 Years STANDARD_DEVIATION 9.29 |
| Age, Customized 65 to younger than 75 years | 14 Participants | 13 Participants | 25 Participants | 52 Participants |
| Age, Customized 75 years and older | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Age, Customized Yonger than 65 years | 129 Participants | 132 Participants | 126 Participants | 387 Participants |
| Race/Ethnicity, Customized Asian Indian | 10 Participants | 11 Participants | 13 Participants | 34 Participants |
| Race/Ethnicity, Customized Chinese | 126 Participants | 127 Participants | 129 Participants | 382 Participants |
| Race/Ethnicity, Customized Korean | 9 Participants | 9 Participants | 10 Participants | 28 Participants |
| Sex/Gender, Customized Female | 59 Participants | 80 Participants | 64 Participants | 203 Participants |
| Sex/Gender, Customized Male | 86 Participants | 67 Participants | 88 Participants | 241 Participants |
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 | 34 / 145 | 43 / 147 | 42 / 152 |
| serious Total, serious adverse events | 6 / 145 | 3 / 147 | 3 / 152 |
Outcome results
Primary
Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF])
HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, 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 during the qualification and lead-in periods and on Day 1 and Weeks 4, 8, 12, 16, 20, and 24 in the double-blind period.
Time frame: From Baseline to Week 24
Population: All randomized participants who received study medication and had nonmissing HbA1c values at baseline and Week 24 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Metformin | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | -0.23 % of hemoglobin | Standard Error 0.0622 |
| Dapagliflozin 5 mg + Metformin | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | -0.82 % of hemoglobin | Standard Error 0.0607 |
| Dapagliflozin 10 mg + Metformin | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | -0.85 % of hemoglobin | Standard Error 0.0601 |
p-value: <0.000195% CI: [-0.76, -0.42]ANCOVA
p-value: <0.000195% CI: [-0.79, -0.45]ANCOVA
Secondary
Adjusted Mean Change From Baseline in 2-hour Post Meal Glucose (PMG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF])
Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Post Meal Glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. PMG measurements were obtained on Day 1 and week 24 in the double-blind period.
Time frame: From Baseline to Week 24
Population: All randomized participants who received study medication and had nonmissing PMG values at baseline and Week 24 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Metformin | Adjusted Mean Change From Baseline in 2-hour Post Meal Glucose (PMG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF]) | -15.5 mg/dL | Standard Error 4.1548 |
| Dapagliflozin 5 mg + Metformin | Adjusted Mean Change From Baseline in 2-hour Post Meal Glucose (PMG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF]) | -57.8 mg/dL | Standard Error 4.1547 |
| Dapagliflozin 10 mg + Metformin | Adjusted Mean Change From Baseline in 2-hour Post Meal Glucose (PMG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF]) | -64.6 mg/dL | Standard Error 4.0357 |
p-value: <0.000195% CI: [-53.84, -30.73]ANCOVA
p-value: <0.000195% CI: [-60.53, -37.74]ANCOVA
Secondary
Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF])
Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Fasting plasma glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, 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 during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 8, 12, 16, 20, and 24 in the double-blind period.
Time frame: From Baseline to Week 24
Population: All randomized participants who received study medication and had nonmissing FPG values at baseline and Week 24 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Metformin | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | 0.5 mg/dL | Standard Error 2.357 |
| Dapagliflozin 5 mg + Metformin | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | -21.6 mg/dL | Standard Error 2.308 |
| Dapagliflozin 10 mg + Metformin | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | -26.6 mg/dL | Standard Error 2.269 |
p-value: <0.000195% CI: [-28.6, -15.6]ANCOVA
p-value: <0.000195% CI: [-33.5, -20.7]ANCOVA
Secondary
Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF])
Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, 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 during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 8, 12, 16, 20, and 24 of the double-blind period.
Time frame: From Baseline to Week 24
Population: All randomized participants who received study medication and had nonmissing body weight values at baseline and Week 24 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Metformin | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | -0.74 kg | Standard Error 0.1975 |
| Dapagliflozin 5 mg + Metformin | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | -1.84 kg | Standard Error 0.1935 |
| Dapagliflozin 10 mg + Metformin | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | -2.56 kg | Standard Error 0.1909 |
p-value: <0.000195% CI: [-1.65, -0.56]ANCOVA
p-value: <0.000195% CI: [-2.36, -1.28]ANCOVA
Secondary
Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])
Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. 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. Percentage of participants were estimated by modified logistic regression model, adjusted for baseline HbA1c.
Time frame: From Baseline to Week 24
Population: All randomized participants who received study medication and had nonmissing HbA1C values at Week 24 (LOCF)
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo + Metformin | Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 17.5 Percentage of Participants | 3.136 |
| Dapagliflozin 5 mg + Metformin | Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 32.9 Percentage of Participants | 3.667 |
| Dapagliflozin 10 mg + Metformin | Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 33.0 Percentage of Participants | 3.528 |
p-value: 0.00195% CI: [6.2, 24.7]Modified logistic regression
p-value: 0.000795% CI: [6.5, 24.5]Modified logistic regression