Type 2 Diabetes
Conditions
Brief summary
The purpose of this clinical research study is to learn if BMS-512148 (Dapagliflozin) can improve (decrease) blood glucose values in Asian patients with Type 2 Diabetes who have never been treated with medication or have been on medication for less than 24 weeks since their original diagnosis of Diabetes. The safety of this treatment will also be studied.
Interventions
DRUGDapagliflozin
Tablets, Oral, 5 mg, Once daily, 24 weeks
DRUGMetformin
Tablets, Oral, 500-2000 mg (as needed for rescue based on protocol specific criteria), Up to 20 weeks
Tablets, Oral, 0 mg, Once daily, 24 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 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 Liquid Meal Glucose (PLMG) (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 Liquid 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. PLMG 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. |
| Percentage of 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. Percent adjusted for baseline HbA1c. 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. Mean and standard error for percentage of participants were estimated by modified logistic regression model. |
Countries
China, India, South Korea, Taiwan
Participant flow
Recruitment details
Of 1179 participants enrolled, 514 completed a qualification period. Of these 514 participants, 393 were randomized and received treatment. Of these 393 participants, 343 completed double-blind treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received dapagliflozin matching placebo once daily for up to 24 weeks (may include the addition of open-label metformin as rescue) | 132 |
| Dapagliflozin 5 mg Participants received dapagliflozin 5 mg once daily for up to 24 weeks (may include the addition of open-label metformin as rescue) | 128 |
| Dapagliflozin 10 mg Participants received dapagliflozin 10 mg once daily for up to 24 weeks (may include the addition of open-label metformin as rescue) | 133 |
| Total | 393 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 | 4 |
| Overall Study | Lack of Efficacy | 3 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 4 |
| Overall Study | non-compliance, not met criteria, etc. | 10 | 6 | 5 |
| Overall Study | Withdrawal by Subject | 4 | 5 | 3 |
Baseline characteristics
| Characteristic | Placebo | Dapagliflozin 5 mg | Dapagliflozin 10 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 49.9 Years STANDARD_DEVIATION 10.87 | 53.0 Years STANDARD_DEVIATION 11.07 | 51.2 Years STANDARD_DEVIATION 9.89 | 51.3 Years STANDARD_DEVIATION 10.67 |
| Age, Customized 65 to younger than 75 years | 11 Participants | 14 Participants | 10 Participants | 35 Participants |
| Age, Customized 75 years and older | 1 Participants | 6 Participants | 0 Participants | 7 Participants |
| Age, Customized Younger than 65 years | 120 Participants | 108 Participants | 123 Participants | 351 Participants |
| Body Mass Index (BMI) | 25.93 kg/m^2 STANDARD_DEVIATION 3.644 | 25.17 kg/m^2 STANDARD_DEVIATION 3.285 | 25.76 kg/m^2 STANDARD_DEVIATION 3.434 | 25.62 kg/m^2 STANDARD_DEVIATION 3.465 |
| Race/Ethnicity, Customized ASIAN INDIAN | 8 Participants | 8 Participants | 9 Participants | 25 Participants |
| Race/Ethnicity, Customized ASIAN OTHER | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized CHINESE | 117 Participants | 114 Participants | 117 Participants | 348 Participants |
| Race/Ethnicity, Customized JAPANESE | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized KOREAN | 5 Participants | 6 Participants | 5 Participants | 16 Participants |
| Sex/Gender, Customized Female | 45 Participants | 44 Participants | 47 Participants | 136 Participants |
| Sex/Gender, Customized Male | 87 Participants | 84 Participants | 86 Participants | 257 Participants |
| Weight | 72.18 kg STANDARD_DEVIATION 13.234 | 68.89 kg STANDARD_DEVIATION 11.429 | 70.92 kg STANDARD_DEVIATION 11.637 | 70.68 kg STANDARD_DEVIATION 12.177 |
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 | 38 / 132 | 28 / 128 | 23 / 133 |
| serious Total, serious adverse events | 2 / 132 | 5 / 128 | 4 / 133 |
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 | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | -0.29 % of hemoglobin | Standard Error 0.0681 |
| Dapagliflozin 5 mg | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | -1.04 % of hemoglobin | Standard Error 0.0695 |
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | -1.11 % of hemoglobin | Standard Error 0.068 |
p-value: <0.000195% CI: [-0.94, -0.56]ANCOVA
p-value: <0.000195% CI: [-1.01, -0.63]ANCOVA
Secondary
Adjusted Mean Change From Baseline in 2-hour Post Liquid Meal Glucose (PLMG) (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 Liquid 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. PLMG 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 PLMG values at baseline and Week 24 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Change From Baseline in 2-hour Post Liquid Meal Glucose (PLMG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF]) | 1.08 mg/dL | Standard Error 4.5663 |
| Dapagliflozin 5 mg | Adjusted Mean Change From Baseline in 2-hour Post Liquid Meal Glucose (PLMG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF]) | -46.8 mg/dL | Standard Error 4.6559 |
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in 2-hour Post Liquid Meal Glucose (PLMG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF]) | -54.9 mg/dL | Standard Error 4.5257 |
p-value: <0.000195% CI: [-60.8, -34.96]ANCOVA
p-value: <0.000195% CI: [-68.66, -43.28]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 | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | 2.5 mg/dL | Standard Error 2.237 |
| Dapagliflozin 5 mg | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | -25.1 mg/dL | Standard Error 2.274 |
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | -31.6 mg/dL | Standard Error 2.255 |
p-value: <0.000195% CI: [-34, -21.4]ANCOVA
p-value: <0.000195% CI: [-40.4, -27.9]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 | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | -0.27 kg | Standard Error 0.2279 |
| Dapagliflozin 5 mg | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | -1.64 kg | Standard Error 0.2315 |
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | -2.25 kg | Standard Error 0.2308 |
p-value: <0.000195% CI: [-2.01, -0.73]ANCOVA
p-value: <0.000195% CI: [-2.62, -1.34]ANCOVA
Secondary
Percentage of 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. Percent adjusted for baseline HbA1c. 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. Mean and standard error for percentage of participants were estimated by modified logistic regression model.
Time frame: From Baseline to Week 24
Population: All randomized participants who received study medication and had nonmissing values at baseline and Week 24 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 21.3 Percentage of participants | Standard Error 3.31 |
| Dapagliflozin 5 mg | Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 42.6 Percentage of participants | Standard Error 4.3 |
| Dapagliflozin 10 mg | Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 49.8 Percentage of participants | Standard Error 4.032 |
p-value: <0.000195% CI: [11.1, 31.6]Modified logistic regression
p-value: <0.000195% CI: [18.6, 38.3]Modified logistic regression