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 subjects with Type 2 Diabetes who are not well controlled on TZD alone. The safety of this treatment will also be studied
Interventions
DRUGDapagliflozin
Tablets, Oral, 5.0 mg, once daily, up to 48 weeks
Tablets, Oral, 0 mg, once daily, up to 48 weeks
DRUGThiazolidinedione (Pioglitazone)
Tablets, ≥ 30 mg, Once daily, up to 48 weeks
Sponsors
Astra Zeneca, Bristol-Myers Squibb
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
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 * All subjects must have central laboratory pre-randomization A1C ≥ 7.0 and ≤ 10.5% * C-peptide ≥ 1.0 ng/mL (0.34 nmol/L) * Body Mass Index ≤ 45.0 kg/m²
Exclusion criteria
* AST and /or ALT \> 2.5 times the upper limit of normal * Serum total bilirubin \> 2 mg/dL (34.2 µmol/L) * Creatinine kinase \> 3.0 times the upper limit of normal * Symptoms of severely uncontrolled diabetes * Serum creatinine ≥ 2.0 mg/dL * Calculated Cr-Clearance \< 50 ml/min (calculated by Cockroft-Gault formula) * 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 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. |
| 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 120-minute Post-challenge Plasma Glucose (PPG) (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. In post oral glucose tolerance test (OGTT), 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. PPG measurements were obtained on Day 1 and week 24 in the double-blind period. |
| Adjusted Mean Change From Baseline in Waist Circumference (cm) 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 waist circumference 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. Waist circumference measurements were obtained during the qualification and lead-in periods and on Day 1 and Week 24 of the double-blind period. |
| Adjusted Mean Change From Baseline in Total Body Weight (kg) Among Subjects With Baseline Body Mass Index (BMI) ≥ 27 kg/m^2 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 among subjects with baseline body mass index (BMI) ≥ 27 kg/m\^2 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
Argentina, Canada, India, Mexico, Peru, Philippines, Puerto Rico, Taiwan, United States
Participant flow
Recruitment details
Of 972 participants enrolled, 558 completed a qualification period. Before entering lead-in period, 344 participants entered dose optimization period and 263 completed. A total of 480 participants entered the lead-in period, 420 randomized and received treatment, 367 completed double-blind treatment period.
Participants by arm
| Arm | Count |
|---|---|
| PLACEBO + Pioglitazone Placebo tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks | 139 |
| Dapagliflozin 5MG + Pioglitazone Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks | 141 |
| Dapagliflozin 10MG + Pioglitazone Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks | 140 |
| Total | 420 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 | 3 |
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 3 | 0 | 1 |
| Overall Study | Lost to Follow-up | 4 | 2 | 4 |
| Overall Study | Non-compliance, not met criteria etc. | 3 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 9 | 8 | 6 |
Baseline characteristics
| Characteristic | PLACEBO + Pioglitazone | Dapagliflozin 5MG + Pioglitazone | Dapagliflozin 10MG + Pioglitazone | Total |
|---|---|---|---|---|
| Age, Continuous | 53.5 Years STANDARD_DEVIATION 11.38 | 53.2 Years STANDARD_DEVIATION 10.9 | 53.8 Years STANDARD_DEVIATION 10.35 | 53.5 Years STANDARD_DEVIATION 10.86 |
| Age, Customized 65 to younger than 75 years | 21 Participants | 16 Participants | 20 Participants | 57 Participants |
| Age, Customized 75 years and older | 3 Participants | 5 Participants | 2 Participants | 10 Participants |
| Age, Customized Yonger than 65 years | 115 Participants | 120 Participants | 118 Participants | 353 Participants |
| Gender Female | 68 Participants | 63 Participants | 81 Participants | 212 Participants |
| Gender Male | 71 Participants | 78 Participants | 59 Participants | 208 Participants |
| Race/Ethnicity, Customized Asian | 24 Participants | 26 Participants | 21 Participants | 71 Participants |
| Race/Ethnicity, Customized Black/African American | 6 Participants | 9 Participants | 7 Participants | 22 Participants |
| Race/Ethnicity, Customized Other | 7 Participants | 4 Participants | 11 Participants | 22 Participants |
| Race/Ethnicity, Customized White | 102 Participants | 102 Participants | 101 Participants | 305 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 | 37 / 139 | 34 / 141 | 45 / 140 |
| serious Total, serious adverse events | 1 / 139 | 4 / 141 | 2 / 140 |
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 + Pioglitazone | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | -0.42 % of hemoglobin | Standard Error 0.0834 |
| Dapagliflozin 5MG + Pioglitazone | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | -0.82 % of hemoglobin | Standard Error 0.0828 |
| Dapagliflozin 10MG + Pioglitazone | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | -0.97 % of hemoglobin | Standard Error 0.0828 |
p-value: 0.000795% CI: [-0.63, -0.17]ANCOVA
p-value: <0.000195% CI: [-0.78, -0.31]ANCOVA
Secondary
Adjusted Mean Change From Baseline in 120-minute Post-challenge Plasma Glucose (PPG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF])
Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. In post oral glucose tolerance test (OGTT), 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. PPG 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 HbA1c values at baseline and Week 24 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO + Pioglitazone | Adjusted Mean Change From Baseline in 120-minute Post-challenge Plasma Glucose (PPG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF]) | -14.1 mg/dL | Standard Error 6.421 |
| Dapagliflozin 5MG + Pioglitazone | Adjusted Mean Change From Baseline in 120-minute Post-challenge Plasma Glucose (PPG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF]) | -65.1 mg/dL | Standard Error 6.325 |
| Dapagliflozin 10MG + Pioglitazone | Adjusted Mean Change From Baseline in 120-minute Post-challenge Plasma Glucose (PPG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF]) | -67.5 mg/dL | Standard Error 6.359 |
p-value: <0.000195% CI: [-68.7, -33.2]ANCOVA
p-value: <0.000195% CI: [-71.1, -35.6]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 + Pioglitazone | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | -5.5 mg/dL | Standard Error 2.893 |
| Dapagliflozin 5MG + Pioglitazone | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | -24.9 mg/dL | Standard Error 2.884 |
| Dapagliflozin 10MG + Pioglitazone | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | -29.6 mg/dL | Standard Error 2.88 |
p-value: <0.000195% CI: [-27.5, -11.4]ANCOVA
p-value: <0.000195% CI: [-32.2, -16.1]ANCOVA
Secondary
Adjusted Mean Change From Baseline in Total Body Weight (kg) Among Subjects With Baseline Body Mass Index (BMI) ≥ 27 kg/m^2 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 among subjects with baseline body mass index (BMI) ≥ 27 kg/m\^2 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) among subjects with baseline body mass index (BMI) ≥ 27 kg/m\^2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO + Pioglitazone | Adjusted Mean Change From Baseline in Total Body Weight (kg) Among Subjects With Baseline Body Mass Index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF]) | 1.83 kg | Standard Error 0.3313 |
| Dapagliflozin 5MG + Pioglitazone | Adjusted Mean Change From Baseline in Total Body Weight (kg) Among Subjects With Baseline Body Mass Index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF]) | 0.26 kg | Standard Error 0.3523 |
| Dapagliflozin 10MG + Pioglitazone | Adjusted Mean Change From Baseline in Total Body Weight (kg) Among Subjects With Baseline Body Mass Index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF]) | -0.07 kg | Standard Error 0.3332 |
95% CI: [-2.53, -0.62]ANCOVA
p-value: <0.000195% CI: [-2.83, -0.98]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 + Pioglitazone | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | 1.64 kg | Standard Error 0.276 |
| Dapagliflozin 5MG + Pioglitazone | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | 0.09 kg | Standard Error 0.2752 |
| Dapagliflozin 10MG + Pioglitazone | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | -0.14 kg | Standard Error 0.2753 |
p-value: <0.000195% CI: [-2.32, -0.79]ANCOVA
p-value: <0.000195% CI: [-2.55, -1.02]ANCOVA
Secondary
Adjusted Mean Change From Baseline in Waist Circumference (cm) 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 waist circumference 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. Waist circumference measurements were obtained during the qualification and lead-in periods and on Day 1 and Week 24 of the double-blind period.
Time frame: From Baseline to Week 24
Population: All randomized participants who received study medication and had nonmissing waist circumference values at baseline and Week 24 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO + Pioglitazone | Adjusted Mean Change From Baseline in Waist Circumference (cm) at Week 24 (Last Observation Carried Forward [LOCF]) | 1.38 cm | Standard Error 0.4301 |
| Dapagliflozin 5MG + Pioglitazone | Adjusted Mean Change From Baseline in Waist Circumference (cm) at Week 24 (Last Observation Carried Forward [LOCF]) | 0.52 cm | Standard Error 0.4198 |
| Dapagliflozin 10MG + Pioglitazone | Adjusted Mean Change From Baseline in Waist Circumference (cm) at Week 24 (Last Observation Carried Forward [LOCF]) | -0.17 cm | Standard Error 0.4182 |
p-value: 0.156695% CI: [-2.03, 0.33]ANCOVA
p-value: 0.010195% CI: [-2.73, -0.37]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 + Pioglitazone | Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 22.4 Percentage of participants | Standard Error 3.276 |
| Dapagliflozin 5MG + Pioglitazone | Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 32.5 Percentage of participants | Standard Error 3.669 |
| Dapagliflozin 10MG + Pioglitazone | Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 38.8 Percentage of participants | Standard Error 3.835 |
p-value: 0.049695% CI: [0, 20.1]Modified logistic regression
p-value: 0.001895% CI: [6.1, 26.7]Modified logistic regression