Type 2 Diabetes
Conditions
Brief summary
The purpose of this clinical research study is to learn if initiating treatment with BMS-51248 (Dapagliflozin) in combination with metformin XR can improve diabetes control in patients with Type 2 Diabetes who do not receive any pharmacological treatment for diabetes, when compared to initial treatment with monotherapy dapagliflozin or metformin XR. The safety of this treatment will also be studied
Interventions
DRUGDapagliflozin
Tablets, Oral, Once daily, 24 weeks
DRUGMetformin XR
Tablets, Oral, Once daily, 24 weeks
Sponsors
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 77 Years
Healthy volunteers
No
Inclusion criteria
* Males & females, 18-77 years old inclusive, with type 2 diabetes and with inadequate glycemic control * Drug naive or treated with anti-diabetic medication for \< 24 weeks since original diagnosis * C-peptide ≥ 1.0 ng/mL * Body Mass Index ≤ 45.0 kg/m * Serum creatinine \< 1.50 mg/dL for men or \< 1.40 mg/dL for women
Exclusion criteria
* AST and/or ALT \>3.0 times the upper limit of normal (ULN) * Serum total bilirubin \> 2.0 mg/dL * Creatine kinase \> 3X the upper limit of normal (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, 3, 4, 6, 8, 12, 16, 20, and 24 in 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 estimated by modified logistic regression model. |
| Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) in Subjects With Baseline HbA1c ≥ 9% 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. |
| 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, 3, 4, 6, 8, 12, 16, 20, and 24 of the double-blind period. |
| Adjusted Mean Change From Baseline in Total Body Weight (kg) in 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 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, 3, 4, 6, 8, 12, 16, 20, and 24 of the double-blind period. |
Countries
Mexico, Philippines, Puerto Rico, Russia, South Korea, Ukraine, United States
Participant flow
Recruitment details
Of 994 participants enrolled, 632 completed a qualification period. Of these 632 participants, 603 were randomized. Of these 603 randomized, 598 received at least one dose of study medication treatment. Of these 598 randomized, 518 completed double-blind treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin 5 mg + Metformin XR Dapagliflozin tablets, oral, once daily for 24 weeks plus metfomin XR tablets (up to 2000mg), oral, once daily for 24 weeks | 194 |
| Dapagliflozin 5 mg Dapagliflozin tablets, oral, once daily for 24 weeks | 203 |
| Metformin XR Metfomin XR tablets (500mg up to 2000mg), oral, once daily for 24 weeks | 201 |
| Total | 598 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 6 | 6 |
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 4 | 6 | 9 |
| Overall Study | Non-compl., not met criteria, etc. | 3 | 4 | 6 |
| Overall Study | Withdrawal by Subject | 8 | 15 | 9 |
Baseline characteristics
| Characteristic | Dapagliflozin 5 mg + Metformin XR | Dapagliflozin 5 mg | Metformin XR | Total |
|---|---|---|---|---|
| Age, Continuous | 51.7 Years STANDARD_DEVIATION 9.31 | 52.3 Years STANDARD_DEVIATION 10.2 | 51.8 Years STANDARD_DEVIATION 9.8 | 52.0 Years STANDARD_DEVIATION 9.77 |
| Age, Customized 65 to younger than 75 years | 17 Participants | 17 Participants | 16 Participants | 50 Participants |
| Age, Customized 75 years and older | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Age, Customized Younger than 65 years | 177 Participants | 183 Participants | 184 Participants | 544 Participants |
| Race/Ethnicity, Customized Asian | 32 Participants | 33 Participants | 35 Participants | 100 Participants |
| Race/Ethnicity, Customized Black/African American | 8 Participants | 4 Participants | 6 Participants | 18 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 153 Participants | 166 Participants | 158 Participants | 477 Participants |
| Sex/Gender, Customized Female | 116 Participants | 111 Participants | 106 Participants | 333 Participants |
| Sex/Gender, Customized Male | 78 Participants | 92 Participants | 95 Participants | 265 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 | 48 / 194 | 32 / 203 | 40 / 201 |
| serious Total, serious adverse events | 6 / 194 | 9 / 203 | 7 / 201 |
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 values at baseline and Week 24 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 5 mg + Metformin XR | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | -2.05 % of hemoglobin | Standard Error 0.0892 |
| Dapagliflozin 5 mg | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | -1.19 % of hemoglobin | Standard Error 0.0866 |
| Metformin XR | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) | -1.35 % of hemoglobin | Standard Error 0.0868 |
p-value: <0.000195% CI: [-1.11, -0.62]ANCOVA
p-value: <0.000195% CI: [-0.94, -0.45]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, 3, 4, 6, 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 |
|---|---|---|---|
| Dapagliflozin 5 mg + Metformin XR | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | -61.0 mg/dL | Standard Error 2.783 |
| Dapagliflozin 5 mg | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | -42.0 mg/dL | Standard Error 2.708 |
| Metformin XR | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | -33.6 mg/dL | Standard Error 2.728 |
p-value: <0.000195% CI: [-26.7, -11.4]ANCOVA
p-value: <0.000195% CI: [-35.1, -19.8]ANCOVA
Secondary
Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) in Subjects With Baseline HbA1c ≥ 9% 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 values at baseline and Week 24 (LOCF) in subjects with baseline HbA1c ≥ 9%
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 5 mg + Metformin XR | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) in Subjects With Baseline HbA1c ≥ 9% at Week 24 (Last Observation Carried Forward [LOCF]) | -3.01 % of hemoglobin | Standard Error 0.1381 |
| Dapagliflozin 5 mg | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) in Subjects With Baseline HbA1c ≥ 9% at Week 24 (Last Observation Carried Forward [LOCF]) | -1.67 % of hemoglobin | Standard Error 0.1361 |
| Metformin XR | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) in Subjects With Baseline HbA1c ≥ 9% at Week 24 (Last Observation Carried Forward [LOCF]) | -1.82 % of hemoglobin | Standard Error 0.132 |
p-value: <0.000195% CI: [-1.72, -0.96]ANCOVA
p-value: <0.000195% CI: [-1.57, -0.82]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, 3, 4, 6, 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 values at baseline and Week 24 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 5 mg + Metformin XR | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | -2.66 kg | Standard Error 0.2428 |
| Dapagliflozin 5 mg | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | -2.61 kg | Standard Error 0.2361 |
| Metformin XR | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | -1.29 kg | Standard Error 0.2378 |
p-value: 0.876995% CI: [-0.72, 0.61]ANCOVA
p-value: <0.000195% CI: [-2.04, -0.71]ANCOVA
Secondary
Adjusted Mean Change From Baseline in Total Body Weight (kg) in 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 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, 3, 4, 6, 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 values at baseline and Week 24 (LOCF) in subjects with BMI ≥ 27 kg/m2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 5 mg + Metformin XR | Adjusted Mean Change From Baseline in Total Body Weight (kg) in Subjects With Baseline Body Mass Index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF]) | -3.04 kg | Standard Error 0.3031 |
| Dapagliflozin 5 mg | Adjusted Mean Change From Baseline in Total Body Weight (kg) in Subjects With Baseline Body Mass Index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF]) | -2.88 kg | Standard Error 0.289 |
| Metformin XR | Adjusted Mean Change From Baseline in Total Body Weight (kg) in Subjects With Baseline Body Mass Index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF]) | -1.47 kg | Standard Error 0.2907 |
95% CI: [-0.98, 0.66]ANCOVA
95% CI: [-2.4, -0.74]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 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 |
|---|---|---|---|
| Dapagliflozin 5 mg + Metformin XR | Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 52.4 Percentage of participants | Standard Error 3.581 |
| Dapagliflozin 5 mg | Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 22.5 Percentage of participants | Standard Error 2.741 |
| Metformin XR | Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) | 34.6 Percentage of participants | Standard Error 3.296 |
p-value: <0.000195% CI: [20.8, 39]modified logistic regression
p-value: 0.000395% CI: [8.1, 27.4]ANCOVA