Diabetes Mellitus, Type 2
Conditions
Brief summary
The purpose of this study is to determine whether dapagliflozin is effective in the treatment of type 2 diabetes in subjects with poor blood sugar control and moderate renal impairment
Detailed description
All eligible subjects will receive a single-blind placebo medication during a 1-week lead-in period prior to randomization. All arms may include the addition of open label medication described (as needed for rescue based on protocol specific criteria). Rescue medication is defined as the addition of an approved, appropriate antihyperglycemic agent, except metformin, used according to conventional standards of care, to treat hyperglycemia, which may therefore allow the subject to remain in the trial
Interventions
DRUGDapagliflozin
Tablets, Oral, 10 mg, Once Daily, 104 weeks
DRUGPlacebo
Tablets, Oral, 0 mg, Once Daily, 104 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 No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females, ≥18 years old, with type 2 diabetes and with inadequate glycemic control * Clinical diagnosis of moderate renal impairment
Exclusion criteria
* AST and /or ALT \> 3.0 times the upper limit of normal * Serum total bilirubin \> 1.5 times ULN * Symptoms of severely uncontrolled diabetes * Currently unstable or serious cardiovascular, 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, 6, 8, 10, 12, 14, 16, 18, 20, 22, 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, 6, 8, 10, 12, 14, 16, 18, 20, 22, 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, 4, 8, 12, 16, 20, and 24 of the double-blind period. |
Countries
Argentina, Australia, Canada, Denmark, France, India, Italy, Mexico, Peru, Puerto Rico, Singapore, Spain, United States
Participant flow
Recruitment details
Of 631 participants enrolled, 276 completed a qualification period. Of these 276 participants, 252 were randomized and received treatment. Of these 252 participants, 204 completed double-blind treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received dapagliflozin matching placebo once daily for up to 24 weeks (Subjects were to continue their original pre-enrollment anti-diabetic therapy; may include the addition of open-label anti-diabetic therapy as rescue) | 84 |
| Dapagliflozin 5 mg Participants received dapagliflozin 5 mg once daily for up to 24 weeks (Subjects were to continue their original pre-enrollment anti-diabetic therapy; may include the addition of open-label metformin as rescue) | 83 |
| Dapagliflozin 10 mg Participants received dapagliflozin 10 mg once daily for up to 24 weeks (Subjects were to continue their original pre-enrollment anti-diabetic therapy; may include the addition of open-label metformin as rescue) | 85 |
| Total | 252 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 12 | 7 | 6 |
| Overall Study | Death | 1 | 0 | 1 |
| Overall Study | Lack of Efficacy | 2 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | non-compliance, not met criteria, etc. | 3 | 2 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 6 |
Baseline characteristics
| Characteristic | Placebo | Dapagliflozin 5 mg | Dapagliflozin 10 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 67 Years STANDARD_DEVIATION 8.6 | 66 Years STANDARD_DEVIATION 8.9 | 68 Years STANDARD_DEVIATION 7.7 | 67 Years STANDARD_DEVIATION 8.4 |
| Age, Customized 65 years and older | 48 Participants | 44 Participants | 56 Participants | 148 Participants |
| Age, Customized Younger than 65 years | 36 Participants | 39 Participants | 29 Participants | 104 Participants |
| Pre-Enrollment Anti-Hyperglycemic Therapy INSULIN-BASED REGIMEN | 55 Participants | 54 Participants | 55 Participants | 164 Participants |
| Pre-Enrollment Anti-Hyperglycemic Therapy OTHER REGIMEN | 7 Participants | 7 Participants | 7 Participants | 21 Participants |
| Pre-Enrollment Anti-Hyperglycemic Therapy SULFONYLUREA-BASED REGIMEN | 21 Participants | 21 Participants | 21 Participants | 63 Participants |
| Pre-Enrollment Anti-Hyperglycemic Therapy THIAZOLIINEDIONE-BASED REGIMEN | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized ASIAN | 6 Participants | 4 Participants | 3 Participants | 13 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 1 Participants | 7 Participants | 4 Participants | 12 Participants |
| Race/Ethnicity, Customized OTHER | 8 Participants | 7 Participants | 1 Participants | 16 Participants |
| Race/Ethnicity, Customized WHITE | 69 Participants | 65 Participants | 77 Participants | 211 Participants |
| Sex/Gender, Customized Female | 31 Participants | 28 Participants | 29 Participants | 88 Participants |
| Sex/Gender, Customized Male | 53 Participants | 55 Participants | 56 Participants | 164 Participants |
| Weight | 89.61 kg STANDARD_DEVIATION 20.046 | 95.23 kg STANDARD_DEVIATION 20.909 | 93.25 kg STANDARD_DEVIATION 17.309 | 92.69 kg STANDARD_DEVIATION 19.529 |
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 | 39 / 84 | 45 / 83 | 42 / 85 |
| serious Total, serious adverse events | 9 / 84 | 7 / 83 | 12 / 85 |
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, 6, 8, 10, 12, 14, 16, 18, 20, 22, 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] | -0.32 % of hemoglobin | Standard Error 0.1701 |
| Dapagliflozin 5 mg | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF] | -0.41 % of hemoglobin | Standard Error 0.1701 |
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF] | -0.44 % of hemoglobin | Standard Error 0.1708 |
p-value: 0.56195% CI: [-0.37, 0.2]ANCOVA
p-value: 0.43595% CI: [-0.4, 0.17]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, 6, 8, 10, 12, 14, 16, 18, 20, 22, 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]) | 8.4 mg/dL | Standard Error 9.621 |
| Dapagliflozin 5 mg | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | -5.2 mg/dL | Standard Error 9.548 |
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) | -0.6 mg/dL | Standard Error 9.524 |
95% CI: [-29.7, 2.4]ANCOVA
95% CI: [-25, 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 | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | 0.27 kg | Standard Error 0.4872 |
| Dapagliflozin 5 mg | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | -1.54 kg | Standard Error 0.4815 |
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) | -1.89 kg | Standard Error 0.4693 |
95% CI: [-2.68, -0.94]ANCOVA
95% CI: [-3.03, -1.29]ANCOVA