Type 2 Diabetes Mellitus
Conditions
Brief summary
The purpose of this study is to evaluate the effects of dapagliflozin on kidney function, as assessed by glomerular filtration rate.
Interventions
DRUGDapagliflozin
Tablets, Oral, 10 mg, once daily, 12 weeks
DRUGPlacebo
Tablets, Oral, 0 mg, once daily, 12 weeks
DRUGHydrochlorothiazide
Tablets, Oral, 25 mg, once daily, 12 weeks
Sponsors
Astra Zeneca, Bristol-Myers Squibb
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes and inadequate glycemic control, defined as A1C ≥ 6.6 and ≤ 9.5% * Stable dose of metformin AND/OR a sulfonylurea, for at least 4 weeks prior to the enrollment visit * Inadequate blood pressure (BP) control, defined as systolic BP (SBP) ≥ 130 and \< 165 mmHg, AND/OR diastolic BP (DBP) ≥ 80 and \< 105 mmHg * C-peptide ≥ 0.8 ng/mL * Estimated GFR by the Modification of Diet in Renal Disease (MDRD) formula \> 60 mL/min/1.73m² and \< 150 mL/min/1.73m² * Urine albumin:creatinine ratio (UACR) \< 300 mg/g * BMI ≤ 45.0 kg/m2
Exclusion criteria
* Administration of diuretics or other medication approved for the treatment of hypertension (with the exception of either ACEI or ARB), at any dose during the 12 weeks prior to the enrollment visit * History of adverse reaction to radio-contrast dye * Allergy or contraindication to use of thiazide diuretics * Aspartate Aminotransferase (AST) \> 3X Upper limit of normal (ULN) * Alanine aminotransferase (ALT) \> 3X ULN * Serum Total Bilirubin \> 1.5X ULN * Serum Creatinine (Scr) ≥ 1.50 mg/dL (133 μmol/l) for men; SCr ≥ 1.40 mg/dL (124 μmol/l) for women * Currently unstable or serious cardiovascular, renal, hepatic, hematological, oncologic, endocrine, psychiatric, or rheumatic diseases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Percent Change From Baseline in Glomerular Filtration Rate (GFR) at Week 12 (Modified Last Observation Carried Forward [MLOCF]) | From Baseline to Week 12 | 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. If no Week 12 measurement was available, the last available post-baseline measurement obtained on or after Day 23 was used regardless of rescue medication. Measurements were obtained during radomization visit, and Week 12 in the double-blind period by a central laboratory. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) | From Baseline to Week 12 | 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. Measurements were obtained during lead-in, and Week 12 in the double-blind period. |
| Adjusted Mean Change From Baseline in Daytime (0900 to 2100 Hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) | From Baseline to Week 12 | 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. Measurements were obtained during lead-in, and Week 12 in the double-blind period. |
| Adjusted Mean Change From Baseline in Nighttime (0100 to 0600 Hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) | From Baseline to Week 12 | 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. Measurements were obtained during lead-in, and Week 12 in the double-blind period. |
Countries
Canada, Netherlands, United States
Participant flow
Recruitment details
Of 154 participants enrolled, 77 completed a qualification period. Of these 77 participants, 75 were randomized and received treatment. Of these 75 participants, 74 completed double-blind treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Tablet, oral, once daily for 12 weeks | 25 |
| Dapagliflozin 10 mg Tablet, oral, once daily for 12 weeks | 24 |
| Hydrochlorothiazide 25 mg Tablet, oral, once daily for 12 weeks | 26 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Dapagliflozin 10 mg | Hydrochlorothiazide 25 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 58.0 Years STANDARD_DEVIATION 9.5 | 53.7 Years STANDARD_DEVIATION 9.38 | 54.8 Years STANDARD_DEVIATION 9.87 | 55.5 Years STANDARD_DEVIATION 9.63 |
| Age, Customized 65 - 75 years | 6 Participants | 2 Participants | 5 Participants | 13 Participants |
| Age, Customized Younger than 65 years | 19 Participants | 22 Participants | 21 Participants | 62 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Black/African American | 4 Participants | 4 Participants | 4 Participants | 12 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 17 Participants | 19 Participants | 20 Participants | 56 Participants |
| Sex/Gender, Customized Female | 7 Participants | 8 Participants | 11 Participants | 26 Participants |
| Sex/Gender, Customized Male | 18 Participants | 16 Participants | 15 Participants | 49 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 | 2 / 25 | 6 / 24 | 9 / 26 |
| serious Total, serious adverse events | 0 / 25 | 3 / 24 | 0 / 26 |
Outcome results
Primary
Adjusted Percent Change From Baseline in Glomerular Filtration Rate (GFR) at Week 12 (Modified Last Observation Carried Forward [MLOCF])
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. If no Week 12 measurement was available, the last available post-baseline measurement obtained on or after Day 23 was used regardless of rescue medication. Measurements were obtained during radomization visit, and Week 12 in the double-blind period by a central laboratory.
Time frame: From Baseline to Week 12
Population: All randomized participants who received study medication and had nonmissing HbA1c values at baseline and Week 12 (MLOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Percent Change From Baseline in Glomerular Filtration Rate (GFR) at Week 12 (Modified Last Observation Carried Forward [MLOCF]) | -2.92 % Change of Baseline GFR | Standard Error 2.0133 |
| Dapagliflozin 10 mg | Adjusted Percent Change From Baseline in Glomerular Filtration Rate (GFR) at Week 12 (Modified Last Observation Carried Forward [MLOCF]) | -10.76 % Change of Baseline GFR | Standard Error 1.9684 |
| Hydrochlorothiazide 25 mg | Adjusted Percent Change From Baseline in Glomerular Filtration Rate (GFR) at Week 12 (Modified Last Observation Carried Forward [MLOCF]) | -3.40 % Change of Baseline GFR | Standard Error 1.9756 |
95% CI: [-13.34, -2.49]
95% CI: [-12.87, -2.06]
Secondary
Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF])
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. Measurements were obtained during lead-in, and Week 12 in the double-blind period.
Time frame: From Baseline to Week 12
Population: All randomized participants who received study medication and had nonmissing ASBP values at baseline and Week 12 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) | -0.88 mmHg | Standard Error 1.6373 |
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) | -3.28 mmHg | Standard Error 1.7674 |
| Hydrochlorothiazide 25 mg | Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) | -6.55 mmHg | Standard Error 1.6833 |
95% CI: [-7.11, 2.31]
95% CI: [-1.55, 8.08]
Secondary
Adjusted Mean Change From Baseline in Daytime (0900 to 2100 Hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF])
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. Measurements were obtained during lead-in, and Week 12 in the double-blind period.
Time frame: From Baseline to Week 12
Population: All randomized participants who received study medication and had nonmissing ASBP values at baseline and Week 12 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Change From Baseline in Daytime (0900 to 2100 Hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) | -1.55 mmHg | Standard Error 1.7247 |
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Daytime (0900 to 2100 Hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) | -5.93 mmHg | Standard Error 1.8673 |
| Hydrochlorothiazide 25 mg | Adjusted Mean Change From Baseline in Daytime (0900 to 2100 Hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) | -6.83 mmHg | Standard Error 1.7671 |
95% CI: [-9.38, 0.63]
95% CI: [-4.18, 5.99]
Secondary
Adjusted Mean Change From Baseline in Nighttime (0100 to 0600 Hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF])
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. Measurements were obtained during lead-in, and Week 12 in the double-blind period.
Time frame: From Baseline to Week 12
Population: All randomized participants who received study medication and had nonmissing ASBP values at baseline and Week 12 (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Change From Baseline in Nighttime (0100 to 0600 Hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) | -0.61 mmHg | Standard Error 1.9468 |
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Nighttime (0100 to 0600 Hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) | -0.45 mmHg | Standard Error 2.0822 |
| Hydrochlorothiazide 25 mg | Adjusted Mean Change From Baseline in Nighttime (0100 to 0600 Hours) Ambulatory Systolic Blood Pressure (ASBP) at Week 12 (Last Observation Carried Forward [LOCF]) | -7.76 mmHg | Standard Error 1.9857 |
95% CI: [-5.39, 5.71]
95% CI: [1.7, 12.93]