Type 2 Diabetes Mellitus, CKD and Albuminuria
Conditions
Brief summary
The purpose of this clinical research study is to determine whether dapagliflozin alone or in combination with saxagliptin can decrease albuminuria and improve glycemic control in patients with Type 2 diabetes, albuminuria and renal impairment (CKD). The study is planned to randomize a total of 450 patients (150 patients per treatment arm)
Interventions
DRUGDapagliflozin 10 mg
Tablets administered orally once daily for 24 weeks.
DRUGSaxagliptin 2.5 mg
Tablets administered orally once daily for 24 weeks.
DRUGMatching Placebo for Dapagliflozin 10 mg and Saxagliptin 2.5mg
Tablets administered orally once daily for 24 weeks.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Provision of informed consent prior to any study specific procedures * Female or male aged ≥18 years * History of type 2 diabetes mellitus for more than 12 months * HbA1c≥7.0% and ≤11.0% * Stable antidiabetic treatment during the last 12 weeks up to randomization * eGFR 25-75 mL/minute/1.73m2, inclusive * Micro or macroalbuminuria (UACR 30 - 3500 mg/g) * Treatment with ACE inhibitor or an ARB for at least 3 months prior to screening * Body mass index between 20 and 45 kg/m2
Exclusion criteria
* Any of the following CV/Vascular Diseases within 3 month prior to signing the consent at Visit 1: * Myocardial infarction * cardiac surgery or revascularization (CABG/PTCA) * unstable angina * unstable HF * New York Heart Association (NYHA) Class III-IV * transient ischemic attack (TIA) or significant cerebrovascular disease * unstable or previously undiagnosed arrhythmia * Significant hepatic disease, including, but not limited to, chronic active hepatitis and/or severe hepatic insufficiency * Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) \> 3X ULN * Total Bilirubin (TB) \>2 mg/dL (34.2 μmol/L) * History of acute kidney injury requiring renal replacement therapy (dialysis or ultrafiltration) or any biopsy or imaging verifying intercurrent kidney disease other than diabetic nephropathy or diabetic nephropathy with nephrosclerosis * Ongoing treatment with a SGLT2 inhibitor, GLP-1 agonist or DPP4 inhibitors * Any condition which, in the judgment of the Investigator, may render the patient unable to complete the study or which may pose a significant risk to the patient or patient suspected or with confirmed poor protocol or medication compliance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in Glycosylated Haemoglobin (HbA1c): Comparison of Dapagliflozin 10 mg Plus Saxagliptin 2.5 mg and Placebo at Week 24 | Baseline and Week 24 | HbA1c was analysed at baseline and every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a mixed model repeated measures (MMRM) model. |
| Adjusted Mean Percent Change From Baseline in Urine Albumin-to-Creatinine Ratio (UACR) at Week 24 | Baseline and Week 24 | UACR was analysed at baseline and every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. UACR values were first transformed to logarithms and the results were based on exponentiation of model estimates and expressed as adjusted mean percent change from baseline at Week 24. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving at Least 30% Reduction in UACR at Week 24 | From baseline up to Week 24 | The percentage of patients meeting the criteria of at least a 30% reduction in UACR, was analysed using a logistic regression model. If no measurement was available at Week 24 the last available post-baseline measurement was carried forward (Last Observation Carried Forward \[LOCF\]). |
| Percentage of Patients Achieving a Reduction in HbA1c of Less Than 7.0% at Week 24 | From baseline to Week 24 | The percentage of patients meeting the criteria of a less than 7% reduction in HbA1c, was analysed using a logistic regression model. If no measurement was available at Week 24 the last available post-baseline measurement was carried forward (LOCF). Only measurements prior to rescue or treatment discontinuation were analysed. |
| Adjusted Mean Percent Change From Baseline in Total Body Weight at Week 24 | Baseline and Week 24 | Total body weight was measured in kilograms (kg) at baseline and at Week 1 then every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. Total body weight values were first transformed to logarithms and the results were based on exponentiation of model estimates and expressed as adjusted mean percent change from baseline at Week 24. |
| Adjusted Mean Change From Baseline in HbA1c: Comparison of Dapagliflozin 10 mg and Placebo at Week 24 | Baseline and Week 24 | HbA1c was analysed at baseline and every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a MMRM model. |
| Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (SBP) at Week 24 | Baseline and Week 24 | Seated SBP was analysed at baseline, Week 1 and every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a MMRM model. |
| Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Baseline and Week 24 | FPG was analysed at baseline and Week 1 then every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a MMRM model. |
Countries
Australia, Canada, Japan, Mexico, South Africa, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus with micro- or macro-albuminuria and treated with ACEi or ARB were enrolled into an international, multi-centre study from 21 Sep 2015. The last patient's last visit was 18 May 2018.
Pre-assignment details
Enrolled patients were screened during a 4-week single-blind placebo lead-in period. Patients who met all of the inclusion and none of the exclusion criteria in this period were eligible to be randomised into the 24-week double-blind placebo-controlled treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin 10 mg + Saxagliptin 2.5 mg Dapagliflozin 10 mg and saxagliptin 2.5 mg tablets were taken orally, once daily (in the morning) for 24 weeks. | 155 |
| Dapagliflozin 10 mg Dapagliflozin 10 mg tablets were taken orally, once daily (in the morning) for 24 weeks. Patients also took placebo tablets to match saxagliptin. | 145 |
| Placebo Placebo tablets to match both active products (dapagliflozin and saxagliptin) were taken orally, once daily (in the morning) for 24 weeks. | 148 |
| Total | 448 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 2 | 1 |
| Overall Study | Other | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Screen Failure | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 4 |
Baseline characteristics
| Characteristic | Dapagliflozin 10 mg + Saxagliptin 2.5 mg | Dapagliflozin 10 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 64.0 years STANDARD_DEVIATION 9.21 | 64.7 years STANDARD_DEVIATION 8.61 | 64.7 years STANDARD_DEVIATION 8.53 | 64.4 years STANDARD_DEVIATION 8.78 |
| Age, Customized <65 years | 78 Participants | 64 Participants | 68 Participants | 210 Participants |
| Age, Customized >=65 years | 77 Participants | 81 Participants | 80 Participants | 238 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 42 Participants | 32 Participants | 38 Participants | 112 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 113 Participants | 113 Participants | 110 Participants | 336 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 57 Participants | 67 Participants | 53 Participants | 177 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants | 7 Participants | 11 Participants | 26 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 13 Participants | 18 Participants | 43 Participants |
| Race/Ethnicity, Customized White | 77 Participants | 55 Participants | 64 Participants | 196 Participants |
| Sex: Female, Male Female | 45 Participants | 43 Participants | 43 Participants | 131 Participants |
| Sex: Female, Male Male | 110 Participants | 102 Participants | 105 Participants | 317 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 152 | 1 / 145 | 0 / 148 |
| other Total, other adverse events | 12 / 152 | 18 / 145 | 8 / 148 |
| serious Total, serious adverse events | 12 / 152 | 12 / 145 | 16 / 148 |
Outcome results
Primary
Adjusted Mean Change From Baseline in Glycosylated Haemoglobin (HbA1c): Comparison of Dapagliflozin 10 mg Plus Saxagliptin 2.5 mg and Placebo at Week 24
HbA1c was analysed at baseline and every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a mixed model repeated measures (MMRM) model.
Time frame: Baseline and Week 24
Population: Patients from the Full Analysis Set (all randomised patients who took at least 1 dose of double-blind study drug and had a non missing baseline value and at least one post-baseline efficacy variable value) with non-missing baseline and Week 24 values for HbA1c.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 10 mg + Saxagliptin 2.5 mg | Adjusted Mean Change From Baseline in Glycosylated Haemoglobin (HbA1c): Comparison of Dapagliflozin 10 mg Plus Saxagliptin 2.5 mg and Placebo at Week 24 | -0.85 Percentage of Glycoslyated HbA1c | Standard Error 0.09 |
| Placebo | Adjusted Mean Change From Baseline in Glycosylated Haemoglobin (HbA1c): Comparison of Dapagliflozin 10 mg Plus Saxagliptin 2.5 mg and Placebo at Week 24 | -0.27 Percentage of Glycoslyated HbA1c | Standard Error 0.09 |
Comparison: A longitudinal repeated measures analysis included the fixed categorical effects of treatment, week, randomisation stratification factor (i.e. anti-diabetic treatment strata), and treatment-by-week interaction, as well as the continuous fixed covariates of baseline measurement and baseline measurement-by-week interaction.p-value: <0.00195% CI: [-0.8, -0.37]MMRM
Primary
Adjusted Mean Percent Change From Baseline in Urine Albumin-to-Creatinine Ratio (UACR) at Week 24
UACR was analysed at baseline and every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. UACR values were first transformed to logarithms and the results were based on exponentiation of model estimates and expressed as adjusted mean percent change from baseline at Week 24.
Time frame: Baseline and Week 24
Population: Patients from the Full Analysis Set with non-missing baseline and Week 24 values for UACR.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 10 mg + Saxagliptin 2.5 mg | Adjusted Mean Percent Change From Baseline in Urine Albumin-to-Creatinine Ratio (UACR) at Week 24 | -39.1 Percent change | Standard Error 5.1 |
| Placebo | Adjusted Mean Percent Change From Baseline in Urine Albumin-to-Creatinine Ratio (UACR) at Week 24 | -22.4 Percent change | Standard Error 6.6 |
| Placebo | Adjusted Mean Percent Change From Baseline in Urine Albumin-to-Creatinine Ratio (UACR) at Week 24 | -1.8 Percent change | Standard Error 8.3 |
Comparison: A longitudinal repeated measures model of the logarithms of the post-baseline to baseline ratios included the fixed categorical effects of treatment, week, treatment-by-week interaction, and randomisation stratification factor (i.e. anti-diabetic treatment strata), as well as the continuous fixed covariates of log-baseline UACR value and log-baseline UACR value-by-week interaction.p-value: <0.00195% CI: [-48.2, -25.8]MMRM
Comparison: A longitudinal repeated measures model of the logarithms of the post-baseline to baseline ratios included the fixed categorical effects of treatment, week, treatment-by-week interaction, and randomisation stratification factor (i.e. anti-diabetic treatment strata), as well as the continuous fixed covariates of log-baseline UACR value and log-baseline UACR value-by-week interaction.p-value: 0.01195% CI: [-34.1, -5.2]MMRM
Secondary
Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
FPG was analysed at baseline and Week 1 then every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a MMRM model.
Time frame: Baseline and Week 24
Population: Patients from the Full Analysis Set with non-missing baseline and Week 24 values for FPG.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 10 mg + Saxagliptin 2.5 mg | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -17.2 mg/decilitre (dL) | Standard Error 5.2 |
| Placebo | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -13.1 mg/decilitre (dL) | Standard Error 5.4 |
| Placebo | Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -11.2 mg/decilitre (dL) | Standard Error 5.5 |
Comparison: A longitudinal repeated measures analysis included the fixed categorical effects of treatment, week, randomisation stratification factor (i.e.anti-diabetic treatment strata), and treatment-by-week interaction, as well as the continuous fixed covariates of baseline measurement and baseline measurement-by-week interaction.p-value: 0.29895% CI: [-17.5, 5.4]MMRM
Comparison: A longitudinal repeated measures analysis included the fixed categorical effects of treatment, week, randomisation stratification factor (i.e.anti-diabetic treatment strata), and treatment-by-week interaction, as well as the continuous fixed covariates of baseline measurement and baseline measurement-by-week interaction.p-value: 0.74695% CI: [-13.6, 9.8]MMRM
Secondary
Adjusted Mean Change From Baseline in HbA1c: Comparison of Dapagliflozin 10 mg and Placebo at Week 24
HbA1c was analysed at baseline and every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a MMRM model.
Time frame: Baseline and Week 24
Population: Patients from the Full Analysis Set with non-missing baseline and Week 24 values for HbA1c.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 10 mg + Saxagliptin 2.5 mg | Adjusted Mean Change From Baseline in HbA1c: Comparison of Dapagliflozin 10 mg and Placebo at Week 24 | -0.43 Percentage of Glycoslyated HbA1c | Standard Error 0.09 |
| Placebo | Adjusted Mean Change From Baseline in HbA1c: Comparison of Dapagliflozin 10 mg and Placebo at Week 24 | -0.27 Percentage of Glycoslyated HbA1c | Standard Error 0.09 |
Comparison: A longitudinal repeated measures analysis included the fixed categorical effects of treatment, week, randomisation stratification factor (i.e. anti-diabetic treatment strata), and treatment-by-week interaction, as well as the continuous fixed covariates of baseline measurement and baseline measurement-by-week interaction.p-value: 0.14295% CI: [-0.38, 0.05]MMRM
Secondary
Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (SBP) at Week 24
Seated SBP was analysed at baseline, Week 1 and every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a MMRM model.
Time frame: Baseline and Week 24
Population: Patients from the Full Analysis Set with non-missing baseline and Week 24 values for SBP.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 10 mg + Saxagliptin 2.5 mg | Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (SBP) at Week 24 | -8.8 Millimetre of mercury (mmHg) | Standard Error 1.6 |
| Placebo | Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (SBP) at Week 24 | -6.9 Millimetre of mercury (mmHg) | Standard Error 1.7 |
| Placebo | Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (SBP) at Week 24 | -4.1 Millimetre of mercury (mmHg) | Standard Error 1.7 |
Comparison: A longitudinal repeated measures model of the logarithms of the post-baseline to baseline ratios, included the fixed categorical effects of treatment, week, treatment-by-week interaction, and randomisation strata, as well as the continuous fixed covariates of log-baseline SBP value and log-baseline SBP value-by-week interaction.p-value: 0.00995% CI: [-8.3, -1.2]MMRM
Comparison: A longitudinal repeated measures model of the logarithms of the post-baseline to baseline ratios, included the fixed categorical effects of treatment, week, treatment-by-week interaction, and randomisation strata, as well as the continuous fixed covariates of log-baseline SBP value and log-baseline SBP value-by-week interaction.p-value: 0.12295% CI: [-6.4, 0.8]MMRM
Secondary
Adjusted Mean Percent Change From Baseline in Total Body Weight at Week 24
Total body weight was measured in kilograms (kg) at baseline and at Week 1 then every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. Total body weight values were first transformed to logarithms and the results were based on exponentiation of model estimates and expressed as adjusted mean percent change from baseline at Week 24.
Time frame: Baseline and Week 24
Population: Patients from the Full Analysis Set with non-missing baseline and Week 24 values for total body weight.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 10 mg + Saxagliptin 2.5 mg | Adjusted Mean Percent Change From Baseline in Total Body Weight at Week 24 | -0.65 Percent change | Standard Error 0.55 |
| Placebo | Adjusted Mean Percent Change From Baseline in Total Body Weight at Week 24 | -1.48 Percent change | Standard Error 0.56 |
| Placebo | Adjusted Mean Percent Change From Baseline in Total Body Weight at Week 24 | -0.61 Percent change | Standard Error 0.56 |
Comparison: A longitudinal repeated measures model of the logarithms of the post-baseline to baseline ratios included the fixed categorical effects of treatment, week, treatment-by-week interaction, and randomisation stratification factor (i.e. anti-diabetic treatment strata), as well as the continuous fixed covariates of log-baseline total body weight value and log-baseline total body weight value-by-week interaction.p-value: 0.95395% CI: [-1.32, 1.26]MMRM
Comparison: A longitudinal repeated measures model of the logarithms of the post-baseline to baseline ratios included the fixed categorical effects of treatment, week, treatment-by-week interaction, and randomisation stratification factor (i.e. anti-diabetic treatment strata), as well as the continuous fixed covariates of log-baseline total body weight value and log-baseline total body weight value-by-week interaction.p-value: 0.19395% CI: [-2.17, 0.44]MMRM
Secondary
Percentage of Patients Achieving a Reduction in HbA1c of Less Than 7.0% at Week 24
The percentage of patients meeting the criteria of a less than 7% reduction in HbA1c, was analysed using a logistic regression model. If no measurement was available at Week 24 the last available post-baseline measurement was carried forward (LOCF). Only measurements prior to rescue or treatment discontinuation were analysed.
Time frame: From baseline to Week 24
Population: Patients from the Full Analysis Set with non-missing baseline and at least one post-baseline HbA1c value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapagliflozin 10 mg + Saxagliptin 2.5 mg | Percentage of Patients Achieving a Reduction in HbA1c of Less Than 7.0% at Week 24 | 35.1 Percentage of patients |
| Placebo | Percentage of Patients Achieving a Reduction in HbA1c of Less Than 7.0% at Week 24 | 15.0 Percentage of patients |
| Placebo | Percentage of Patients Achieving a Reduction in HbA1c of Less Than 7.0% at Week 24 | 10.3 Percentage of patients |
Comparison: Logistic regression model analysis with adjustment for baseline HbA1c and pooled randomisation strata.p-value: <0.00195% CI: [2.6, 11.2]Regression, Logistic
Comparison: Logistic regression model analysis with adjustment for baseline HbA1c and pooled randomisation strata.p-value: 0.16795% CI: [0.8, 3.8]Regression, Logistic
Secondary
Percentage of Patients Achieving at Least 30% Reduction in UACR at Week 24
The percentage of patients meeting the criteria of at least a 30% reduction in UACR, was analysed using a logistic regression model. If no measurement was available at Week 24 the last available post-baseline measurement was carried forward (Last Observation Carried Forward \[LOCF\]).
Time frame: From baseline up to Week 24
Population: Patients from the Full Analysis Set with non-missing baseline and at least one post-baseline UACR value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapagliflozin 10 mg + Saxagliptin 2.5 mg | Percentage of Patients Achieving at Least 30% Reduction in UACR at Week 24 | 57.0 Percentage of patients |
| Placebo | Percentage of Patients Achieving at Least 30% Reduction in UACR at Week 24 | 45.0 Percentage of patients |
| Placebo | Percentage of Patients Achieving at Least 30% Reduction in UACR at Week 24 | 31.3 Percentage of patients |
Comparison: Logistic regression model analysis with adjustment for baseline UACR and pooled randomisation strata.p-value: <0.00195% CI: [1.8, 4.8]Regression, Logistic
Comparison: Logistic regression model analysis with adjustment for baseline UACR and pooled randomisation strata.p-value: 0.01395% CI: [1.1, 3]Regression, Logistic