Chronic Kidney Disease
Conditions
Keywords
Chronic Kidney Disease (CKD), Cardiovascular Events (CV), Phase III outcome trial
Brief summary
The purpose of this study is to evaluate the effect of dapagliflozin on renal outcomes and cardiovascular mortality in patients with chronic kidney disease.
Detailed description
This is an international, multicentre, event-driven, randomized, double-blind, parallel group, placebo-controlled study, evaluating the effect of dapagliflozin versus placebo, given once daily in addition to standard of care, to prevent the progression of chronic kidney disease (CKD) or cardiovascular (CV)/renal death.
Interventions
DRUGDapagliflozin
10 mg or 5 mg tablets given once daily, per oral use.
DRUGPlacebo
Placebo matching dapagliflozin 10 mg or 5 mg
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Provision of signed informed consent prior to any study specific procedures * Female or male aged ≥18 years at the time of consent * eGFR ≥25 and ≤75 mL/min/1.73m2 (CKD-EPI Formula) at visit 1 * Evidence of increased albuminuria 3 months or more before visit 1 and UACR ≥200 and ≤5000 mg/g at visit 1 * Stable, and for the patient maximum tolerated labelled daily dose, treatment with ACE-I or ARB for at least 4 weeks before visit 1, if not medically contraindicated,
Exclusion criteria
* Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or ANCA-associated vasculitis * Receiving cytotoxic therapy, immunosuppressive therapy or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment * History of organ transplantation * Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrolment or previous intolerance of an SGLT2 inhibitor * Type 1 diabetes mellitus * New York Heart Association (NYHA) class IV Congestive Heart Failure at the time of enrolment * MI, unstable angina, stroke or transient ischemic attack within 12 weeks prior to enrolment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to the First Occurrence of Any of the Components of the Composite: ≥50% Sustained Decline in eGFR or Reaching ESRD or CV Death or Renal Death. | Up to 38.2 months | End Stage Renal Disease (ESRD) is defined as: * Sustained eGFR \<15 mL/min/1.73m2 or, * Chronic dialysis treatment or, * Receiving a renal transplant The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to the First Occurrence of Any of the Components of the Composite: ≥50% Sustained Decline in eGFR or Reaching ESRD or Renal Death. | Up to 38.2 months | End Stage Renal Disease (ESRD) is defined as: * Sustained eGFR \<15 mL/min/1.73m2 or, * Chronic dialysis treatment or, * Receiving a renal transplant The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table. |
| Time to the First Occurrence of Either of the Components of the Composite: CV Death or Hospitalization for Heart Failure. | Up to 38.2 months | The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table. |
| Time to Death From Any Cause. | Up to 38.2 months | The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table. |
Countries
Argentina, Brazil, Canada, China, Denmark, Germany, Hungary, India, Japan, Mexico, Peru, Philippines, Poland, Russia, South Korea, Spain, Sweden, Ukraine, United Kingdom, United States, Vietnam
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin Dapagliflozin 10 mg, given once daily per oral use | 2,152 |
| Placebo Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use | 2,152 |
| Total | 4,304 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Withdrawal by Subject | 8 | 3 |
Baseline characteristics
| Characteristic | Placebo | Dapagliflozin | Total |
|---|---|---|---|
| Age, Continuous | 61.9 Years STANDARD_DEVIATION 12.1 | 61.8 Years STANDARD_DEVIATION 12.1 | 61.8 Years STANDARD_DEVIATION 12.1 |
| Age, Customized <= 50 years | 370 Participants | 362 Participants | 732 Participants |
| Age, Customized > 50 years | 1782 Participants | 1790 Participants | 3572 Participants |
| Age, Customized <= 65 years | 1239 Participants | 1247 Participants | 2486 Participants |
| Age, Customized <=65 years | 1239 Participants | 1247 Participants | 2486 Participants |
| Age, Customized > 65 years | 913 Participants | 905 Participants | 1818 Participants |
| Age, Customized 66-75 years | 667 Participants | 663 Participants | 1330 Participants |
| Age, Customized > 75 years | 246 Participants | 242 Participants | 488 Participants |
| eGFR | 43.0 mL/min/1.73 m2 STANDARD_DEVIATION 12.4 | 43.2 mL/min/1.73 m2 STANDARD_DEVIATION 12.3 | 43.1 mL/min/1.73 m2 STANDARD_DEVIATION 12.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 550 Participants | 522 Participants | 1072 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1602 Participants | 1630 Participants | 3232 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Most likely etiology of CKD Chronic Glomerulonephritis | 352 Participants | 343 Participants | 695 Participants |
| Most likely etiology of CKD Diabetic Nephropathy | 1239 Participants | 1271 Participants | 2510 Participants |
| Most likely etiology of CKD Ischaemic/Hypertensive Nephropathy | 363 Participants | 324 Participants | 687 Participants |
| Most likely etiology of CKD Other or unknown cause of CKD | 198 Participants | 214 Participants | 412 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 74 Participants | 62 Participants | 136 Participants |
| Race/Ethnicity, Customized Asian | 718 Participants | 749 Participants | 1467 Participants |
| Race/Ethnicity, Customized Black or African American | 87 Participants | 104 Participants | 191 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 106 Participants | 112 Participants | 218 Participants |
| Race/Ethnicity, Customized White | 1166 Participants | 1124 Participants | 2290 Participants |
| Sex: Female, Male Female | 716 Participants | 709 Participants | 1425 Participants |
| Sex: Female, Male Male | 1436 Participants | 1443 Participants | 2879 Participants |
| Type 2 Diabetes Mellitus at Baseline No | 701 Participants | 697 Participants | 1398 Participants |
| Type 2 Diabetes Mellitus at Baseline Yes | 1451 Participants | 1455 Participants | 2906 Participants |
| Urine albumin creatinine ratio | 934 mg/g | 965 mg/g | 949 mg/g |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 107 / 2,152 | 159 / 2,152 |
| other Total, other adverse events | 479 / 2,149 | 500 / 2,149 |
| serious Total, serious adverse events | 633 / 2,149 | 729 / 2,149 |
Outcome results
Primary
Time to the First Occurrence of Any of the Components of the Composite: ≥50% Sustained Decline in eGFR or Reaching ESRD or CV Death or Renal Death.
End Stage Renal Disease (ESRD) is defined as: * Sustained eGFR \<15 mL/min/1.73m2 or, * Chronic dialysis treatment or, * Receiving a renal transplant The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table.
Time frame: Up to 38.2 months
Population: For the primary endpoint the Full Analysis Set was used. This included all patients who were randomized to study treatment. Patients were analyzed according to their randomized treatment assignment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapagliflozin | Time to the First Occurrence of Any of the Components of the Composite: ≥50% Sustained Decline in eGFR or Reaching ESRD or CV Death or Renal Death. | 197 Participants |
| Placebo | Time to the First Occurrence of Any of the Components of the Composite: ≥50% Sustained Decline in eGFR or Reaching ESRD or CV Death or Renal Death. | 312 Participants |
p-value: <0.000195% CI: [0.51, 0.72]Regression, Cox
Secondary
Time to Death From Any Cause.
The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table.
Time frame: Up to 38.2 months
Population: For the secondary endpoints the Full Analysis Set was used. This included all patients who were randomized to study treatment. Patients were analyzed according to their randomized treatment assignment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapagliflozin | Time to Death From Any Cause. | 101 Participants |
| Placebo | Time to Death From Any Cause. | 146 Participants |
p-value: 0.003595% CI: [0.53, 0.88]Regression, Cox
Secondary
Time to the First Occurrence of Any of the Components of the Composite: ≥50% Sustained Decline in eGFR or Reaching ESRD or Renal Death.
End Stage Renal Disease (ESRD) is defined as: * Sustained eGFR \<15 mL/min/1.73m2 or, * Chronic dialysis treatment or, * Receiving a renal transplant The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table.
Time frame: Up to 38.2 months
Population: For the secondary endpoints the Full Analysis Set was used. This included all patients who were randomized to study treatment. Patients were analyzed according to their randomized treatment assignment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapagliflozin | Time to the First Occurrence of Any of the Components of the Composite: ≥50% Sustained Decline in eGFR or Reaching ESRD or Renal Death. | 142 Participants |
| Placebo | Time to the First Occurrence of Any of the Components of the Composite: ≥50% Sustained Decline in eGFR or Reaching ESRD or Renal Death. | 243 Participants |
p-value: <0.000195% CI: [0.45, 0.68]Regression, Cox
Secondary
Time to the First Occurrence of Either of the Components of the Composite: CV Death or Hospitalization for Heart Failure.
The proportional hazards Cox regression model takes into account the time to the event. Data is reported as the numbers of subjects with the event and the Hazard ratio is included in the Statistical Analysis section attached to the Outcome Measure data table.
Time frame: Up to 38.2 months
Population: For the secondary endpoints the Full Analysis Set was used. This included all patients who were randomized to study treatment. Patients were analyzed according to their randomized treatment assignment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapagliflozin | Time to the First Occurrence of Either of the Components of the Composite: CV Death or Hospitalization for Heart Failure. | 100 Participants |
| Placebo | Time to the First Occurrence of Either of the Components of the Composite: CV Death or Hospitalization for Heart Failure. | 138 Participants |
p-value: 0.008995% CI: [0.55, 0.92]Regression, Cox