Chronic Kidney Disease
Conditions
Keywords
CKD, Diabetic Kidney Disease, Type 2 Diabetes, Kidney diseases
Brief summary
The primary objective of this study was to demonstrate whether, in addition to standard of care, finerenone is superior to placebo in delaying the progression of kidney disease, as measured by the composite endpoint of time to first occurrence of kidney failure, a sustained decrease of estimated glomerular filtration rate (eGFR) ≥40% from baseline over at least 4 weeks, or renal death.
Interventions
Oral tablet; starting dose at 10 mg for subjects with an eGFR between 25 to \< 60 mL/min/1.73m² at the Screening Visit; starting dose at 20 mg for subjects with an eGFR ≥ 60 mL/min/1.73m² at the Screening Visit; dose could be up-titrated from Month 1 onwards or down-titrated at any time during the study; once daily in the morning, until the trial was completed provided there were no safety grounds for discontinuing treatment
DRUGPlacebo
Matching placebo, oral tablet, once daily in the morning, until the trial was completed provided there were no safety grounds for discontinuing treatment
Sponsors
Bayer
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Men or women ≥18 years of age * Type 2 diabetes mellitus (T2D) as defined by the American Diabetes Association * Diagnosis of chronic kidney disease (CKD) with at least one of the following criteria at run-in and screening visits: * persistent high albuminuria (UACR ≥30 to \<300 mg/g in 2 out of 3 first morning void samples) and estimated glomerular filtration rate (eGFR) ≥25 but \<60 mL/min/1.73 m² (CKD EPI) and presence of diabetic retinopathy or * persistent very high albuminuria (UACR ≥300 mg/g in 2 out of 3 first morning void samples) and eGFR ≥25 to \<75 mL/min/1.73 m² (CKD-EPI) * Prior treatment with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) as follows: * For at least 4 weeks prior to the run-in visit, subjects should be treated with either an ACEI or ARB, or both * Starting with the run-in visit, subjects should be treated with only an ACEI or ARB * For at least 4 weeks prior to the screening visit, subjects should be treated with the maximum tolerated labeled dose (but not below the minimal labeled dose) of only an ACEI or an ARB (not both) preferably without any adjustments to dose or choice of agent or to any other antihypertensive or antiglycemic treatment * Serum potassium ≤4.8 mmol/L at both the run-in and the screening visit
Exclusion criteria
* Known significant non-diabetic renal disease, including clinically relevant renal artery stenosis * Uncontrolled arterial hypertension (ie, mean sitting systolic blood pressure (SBP) ≥170 mmHg, sitting diastolic blood pressure (DBP) ≥110 mmHg at run-in visit, or mean sitting SBP ≥160 mmHg, sitting DBP ≥100 mmHg at screening) * Glycated hemoglobin (HbA1c) \>12% * Mean SBP \< 90 mmHg at the run-in visit or at the screening visit * Clinical diagnosis of chronic heart failure with reduced ejection fraction (HFrEF) and persistent symptoms (New York Heart Association \[NYHA\] class II - IV) at run-in visit (class 1A recommendation for mineralcorticoid receptor antagonists \[MRAs\]) * Stroke, transient ischemic cerebral attack, acute coronary syndrome, or hospitalization for worsening heart failure, in the last 30 days prior to the screening visit * Dialysis for acute renal failure within 12 weeks of run-in visit * Renal allograft in place or scheduled within next 12 months from the run-in visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The First Occurrence of the Composite Endpoint of Onset of Kidney Failure, a Sustained Decrease of eGFR ≥40% From Baseline Over at Least 4 Weeks, or Renal Death | From randomization up until the first occurrence of the primary renal composite endpoint, or censoring at the end of the study, with an average follow-up time of 32 months | Count of participants and time from randomization to the first occurrence of the primary renal composite outcome, onset of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death were evaluated. Number of participants with the outcome event is reported as descriptive result and hazard ratio is reported as statistical analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The First Occurrence of the Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, or Hospitalization for Heart Failure | From randomization up until the first occurrence of the key secondary CV composite endpoint, or censoring at the end of the study, with an average of 32 months | Count of participants and time from randomization to the first occurrence of the key secondary cardiovascular (CV) composite outcome, CV death, non-fatal myocardial infarction (MI), non-fatal stroke, or hospitalization for heart failure were evaluated. Number of participants with the outcome event is reported as descriptive result and hazard ratio is reported as statistical analysis. |
| All-cause Mortality | From randomization up until death due to any cause, or censoring at the end of the study visit, with an average of 32 months | Count of participants and time from randomization until death due to any cause were evaluated. Number of participants with outcome death is reported as descriptive result and hazard ratio is reported as statistical analysis. Number of participants with outcome death reported here includes deaths occurred after randomization until the end of the study visit. Deaths after end of study visit are not included in this table. |
| All-cause Hospitalization | From randomization up until the first occurrence of the hospitalization due to any cause, or censoring at the end of study, with an average of 32 months | Count of participants and time from randomization to the first occurrence of a hospitalization event were evaluated. Number of participants with the event is reported as descriptive result and hazard ratio is reported as statistical analysis. |
| Change in Urinary Albumin-to-creatinine Ratio (UACR) From Baseline to Month 4 | From baseline up until Month 4 | First morning void urine samples were collected to evaluate the urinary albumin-to-creatinine ratio (UACR). Month 4 was the visit closest to day 120 within a time window of 120 ± 30 days after randomization. If no measurements were available in this time window, the participant was excluded from this analysis. Ratio of UACR at Month 4 to UACR at baseline is reported as the change. |
| The First Occurrence of the Composite Endpoint of Onset of Kidney Failure, a Sustained Decrease in eGFR of ≥57% From Baseline Over at Least 4 Weeks, or Renal Death | From randomization up until the first occurrence of the composite primary endpoint, or censoring at the end of the study, with an average of 32 months | Count of participants and time from randomization to the first occurrence of the secondary renal composite outcome, onset of kidney failure, a sustained decrease in eGFR of ≥57% from baseline over at least 4 weeks, or renal death were evaluated. Number of participants with the outcome event is reported as descriptive result and hazard ratio is reported as statistical analysis. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Norway, Philippines, Poland, Portugal, Puerto Rico, Romania, Russia, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States, Vietnam
Participant flow
Recruitment details
Study was conducted at multiple centers in 48 countries/regions between 17-SEP-2015 (first participant first visit) and 14-APR-2020 (last participant last visit).
Pre-assignment details
Overall, 13911 participants were screened. Of them, 8177 participants were screening failures and 5734 participants were randomized to study treatment. 60 participants were prospectively excluded from the analyses because of Good Clinical Practice (GCP) violations, resulting in 5674 participants in the full analysis set (FAS). 16 participants did not take any study drug, resulting in 5658 participants who received study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Finerenone Participants received finerenone 10 mg or 20 mg once daily in addition to standard of care therapy | 2,833 |
| Placebo Participants received matching placebo once daily in addition to standard of care therapy | 2,841 |
| Total | 5,674 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | GCP violations | 33 | 27 |
| Overall Study | Lost to Follow-up | 5 | 3 |
| Overall Study | Withdrawal by Subject | 4 | 6 |
Baseline characteristics
| Characteristic | Finerenone | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 65.44 Years STANDARD_DEVIATION 8.94 | 65.67 Years STANDARD_DEVIATION 9.16 | 65.56 Years STANDARD_DEVIATION 9.05 |
| Estimated glomerular filtration rate (eGFR) | 44.36 mL/min/1.73m^2 STANDARD_DEVIATION 12.54 | 44.32 mL/min/1.73m^2 STANDARD_DEVIATION 12.57 | 44.34 mL/min/1.73m^2 STANDARD_DEVIATION 12.56 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 447 Participants | 431 Participants | 878 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2376 Participants | 2397 Participants | 4773 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 13 Participants | 23 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 78 Participants | 76 Participants | 154 Participants |
| Race (NIH/OMB) Asian | 717 Participants | 723 Participants | 1440 Participants |
| Race (NIH/OMB) Black or African American | 140 Participants | 124 Participants | 264 Participants |
| Race (NIH/OMB) More than one race | 101 Participants | 86 Participants | 187 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 11 Participants | 7 Participants | 18 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 10 Participants | 19 Participants |
| Race (NIH/OMB) White | 1777 Participants | 1815 Participants | 3592 Participants |
| Sex: Female, Male Female | 880 Participants | 811 Participants | 1691 Participants |
| Sex: Female, Male Male | 1953 Participants | 2030 Participants | 3983 Participants |
| Urinary albumin-to-creatinine ratio (UACR) | 832.72 milligram/gram (mg/g) | 867.01 milligram/gram (mg/g) | 851.87 milligram/gram (mg/g) |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 222 / 2,833 | 250 / 2,841 |
| other Total, other adverse events | 1,602 / 2,827 | 1,584 / 2,831 |
| serious Total, serious adverse events | 902 / 2,827 | 971 / 2,831 |
Outcome results
Primary
The First Occurrence of the Composite Endpoint of Onset of Kidney Failure, a Sustained Decrease of eGFR ≥40% From Baseline Over at Least 4 Weeks, or Renal Death
Count of participants and time from randomization to the first occurrence of the primary renal composite outcome, onset of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death were evaluated. Number of participants with the outcome event is reported as descriptive result and hazard ratio is reported as statistical analysis.
Time frame: From randomization up until the first occurrence of the primary renal composite endpoint, or censoring at the end of the study, with an average follow-up time of 32 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Finerenone | The First Occurrence of the Composite Endpoint of Onset of Kidney Failure, a Sustained Decrease of eGFR ≥40% From Baseline Over at Least 4 Weeks, or Renal Death | 504 Participants |
| Placebo | The First Occurrence of the Composite Endpoint of Onset of Kidney Failure, a Sustained Decrease of eGFR ≥40% From Baseline Over at Least 4 Weeks, or Renal Death | 600 Participants |
p-value: =0.001495% CI: [0.732, 0.928]Log Rank
Secondary
All-cause Hospitalization
Count of participants and time from randomization to the first occurrence of a hospitalization event were evaluated. Number of participants with the event is reported as descriptive result and hazard ratio is reported as statistical analysis.
Time frame: From randomization up until the first occurrence of the hospitalization due to any cause, or censoring at the end of study, with an average of 32 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Finerenone | All-cause Hospitalization | 1263 Participants |
| Placebo | All-cause Hospitalization | 1321 Participants |
p-value: =0.162395% CI: [0.876, 1.022]Log Rank
Secondary
All-cause Mortality
Count of participants and time from randomization until death due to any cause were evaluated. Number of participants with outcome death is reported as descriptive result and hazard ratio is reported as statistical analysis. Number of participants with outcome death reported here includes deaths occurred after randomization until the end of the study visit. Deaths after end of study visit are not included in this table.
Time frame: From randomization up until death due to any cause, or censoring at the end of the study visit, with an average of 32 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Finerenone | All-cause Mortality | 219 Participants |
| Placebo | All-cause Mortality | 244 Participants |
p-value: =0.234895% CI: [0.746, 1.075]Log Rank
Secondary
Change in Urinary Albumin-to-creatinine Ratio (UACR) From Baseline to Month 4
First morning void urine samples were collected to evaluate the urinary albumin-to-creatinine ratio (UACR). Month 4 was the visit closest to day 120 within a time window of 120 ± 30 days after randomization. If no measurements were available in this time window, the participant was excluded from this analysis. Ratio of UACR at Month 4 to UACR at baseline is reported as the change.
Time frame: From baseline up until Month 4
Population: Subjects in full analysis set with measurements available within the time window of Month 4
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Finerenone | Change in Urinary Albumin-to-creatinine Ratio (UACR) From Baseline to Month 4 | 0.655 Ratio |
| Placebo | Change in Urinary Albumin-to-creatinine Ratio (UACR) From Baseline to Month 4 | 0.952 Ratio |
p-value: <0.000195% CI: [0.662, 0.715]ANCOVA
Secondary
The First Occurrence of the Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, or Hospitalization for Heart Failure
Count of participants and time from randomization to the first occurrence of the key secondary cardiovascular (CV) composite outcome, CV death, non-fatal myocardial infarction (MI), non-fatal stroke, or hospitalization for heart failure were evaluated. Number of participants with the outcome event is reported as descriptive result and hazard ratio is reported as statistical analysis.
Time frame: From randomization up until the first occurrence of the key secondary CV composite endpoint, or censoring at the end of the study, with an average of 32 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Finerenone | The First Occurrence of the Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, or Hospitalization for Heart Failure | 367 Participants |
| Placebo | The First Occurrence of the Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, or Hospitalization for Heart Failure | 420 Participants |
p-value: =0.033995% CI: [0.747, 0.989]Log Rank
Secondary
The First Occurrence of the Composite Endpoint of Onset of Kidney Failure, a Sustained Decrease in eGFR of ≥57% From Baseline Over at Least 4 Weeks, or Renal Death
Count of participants and time from randomization to the first occurrence of the secondary renal composite outcome, onset of kidney failure, a sustained decrease in eGFR of ≥57% from baseline over at least 4 weeks, or renal death were evaluated. Number of participants with the outcome event is reported as descriptive result and hazard ratio is reported as statistical analysis.
Time frame: From randomization up until the first occurrence of the composite primary endpoint, or censoring at the end of the study, with an average of 32 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Finerenone | The First Occurrence of the Composite Endpoint of Onset of Kidney Failure, a Sustained Decrease in eGFR of ≥57% From Baseline Over at Least 4 Weeks, or Renal Death | 252 Participants |
| Placebo | The First Occurrence of the Composite Endpoint of Onset of Kidney Failure, a Sustained Decrease in eGFR of ≥57% From Baseline Over at Least 4 Weeks, or Renal Death | 326 Participants |
p-value: =0.001295% CI: [0.648, 0.9]Log Rank