Chronic Kidney Disease, Type 2 Diabetes Mellitus
Conditions
Brief summary
Finerenone works by blocking a group of proteins, called mineralocorticoid receptor. An increased stimulation of mineralocorticoid receptor is known to trigger injury and inflammation in the kidney and is therefore thought to play a role in CKD. Empagliflozin lowers blood sugar levels by increasing the excretion of glucose from the blood into the urine. In this study, the researchers want to learn how well the combination of finerenone and empagliflozin helps to slow down the worsening of the participants' kidney function compared to either treatment alone. For this, the level of protein in the urine will be measured. The investigators also want to know how safe the combination is compared to either treatment alone. Depending on the treatment group, the participants will either take the combination of finerenone and empagliflozin, or finerenone together with a placebo, or empagliflozin together with a placebo, once a day as tablets by mouth. A placebo looks like a treatment but does not have any medicine in it. Importantly, the participants will also continue to take their other current medicine for CKD and T2D. The participants will be in the study for up to 7.5 months and will take the study treatments for 6 months. During the study, participants will visit the study site 7 times. The study team will: * collect blood and urine samples * check the participants' vital signs * do a physical examination including height and weight * check the participants' heart health by using an electrocardiogram (ECG) * monitor the participants' blood pressure * ask the participants questions about how they are feeling and what adverse events they may be having An adverse event is any problem that happens during the trial. Doctors keep track of all events that happen in trials, even if they do not think the events might be related to the study treatments.
Interventions
DRUGFinerenone (BAY94-8862 ) 10 mg
oral administration, once daily if screening eGFR (Estimated glomerular filtration rate) results are: \<60 mL/min/1.73 m2
DRUGEmpagliflozin
oral administration, once daily
Matching placebo to empagliflozin oral administration, once daily
DRUGFinerenone (BAY94-8862 ) 20 mg
oral administration, once daily if screening eGFR (Estimated glomerular filtration rate) results are: ≥60 mL/min/1.73 m2
Matching Placebo to Finerenone oral administration once daily
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
* Participant with a clinical diagnosis of chronic kidney disease (CKD) and the following: * In Part A: eGFR 40-90 ml/min/1.73m\^2 (with no more than 20% having an eGFR \>75 ml/min/1.73m\^2) using Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula at screening visit and at least one historical value of eGFR \<60 mL/min/1.73 m\^2 within 3 months or have a registered diagnosis of CKD. * In Part B: eGFR 30-90 ml/min/1.73m\^2 (with no more than 20% having an eGFR \>75 ml/min/1.73m\^2) using CKD-EPI formula at screening visit and at least one historical value of eGFR \<60 mL/min/1.73 m\^2 within 3 months or have a registered diagnostic of CKD. * 100 ≤UACR \<5000 mg/g at screening visit (mean value from 3 morning void samples) and documentation of albuminuria/proteinuria (quantitative or semi-quantitative measurement) in the participant's medical records at least 3 months prior to screening * Participant with type 2 diabetes (T2D) as defined by the American Diabetes Association (ADA 2021), with glycated hemoglobin (HbA1c) at screening \<11%. * Participant treated with the clinically maximum tolerated dose, as per investigator judgment, of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), but not both, for more than 1 month at screening visit.
Exclusion criteria
* Participants with type 1 diabetes (T1D). * Participant with hepatic insufficiency classified as Child-Pugh C. * Participant with blood pressure at Day 1 visit (Visit 2) higher than 160 systolic blood pressure (SBP) or 100 diastolic blood pressure (DBP) or SBP lower than 90 mmHg. * Participant currently treated with a sodium/glucose cotransporter-2 inhibitor (SGLT2i) or SGLT-1/2i or who received a SGLT2i or SGLT-1/2i which cannot be discontinued at least 8 weeks prior to the screening visit and during study intervention treatment. * Participant treated with another mineralocorticoid receptor antagonist (MRA) (e.g., eplerenone, esaxerenone, spironolactone, canrenone), a renin inhibitor, potassium supplements, a potassium sparing diuretic (e.g., amiloride, triamterene), a potassium binder agent, or angiotensin receptor-neprilysin inhibitor (ARNI) which cannot be discontinued at least 8 weeks prior to the screening visit and during study intervention treatment. * Participants currently treated or who were treated with Finerenone (Kerendia©) within 8 weeks prior to the screening visit. * Participant with serum/plasma potassium (K+) above 4.8 mmol/L at screening visit (central laboratory value).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Least Squares Mean Ratio of Urinary Albumin-to-Creatinine Ratio (UACR) at Day 180 Relative to Baseline in the Combination Therapy Group Versus Empagliflozin Alone | Baseline and Day 180 | Least squares mean ratio of urinary albumin-to-creatinine ratio (UACR) at Day 180 relative to baseline, estimated using a mixed model for repeated measures. The treatment effect is expressed as the ratio of LS means for the combination therapy group compared with empagliflozin alone. A ratio below 1 indicates a reduction in UACR relative to baseline. UACR is a marker of albuminuria and a predictor of long-term renal and cardiovascular outcomes in participants with chronic kidney disease and type 2 diabetes. |
| Least Squares Mean Ratio of Urinary Albumin-to-Creatinine Ratio (UACR) at Day 180 Relative to Baseline in the Combination Therapy Group Versus Finerenone Alone | Baseline and Day 180 | Least squares mean ratio of urinary albumin-to-creatinine ratio (UACR) at Day 180 relative to baseline in the combination therapy group compared with finerenone alone, estimated using a mixed model for repeated measures. A ratio below 1 indicates a reduction in UACR relative to baseline. UACR is a measurement of albuminuria and a predictor of long-term renal and cardiovascular outcomes in participants with type 2 diabetes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Least Squares Mean Ratio of Urinary Albumin-to-Creatinine Ratio (UACR) at Day 210 Relative to Day 180 | Up to 210 days | Least squares mean ratio of urinary albumin-to-creatinine ratio (UACR) at Day 210 (30 days after stopping the treatment) relative to Day 180, estimated using a mixed model for repeated measures. A ratio above 1 indicates an increase in UACR at Day 210 compared with Day 180. UACR is a measurement of albuminuria, a predictor of long-term renal and cardiovascular outcomes in participants with type 2 diabetes. |
| Least Squares Mean Ratio of Urinary Albumin-to-Creatinine Ratio (UACR) at 30 Days After End of Treatment Relative to Baseline | Baseline to Day 210 (30 days after End of Treatment) | Least squares mean ratio of urinary albumin-to-creatinine ratio (UACR) relative to baseline, estimated using a mixed model for repeated measures. A ratio below 1 indicates a reduction in UACR relative to baseline. UACR is a marker of albuminuria and a predictor of long-term renal and cardiovascular outcomes in participants with type 2 diabetes. |
| Number of Participants by Relative Change in UACR Category at Day 180 (>30%, >40%, >50%) | At Day 180 | This outcome summarizes the number of participants whose relative change from baseline in urine albumin-to-creatinine ratio (UACR) at Day 180 met prespecified category thresholds (\>30%, \>40%, or \>50%). Relative change was assessed based on baseline and post-baseline UACR measurements. Percentages were calculated using as denominator the number of participants with both a baseline and at least one post-baseline UACR assessment within the specified timeframe. Participants were classified independently within each category. |
| Change From Baseline in eGFR at 30 Days | At Day 30 | Change from baseline to Day 30 in estimated glomerular filtration rate (eGFR) was evaluated for each treatment group. Change was calculated as the value at Day 30 minus the baseline value. Negative values indicate a decrease from baseline and positive values indicate an increase from baseline. |
| Number of Participants With an eGFR Decline Greater Than 30% at 30 Days From Baseline | Up to 30 days | — |
| Change in eGFR at 180 Days and 210 Days From Day 30 | At Day 180 and Day 210 | Change in estimated glomerular filtration rate (eGFR) from Day 30 to Day 180 and Day 210 was evaluated for each treatment group. Change was calculated as the value at Day 180 or Day 210 minus the value at Day 30. Positive values indicate an increase from Day 30 and negative values indicate a decrease from Day 30. |
| Number of Participants With AKI Events | Up to 180 days | AKI is defined as any of the following: * An increase in serum creatinine by greater than or equal to 0.3 mg/dL within 48 hours; or * An increase in serum creatinine by greater than or equal to 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or * A urine volume less than 0.5 ml/kg/h for 6 hours Total number of AKI events Up to 180 days |
| Total Number of AKI Events | Up to 180 days | AKI is defined as any of the following: * An increase in serum creatinine by greater than or equal to 0.3 mg/dL within 48 hours; or * An increase in serum creatinine by greater than or equal to 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or * A urine volume less than 0.5 ml/kg/h for 6 hours Total number of AKI events Up to 180 days |
| Number of Participants With Hyperkalemia Events (Moderate Hyperkalemia [5.5 <K+ ≤6.0 mmol/L], Severe Hyperkalemia [K+ >6.0 mmol/L]) | Up to 180 days | Moderate hyperkalemia was defined as K+ \>5.5 to ≤6.0 mmol/L and severe hyperkalemia was defined as K+ \>6.0 mmol/L). |
| Change From Baseline in K+ | At baseline, day 14 and day 180 | Serum potassium values (mmol/L) were assessed at baseline and scheduled post-baseline visits. Results are presented as observed mean potassium concentrations at each time point. |
| Number of Participants With Symptomatic Hypotension Events | Up to 180 days | Number of participants who experienced at least one symptomatic hypotension event during the study period |
| Total Number of Symptomatic Hypotension Events | Up to 180 days | Symptomatic hypotension events were assessed at all study visits and were documented as adverse events. The outcome represents the total number of symptomatic hypotension events reported during the study period. |
| Number of Participants With Genital Mycotic Events | Up to 180 days | The outcome represents the number of participants who experienced at least one genital mycotic event during the study period. |
| Total Number of Genital Mycotic Events | Up to 180 days | Occurrence of urinary tract infection events were assessed at all study visits and documented as AEs. |
| Number of Participants With Urosepsis and Pyelonephritis Events | Up to 180 days | — |
| Total Number of Urosepsis and Pyelonephritis Events | Up to 180 days | Occurrence of urosepsis and pyelonephritis events were assessed at all study visits and documented as AEs. |
| Number of Participants With Ketoacidosis Events | Up to 180 days | — |
| Total Number of Ketoacidosis Events | Up to 180 days | Occurrence of ketoacidosis events were assessed at all study visits and documented as AEs. |
| Number of Participants With Necrotizing Fasciitis of the Perineum Events | Up to 180 days | — |
| Number of Participants With Severe Hypoglycemia Events | Up to 180 days | Severe hypoglycemia was defined as glucose level of \<3.0 mmol/L (\<54 mg/dL) is sufficiently low to indicate serious, clinically important hypoglycemia. In addition, severe hypoglycemia, as defined by the ADA denotes severe cognitive impairment requiring external assistance for recovery. |
Countries
Belgium, Canada, Denmark, France, Germany, India, Israel, Italy, Japan, Netherlands, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
A total of 1664 participants were screened and signed the informed consent form for the study. 846 participants were screen failures and did not complete screening. The study was conducted at 163 centers in 14 countries/regions across Asia, Europe and North America from 23 Jun 2022 (First Patient First Visit) to 17 Mar 2025 (Last Patient Last Visit).
Pre-assignment details
Overall, 818 participants were randomized. Of these, 14 participants were prospectively excluded from the analyses because of Good Clinical Practice (GCP) violations, 4 participants were excluded from the FAS (Full Analysis Set) because they were mis-randomized and did not take at least one dose of treatment. FAS and SAF (Safety Analysis Set) differed by only 2 participants who never received any study intervention.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 66.5 years STANDARD_DEVIATION 10.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 235 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants |
| Race (NIH/OMB) Asian | 125 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 351 Participants |
| Sex: Female, Male Female | 198 Participants |
| Sex: Female, Male Male | 202 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 268 | 0 / 264 | 3 / 266 | 0 / 2 |
| other Total, other adverse events | 141 / 268 | 136 / 264 | 129 / 266 | 0 / 2 |
| serious Total, serious adverse events | 19 / 268 | 16 / 264 | 17 / 266 | 0 / 2 |
Outcome results
None listed