COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with chronic kidney disease and type 2 diabetes using a UACR Endpoint (CONFIDENCE) trial: baseline clinical characteristics

The study rationale and design of CONFIDENCE have previously been reported [11]. Briefly, CONFIDENCE is an ongoing, fully enrolled, randomized, controlled, double-blind, double-dummy, global, multicentre, phase 2 clinical trial in people (≥18 years of age) with CKD and T2D. There has been one key amendment made to the CONFIDENCE trial protocol, dated 24 October 2023, to increase generalizability and enrolment. The most clinically relevant change was related to study eligibility; specifically, the lower limit of the UACR inclusion criterion was amended to allow enrolment of participants with a lower range of UACRs (≥100 mg/g instead of previously ≥300 mg/g).

As finerenone and empagliflozin both moderately decrease blood pressure and eGFR after initiation of treatment [15–18], their combined effect on blood pressure (using 24-h blood pressure monitoring) and other safety parameters were assessed by the Internal Displacement Monitoring Centre in a subgroup of participants with eGFR between 40 and 90 mL/min/1.73 m², prior to extending enrolment to include participants with eGFR as low as 30 mL/min/1.73 m² [11]. As such, CONFIDENCE comprised two consecutive parts. In Part A, participants with an eGFR of 40–90 mL/min/1.73 m² were enrolled and underwent ambulatory blood pressure monitoring (ABPM) for 24 h after administration of their first study drug dose on Day 1. To monitor the risk of hypotension, all participants included in Part A were equipped with an ABPM device 1 h before the first intake at the study sites, remained at the study site for 4–6 h for office blood pressure monitoring, and kept the ABPM device on for 24 h. eGFR was monitored at each study visit, with a first assessment 14 days after the initial intake. A decision to progress from Part A to Part B, which includes extension of enrolment to participants with an eGFR as low as 30 mL/min/1.73 m², was made by the sponsor and steering committee following a blinded analysis of safety findings for the participants in Part A and an unblinded review by the independent data monitoring committee. In Part B, participants were not required to undergo ABPM.

Participants had to have T2D with a glycated haemoglobin (HbA1c) level of <11% at screening and be treated with the maximum tolerated dose of an ACEi or ARB for >1 month at their screening visit (Visit 1). Participants also had to have a UACR of ≥100 to <5000 mg/g and an eGFR of 30–90 mL/min/1.73 m² (Fig. 1).

Demographic characteristics, medical history, and prior and concomitant medication were documented for participants at the screening visit. Prior and concomitant medications were also documented at Day 1 before the allocation of the study drug. Demographic characteristics included age, sex, race, ethnicity, geographic region, body height and smoking history. Other measurements at screening included UACR, creatinine-based eGFR [the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used for eGFR [19] with a modification (year 2010) to the equation for Japanese participants [20] and serum potassium. Historical values for HbA1c were acceptable providing they were obtained within 3 months of the screening visit. Medical history was coded using MedDRA. Screening visits were used for assessing study eligibility only. Participants with certain medical conditions were excluded, including those with bilateral clinically relevant kidney artery stenosis (>75%) or other nondiabetic kidney disease, heart failure with reduced ejection fraction (New York Heart Association class II–IV), or an event within 90 days prior to the screening visit of stroke, transient ischaemic cerebral attack, acute coronary syndrome or hospitalization for worsening heart failure. The full list of exclusion criteria is in Supplementary data, Table S1.

The randomization visit (Visit 2) occurred up to 2 weeks after the screening visit and was defined as baseline. Participant eligibility and clinical status were rechecked at the baseline visit prior to randomization. A complete physical examination was performed at baseline. Participant body weight was also measured. Vital signs (pulse rate and blood pressure) were assessed at the baseline visit. Creatinine-based eGFR, serum potassium and UACR measurements were assessed at a central laboratory. Clinical chemistry and haematology were measured at both the screening and baseline visits. Lipids (low-density lipoprotein, high-density lipoprotein, total cholesterol and triglycerides) were measured at the screening visit only; HbA1c was measured at the baseline visit only (both fasting and not-fasting conditions were permitted for glucose testing).

Participants were randomized 1:1:1 to once-daily 10 or 20 mg finerenone plus 10 mg empagliflozin, once-daily 10 or 20 mg finerenone plus placebo, or once-daily 10 mg empagliflozin plus placebo. Randomization was stratified by eGFR (<60 mL/min/1.73 m², ≥60 mL/min/1.73 m²) and UACR (≤850 mg/g, >850 mg/g) values at screening. Investigators and participants are blinded to each participant's assigned study intervention throughout the course of the study. Each study intervention and its matching placebo are identical in appearance (size, shape and colour). The packaging and labelling are designed to maintain the blinding of the investigator's team and the participants. The study data will remain blinded until database lock and authorization of data release according to standard operating procedures.

The starting dose of finerenone was based on the participant's eGFR level at the screening visit: 10 mg once daily if eGFR was <60 mL/min/1.73 m² and 20 mg once daily (target dose) if eGFR was ≥60 mL/min/1.73 m². For participants on the lower dose, this can be uptitrated to 20 mg after 30 days if serum/plasma potassium concentration is ≤4.8 mmol/L and the eGFR decrease is <30% compared with the value measured at the previous visit. Corresponding sham uptitrations will be performed for placebo. Downtitration from a 20-mg to a 10-mg dose is permitted for safety reasons at any time.

The primary efficacy outcome is the relative change in log-transformed UACR from baseline at Day 180. Secondary key outcomes include the proportion of individuals achieving a reduction in UACR >30% from baseline to Day 180, the incidence of hyperkalaemia (moderate hyperkalaemia defined as serum potassium levels ≥5.5 to ≤6.0 mmol/L; severe hyperkalaemia defined as serum potassium levels >6.0 mmol/L) and acute kidney injury [defined as an increase in serum creatinine ≥0.3 mg/dL within 48 h or ≥1.5 times the baseline (known or presumed to have occurred within the prior 7 days), or a urine volume <0.5 mL/kg/hour for 6 h], and the assessment of initial and longer-term changes in eGFR.

Participant analysis sets include the full analysis set (defined as all randomized participants) and the safety analysis set (defined as all randomized participants who received at least one dose of study medication).

The study protocol, protocol amendment and informed consent forms were approved by independent review boards and independent ethics committees according to country-specific requirements. The study was conducted in compliance with the principles of the Declaration of Helsinki and in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice. All study participants provided written informed consent prior to study enrolment. The study is registered with www.clinicaltrials.gov↗ (NCT05254002; EudraCT 2021-003037-11).

In total, 1664 participants were screened. A total of 805 participants did not pass screening; of those, 314 (39%) did not meet the inclusion criteria of a clinical diagnosis of CKD as defined by eGFR, UACR and other specified criteria, and 289 (36%) met the exclusion criteria of serum potassium levels >4.8 mmol/L at the screening visit. Of the screened participants, 818 were randomized across 143 sites in 14 countries (Fig. 2). The first participant was randomized in July 2022 and randomization was completed in August 2024. Seventeen participants were excluded from the full analysis set (N = 801) due to Good Clinical Practice violations or randomization errors.

The numbers of patients in the lower (≤850 mg/g) and higher (>850 mg/g) UACR categories were 529 and 289, respectively (Fig. 2 and Table 1).

Baseline demographic and clinical characteristics based on the full analysis set population and displayed by UACR stratification are shown in Table 1. Overall baseline characteristics were similar between the participants in the lower and higher UACR groups.

For the overall study population, the mean [standard deviation (SD)] age was 66.5 (10.3) years and 499 (62.3%) participants were ≥65 years of age. Overall, 603 (75.3%) and 198 (24.7%) of the trial population were male and female, respectively. CONFIDENCE enrolled participants globally, with 360 (44.9%), 225 (28.1%) and 216 (27.0%) enrolled in Asia, North America and Europe, respectively. Overall, 371 (46.3%), 352 (43.9%) and 67 (8.4%) participants were Asian, White and Black/African American, respectively; 83 (10.4%) participants were of Hispanic or Latino ethnicity. At the time of participant consent, 117 (14.6%) and 257 (32.1%) participants were current and former smokers, respectively. A total of 427 (53.3%) participants had never smoked.

Baseline mean ± SD eGFR was 54.2 ± 17.1 mL/min/1.73 m². In addition, the number of participants in eGFR (mL/min/1.73 m²) categories <30, ≥30 to <45, ≥45 to <60, ≥60 to 75, and >75 was 27 (3.4%), 264 (33.0%), 230 (28.7%), 173 (21.6%) and 107 (13.4%), respectively. The median (interquartile range) UACR was 583.44 (291.72 to 1140.00) mg/g. There were 2 (0.2%) participants in the albuminuria A1 category and 207 (25.8%) in the albuminuria A2 category. Within the albuminuria A3 category, 365 (45.6%) participants had a UACR >300 to 1000 mg/g, and 225 (28.1%) had a UACR >1000 mg/g. The cohort distribution of KDIGO categories of kidney disease risk is displayed in Supplementary data, Fig. S1.

Mean ± SD body mass index was 29.3 ± 6.1 kg/m². Mean ± SD systolic blood pressure and diastolic blood pressure was 135 ± 13 and 77 ± 10 mmHg, respectively. Mean ± SD HbA1c was 7.3 ± 1.2%. Mean ± SD serum potassium was 4.48 ± 0.42 mmol/L (mEq/L).

In total, 788 (98.4%) study participants were using an ACEi or ARB. Statins were used in 313 (39.1%) participants, antiplatelet agents in 319 (39.8%) participants and centrally acting antihypertensive drugs in 37 (4.6%) participants. Diuretics were used by 291 (36.3%) and beta-blockers by 268 (33.5%) participants. Diabetes medications included insulin (39.1%) and oral hypoglycaemic agents [sulfonylureas (n = 189; 23.6%), dipeptidyl peptidase-4 inhibitors (n = 249; 31.1%) and metformin (n = 481; 60.0%)]. GLP-1 RAs were used by 182 (22.7%) participants.

Atherosclerotic CV disease was present in 223 (27.8%) participants. A history of heart failure prior to screening was present in 30 (3.7%) participants. Diabetic retinopathy was present in 126 (15.7%) participants. Atrial fibrillation was present in 51 (6.4%) participants. Hypertension was present in 703 (87.8%) participants.

The data monitoring committee reviewed (unblinded) ABPM data for participants in Part A. The assessment of safety in the ABPM substudy confirmed there was no elevated hypotension risk in the first 24 h following combined initiation of study medication. Following feedback from the data monitoring committee, the sponsor and the study's steering committee made the decision to move from Part A to Part B of the study, resulting in an extension of enrolment to participants with an eGFR as low as 30 mL/min/1.73 m².