A parallel-group treatment, Phase 2, double-blind, three-arm study to assess efficacy and safety of finerenone plus empagliflozin compared with either finerenone or empagliflozin in participants with chronic kidney disease and type 2 diabetes

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. They also want to know how safe
the combination is compared to either treatment alone.


This is the first parallel-group randomized controlled trial to evaluate the
safety, tolerability, and additive efficacy of the combined use of finerenone
and empagliflozin using the surrogate endpoint of UACR (urinary
albumin-to-creatinine ratio). This study will also investigate, for the first
time, simultaneous initiation of finerenone and empagliflozin.
The goal of this study is to show that the combined use of finerenone and
empagliflozin is superior to either empagliflozin alone, or finerenone alone in
reducing UACR at 180 days.

This study has been transitioned to CTIS with ID 2023-506981-30-00 check the CTIS register for the current data.

Main objective:
The primary objective is to demonstrate that combination therapy using
finerenone and empagliflozin is superior in reducing UACR than either
empagliflozin or finerenone alone.

Secondary objectives:
- To further investigate the efficacy of combination therapy using finerenone
and empagliflozin versus either finerenone or empagliflozin
alone.
- To evaluate the safety of combination therapy using finerenone and
empagliflozin versus either finerenone or empagliflozin alone.

Phase 2, randomized, controlled, double-blind (participants and investigators),
doubledummy, multicenter study in participants with CKD and T2D.

Participants and investigators will be blinded to study intervention allocation
ensuring a double-blind design, thus limiting bias.

The study will consist of 2 consecutive parts:
o Part A: participants will be recruited if their eGFR is between 40 and 90
ml/min/1.73 m², and they will be equipped with an ABPM at Visit 2 for a
duration of 24 hours. An interactive web response system (IWRS) will allow
capping the number of participants as follows:
* 80% with an eGFR between <=75 ml/min/1.73 m²
* 20% with an eGFR between >75 ml/min/1.73 m².
o Part B: participants will be recruited if their eGFR is between 30 and 90
ml/min/1.73 m², and they will not have an ABPM. The IWRS will allow
capping the number of participants as follows:
* 80% with an eGFR between <=75 ml/min/1.73 m²
* 20% with an eGFR between >75 ml/min/1.73 m².
o The decision to move from Part A to Part B will be taken by the sponsor and
the study*s SC upon feedback from the DMC. The safety analysis from the first
50 participants in Part A, as well as their unblinded review by the independent
DMC will be used to confirm the enrollment/recruitment start for Part B. This
decision shall be effective immediately or after IRB/IEC and/or local Health
Authority approval, where applicable.
o Other inclusion/exclusion criteria or study*s schedule or procedure should
not be affected.

Participants will be randomized in a 1:1:1 ratio stratified by eGFR at
screening (<60, >=60 mL/min/1.73m²) and UACR (<= 850mg/g, > 850 mg/g), using the
baseline median from FIDELIO-DKD study) in one of the 3 parallel groups:
o Finerenone (10 or 20 mg once daily [OD]) and empagliflozin (10 mg OD)
o Finerenone (10 or 20 mg OD) and matching placebo to empagliflozin (OD)
o Empagliflozin (10 mg OD) and matching placebo to finerenone (OD).

Depending on the treatment group, the participants will either take:

- the combination of finerenone and empagliflozin,
- finerenone together with a placebo,
- empagliflozin together with a placebo,
once a day as tablets by mouth.

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, they 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

- 7 visits to the hospital divided over 7.5 months
- 4 x (max.) 19 ml blood is collected = 133 ml in total
- blood pressure measurement at home (24-hour collection)
- pregnancy test (if applicable) (3x)
- ECGs (2x)
- other urine tests for safety and how the medication works (UACR).

CONFIDENCE will be the first controlled clinical trial where finerenone and
empagliflozin are simultaneously initiated. As mentioned above (protocol p23),
initiation of each single drug can lead to a decrease in BP and eGFR. The
additive effect of both drugs on BP and eGFR is not yet known. To monitor the
risk of hypotension, all participants will be equipped with an ABPM device 1
hour before the first intake at the study site. The participant will remain 4
to 6 hours at the study site for office BP monitoring and will keep the ABPM
for 24 hours. eGFR will be monitored at each study visit with a first
assessment 14 days after the initial intake. With regards to risks specific to
empagliflozin, participants with risks factors for ketoacidosis or volume
depletion will be excluded from the study. Participants will also be monitored
to look for signs and symptoms of ketoacidosis. Concomitant therapy with
insulin will also be carefully monitored and assessed during the medical review.

Reduction in UACR, a surrogate marker for renal outcomes, is correlated with
improved renal and cardiovascular outcomes. Therefore, early and efficient
intervention, resulting in slower disease progression and potentially
prevention of disease progression, may provide long-term benefits for patients
with CKD and T2D. By taking part in this study, participants treated with
finerenone and empagliflozin combination could benefit from a more effective
treatment to reduce CKD progression together with decreased risk of adverse
drug reactions.