Diabetic kidney disease

The primary objective of this study is to:  Demonstrate whether, in addition to standard of care (SoC), finerenone is superior to placebo in delaying the time to first occurrence of cardiovascular (CV) mortality and morbidity in subjects with type 2 diabetes mellitus (T2DM) and the clinical diagnosis of diabetic kidney disease (DKD). The secondary objectives of this study are to determine whether, in addition to SoC, finerenone compared to placebo:  Delays the time to first occurrence of the following composite endpoint: onset of kidney failure, a sustained decrease in estimated glomerular filtration rate (eGFR) of ≥40% from baseline over at least 4 weeks or renal death  Delays the time to all-cause hospitalization  Delays the time to all-cause mortality  Change in UACR from baseline to Month 4  Delays the time to first occurrence of the following composite endpoint: onset of kidney failure, a sustained decrease in eGFR of ≥57% from baseline over at least 4 weeks or renal death.

BAY 94-8862/ Finerenone

(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

Tablet

10/20 mg

Primary variable Time to the first occurrence of the composite endpoint of CV death or non-fatal CV event (i.e. myocardial infarction, stroke, or hospitalization for heart failure)

The secondary endpoint of this study are to determine whether, in addition
to SoC, finerenone compared to placebo:
 Delays the time to first occurrence of the following composite endpoint:
onset of kidney failure, a sustained decrease in estimated glomerular
filtration rate (eGFR) of ≥40% from baseline over at least 4 weeks or
renal death
 Delays the time to all-cause hospitalization
 Delays the time to all-cause mortality
 Change in UACR from baseline to Month 4
 Delays the time to first occurrence of the following composite endpoint:
onset of kidney failure, a sustained decrease in eGFR of ≥57% from
baseline over at least 4 weeks or renal death.

1. Written informed consent signed before any study-specific procedure
2. Men or women aged 18 years and older. The lower age limit may be higher if legally required in the participating country.
3. Women of childbearing potential can only be included in the study if a pregnancy test is negative at the screening visit and if they agree to use adequate contraception. Adequate contraception is defined as any combination of at least 2 effective methods of birth control, of which at least one is a physical barrier (e.g. condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices). Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate) or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only: FSH levels > 40 mIU/mL and estradiol < 20 pg/mL] or have had surgical treatment such as bilateral tubal ligation, bilateral ovarectomy, or hysterectomy.
4. Subjects with type 2 diabetes mellitus as defined by the American Diabetes Association (35)
5. Subjects with a clinical diagnosis of DKD based on either of the following criteria at the
Run-in and Screening Visit:
--Persistent high albuminuria defined as UACR of  30 mg/g ( 3.4 mg/mmol) but < 300 mg/g (< 33.9 mg/mmol) in 2 out of 3 first morning void samples and eGFR  25 but ≤ 90 mL/min/1.73 m2 (CKD-EPI) (36, 37) 3
OR
-- Persistent very high albuminuria defined as UACR of ≥300 mg/g (≥33.9 mg/mmol) in 2 out of 3 first morning void samples and eGFR ≥60 mL/min/1.73 m2 (CKD-EPI)
(36, 37)
Note: One re-assessment of eGFR and UACR is allowed at the Run-in Visit and the Screening Visit. If one of the 3 UACR measurements is missing but the other 2 are valid, these values can be used to assess subject’s eligibility for this study.
6. Prior treatment with ACEIs and 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 (see Section 8.1).
7. Serum potassium ≤ 4.8 mmol/L at both the Run-in and the Screening Visit
Note: One re-assessment of potassium is allowed at the Run-in and the Screening Visit.
8. Ability to understand and follow study-related instructions.

Medical and surgical history
1. Known significant non-diabetic renal disease, including clinically relevant renal artery
stenosis
2. UACR > 5000 mg/g (> 565 mg/mmol) at the Run-in Visit or Screening Visit
3. HbA1c > 12% (> 108 mmol/mol) at the Run-in Visit or Screening Visit
4. Uncontrolled arterial hypertension with mean sitting systolic blood pressure (SBP)
170 mmHg or mean sitting diastolic blood pressure (DBP) 110 mmHg at the
Run-in Visit or mean sitting SBP 160 mmHg or mean sitting DBP 100 mmHg at the
Screening Visit
5. SBP < 90 mmHg at the Run-in Visit or at the Screening Visit
6. Subjects with a clinical diagnosis of chronic heart failure with reduced ejection fraction
(HFrEF) and persistent symptoms (New York Heart Association class II - IV) at the
Run-in Visit (class 1A recommendation for MRAs)
7. Stroke, transient ischemic cerebral attack, acute coronary syndrome, or hospitalization for
worsening heart failure, in the last 30 days prior to the Run-in Visit
8. Dialysis for acute renal failure within 12 weeks prior to the Run-in Visit
9. Renal allograft in place or a scheduled kidney transplant within the next 12 months from
the Run-in Visit
10. Known hypersensitivity to the study treatment (active substance or excipients)
11. Addison’s disease
12. Hepatic insufficiency classified as Child-Pugh C (see Section 16.2).
Medication and drug use
13. Concomitant therapy with eplerenone, spironolactone, any renin inhibitor, or potassium-sparing diuretic which cannot be discontinued at least 4 weeks prior to the Screening Visit
14. Concomitant therapy with both ACEI and ARBs which cannot be discontinued for the purpose of the study
15. Concomitant therapy with potent cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors or inducers (to be stopped at least 7 days before randomization) (see Section 16.1).
Other
16. Any other condition or therapy, which would make the subject unsuitable for this study and will not allow participation for the full planned study period (e.g. active malignancy or other condition limiting life expectancy to less than 12 months)
17. Pregnant or breast-feeding or intention to become pregnant during the study
18. Previous assignment to treatment during this study or Studies 16244 or 16275
19. Previous (within 30 days prior to randomization) or concomitant participation in another clinical study (i.e. Phase I-III clinical studies) with investigational medicinal product(s), except for participation in the Run-in and Screening period of Study 16244 (see also
details on switch over in Section 6.4.2.2)
20. Close affiliation with the investigational site; e.g. a close relative of the investigator,
dependent person (e.g. employee or student of the investigational site).