E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type II Diabetes Mellitus and Diabetic Kidney Disease |
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E.1.1.1 | Medical condition in easily understood language |
Type II Diabetes Mellitus and Diabetic Kidney Disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061835 |
E.1.2 | Term | Diabetic nephropathy |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Demonstrate whether, in addition to standard of care, finerenone is superior to placebo in delaying the time to first occurrence of cardiovascular mortality and morbidity in subjects with type 2 diabetes mellitus and the clinical diagnosis of diabetic kidney disease. |
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E.2.2 | Secondary objectives of the trial |
•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.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Echocardiography sub-study (section 9.7.8.1.1 of the CSP): The objective of the echocardiography imaging sub-study is to assess and characterize any important structural and functional cardiac abnormalities in patients with type 2 diabetes mellitus and diabetic kidney disease, at baseline, and to explore changes over time with finerenone treatment. These findings will enhance the understanding of cardiac function in the diabetic kidney disease Population.
Biomarker sub-study (section 9.7.8.1.2 of the CSP): The objective of the biomarker sub-study is to assess the levels of pathophysiological markers associated with cardiovascular and renal disease in patients with type 2 diabetes mellitus and diabetic kidney disease, at baseline, and to explore changes over time with finerenone treatment. These findings will enhance the understanding of the effects of finerenone on cardiovascular and renal disease progression, by evaluating these biological markers in addition to clinical outcomes |
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E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be included in the study:
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
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)
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).
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
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. |
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be excluded from the study:
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 HFrEF and persistent symptoms (NYHA class II – IV) at 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 of Run-in visit
9. Renal allograft in place or scheduled kidney transplant within 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
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).
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.
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). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to first occurrence of the composite endpoint of CV death or non-fatal CV event (i.e. myocardial infarction, stroke, or hospitalization for HF). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From randomization (Visit 1) until the end of study following the study termination decision, approximately from 18 to 36 months |
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E.5.2 | Secondary end point(s) |
Time to first occurrence of the following composite endpoint:
onset of kidney failure, a sustained decrease of eGFR ≥ 40% from baseline over at least 4 weeks or renal death
Time to all-cause hospitalization
Time to all-cause mortality
Change in UACR from baseline to Month 4*
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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For all endpoints:
From randomization (Visit 1) until the end of study following the study termination decision, approximately from 18 to 36 months
Except endpoint*:
From baseline / randomization to Month 4 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 24 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 300 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
Chile |
China |
Colombia |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Greece |
Hong Kong |
Hungary |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Lithuania |
Malaysia |
Mexico |
Netherlands |
New Zealand |
Norway |
Philippines |
Poland |
Portugal |
Romania |
Russian Federation |
Saudi Arabia |
Singapore |
Slovakia |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Turkey |
Ukraine |
United Kingdom |
United States |
Vietnam |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 52 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 53 |
E.8.9.2 | In all countries concerned by the trial days | 0 |