Finerenone for Regression of Albuminuria in Type 2 Diabetes With Chronic Kidney Disease

Официальное название

Efficacy and Safety of Finerenone for the Early Regression of Albuminuria in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Обзор

This is a multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy and safety of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, for the early regression of albuminuria in adults with type 2 diabetes mellitus and chronic kidney disease (eGFR \>= 30 mL/min/1.73 m\^2 and UACR 30-2000 mg/g) who are already receiving a maximum tolerated dose of an ACE inhibitor or ARB. A total of 148 participants are randomized 1:1, stratified by baseline UACR (\<300 vs \>=300 mg/g), to oral finerenone (10 or 20 mg once daily, titrated by serum potassium and eGFR) or matching placebo, on top of standard background therapy, for 180 days, followed by a 30-day off-treatment follow-up. Albuminuria regression is defined as both an improvement in Kidney Disease: Improving Global Outcomes albuminuria category, from A3 to A2 or A1, or from A2 to A1, and a more than 30% reduction in urinary albumin-to-creatinine ratio from baseline. The outcome will be reported as the percentage of participants meeting this definition at Day 180.

Подробное описание

Background and rationale: Finerenone is an oral, highly selective nonsteroidal mineralocorticoid receptor antagonist approved in China for the treatment of chronic kidney disease associated with type 2 diabetes (with albuminuria). In the phase III FIDELIO-DKD and FIGARO-DKD trials, finerenone added to a maximum tolerated dose of a renin-angiotensin system inhibitor significantly and durably reduced the urine albumin-to-creatinine ratio (UACR) and lowered the risk of kidney and cardiovascular events, with a manageable hyperkalemia risk. A meaningful reduction in albuminuria is an established early surrogate for slowing CKD progression and reducing cardiovascular risk. This study evaluates whether finerenone can achieve early regression of albuminuria in patients with type 2 diabetes and CKD.

Design: This is a multicenter, randomized, double-blind, placebo-controlled trial conducted at up to 12 sites in China. A planned 148 participants are allocated 1:1 to finerenone or matching placebo using central, block randomization (interactive response technology), stratified by baseline UACR (\<300 vs \>=300 mg/g). Participants and investigators are blinded; placebo tablets are identical in appearance to finerenone, and intervention-period UACR samples are assayed centrally after study completion to preserve blinding.

Population: Eligible participants are adults with type 2 diabetes and CKD (eGFR \>= 30 mL/min/1.73 m\^2 and UACR 30-2000 mg/g) who have received a maximum tolerated dose of an ACE inhibitor or ARB for at least 90 days and have serum potassium \<= 5.0 mmol/L.

Intervention and dose titration: The starting dose is determined by screening eGFR: 10 mg once daily for 30 \<= eGFR \< 60 mL/min/1.73 m\^2, or 20 mg once daily for eGFR \>= 60 mL/min/1.73 m\^2. The dose is up-titrated to 20 mg, maintained, interrupted, or down-titrated to 10 mg based on serum potassium and eGFR at scheduled and, if needed, unscheduled safety visits. Treatment continues for 180 days.

Visit schedule: a screening period (Day -30 to -1; V1); a treatment period ; and an off-treatment follow-up at Day 210 +/- 5 (V7). Unscheduled safety visits and early-discontinuation visits are performed as needed.

Endpoints: The primary endpoint is the albuminuria regression rate at 180 days, defined as a reduction in UACR KDIGO albuminuria category (A3 to A2 or A1, or A2 to A1) together with a \>=30% reduction in UACR from baseline. Secondary endpoints include the change in UACR, the rate of regression to normoalbuminuria, the proportions achieving \>=30/40/50% UACR reduction, KDIGO GFR-Albuminuria category improvement, the change in UACR 30 days after discontinuation, the change in eGFR slope, and the change in blood pressure. Safety endpoints include adverse events, serious adverse events, and adverse events of special interest (notably serum potassium changes and hyperkalemia). Exploratory endpoints also included.

Вмешательства

• Препарат Finerenone (BAY 94-8862)
  Oral finerenone 10 mg or 20 mg once daily, with dose titration by serum potassium and eGFR, for 180 days.
• Препарат Placebo
  Matching placebo tablets, identical in appearance to finerenone, orally once daily, following the same dosing and titration schedule, for 180 days.

Первичные конечные точки

• Albuminuria regression rate [Срок оценки: 180 days]

Вторичные конечные точки (8)

• Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio [Срок оценки: Baseline and 180 days]
• Percentage of Participants With Normoalbuminuria [Срок оценки: 180 days]
• Percentage of Participants by UACR Reduction Response Category at Day 180 [Срок оценки: Baseline to Day 180]
• Percentage of Participants With Improvement in Kidney Disease: Improving Global Outcomes Albuminuria Category at Day 180 [Срок оценки: Baseline to Day 180]
• Change From Day 180 to Day 210 in Urinary Albumin-to-Creatinine Ratio [Срок оценки: Day 180 to Day 210]
• Estimated Glomerular Filtration Rate Slope Through Day 180 [Срок оценки: Baseline through Day 180]
• Change From Baseline in Systolic Blood Pressure at Day 180 [Срок оценки: Baseline to Day 180]
• Change From Baseline in Diastolic Blood Pressure at Day 180 [Срок оценки: Baseline to Day 180]

Критерии участия

Критерии включения

• 1\. Age >= 18 years at the time of signing informed consent, male or female.
• 2\. Type 2 diabetes mellitus.
• 3\. Chronic kidney disease meeting BOTH of the following: eGFR (CKD-EPI) >= 30 mL/min/1.73 m\^2, and UACR 30-2000 mg/g (mean of 3 measurements).
• 4\. Serum potassium <= 5.0 mmol/L.
• 5\. On a maximum tolerated dose of an ACE inhibitor or ARB for at least 90 days.
• 6\. Treatment with an SGLT-2 inhibitor, GLP-1 receptor agonist, or other agents affecting UACR is permitted, but the type and dose must be stable for at least 30 days before screening.

Критерии исключения

• 1\. Type 1 diabetes, other specific types of diabetes, or gestational diabetes.
• 2\. HbA1c >= 8.0%.
• 3\. On renal replacement therapy.
• 4\. Acute kidney injury within 180 days before the screening visit.
• 5\. Hepatic impairment (Child-Pugh class C).
• 6\. Blood pressure > 160/100 mmHg, or systolic blood pressure < 90 mmHg, at the screening visit.
• 7\. Bilateral renal artery stenosis.
• 8\. Known hypersensitivity to the study drug (active substance or excipients).
• 9\. Treatment with finerenone within 60 days before screening.
• 10\. Stroke, transient ischemic attack, acute coronary syndrome (myocardial infarction, CABG, PCI), or hospitalization for worsening heart failure within 90 days before the screening visit.
• 11\. NYHA class II-IV heart failure.
• 12\. Addison's disease.
• 13\. Gastrointestinal surgery that may affect drug absorption.
• 14\. Any other history, condition, therapy, or uncontrolled concomitant disease that makes the participant unsuitable for the study or unlikely to complete it (e.g., active malignancy or other disease with life expectancy < 12 months).
• 15\. Treatment with a strong CYP3A4 inhibitor (e.g., itraconazole, clarithromycin, ketoconazole, ritonavir, nelfinavir, cobicistat, telithromycin, nefazodone), a strong CYP3A4 inducer (e.g., carbamazepine, phenytoin, phenobarbital, St. John's wort), or a moderate CYP3A4 inducer (e.g., efavirenz) that cannot be discontinued for at least 7 days before randomization.
• 16\. Treatment with another mineralocorticoid receptor antagonist (e.g., spironolactone, eplerenone, esaxerenone) or a potassium-sparing diuretic (e.g., amiloride, triamterene) that cannot be discontinued for at least 60 days before the screening visit.
• 17\. Biopsy-confirmed non-diabetic kidney disease (e.g., IgA nephropathy).
• 18\. Immunosuppressive therapy, or glucocorticoid use by any route other than topical or inhaled, within the past 180 days.
• 19\. Participation in another interventional clinical study or use of any investigational product within 90 days before randomization.
• 20\. History of alcohol or drug abuse.
• 21\. Women of childbearing potential who are pregnant, breastfeeding, intend to become pregnant, or are not using adequate contraception during the study.
• 22\. Any other condition deemed by the investigator to make the participant unsuitable for the study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

Китай · 13 центров

• The First Affiliated Hospital of Chongqing Medical University — Чунцин
• Fujian Provincial Hospital — Фучжоу
• Sanshui Hospital, Zhujiang Hospital, Southern Medical University — Foshan
• Nanfang Hospital, Southern Medical University — Гуанчжоу
• Nantong First People's Hospital — Nantong
• The First People's Hospital of Suqian — Suqian
• Suzhou Science and Technology City Hospital — Сучжоу
• Xi'an Daxing Hospital — Сиань
• … и ещё 5 центров

Публикации

• Heerspink HJ, Gao P, de Zeeuw D, Clase C, Dagenais GR, Sleight P, Lonn E, Teo KT, Yusuf S, Mann JF. The effect of ramipril and telmisartan on serum potassium and its association with cardiovascular and renal events: results from the ONTARGET trial. Eur J Prev Cardiol. 2014 Mar;21(3):299-309. doi: 10.1177/2047487313510678. Epub 2013 Nov 4. PMID 24191305
• Coresh J, Grams ME, Chen TK. Using GFR, Albuminuria, and Their Changes in Clinical Trials and Clinical Care. Am J Kidney Dis. 2021 Sep;78(3):333-334. doi: 10.1053/j.ajkd.2021.04.003. Epub 2021 May 28. No abstract available. PMID 34059333
• Inker LA, Heerspink HJL, Tighiouart H, Chaudhari J, Miao S, Diva U, Mercer A, Appel GB, Donadio JV, Floege J, Li PKT, Maes BD, Locatelli F, Praga M, Schena FP, Levey AS, Greene T. Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis. Am J Kidney Dis. 2021 Sep;78(3):340-349.e1. doi: 10.1053/j PMID 33775708
• Lambers Heerspink HJ, Gansevoort RT. Albuminuria Is an Appropriate Therapeutic Target in Patients with CKD: The Pro View. Clin J Am Soc Nephrol. 2015 Jun 5;10(6):1079-88. doi: 10.2215/CJN.11511114. Epub 2015 Apr 17. PMID 25887073
• Levey AS, Gansevoort RT, Coresh J, Inker LA, Heerspink HL, Grams ME, Greene T, Tighiouart H, Matsushita K, Ballew SH, Sang Y, Vonesh E, Ying J, Manley T, de Zeeuw D, Eckardt KU, Levin A, Perkovic V, Zhang L, Willis K. Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US PMID 31473020
• Heerspink HJL, Greene T, Tighiouart H, Gansevoort RT, Coresh J, Simon AL, Chan TM, Hou FF, Lewis JB, Locatelli F, Praga M, Schena FP, Levey AS, Inker LA; Chronic Kidney Disease Epidemiology Collaboration. Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials. Lancet Diabetes Endocrinol. 2019 Feb;7(2):128- PMID 30635226
• Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJ, Lee BJ, Perkins RM, Rossing P, Sairenchi T, Tonelli M, Vassalotti JA, Yamagishi K, Coresh J, de Jong PE, Wen CP, Nelson RG; Chronic Kidney Disease Prognosis Consortium. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet. 2012 Nov 10; PMID 23013602
• Marup FH, Thomsen MB, Birn H. Additive effects of dapagliflozin and finerenone on albuminuria in non-diabetic CKD: an open-label randomized clinical trial. Clin Kidney J. 2023 Sep 26;17(1):sfad249. doi: 10.1093/ckj/sfad249. eCollection 2024 Jan. PMID 38186886

Идентификаторы

NCT: NCT07667517 · [2026C]IIT No.001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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