Obesity; Chronic Kidney Disease; Albuminuria
Conditions
Keywords
Obesity-related chronic kidney disease; Non-diabetic; Albuminuria; Finerenone; Semaglutide; Mineralocorticoid receptor antagonist; GLP-1 receptor agonist; UACR
Brief summary
This multicenter, randomized, double-blind, placebo-controlled, parallel-group study will evaluate whether starting finerenone together with semaglutide provides an additional reduction in urinary albumin-to-creatinine ratio compared with semaglutide plus matching placebo in adults in China with obesity, albuminuric chronic kidney disease, and without diabetes. Approximately 266 participants will be randomized in a 1:1 ratio. The treatment period will last 24 weeks, followed by a 4-week off-treatment follow-up period.
Detailed description
Eligible participants will be randomized 1:1 to semaglutide plus finerenone or semaglutide plus matching finerenone placebo. Randomization will be stratified by baseline UACR category and BMI category. Semaglutide will be initiated at 0.25 mg once weekly and escalated every 4 weeks to a maximum of 2.4 mg once weekly as tolerated. Finerenone or matching placebo will start at 10 mg or 20 mg once daily according to baseline eGFR, with protocol-defined dose adjustment based on serum potassium and eGFR. The double-blind treatment period is 24 weeks, followed by 4 weeks off treatment. The primary objective is to compare change from baseline in UACR at Week 24. Secondary and other outcomes assess albuminuria response, kidney function, body size, blood pressure, inflammation, metabolic markers, and safety.
Interventions
DRUGFinerenone
Oral finerenone once daily for 24 weeks. Starting dose is 10 mg for eGFR 25 to \<60 mL/min/1.73 m2 and 20 mg for eGFR \>=60 mL/min/1.73 m2, with protocol-defined adjustment based on serum potassium and eGFR.
Oral matching placebo once daily for 24 weeks, with tablet number and protocol-defined adjustment procedures matched to finerenone.
DRUGSemaglutide
Subcutaneous semaglutide once weekly: 0.25 mg for Weeks 1-4, 0.5 mg for Weeks 5-8, 1.0 mg for Weeks 9-12, 1.7 mg for Weeks 13-16, and 2.4 mg from Week 17 through Week 24, or the maximum tolerated dose.
Sponsors
Peking University People's Hospital
Daqing Oil Field Hospital
First Affiliated Hospital Xi'an Jiaotong University
The Second Affiliated Hospital of Qiqihar Medical University
Capital Medical University
Huai'an Fifth People's Hospital
Heilongjiang Provicial Hospital
The First Affiliated Hospital of Henan University of Science and Technology
Shenzhen University General Hospital
Qiqihar First People's Hospital
Zibo Central Hospital
Hebei General Hospital
Suzhou Municipal Hospital
Yan'an University Affiliated Hospital
Tianjin People's Hospital
The First Hospital of Hebei Medical University
Daqing Longnan Hospital
Bayer Healthcare Co., Ltd.
Luoyang First People's Hospital
Beijing Pinggu District Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\. Age \>=18 years at the time of signing the informed consent form, without gender restriction; * 2\. Meet one of the following definitions of excess adiposity at screening: 1. BMI \>=28 kg/m\^2 and waist-to-height ratio \>=0.5; 2. Direct body fat measurement shows significantly elevated body fat percentage (\>=25% for adult males and \>=30% for adult females), which can be measured by bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA), or other methods; * 3\. Clinically diagnosed with chronic kidney disease (CKD), and meet all of the following: 1. At least 2 consecutive documented UACR values \>30 mg/g within 12 weeks prior to screening; UACR ranges from 100 to 3500 mg/g (11.4-395.9 mg/mmol) at screening; 2. eGFR \>=25 mL/min/1.73 m\^2 at screening (calculated using the CKD-EPI equation); * 4\. Stable renal function at screening, defined as a change in eGFR of less than 30% within 12 weeks prior to screening; * 5\. Voluntarily sign the informed consent form and be willing to strictly comply with all requirements and restrictions specified in the informed consent form and this protocol throughout the study period.
Exclusion criteria
* 1\. Known allergy to the study drug (active ingredients or excipients) or similar drugs. * 2\. A previous diagnosis of type 1 diabetes mellitus \[including latent autoimmune diabetes in adults (LADA)\], type 2 diabetes mellitus, or other types of diabetes mellitus; or HbA1c \>= 6.5% or fasting blood glucose \>= 7.0 mmol/L at screening. * 3\. Serum potassium \> 5 mmol/L at screening. * 4\. Patients with chronic kidney disease (CKD) requiring hormonal or immunosuppressant therapy within 6 months prior to screening. * 5\. Mean blood pressure \> 160/100 mmHg or mean systolic blood pressure \< 90 mmHg at screening. * 6\. History of renal transplantation, or acute kidney injury requiring dialysis within 24 weeks prior to the screening visit. * 7\. Occurrence of any acute cardiovascular or cerebrovascular events within 12 weeks prior to screening, including decompensated heart failure, myocardial infarction, stroke, transient ischemic attack, pulmonary embolism, elective percutaneous coronary intervention, or coronary artery bypass grafting. * 8\. Prior treatment with mineralocorticoid receptor antagonists (MRAs) (e.g., finerenone, eplerenone, esaxerenone, spironolactone, canrenone) or renin inhibitors within 8 weeks prior to screening. * 9\. Prior treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) within 8 weeks prior to screening. * 10\. Ongoing or planned treatment with potassium supplements, potassium-sparing diuretics (e.g., amiloride, triamterene), or potassium-binding agents within 8 weeks prior to screening. * 11\. Use of traditional Chinese medicines that may affect urinary protein excretion. * 12\. Receiving continuous treatment with strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ketoconazole, ritonavir, nelfinavir, cobicistat, telithromycin, nefazodone), strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, phenobarbital, St. John's wort), or moderate CYP3A4 inducers (e.g., efavirenz) that cannot be discontinued, with no drug washout for at least 7 days prior to randomization. * 13\. Hepatic insufficiency (Child-Pugh Class C). * 14\. Addison's disease. * 15\. Symptomatic heart failure with reduced ejection fraction that requires MRA administration as standard therapy. * 16\. Uncontrolled thyroid disease at screening (defined as TSH \> 6.0 mIU/L or \< 0.4 mIU/L), personal or family history of medullary thyroid carcinoma, or diagnosis of multiple endocrine neoplasia type 2 syndrome. * 17\. History of acute pancreatitis within 24 weeks prior to screening, or current chronic pancreatitis. * 18\. Participation in any other interventional clinical trial or use of any investigational product within 12 weeks prior to randomization. * 19\. History of alcohol or substance abuse. * 20\. Females of childbearing potential who are pregnant, breastfeeding, intend to become pregnant during the study period, or fail to adopt effective contraceptive measures. * 21\. Any other medical conditions that, in the investigator's judgment, may interfere with the efficacy or safety assessment of the study and make the subject inappropriate for study participation.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) at Week 24 | Baseline to Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With UACR <30 mg/g at Week 24 | Baseline to Week 24 | Percentage of participants meeting the protocol-defined albuminuria remission threshold. |
| Proportion of Participants Achieving a ≥30%, ≥40%, or ≥50% Reduction in UACR from Baseline | Baseline to Week 24 | Percentage of participants with a reduction in UACR of at least 30%, 40%, or 50% from baseline. |
| Proportion of Participants With Regression of Albuminuria Category | Baseline to Week 24 | Regression is defined as a change from UACR \>=300 mg/g to 30-299 mg/g, or from UACR 30-299 mg/g to \<30 mg/g. |
| Change From Baseline in Creatinine-based Estimated Glomerular Filtration Rate (Cr-eGFR) | Baseline to Week 24 | Cr-eGFR will be calculated using the CKD-EPI equation. |
| Change From Baseline in Cystatin C-based Estimated Glomerular Filtration Rate (Cys-C-eGFR) | Baseline to Week 24 | Change in Cys-C-eGFR from baseline. |
| Estimated Glomerular Filtration Rate Slope Through Week 24 | Baseline through Week 24 | Rate of change in eGFR over the 24-week treatment period. |
| Change From Baseline in Body Weight | Baseline to Week 24 | — |
| Change From Baseline in Waist Circumference | Baseline to Week 24 | — |
| Change From Baseline in Body Mass Index (BMI) | Baseline to Week 24 | — |
| Change From Baseline in Waist-to-Height Ratio | Baseline to Week 24 | — |
| Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) | Baseline to Week 24 | — |
| Change From Baseline in Systolic Blood Pressure | Baseline to Week 24 | — |
| Change From Baseline in Diastolic Blood Pressure | Baseline to Week 24 | — |
| Change From Baseline in Serum Uric Acid | Baseline to Week 24 | — |
| Change From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) | Baseline to Week 24 | — |
Outcome results
None listed