This study employs a prospective, randomized, double-blind, parallel-controlled design, aiming to enroll adult participants with type 2 diabetic kidney disease (DKD) who meet the eligibility criteria. With an angiotensin receptor blocker (ARB) as the background therapy, all participants will be randomized in a 1:1:1:1 ratio into four treatment groups: Group 1 (G1): ARB + empagliflozin + finerenone placebo + mazdutide placebo; Group 2 (G2): ARB + empagliflozin + finerenone + mazdutide placebo; Group 3 (G3): ARB + empagliflozin + mazdutide + finerenone placebo; Group 4 (G4): ARB + empagliflozin + mazdutide + finerenone. The primary comparisons include G2 vs. G1, G3 vs. G1, G4 vs. G2, and G4 vs. G3, designed to evaluate the superiority of triple therapy over dual therapy, and quadruple therapy over triple therapy, in reducing the urine albumin-to-creatinine ratio (UACR).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
820
Oral tablet, administered at a fixed dose of 10 mg once daily for 6 months.
Oral tablet, taken once daily for 6 months. Initial dose is 10 mg or 20 mg once daily adjusted based on baseline eGFR (20 mg for eGFR \>= 60 mL/min/1.73m²; 10 mg for eGFR 30-60 mL/min/1.73m²). Subsequent dose adjustments are guided by serum potassium levels and renal function.
Once-weekly subcutaneous injection for 6 months, following a mandatory dose-escalation schedule: initiated at 2 mg once weekly for 4 weeks, up-titrated to 4 mg once weekly for 4 weeks (if tolerated), and further increased to 6 mg once weekly as the target maintenance dose.
Oral tablet matching active finerenone in appearance and scheduling, without active ingredients, taken once daily for 6 months.
Once-weekly subcutaneous injection matching active mazdutide in appearance and scheduling, without active ingredients, for 6 months.
Standard background therapy, titrated to a stable dose for at least 4 weeks prior to enrollment and maintained throughout the 6-month study period.
Zhongshan Hospital, Fudan University
Shanghai, Shanghai Municipality, China
Relative Change From Baseline in Urine Albumin-to-Creatinine Ratio (UACR) at Month 6
Relative change of UACR from baseline to Month 6 will be utilized for comparison between the treatment groups.
Time frame: Baseline and Month 6
Percentage of Participants Achieving UACR Reductions of ≥30% and ≥50%
The proportion of patients in each group who achieve a clinical response, defined as a reduction of ≥30% and ≥50% in UACR compared to their respective baseline values.
Time frame: Baseline and Month 6
Regression Rate of Albuminuria Stages
The percentage of participants demonstrating a regression in albuminuria category, including regression from macroalbuminuria to microalbuminuria, or from microalbuminuria to normoalbuminuria.
Time frame: Baseline and Month 6
Relative Change From Baseline in UACR at Day 30
Early relative change in UACR to evaluate the short-term response between treatment groups
Time frame: Baseline and Day 30
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
eGFR is calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation to monitor renal function progression.
Time frame: Baseline and Month 6
Change From Baseline in Body Weight and Body Mass Index (BMI)
Evaluation of the metabolic impact of the multi-drug regimens on body weight (measured in kilograms) and BMI (measured in kg/m²).
Time frame: Baseline and Month 6
Change From Baseline in Hemoglobin A1c (HbA1c) and Fasting Plasma Glucose (FPG)
Assessment of glycemic control efficacy across different treatment groups.
Time frame: Baseline and Month 6
Change From Baseline in Systolic Blood Pressure (SBP)
Evaluation of the blood pressure-lowering effects between different treatment groups.
Time frame: Baseline and Month 6
Change From Baseline in Serum Potassium Levels
Monitoring the safety profile regarding potassium homeostasis, particularly concerning the use of the non-steroidal MRA (finerenone).
Time frame: Baseline and Month 6
Incidence of Adverse Events of Special Interest (AESIs)
The percentage of participants experiencing predefined adverse events of interest, including hyperkalemia, symptomatic hypotension, urinary tract infections, hypoglycemia, and diabetic ketoacidosis.
Time frame: Through Month 6
Incidence of Acute Kidney Injury (AKI)
The percentage of patients who meet the clinical diagnostic criteria for Acute Kidney Injury during the treatment period.
Time frame: Through Month 6
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