Phase III Randomized Double‑Blind Study of Balcinrenone + Dapagliflozin vs Dapagliflozin on Renal and Cardiovascular Outcomes in Patients with CKD Stages 3b‑4

The primary objective is to assess whether the combination of balcinrenone and dapagliflozin is superior to dapagliflozin alone in reducing a composite endpoint of cardiovascular death, death from renal failure, incident renal failure, a sustained ≥ 50 % decline in eGFR, and heart‑failure events in patients with chronic kidney disease stage 3b–4, thereby addressing key renal and cardiovascular risk drivers in this population.

Secondary objectives include:

• Evaluation of superiority in reducing the combined risk of cardiovascular death, death from renal failure, incident renal failure, and a sustained ≥ 50 % decline in eGFR.
• Assessment of the effect on albuminuria reduction.
• Determination of superiority in lowering the risk of cardiovascular death and heart‑failure events.
• Evaluation of superiority in reducing cardiovascular death alone.
• Assessment of superiority in reducing all‑cause mortality.

In total, 2,133 individuals were enrolled; the cohort comprised adult men and women aged 18 years and older, all diagnosed with chronic kidney disease (renal insufficiency, chronic). Participants were selected on the basis of a confirmed diagnosis of CKD with specified ranges of estimated glomerular filtration rate (eGFR) and albuminuria, serum potassium ≤5.0 mmol/L, and receipt of a stable, maximally tolerated dose of an ACE inhibitor or angiotensin‑II receptor blocker for at least four weeks prior to screening. Both sexes were represented, and the trial included participants classified as vulnerable. The population was otherwise required to be in general stable health aside from the underlying renal condition.

The study is a randomized, double-blind, placebo-controlled Phase III trial evaluating the effect of balcinrenone/dapagliflozin versus dapagliflozin on renal and cardiovascular outcomes in adults with Chronic Kidney Disease stage 3b–4. Participants are screened during an initial visit to confirm eligibility criteria, including eGFR 15–<45 mL/min/1.73 m² and albuminuria thresholds, stable ACE‑inhibitor or ARB therapy, and serum potassium ≤5.0 mmol/L. After randomization, subjects receive either the test combination (balcinrenone + dapagliflozin) or the comparator (dapagliflozin) with matching placebo capsules to maintain blinding. Follow‑up visits occur at regular intervals (e.g., weeks 4, 12, 24, and every 12 weeks thereafter) to assess safety, laboratory parameters, and efficacy endpoints, with the primary outcome defined as time to first occurrence of any component of the composite primary endpoint (cardiovascular death, death from kidney failure, initiation of dialysis or transplantation, sustained ≥50 % decline in eGFR, or heart‑failure event). The end‑of‑study visit is scheduled after the final follow‑up period, concluding participant involvement, which may extend up to approximately 4 years from the screening visit, corresponding to the overall trial timeline from September 2026 to July 2030. Early termination may occur if a participant withdraws consent, experiences a serious adverse event requiring discontinuation, fails to adhere to protocol‑defined medication stability, or initiates renal replacement therapy before the scheduled end‑of‑study assessment.

The investigational product, identified as Balcinrenone/Dapagliflozin, is supplied as a hard‑filled capsule for oral administration. The capsule contains balcinrenone and dapagliflozin; the specified dose is recorded as 0 mg for each component in the source data, and dosing is performed once daily in accordance with the study protocol. Administration occurs under double‑blind conditions, and compliance is monitored through returned capsule counts and electronic medication diaries.

The active comparator is dapagliflozin 10 mg film‑coated tablets, marketed as Forxiga. This formulation is taken orally once daily, with the dose explicitly defined as 10 mg per tablet. Participants receive the active tablet or a matching placebo, and adherence is assessed by tablet count and patient‑reported dosing logs.

A matched placebo corresponding to the Forxiga tablet, labeled Forxiga Placebo, is provided in a film‑coated tablet form that mimics the appearance of the active comparator. The placebo is administered orally once daily, and dosing frequency mirrors that of the active dapagliflozin tablet. Compliance monitoring follows the same procedures as for the active treatments.

A second placebo preparation contains balcinrenone combined with dapagliflozin in a formulation that does not contain active drug. This product is also administered orally once daily, matching the schedule of the investigational capsule. Pill counts and electronic diaries are employed to evaluate participant adherence.

Efficacy will be evaluated primarily by measuring the time from randomization to the first occurrence of any component of a predefined composite endpoint. The composite includes cardiovascular death, death from kidney failure, onset of kidney failure (initiation of maintenance dialysis or kidney transplantation), a sustained decline of ≥ 50 % from baseline in eGFR, and a heart failure event.

Key secondary efficacy assessments comprise:

• Time from randomization to the first occurrence of each individual component of the primary composite, including death from kidney failure, heart failure (with or without hospitalization), and isolated cardiovascular death.
• Change from baseline to Week 24 in urinary albumin‑to‑creatinine ratio, evaluated using spot urine albumin and creatinine measurements.
• Time from randomization to death from any cause.

All time‑to‑event outcomes will be analyzed using appropriate survival‑analysis methods, and the change in urinary albumin‑to‑creatinine ratio will be assessed by comparing baseline and Week 24 values.