Phase III Randomized Double‑Blind Placebo‑Controlled Trial of Elecoglipron (AZD5004) on Renal Decline and Mortality in Adults with Chronic Kidney Disease

The primary objective is to determine whether elecoglipron reduces the risk of the predefined composite endpoint of a ≥50% sustained decline in estimated glomerular filtration rate (eGFR), progression to end‑stage kidney disease (ESKD), or all‑cause mortality compared with placebo in adults with chronic kidney disease. Secondary objectives assess additional efficacy and safety outcomes, including:

• Effect of elecoglipron versus placebo on (a) the composite of ≥50% sustained eGFR decline, ESKD, or cardiovascular/renal death; (b) a renal‑specific composite of ≥50% eGFR decline, ESKD, or renal death; (c) cardiovascular death or heart‑failure hospitalization; (d) a composite of cardiovascular death, myocardial infarction, stroke, or heart‑failure hospitalization; and (e) all‑cause hospitalization.
• Impact on (1) a composite of all‑cause mortality, myocardial infarction, and stroke; (2) all‑cause mortality alone; (3) MACE (cardiovascular death, myocardial infarction, stroke); and (4) time to first cardiovascular death.

The trial enrolled 5,320 participants who were adults aged 18 years and older, inclusive of all gender identities. All subjects had Chronic kidney disease meeting predefined ranges of estimated glomerular filtration rate and urine albumin‑to‑creatinine ratio, regardless of type 2 diabetes status, and were receiving stable background therapy with dapagliflozin 10 mg and a maximally tolerated dose of an ACE inhibitor or ARB for at least 28 days. Eligibility required legal capacity to consent, the ability to adhere to study procedures, and, for those who chose, consent for optional genomics sampling. Both male and female patients were enrolled, and vulnerable individuals were not excluded. No specific dietary or physical‑activity restrictions were imposed beyond standard clinical care for chronic kidney disease.

The study is a Phase III, randomized, double‑blind, parallel‑group, placebo‑controlled trial evaluating elecoglipron versus placebo in adults with chronic kidney disease receiving background dapagliflozin 10 mg daily. Participants are screened at an initial inclusion visit to confirm eligibility criteria, obtain informed consent, and record baseline laboratory values, including eGFR and albumin‑creatinine ratio. Eligible subjects are then randomized in a 1:1 ratio and commence study medication at the baseline visit, which also documents concomitant therapy and provides dosing instructions. Subsequent follow‑up visits occur at regular intervals (e.g., every 12 weeks) to assess safety, collect blood and urine samples for eGFR and UACR, monitor adherence, and record any adverse events. The trial continues for the duration of the participant’s involvement, which may extend up to approximately four years from randomization, culminating in an end‑of‑study visit that captures final outcome data for the primary composite endpoint of ≥50 % sustained eGFR decline, end‑stage kidney disease, or all‑cause mortality. Early termination may occur if a participant withdraws consent, experiences a serious adverse event, violates major protocol provisions, requires prohibited concomitant therapy, or progresses to dialysis or transplantation that precludes continued assessment.

The investigational product Elecoglipron is supplied as a film‑coated tablet for oral administration. Each tablet contains 0 mg of the active substance elecoglipron and is administered according to the dosing schedule defined in the study protocol.

The matched placebo for Elecoglipron (AZD5004) contains no active pharmaceutical ingredient and is presented in a form indistinguishable from the active tablet. It is administered orally in the same manner and schedule as the active investigational product.

All participants receive background therapy with dapagliflozin 10 mg film‑coated tablets (commercial name Forxiga). The tablet is taken orally, once daily, as part of standard‑of‑care management for the study population.

Efficacy will be evaluated by time‑to‑event analysis of the predefined composite outcomes. The primary efficacy endpoint is the time to first occurrence of any component of the composite of a ≥50% sustained decline in eGFR, end‑stage kidney disease (sustained eGFR < 10 mL/min/1.73 m², chronic dialysis, or renal transplant), or all‑cause mortality.

Secondary efficacy assessments include time to first occurrence of additional composites such as ≥50% sustained decline in eGFR, end‑stage kidney disease, or cardiovascular and renal death; all‑cause mortality, myocardial infarction, or stroke; 3‑point major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke); cardiovascular death; pure renal composite (≥50% sustained decline in eGFR, end‑stage kidney disease, or renal death); cardiovascular death or hospitalization for heart failure; cardiovascular death, myocardial infarction, stroke, or heart‑failure hospitalization; and all‑cause hospitalization. All time‑to‑event endpoints will be analyzed using appropriate survival‑analysis methods, including Kaplan‑Meier estimation and Cox proportional‑hazards modeling, as defined in the statistical analysis plan.