Phase III Randomized Double‑Blind Trial of Elecoglipron (AZD5004) on Cardiovascular Mortality and Hospitalization in Adults with HFpEF or HFmrEF on Background Dapagliflozin

Primary objective: To assess whether elecoglipron reduces the incidence of cardiovascular death or heart failure hospitalization/urgent heart failure visit compared with placebo in adults with HFpEF or HFmrEF.

Secondary objectives:

• Evaluate the effect of elecoglipron versus placebo on the total rate of heart failure events (first and recurrent hospitalizations or urgent visits).
• Assess change in patient-reported outcomes using a validated questionnaire total score from baseline to week 52 among participants below a predefined baseline threshold.
• Determine the impact of elecoglipron versus placebo on the time to first occurrence of a 4‑point composite endpoint of all‑cause mortality, heart failure hospitalization, myocardial infarction, or stroke.

The trial enrolled 4,607 participants diagnosed with heart failure with preserved ejection fraction (including mildly reduced ejection fraction) and receiving background SGLT2‑inhibitor therapy. Eligible individuals were adults 18 years of age or older, of both sexes, and were ambulatory or recently hospitalized but off intravenous heart‑failure treatments for at least 12 hours. Inclusion required a left ventricular ejection fraction >40 % with documented structural heart disease, elevated NT‑proBNP, and symptomatic heart failure within predefined functional class ranges. Participants could be SGLT2‑inhibitor naïve or have initiated a dapagliflozin run‑in during hospitalization, provided randomization occurred after discharge. All subjects provided written informed consent and were capable of complying with protocol requirements. The population comprised generally stable patients with chronic heart failure, without further specified lifestyle restrictions.

The study is a Phase III, randomized, double-blind, parallel‑group, placebo-controlled trial evaluating oral Elecoglipron (film‑coated tablet) versus matching placebo in adults with HFpEF or HFmrEF who are receiving background dapagliflozin 10 mg daily. After an initial screening visit to confirm eligibility criteria, participants are randomized and receive the first dose of study medication. Follow‑up visits are scheduled at Weeks 4, 12, 24, 36, and 52 to assess safety, adherence, and efficacy, with the primary efficacy assessment occurring at the end‑of‑study visit at Week 52. The primary efficacy measure is the time to first occurrence of any component of the composite of cardiovascular death, hospitalization for heart failure, or urgent heart‑failure visit (primary endpoint), and secondary measures include total heart‑failure events, change in a patient‑reported outcome score, and time to a composite of all‑cause death, hospitalization for heart failure, myocardial infarction, or stroke (secondary endpoints). Participant involvement spans approximately one year from randomization to the final assessment. Early termination may occur if a participant withdraws consent, experiences a serious adverse event requiring discontinuation, violates major protocol provisions, or requires prohibited concomitant therapy.

The investigational product, Elecoglipron, is administered as a film‑coated tablet for oral use. Each tablet contains 0 mg of the active substance elecoglipron. The dosing regimen, including frequency and duration, follows the protocol‑specified schedule and is delivered under double‑blind conditions. Compliance is monitored through pill counts and electronic medication diaries at each study visit.

All participants receive background therapy with dapagliflozin 10 mg film‑coated tablets (commercially known as Forxiga). The medication is taken orally once daily throughout the study period. Adherence to the background therapy is assessed by regular pill counts and patient logs.

The comparator arm utilizes a matching placebo for Elecoglipron (AZD5004), provided as an identical‑appearing film‑coated tablet for oral administration. The placebo is administered according to the same schedule as the active investigational product, ensuring blinding of participants and investigators. Placebo compliance is similarly tracked via pill counts and electronic records.

Efficacy will be evaluated primarily by Time to first occurrence of any component of the composite of cardiovascular death, hospitalization for heart failure, or urgent heart failure visit. This time‑to‑event endpoint will be captured from randomization until the end of the treatment period, with events adjudicated by an independent committee. Survival analysis techniques will be applied to compare the incidence between the elecoglipron and placebo groups.

Key secondary efficacy assessments include:

• Total number of heart failure events (first and recurrent; hospitalization for heart failure and urgent heart failure visits) recorded throughout the study.
• Change from baseline to Week 52 in a prespecified HF patient‑reported outcome total score among participants whose baseline score falls below a defined threshold, measured using the designated patient‑reported outcome instrument.
• Time to first occurrence of the composite of all‑cause death, hospitalization for heart failure, myocardial infarction, or stroke, defined as the 4point MACE endpoint, analyzed using time‑to‑event methods.