The primary purpose of the study is to evaluate the safety and efficacy of 2 doses of AC01 compared to placebo over 12 weeks in participants with chronic advanced HFrEF.

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study designed to evaluate the safety and efficacy of the ghrelin-receptor agonist AC01 compared to placebo in participants with chronic advanced HFrEF. Approximately 400 participants will be randomized to 1 of 3 treatment arms: 3 milligram (mg) AC01, 1 milligram (mg) AC01, or placebo twice daily for 12 weeks. The primary objective is to evaluate the effect of AC01 compared to placebo on cardiac structure and function assessed by echocardiography.

Key Inclusion Criteria:

• History of Chronic Heart Failure (CHF) diagnosed greater than or equal to (>=6) months before screening, and in NYHA Class II to IV at screening.

• Chronic advanced HFrEF defined as:

  • LVEF less than or equal to (<=) 35 percentage (%) by local reading >=6 months before screening or a record of LVEF qualitatively described as severely reduced or moderately-severely reduced >=6 months before screening, and
  • LVEF <=35% at the screening echocardiography (confirmed by core lab), and
  • no known LVEF greater than (>) 35% (or qualitatively described as less than moderately-severely reduced) between the 2 readings.

• Sinus rhythm or permanent, persistent, or paroxysmal atrial fibrillation flutter (AFF) (AFF at screening is capped at maximum 15% of participants enrolled) with mean resting heart rate of >=55 and <=90 beats per minute (bpm) at screening, and >=50 and <=95 bpm at randomization, regardless of rhythm.

• NT-proBNP >=400 picograms per milliliter (pg/mL) in sinus rhythm and >=800 pg/mL in AFF at screening (confirmed by central laboratory).

• Transvenous implantable cardioverter-defibrillator (ICD) for primary prevention with back-up pacing set at 40 bpm.

• Treated with optimal, stable, medical therapy for HF consistent with prevailing local and international guidelines unless contraindicated or not tolerated, as judged and documented by the investigator.

Key Exclusion Criteria:

• Any acute or serious co-morbid condition that could lead to premature termination of study participation or interfere with the measurement or interpretation of the efficacy and safety assessments in the study.
• Admitted to hospital with the primary reason of HF within 24 hours before randomization or currently hospitalized with the primary reason of HF for more than 10 days. Current hospitalization (>24 hours and <=10 days) is capped at a maximum of 15% of participants enrolled.
• Acute coronary syndrome, stroke or transient ischemic attack, severe ventricular arrhythmia, or major cardiac intervention, percutaneous coronary intervention, valvuloplasty/other cardiac valve repair or implantation, or cardiac surgery within 60 days before randomization.
• Systolic blood pressure >130 or ˂90 millimeters of mercury (mmHg) at screening, or >140 or ˂85 mmHg at randomization.
• Uncontrolled diabetes mellitus, defined as Hemoglobin A1c (HbA1c) >=9.0% (>=75 millimoles per mole [mmol/mol]) at screening, or severe complications of diabetes.
• Body weight <50 kilogram (kg) or body mass index (BMI) <18 kilograms per square meter (kg/m^2) or >45 kg/m^2 at screening.
• Any of the following electrocardiogram (ECG) findings at screening: Corrected QT interval using Fridericia's formula (QTcF) >450 milliseconds (ms), 1st degree atrioventricular (AV) block with PQ >240 ms, or AV block 2nd or 3rd degree.
• History of aborted cardiac arrest, sustained ventricular tachycardia, or Torsades-de Pointes, or congenital long QT syndrome. Family history of sudden cardiac death, unexplained death, long QT syndrome, or death from a primary dysrhythmia.
• Cardiac resynchronization therapy, Cardiac Contractility Modulation, or pacemaker device other than the back-up pacing function of the ICD.
• Mechanical hemodynamic support, kidney support, or ventilation within 7 days before randomization.
• Treatment with i.v. inotropes, i.v. vasodilators, or i.v. vasopressors within 3 days before randomization.
• Treatment with any i.v. diuretics or supplemental oxygen within 6 hours before randomization.
• Use of any drugs or substances known to be strong inducers of Cytochrome P450 3A4 (CYP3A4) enzyme within 28 days before randomization or planned to be used during the study period or strong inhibitors of CYP3A4 within 7 days before randomization or planned to be used during the study period.
• Use of any drug that is known to prolong the QT interval (for example, sotalol, dofetilide, macrolides, some antidepressants, and some antipsychotics) within 28 days before randomization or planned to be used during the study period.
• Treatment changes in glucose lowering therapy within 28 days before randomization.
• Estimated glomerular filtration rate (eGFR) <20 milliliters per minute per 1.73 square meters (mL/min/1.73 m2) according to the Chronic Kidney Disease Epidemiology Collaboration formula, planned renal replacement therapy within the next 6 months, or receiving dialysis at screening.
• Serum potassium <3.5 or >5.2 milliequivalents per liter (mEq/L) at screening.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 *upper limit of normal (ULN) or total bilirubin >2 * ULN, or known cirrhosis, severe liver, or pancreatic disease at screening.
• Use of any anti-arrhythmic drugs within 28 days before randomization or planned to be used during the study period, except for amiodarone, ivabradine, digoxin, and beta blockers.

Individual de-identified participant data will be shared with qualified scientific and medical researchers whose proposed use of data has been approved by the study executive committee, beginning 9 months and ending 36 months following article publication. Proposals should be directed to the Central Contact Person.

Links to the Study Protocol and Statistical Analysis Plan will be made available on ClinicalTrials.gov