Heart Failure With Reduced Ejection Fraction (HFrEF)
Conditions
Keywords
Heart Diseases, Cardiovascular Diseases, Heart Failure
Brief summary
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.
Detailed description
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.
Interventions
DRUGAC01
AC01 tablets for oral administration.
OTHERPlacebo
AC01 matching placebo tablets for oral administration.
Sponsors
AnaCardio AB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change from Baseline in Composite Echocardiography Z-Score at Week 12 | Baseline and Week 12 | The composite echocardiography Z-score integrates left ventricular stroke volume (LVSV), left ventricular end systolic volume (LVESV), left ventricular ejection fraction (LVEF), and left atrial minimal volume index (LAVImin). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change from Baseline in LVSV at Week 12 | Baseline and Week 12 | — |
| Absolute Change from Baseline in LVEF at Week 12 | Baseline and Week 12 | — |
| Absolute Change from Baseline in LVESV at Week 12 | Baseline and Week 12 | — |
| Absolute Change From Baseline in LAVImin at Week 12 | Baseline and Week 12 | — |
| Absolute Change from Baseline in N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP) | Baseline and Week 12 | — |
| Absolute Change From Baseline in Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) at Week 12 | Baseline and Week 12 | The KCCQ is a validated, 23-item, self-administered questionnaire designed to assess health status in participants with congestive heart failure. It evaluates six domains: symptoms, physical function, quality of life, social limitation, self-efficacy, and symptom stability. Each domain score is transformed to a scale of 0 to 100, with higher scores indicating better health status. The KCCQ-TSS is derived from the domain scores. |
| Absolute Change From Baseline in Patient Global Impression of Severity (PGIS) at Week 12 | Baseline and Week 12 | PGIS is 1-item questionnaire used to rate the severity of a specific condition. Participants record their perceived severity of heart failure (HF) symptoms, specifically shortness of breath, fatigue, and swelling, and choose 1 response that best described the extent of their symptoms based on a 5-point scale. Response options include none, mild, moderate, severe, and very severe. Higher PGIS scores indicate more severe HF symptoms; lower scores indicate less severe symptoms. |
| Patient Global Impression of Change (PGIC) at Week 12 | At Week 12 | The PGIC questionnaire is administered to assess the participant's impression of change in HF symptoms since the initiation of study treatment, specifically changes in shortness of breath, fatigue, and swelling. Participants select one response to describe the overall change (if any) in HF symptoms on a 7-category scale: 7=very much improved, 6 =much improved, 5 =minimally improved, 4 =no change, 3 =minimally worse, 2 =much worse, and 1 =very much worse. Higher PGIC scores indicate greater improvement in HF symptoms, while lower scores indicate worsening or no change. |
| Number of Participants With Death, Cardiovascular Death, Hospitalization, Cardiovascular Hospitalization, Heart Failure Hospitalization, Heart Failure Events, Other Adjudicated Events, and Listed for Heart Transplantation | At Week 12 | — |
| Change From Baseline in Guideline-directed Medical Therapy (GDMT) Use for HFrEF at Week 12 | Baseline and Week 12 | — |
| Absolute Change from Baseline in Estimated Glomerular Filtration Rate (eGFR) | Baseline and Week 12 | — |
| Number of Participants With Dialysis | At Week 12 | — |
| Absolute Change from Baseline in Council on Nutrition Appetite Questionnaire (CNAQ) Total Score | Baseline and Week 12 | The CNAQ is an 8-item, self-administered questionnaire used to assess appetite over time. Each item is scored on a scale of 1 to 5, and the total score is calculated as the sum of all item scores. The instrument has demonstrated acceptable psychometric properties, including internal consistency, construct validity, and predictive validity, for assessing appetite in participants with heart failure. Higher CNAQ scores indicate better appetite. |
| Absolute Change From Baseline in New York Heart Association (NYHA) Class | Baseline and Week 12 | — |
| AUC,ss: Area Under the Concentration-Time Curve at Steady State of AC01 and its Metabolite M6 | At Week 4 and Week 12 | Population pharmacokinetic parameters |
| Cmax,ss: Maximum Observed Concentration at Steady State of AC01 and its Metabolite M6 | At Week 4 and Week 12 | Population pharmacokinetic parameters |
| Tmax,ss: Time to Reach Maximum Concentration at Steady State | At Week 4 and Week 12 | Population pharmacokinetic parameters |
| Ctrough: Trough concentration at steady state of AC01 and its Metabolite M6 | At Week 4 and Week 12 | Population pharmacokinetic parameters |
| Rac (Cmax): Accumulation Ratio of Cmax for AC01 and its Metabolite M6 | At Week 4 and Week 12 | Population pharmacokinetic parameters. Accumulation ratio of Cmax calculated as Cmax at Week 12/Cmax at Week 4. |
| Rac (AUC): Accumulation Ratio of AUC for AC01 and its Metabolite M6 | At Week 4 and Week 12 | Population pharmacokinetic parameters. Accumulation ratio of AUC calculated as AUC at Week 12/AUC at Week 4. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESIs) | From first dose of study drug up to end of follow up (up to Week 16) | — |
Contacts
CONTACTRobert Edfors, MD, PhD
Outcome results
None listed