Decompensatio cordis Heart failure
Conditions
Interventions
Approximately 400 participants will be randomized into one of four groups:
JTT-251 50 mg, 150 mg, 300 mg or placebo QD in a 1:1:1:1 ratio
~ 100
participants per group.
Sponsors
Akros Pharma
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Male or female, age 18 to 85 years (inclusive), at the Screening Visit; 2. Participants with a clinical diagnosis of symptomatic HF >=3 months prior to the Screening Visit; 3. Participants with NYHA functional class II or III at the Screening Visit; 4. Participants must be on stable, guideline-directed medical therapy for HF, consistent with AHA, ACC, HFSA or ESC guidelines for at least 30 days prior to the Screening Visit. These therapies include an ACEI or ARB with/without a neprilysin inhibitor, in combination with an evidence-based β-blocker and a MRA, in appropriate participants, or documentation justifying why optimal therapy is not being used (e.g., intolerance, contraindication, participant preference or physician*s judgement); 5. Participants must have a documented history of LVEF 6 months prior to the Screening Visit, a local echocardiography measurement and interpretation will be used to determine eligibility (i.e., LVEF =900 pg/mL at the Screening Visit; 7. Females may participate if they meet one of the following criteria: • surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy), or • post-menopausal, as defined by: 1) Permanent cessation of menstruation for >=12 months without an alternative medical cause [regardless of follicle-stimulating hormone (FSH) value] at the Screening Visit, or 2) Cessation of menstruation for 40 mIU/mL at the Screening Visit. All other females will be considered of childbearing potential and must either: a. practice abstinence, or b. have same-sex partner, or c. use one highly effective contraceptive method of birth control, which includes intrauterine devices, male partner sterilization (at least six months prior to screening with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate, and the vasectomized male partner should be the sole partner for that participant), tubal ligation, bilateral tubal occlusion, intrauterine hormone-releasing systems, or d. use a double-barrier method of birth control, which includes a combination of male condom with either diaphragm, cervical cap or vaginal sponge, all with spermicide. Note: Concomitant use of a female condom and a male condom is not considered an acceptable double barrier method of contraception for the study. The above-described contraception methods must be maintained during treatment and until 30 days after the last dose of study drug. 8. Males must either practice abstinence, have same-sex partner, use a barrier contraceptive method with spermicide (for the duration of the treatment period and until 30 days after the last dose of study drug), or be sterilized at least six months prior to screening (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). Notes: Males with sterile or post-menopausal female partners are not required to use contraception if said female
Exclusion criteria
Exclusion criteria: 1. Participants with confirmed acute MI (i.e., Type 1) within 30 days prior to the Screening Visit or unstable angina, a history of coronary revascularization (percutaneous coronary intervention and/or coronary artery bypass grafting) or other cardiovascular surgery within 90 days prior to the Screening Visit; 2. Participants whose HF is due to congenital heart disease, active myocarditis or constrictive pericarditis; 3. Participants who have received a heart transplant or are on a transplant list or who have a history of LV assist device implantation; 4. Participants with severe stenotic valvular disease or severe outflow tract obstruction; 5. Participants with a history of stroke or cerebral transient ischemic attack within 30 days prior to the Screening Visit; 6. Participants who started cardiac resynchronization therapy within 90 days prior to the Screening Visit; Note: Implantable cardioverter defibrillator (ICD) placement alone or generator change is acceptable. 7. Participants with planned cardiovascular surgery and/or cardiac resynchronization therapy during the double-blind treatment period; 8. Participants who were admitted to hospital for HF within 30 days prior to Visit 2; 9. Participants with known active liver disease or with aminotransferases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) >3.0x upper limit of normal (ULN) or total bilirubin >1.5x ULN at the time of screening; Note: Participants with documented benign liver condition that can result in elevated bilirubin levels (e.g., Gilbert*s Syndrome) are eligible to participate in the study. 10. Participants unable to perform a six minute walk distance (6MWD) test at Visit 2; 11. Participants with resting symptomatic hypotension or uncontrolled hypertension (i.e., systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg) at the Screening Visit; 12. Participants with clinically significant chronic renal insufficiency (i.e., estimated glomerular filtration rate [eGFR] 10% measured at the Screening Visit; 14. Participants with hemoglobin =100.4°F [38.0°C]) at Visit 2; Note: Participants with successfully treated infections or infections that required antibiotics will be permitted if resolved >7 days prior to Visit 2. 20.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Efficacy Parameters • Change from baseline to end of treatment (EOT) in: o LVEF as assessed by two-dimensional echocardiography (2D-echo) o Left ventricular end-systolic volume (LVESV) index as assessed by 2D-echo o Left ventricular end-diastolic volume (LVEDV) index as assessed by 2D-echo o NT-pro-BNP o 6MWD test o NYHA functional class Exploratory Parameters • Change from baseline to EOT in: o Supplementary cardiac function estimates as determined by echocardiography o Health-related quality of life (QoL) assessment as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ) o HbA1c and fasting plasma glucose o Branched-chain amino acids (BCAAs), alanine, pyruvic and lactic acid o Cardiac troponin I, suppression of tumorigenicity 2 (ST2) and galectin-3 o eGFR and cystatin C o Albumin-to-creatinine ratio (ACR) o Serum myostatin and brain-derived neurotrophic factor (BDNF) • All-cause death, cardiovascular death and heart failure hospitalizations up to EOT Pharmacokinetic and Pharmacodynamic Parameters • JTT-251 trough plasma concentrations will be measured at Visit 5 (Week 4), Visit 7 (Week 12) and Visit 10 (Week 24) • JTT-251 plasma concentrations (post-dose) will be measured at Visit 5 (Week 4) • Relationship between JTT-251 exposure and efficacy, and safety parameters Safety Parameters The number of participants with adverse events (AEs), type and severity of AEs, change from baseline in safety laboratory, vital sign and electrocardiogram (ECG) parameters and AEs leading to permanent discontinuation of study drug. | — |
Secondary
| Measure | Time frame |
|---|---|
| See above. | — |
Countries
Netherlands
Outcome results
None listed