E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart Failure with Reduced Ejection Fraction (HFrEF) |
|
E.1.1.1 | Medical condition in easily understood language |
HFrEF or systolic (it's phase of the heartbeat when the heart pumps out the blood) heart failure is a condition where the left ventricle doesn't pump blood out to the body as normal during a systole. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10078289 |
E.1.2 | Term | Heart failure with reduced ejection fraction |
E.1.2 | System Organ Class | 100000004849 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To evaluate the efficacy of JTT-251 in participants with Heart Failure with Reduced Ejection Fraction (HFrEF) - To evaluate the safety and tolerability of JTT-251 following administration for 24 weeks in participants with HFrEF - To evaluate the exposure-response of the efficacy and safety of JTT-251 in participants with HFrEF - To evaluate the PK of JTT-251 in participants with HFrEF |
|
E.2.2 | Secondary objectives of the trial |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To qualify for the study, the participant must satisfy the following 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 5. Participants must have a documented history of LVEF ≤35% within 6 months prior to the Screening Visit using any of the following modalities: echocardiography, single-photon emission computed tomography (SPECT), multigated acquisition (MUGA), computed tomography (CT) scanning, magnetic resonance imaging (MRI) or ventricular angiography; if more than one measurement was performed, then the most recent one should be used for eligibility; Note: If LVEF measurement was obtained >6 months prior to the Screening Visit, a local echocardiography measurement and interpretation will be used to determine eligibility (i.e., LVEF ≤35%). 6. Participants with a plasma NT-pro-BNP level ≥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 permanent cessation of menstruation for ≥12 months without an alternative medical cause at the Screening Visit. a. practice abstinence, or b. have same-sex partner, and not planning a pregnancy, 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, 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. All other females will be considered of childbearing potential and must either: Note: Periodic abstinence (calendar, symptothermal, post ovulation methods), withdrawal (coitus interruptus), spermicides only, and concomitant use of a female and male condom are not acceptable methods of contraception. 8. Males must either practice sexual abstinence, have same-sex partner, use a barrier contraceptive method with spermicide (for the duration of the treatment period and until 28 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 who are sterile or who have sterile or post-menopausal female partners are not required to use contraception if said female partner is the sole partner for that participant. Males must not donate sperm for the duration of the study and for 28 days after the last dose of study drug. If the female partner is of childbearing potential, she must agree to use at least one of the acceptable forms of birth control listed above (in addition to the method utilized by the male subject) for the duration of the study and for at least 28 days after the participant takes the last dose of study drug. 9. Able and willing to give written informed consent. |
|
E.4 | Principal exclusion criteria |
The following criteria will exclude a participant from participating in the study: 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 >160 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] <30 mL/min/1.73 m2 using the 4-variable Modification of Diet in Renal Disease [MDRD] formula) or who are on or indicated to start renal dialysis within the next 90 days; eGFR (in mL/min/1.73 m2) = 175 × Serum Creatinine -1.154 × age -0.203 × 1.212 (for black participant) × 0.742 (for female participant) 13. Diabetic participants with hemoglobin A1c (HbA1c) >10% measured at the Screening Visit; 14. Participants with hemoglobin <8 g/dL at the Screening Visit; 15. Participants currently receiving or have received an investigational product (including an investigational drug or other investigational therapeutic intervention) within 28 days, five half-lives or twice the duration of the biological effect of the investigational product, if known (whichever is longer) prior to the Screening Visit; 16. Participants with a history of recreational drug abuse within six months of the Screening Visit; Note: Medical marijuana prescribed by a physician is acceptable. 17. Participants with a history of alcohol abuse within six months of the Screening Visit; 18. Participants with an ANC <1200/μL at the Screening Visit; 19. Participants with systemic effects of untreated active infection(s) (e.g., fever ≥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. Participants who test positive for human immunodeficiency virus (HIV) antibodies at the Screening Visit; 21. Participants with current malignancies or who are receiving or require active cancer treatment (exceptions include adequately treated or excised non-metastatic basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ); 22. Participants who have unstable physical or major psychiatric conditions (e.g., schizophrenia, clinically unstable major psychiatric disorder) that would put the participant at risk, or would interfere with study procedures according to the Investigator’s clinical judgement; 23. Females who are pregnant as determined by a positive serum human chorionic gonadotropin (hCG) test result at the Screening Visit or urine hCG at Visit 2; Note: Any positive urine pregnancy test result at Visit 2 must be verified with a serum pregnancy test prior to randomization. 24. Females who are lactating at the Screening Visit or at Visit 2; 25. Participants who are unwilling or unable to comply with the requirements of the study. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
• Change from baseline to end of treatment (EOT) in: - Left ventricular ejection fraction (LVEF), Left ventricular end systolic volume (LVESV) index and Left ventricular end diastolic volume (LVEDV) index as assessed by two-dimensional echocardiography (2D-echo) - NT-pro-BNP - 6MWD test - NYHA functional class • JTT-251 trough plasma levels at Weeks 4, 12 and 24 and JTT-251 plasma concentrations (post-dose) at Week 4 • Relationship between JTT-251 exposure and efficacy, and safety parameters • Safety - Number of participants with adverse events (AEs), type and severity of AEs - Change from baseline in safety laboratory, vital sign and electrocardiogram (ECG) parameters - AEs leading to permanent discontinuation of study drug. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 0, 1, 2, 4, 8, 12, 16, 20, 24, 28 |
|
E.5.2 | Secondary end point(s) |
• Change from baseline to EOT in: - Supplementary cardiac function estimates as determined by echocardiography - Health-related quality of life (QoL) assessment as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ) - HbA1c and fasting plasma glucose - Branched-chain amino acids (BCAAs), alanine, pyruvic and lactic acid - Cardiac troponin I, suppression of tumorigenicity 2 (ST2) and galectin 3 - eGFR and cystatin C - Albumin-to-creatinine ratio (ACR) - Serum myostatin and brain-derived neurotrophic factor (BDNF) • All deaths (cardiovascular or non-cardiovascular) and cardiovascular hospitalizations up to Week 28 as defined in the Clinical Events Committee (CEC) charter
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 0, 1, 2, 4, 8, 12, 16, 20, 24, 28 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 58 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Chile |
Denmark |
Germany |
Hungary |
Israel |
Netherlands |
Poland |
Romania |
Russian Federation |
Serbia |
Ukraine |
United Kingdom |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |