| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Heart Failure with Reduced Ejection Fraction |
|
| E.1.1.1 | Medical condition in easily understood language |
| Heart Failure with Reduced Ejection Fraction |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| 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 establish preliminary safety and tolerability of single and multiple ascending oral doses of MYK-491 in ambulatory patients with stable heart failure with reduced ejection fraction (HFrEF). |
|
| E.2.2 | Secondary objectives of the trial |
To establish preliminary human pharmacokinetics (PK) of MYK-491 after single and multiple ascending oral doses of MYK-491 in patients with HFrEF.
To determine changes in left ventricular stroke volume [LVSV] derived from left ventricular outflow tract-velocity time integral [LVOT-VTI]), left ventricular ejection fraction (LVEF) and change in left ventricular fractional shortening [LVFS] with MYK-491 after ascending single and multiple doses compared with Baseline and placebo as measured by transthoracic echocardiography (TTE).
To determine changes in systolic ejection time (SET) with MYK-491 after ascending single and multiple doses compared with Baseline and placebo as measured by TTE.
To determine changes in pharmacodynamics (PD) dose/concentration effects (change in LVSV [derived from LVOT-VTI], LVEF, LVFS) with MYK-491 compared with Baseline and placebo after ascending single and multiple doses, as measured by TTE |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent according to federal, local, and institutional guidelines before the first study-specific procedure.
2. Men or women 18 to 80 years of age at the Screening visit.
3. Body mass index (BMI) 18 to 32 kg/m2, inclusive, at the Screening visit and all required assessments can be reliably performed.
4. Sinus rhythm or stable atrial pacing with mean resting heart rate (HR) 50-95 beats per minute (bpm), inclusive. (Patient will be ineligible to dose if, on Day 1, the predose HR measurement is ≥ 95 bpm. Heart rate is the mean of 3 measurements taken 1 minute apart. A single measurement would not make a patient ineligible).
5. Has stable, chronic HFrEF of moderate severity as defined by all of the following:
• For the first 3 patients in each multiple-ascending dose (MAD) cohort testing a new (higher) daily dose:
documented LVEF 25% to 35% during Screening (as confirmed by ECHO Central Lab)
• For other patients in the MAD Cohorts (and all patients in SAD Cohorts): documented documented LVEF 15% to 35%
during Screening (as confirmed by ECHO Central Lab)
• LVEF must be confirmed with second screening ECHO to be performed at least 7 days after initial screening ECHO. Results of both must meet
inclusion criteria and must be received from core lab prior to dosing. In the event of extended screening windows due to SRC reviews, effort
should be made to ensure second ECHO is near planned time of randomization.
• Chronic medication for the treatment of heart failure consistent with current guidelines that has been given at stable doses for ≥ 2 weeks with no plan to modify during the study. This includes treatment with at least one of the following unless not tolerated or contraindicated: beta-blocker, angiotensin converting enzyme (ACE) inhibitor/ angiotensin receptor blocker (ARB)/ angiotensin receptor neprilysin inhibitor (ARNI).
6. Female patients must not be pregnant or lactating. Male patients (including men who have had vasectomies), as there may be a risk of drug being secreted in the ejaculate, should use barrier methods for the duration of the study and for 3 months after the last dose of study medication. All patients, if sexually active, must be using one of the following highly-effective birth control methods from the Screening visit through 3 months after the last dose of investigational medicinal product (IMP):
• Hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), or intrauterine hormone-release system (IUS) plus barrier (eg, male using condom or female using diaphragm or cervical cap).
• Vasectomy plus barrier.
• Female is surgically sterile for 6 months or postmenopausal for 1 year. Permanent sterilization includes hysterectomy, bilateral oophorectomy, bilateral salpingectomy, and/or documented bilateral tubal occlusion at least 6 months prior to Screening. Females are considered postmenopausal if they have had amenorrhea for at least 1 year or more following cessation of all exogenous hormonal treatments, and follicle-stimulating hormone (FSH) levels are in the postmenopausal range. |
|
| E.4 | Principal exclusion criteria |
1. Inadequate echocardiographic acoustic windows.
2. Any of the following ECG abnormalities (a) QTcF > 450 ms (Fridericia’s correction, not attributable to pacing or prolonged QRS duration, average of triplicate Screening ECGs) or (b) second-degree atrioventricular block type II or higher.
3. Hypersensitivity to MYK-491 or any of the components of the MYK-491 formulation.
4. Active infection as indicated clinically as determined by the investigator.
5. History of malignancy of any type within 5 years prior to Screening, with the exception of the following surgically excised cancers occurring more than 2 years prior to Screening: in situ cervical cancer, nonmelanomatous skin cancers, ductal carcinoma in situ, and nonmetastatic prostate cancer.
6. Positive serologic test at Screening for infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV).
7. Hepatic impairment (defined as alanine aminotransferase [ALT]/ aspartate aminotransferase [AST] > 3 times upper limit of normal [ULN] and/or total bilirubin [TBL] > 2 times ULN).
8. Severe renal insufficiency (defined as current estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2 by simplified Modification of Diet in Renal Disease equation [sMDRD]).
9. Serum potassium < 3.5 or > 5.5 mEq/L.
10. Any persistent out-of-range safety laboratory parameters (chemistry, hematology, urinalysis), considered by the investigator and medical monitor to be clinically significant.
11. History or evidence of any other clinically significant disorder, condition, or disease (including substance abuse) that, in the opinion of the investigator or MyoKardia physician would pose a risk to patient safety or interfere with the study evaluation, procedures, completion, or lead to premature withdrawal from the study.
12. Participated in a clinical trial in which the patient received any investigational drug (or is currently using an investigational device) within 30 days prior to Screening, or at least 5 times the respective elimination half-life (whichever is longer).
13. Previous participation in a clinical trial with MYK-491, with the exception that patients that participated or were screen failures in Part 1 of this trial (single-dose cohorts) may subsequently participate in Part 2 (multiple-dose cohorts).
14. Unable to comply with the study restrictions/requirements, including, in particular, the number of required overnight stays at the clinical site.
15. Is employed by, or is a first-degree relative of someone employed by, MyoKardia or Sanofi, the investigator, or his/her staff or family.
16. At Screening, symptomatic hypotension, or systolic blood pressure (BP) > 170 mmHg or < 90 mmHg, or diastolic BP > 95 mmHg, or HR < 50 bpm. Heart rate and BP will be the mean of 3 measurements taken at least 1 minute apart.
17. Current angina pectoris.
18. Recent (<90 days) acute coronary syndrome.
19. Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) within the prior 3 months.
20. Recent (<90 days) hospitalization for heart failure, use of chronic IV inotropic therapy or other cardiovascular event (e.g., cerebrovascular accident).
21. Uncorrected severe valvular disease.
22. Elevated troponin (> 0.15 ng/mL) at Screening, based on Central Laboratory assessments. Note: Central Laboratory assay ULN is 0.03 ng/mL.
23. Presence of disqualifying cardiac rhythms that would preclude study ECG or echocardiographic assessments, including: (a) Current atrial fibrillation, (b) recent (<2 weeks) persistent atrial fibrillation, or (c) frequent premature ventricular contractions. Note: Patients with active cardiac resynchronization therapy (CRT) or pace-maker (PM) are eligible if initiated at least 2 months prior with no plan to change CRT or PM settings during the study.
24. A life expectancy of <6 months.
25. Patients classified as New York Heart Association (NYHA) functional class IV
26. Persons who have been placed in an establishment as a result of an administrative or judicial order |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Treatment-emergent AEs and SAEs
• ECG recordings (Central Laboratory manual over-read), interpretation, and intervals
• Vital signs
• Serum troponin I concentrations
• Laboratory abnormalities
• Physical examination abnormalities |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| As they appear during the study. |
|
| E.5.2 | Secondary end point(s) |
• The human PK profile of MYK-491. The analysis includes at a minimum the following PK parameters. Additional PK parameters may be determined as appropriate.
- Cmax for each dose level
- Tmax for each dose level
- AUC for each dose level dose
- Apparent first-order terminal elimination half-life (t1/2)
- Mean residence time (MRT) for each dose level
- Accumulation ratios determined (with the appropriate confidence intervals) for Cmax and AUC0-t (Part 2 only)
• SET as determined using TTE. The main parameters are the change from Baseline at each timepoint by treatment levels and the maximum change from Baseline.
• The following as assessed by TTE:
- Change from Baseline in LVSV (derived from LVOT-VTI)
- Change from Baseline in LVEF
- Change from Baseline in LVFS
- Change from Baseline in SET
- Change from Baseline in PEP (in Part 1) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints as suggested in the endpoint description. |
|
| 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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, genetic testing (optional). |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | No |
| 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 | 8 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| France |
| Germany |
| Netherlands |
| Poland |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 24 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 24 |
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