| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Dilated Cardiomyopathy due to MYH7 Mutation. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Heart Failure with reduced heart function caused by gene mutation. |
|
| 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 treatment with MYK 491 in MYH7-DCM subjects. |
|
| E.2.2 | Secondary objectives of the trial |
| To establish preliminary effect, compared with baseline, of treatment with MYK-491 on cardiac pharmacodynamics (PD), as determined by transthoracic echocardiography (TTE) in MYH7-DCM subjects. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Informed Consent:
I1.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.
Age:
I2. Men or women 18 to 80 years of age (inclusive) at the Screening visit.
Type of Participant and Disease Characteristics:
I3. Diagnosis of primary dilated cardiomyopathy (DCM), clinically stable and associated with MYH7 mutation as defined by all of the following:
a. Primary DCM subjects with a diagnosis of heart failure with reduced ejection fraction that has no identified etiology other than MYH7 mutation (e.g., coronary artery disease or severe valvulopathy) as determined by the Investigator.
NOTE: Presence of coronary artery disease, functional mitral regurgitation, or mild to moderate valvular disease may be allowed if not considered the primary cause of the heart failure based on evaluation by Investigator. Moderate aortic stenosis should be excluded.
b. Pathogenic or likely pathogenic mutation in MYH7 gene documented during or after 2016 by a genetic laboratory approved by the Sponsor. Pathogenic or likely pathogenic mutations in reports prior to 2016 will be reviewed centrally by the Sponsor and Coordinating Investigator for eligibility. Some MYH7 VUS mutations may also be permitted upon central review.
c. DCM is not secondary to long-standing MYH7-related hypertrophic cardiomyopathy (HCM) or LV noncompaction cardiomyopathy, as determined by the Investigator.
NOTE: Hypertrabeculation of the LV myocardium is not, in and of itself, a criterion for exclusion.
d. Documented LVEF 15-40% (on 2 occasions), including at least once during Screening and confirmed by the Echo Core Laboratory.
If a subject’s most recent prior TTE (within past 12 months) documents an LVEF ≤ 40%, then only a single screening visit confirming LVEF ≤ 40% by the Echo Core Laboratory is required.
If no prior documented LVEF ≤ 40% by TTE within past 12 months is available, then 2 screening TTEs are needed at least one week (7 days) apart.
In addition, the absolute difference between the 2 LVEF values qualifying the subject should < 12%.
e. At least mild left ventricular enlargement by ASE criteria (LVEDD ≥ 3.1 cm/ m2 for males, ≥ 3.2 cm/m2 for females) (Lang 2015) confirmed by the Echo Core Laboratory.
f. Subject receives chronic medication for the treatment of heart failure reflecting current guidelines, including at least one of the following, unless not tolerated or contraindicated: β-blocker, angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), angiotensin receptor neprilysin inhibitor (ARNI). Such treatments should have been given at stable doses for ≥ 2 weeks with no plan to modify during the study.
I4. Sinus rhythm or stable atrial or ventricular pacing or persistent atrial fibrillation that is adequately rate-controlled to allow PD assessments by TTE.
NOTE: Patients with ICD, pacing or cardiac resynchronization therapy (CRT) are eligible provided device programming is unchanged starting 2 months prior to and throughout the dosing period.
I5. If multiple members of a family meet eligibility criteria, a maximum of three eligible subjects per family may enroll in the study.
I6. Female subjects must not be pregnant (as evidenced by a negative pregnancy test) or lactating. Male subjects (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 subjects, if sexually active, must use 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):
a. Hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), or intrauterine hormone-release system (IUS) plus barrier (e.g., male using condom or female using diaphragm or cervical cap).
b. Vasectomy plus barrier.
c. Female is surgically or permanently 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.
d. Male subjects with postmenopausal partners. |
|
| E.4 | Principal exclusion criteria |
E1. Inadequate echocardiographic acoustic windows.
E2. A patient has a QTcF interval > 480 msec (Fridericia’s correction, not attributable to ventricular pacing or prolonged QRS duration ≥ 120 msec, average of triplicate ECGs.
E3. Subjects with known pathogenic mutation of another gene implicated in DCM in addition to an MYH7 VUS mutation.
E4. HFrEF that is considered to be caused primarily by ischemic heart disease, chronic valvulopathy, or another condition, as determined by the Investigator.
E5. Recent (< 90 days) acute coronary syndrome or angina pectoris.
E6. Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) within prior 90 days.
E7. Recent (< 90 days) hospitalization for heart failure, use of IV diuretic or chronic IV inotropic therapy or other cardiovascular event (e.g., cerebrovascular accident).
E8. Known aortic stenosis of moderate or greater severity.
E9. Presence of disqualifying cardiac rhythms that would preclude echocardiographic assessments, as determined by the Investigator, including: (a) rapid, inadequately rate-controlled atrial fibrillation or (b) frequent premature ventricular contractions that might interfere with reliable echocardiographic measurements of LV function.
E10. Hypersensitivity to MYK-491 or any of the components of the MYK 491 formulation.
E11. Active infection, indicated clinically as determined by the investigator.
E12. 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.
E13. 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]).
E14. Serum potassium < 3.5 or > 5.5 mEq/L.
E15. Any persistent (2 or more) out-of-range safety laboratory parameters (chemistry, hematology), considered by the investigator and medical monitor to be clinically significant.
E16. 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 subject safety or interfere with the study evaluation, procedures, completion, or lead to premature withdrawal from the study.
E17. A life expectancy of < 6 months.
Prior/Concurrent Clinical Study Experience:
E18. Participated in a clinical trial in which the subject 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).
Other Exclusions:
E19. Female subjects with a positive pregnancy test.
E20. Is employed by or is a first-degree relative of someone employed by MyoKardia, the investigator, or his/her staff or family.
E21. Currently placed in hospital or facility due to legal or administrative order. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Treatment-emergent AEs and SAEs
• Clinically significant abnormalities from vital signs, physical examination, ECG recordings, and safety labs |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| V1A (screening, Day -56 to -1); V2 (Baseline); V3 (End of Period 1; dose change day); V4/EoT (End of Period 2); V5/EoS (7d ±1d post last dose) |
|
| E.5.2 | Secondary end point(s) |
• Systolic ejection time
• Parameters of left ventricular systolic function including but not limited to LVSV, LVEF, LVESV, and LV strain will be evaluated
• Parameters of left atrial function including but not limited to LAmaxVi, LAminVi, LAEF, and LAFI will be evaluated
• Parameters of left ventricular diastolic function including but not limited to TDI (e’), E/A, and E/e’ will be evaluated |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| V1A (screening, Day -56 to -1); V2 (Baseline); V3 (End of Period 1; dose change day); V4/EoT (End of Period 2); V5/EoS (7d ±1d post last dose). |
|
| 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 | Yes |
| 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; Cardiomyopathy genetic testing. |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 |
| Germany |
| Spain |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 14 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 14 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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