Primary Dilated Cardiomyopathy due to MYH7 Mutation.
Conditions
Interventions
Product Code: MYK-491
Pharmaceutical Form: Tablet
Current Sponsor code: MYK-491
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Product Code: MYK-491
Pharmaceut
Sponsors
MyoKardia Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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: ß-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), a
Exclusion criteria
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 ( 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To establish preliminary safety and tolerability of treatment with MYK 491 in MYH7-DCM subjects.;Secondary Objective: 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.;Primary end point(s): • Treatment-emergent AEs and SAEs • Clinically significant abnormalities from vital signs, physical examination, ECG recordings, and safety labs;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) | — |
Secondary
| Measure | Time frame |
|---|---|
| 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;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). | — |
Countries
Germany, Spain, United Kingdom, United States
Contacts
Public ContactClinical Trial or Medical Inquiries
MyoKardia, Inc.
Outcome results
None listed