Randomized, Double-blind, Placebo-controlled, Two-Part, Adaptive Design Study of Safety, Tolerability, Preliminary Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of MYK-491 in Patients with Stable Heart Failure with Reduced Ejection Fractio

Phase 2

Completed

Conditions: chronic heart failure
heart failure
10019280

Registration Number: NL-OMON48219

Lead Sponsor: MyoKardia, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 12

Inclusion Criteria

This study is to be performed in patients with HFrEF due to any etiology. Each
patient must meet the following criteria to be included in this study:
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 40 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 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) level

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from the study.
1. Inadequate echocardiographic acoustic windows.
2. Any of the following ECG abnormalities (a) QTcF > 480 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 in a patient who has no pacemaker.
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 one part of this
trial may participate in the other part, ie patients may enroll in Part 1 (SAD)
followed by Part 2 (MAD) or Part 2 (MAD) followed by Part 1 (SAD), with the
following caveats:
* If the patient has an ongoing adverse event (AE), has had a serious adverse
event (SAE), or has met any stopping criteria, the investigator should contact
the Sponsor prior to enrolling the patient in a subsequent cohort.
* Patients must have at least 1 week washout after the end of MAD dosing prior
to SAD dosing, or at the end of SAD dosing prior to MAD dosing.
* Patients do not need to rescreen if MAD screening occurred within 12 weeks of
the first SAD dosing, or if SAD screening occurred within 12 weeks of the first
MAD dosing. Investigators should verify that patients are clinically stable and
no exclusions have occurred during the interim; if > 12 weeks have elapsed or
there is clinical instability, then patients should be rescreened.
14. Unable to comply with the study rest

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>* Treatment-emergent AEs and SAEs<br /><br>* ECG recordings (Central Laboratory manual over read), interpretation, and<br /><br>intervals<br /><br>* Vital signs<br /><br>* Serum Troponin I concentrations<br /><br>* Laboratory abnormalities<br /><br>* Physical examination abnormalities</p><br>

Secondary Outcome Measures