Safety, PK, and Efficacy of Omecamtiv Mecarbil in Japanese Subjects With Heart Failure With Reduced Ejection Fraction

Study Overview
=================
Brief Summary
-----------------
To evaluate pharmacokinetics (PK) of omecamtiv mecarbil in Japanese subjects with heart failure (HF) with reduced ejection fraction To evaluate the safety and tolerability of oral omecamtiv mecarbil

Detailed Description
-----------------
This study was conducted by Amgen as the IND holder, with Cytokinetics as a collaborator. Due to the termination of the collaboration agreement between Amgen and Cytokinetics in May 2021 and subsequent transfer of the omecamtiv mecarbil IND from Amgen to Cytokinetics, Cytokinetics is now listed as the sponsor.

Official Title
-----------------
A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Omecamtiv Mecarbil in Japanese Subjects With Heart Failure With Reduced Ejection Fraction

Conditions
-----------------
Heart Failure With Reduced Ejection Fraction

Intervention / Treatment
-----------------
* Drug: 25 mg Omecamtiv Mecarbil
* Drug: Placebo
* Drug: 37.5 mg Omecamtiv Mecarbil
* Drug: 50 mg Omecamtiv Mecarbil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Japanese male or female ≥ 20 years and ≤ 85 years of age History of chronic stable heart failure (HF) with reduced ejection fraction, defined as requiring treatment for HF for a minimum of 4 weeks prior to screening Treated for HF with optimal pharmacological therapy Left ventricular ejection fraction ≤ 40% at screening Exclusion Criteria: Severe uncorrected valvular heart disease Hypertrophic obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease Acute myocardial infarction, unstable angina, or persistent angina at rest within 30 days prior to randomization Systolic blood pressure (BP) > 160 mmHg or < 90 mmHg, or diastolic BP > 90 mmHg, or heart rate (HR) > 110 beats per minute (bpm) or HR < 50 bpm Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m^2 Total bilirubin (TBL) ≥ 2x upper limit of normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3x ULN Other Exclusion Criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo BID<br>Participants will receive placebo BID. | Drug: 25 mg Omecamtiv Mecarbil<br>* oral tablet<br>|
| Experimental: 25 mg Omecamtiv Mecarbil BID<br>Participants will receive 25 mg omecamtiv mecarbil BID. | Drug: Placebo<br>* oral tablet<br>|
| Experimental: 37.5 mg Omecamtiv Mecarbil BID Target Dose<br>Participants will receive omecamtiv mecarbil 25 mg BID up to Week 4 or Week 8 and 25 mg or 37.5 mg BID after Week 4 or Week 8, based on Week 2 PK. | Drug: 25 mg Omecamtiv Mecarbil<br>* oral tablet<br>Drug: 37.5 mg Omecamtiv Mecarbil<br>* oral tablet<br>|
| Experimental: 50 mg Omecamtiv Mecarbil BID Target Dose<br>Participants will receive Omecamtiv Mecarbil 25 mg BID up to Week 4 or Week 8 and 25 mg or 50 mg BID after Week 4 or Week 8, based on Week 2 PK. | Drug: 25 mg Omecamtiv Mecarbil<br>* oral tablet<br>Drug: 50 mg Omecamtiv Mecarbil<br>* oral tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Concentration Before Morning Dose (Cpredose) Over Time |  | Before morning dose on Week 2 (Day 15), Week 4 (Day 28), Week 12 (Day 84), Week 16 (Day 112) | 
| PK: Area Under the Curve Until 8 Hours After Morning Dose at Week 8 (AUC0-8) |  | Week 8 (Day 56) at predose, at 2 hours ±30 minutes; 4 hours ±30 minutes; 6 hours ±30 minutes; 8 hours ±30 minutes after morning dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline at Week 16 in Systolic Ejection Time (SET) | LS mean was from the repeated measures model, which included treatment group, stratification factor (from IVRS), scheduled visit, baseline value, and the interaction of treatment group with scheduled visit as covariates. | Baseline, Week 16 (Day 112) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Heart Failure