COSMIC-HF - Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure

Study Overview
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Brief Summary
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The primary objectives of this study are (i) to select an oral modified release (MR) formulation and dose of omecamtiv mecarbil for chronic twice daily (BID) dosing in adults with heart failure and left ventricular systolic dysfunction and (ii) to characterize its pharmacokinetics (PK) over 20 weeks of treatment.

Detailed Description
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Omecamtiv mecarbil (AMG 423, CK-1827452) is a novel small molecule that increases cardiac contractility by selectively and directly activating the enzymatic domain of cardiac myosin heavy chain, the force-generating motor protein of the cardiac sarcomere. This is a randomized, placebo-controlled, multicenter, phase 2 study, consisting of a dose escalation phase to select 1 of 3 omecamtiv mecarbil oral formulations in 2 dose escalation cohorts, followed by an expansion phase to evaluate 20 weeks of administration of the selected omecamtiv mecarbil formulation at 2 target dose levels, compared with placebo. 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
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A Double-blind, Randomized, Placebo-controlled, Multicenter, Dose Escalation Study to Select and Evaluate an Oral Modified Release Formulation of Omecamtiv Mecarbil in Subjects With Heart Failure and Left Ventricular Systolic Dysfunction

Conditions
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Modified Release Oral Formulation, Left Ventricular Systolic Dysfunction, Chronic Heart Failure, History of Chronic Heart Failure, Left Ventricular Ejection Fraction, Pharmacokinetics, Echocardiogram

Intervention / Treatment
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* Drug: Omecamtiv Mecarbil Matrix F1 Formulation
* Drug: Omecamtiv Mecarbil Matrix F2 Formulation
* Drug: Placebo
* Drug: Omecamtiv Mecarbil Swellable Core Technology F2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of chronic heart failure (HF), defined as requiring treatment for HF for a minimum of 4 weeks prior to screening Treated with stable, optimal pharmacological therapy for ≥ 4 weeks History of left ventricular ejection fraction (LVEF) ≤ 40% Elevated N-terminal prohormone B-type natriuretic peptide (NT-proBNP) Exclusion criteria: Severe uncorrected valvular heart disease Hospitalization within 30 days prior to enrollment 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 > 160 mmHg or < 90 mmHg or diastolic blood pressure > 90 mmHg Total bilirubin ≥ 2 x upper limit of normal (ULN); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 x ULN Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m^2

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Dose-escalation Cohort 1: Placebo<br>Participants received placebo tablets twice a day (BID) for 7 days. | Drug: Placebo<br>* Modified release tablets matching to omecamtiv mecarbil<br>|
| Experimental: Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1<br>Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days. | Drug: Omecamtiv Mecarbil Matrix F1 Formulation<br>* Modified release tablets for oral administration<br>* Other names: CK-1827452;|
| Experimental: Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2<br>Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days. | Drug: Omecamtiv Mecarbil Matrix F2 Formulation<br>* Modified release tablets for oral administration<br>* Other names: CK-1827452;|
| Experimental: Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2<br>Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days. | Drug: Omecamtiv Mecarbil Swellable Core Technology F2<br>* Modified release tablets for oral administration<br>* Other names: CK-1827452;|
| Placebo Comparator: Dose-escalation Cohort 2: Placebo<br>Participants received placebo tablets twice a day for 7 days. | Drug: Placebo<br>* Modified release tablets matching to omecamtiv mecarbil<br>|
| Experimental: Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1<br>Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days. | Drug: Omecamtiv Mecarbil Matrix F1 Formulation<br>* Modified release tablets for oral administration<br>* Other names: CK-1827452;|
| Experimental: Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2<br>Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days. | Drug: Omecamtiv Mecarbil Matrix F2 Formulation<br>* Modified release tablets for oral administration<br>* Other names: CK-1827452;|
| Experimental: Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2<br>Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days. | Drug: Omecamtiv Mecarbil Swellable Core Technology F2<br>* Modified release tablets for oral administration<br>* Other names: CK-1827452;|
| Placebo Comparator: Expansion Phase: Placebo<br>Participants received placebo tablets twice a day for 20 weeks. | Drug: Placebo<br>* Modified release tablets matching to omecamtiv mecarbil<br>|
| Experimental: Expansion Phase: Omecamtiv Mecarbil 25 mg M-F1<br>Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. | Drug: Omecamtiv Mecarbil Matrix F1 Formulation<br>* Modified release tablets for oral administration<br>* Other names: CK-1827452;|
| Experimental: Expansion Phase: OM M-F1 PK-based Titration<br>All participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day. At week 8 the dose escalated to 50 mg twice a day if the week 2 predose plasma concentration of OM was less than the predefined cutoff of 200 ng/mL. | Drug: Omecamtiv Mecarbil Matrix F1 Formulation<br>* Modified release tablets for oral administration<br>* Other names: CK-1827452;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) |  | Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours, and 7 days post-dose. | 
| Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) |  | Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours, and 7 days post-dose. | 
| Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7 |  | Day 7 at predose | 
| Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil |  | Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose | 
| Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing |  | Predose (before morning dose) at weeks 2, 8, 12, 16, and 20 | 
| Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil |  | Weeks 2 and 12 at predose and 1, 2, 4, 6, and 8 hours post-dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20 | Systolic ejection time was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates. | Baseline and week 20 | 
| Expansion Phase: Change From Baseline in Stroke Volume at Week 20 | Stroke volume was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates. | Baseline and week 20 | 
| Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20 | LVESD was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates. | Baseline and week 20 | 
| Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20 | LVEDD was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates. | Baseline and week 20 | 
| Expansion Phase: Change From Baseline in Heart Rate at Week 20 | Heart rate was measured using electrocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates. | Baseline and week 20 | 
| Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20 | Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates. | Baseline and week 20 | 
| Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events | An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant, including worsening of a preexisting medical condition. The event does not necessarily have a causal relationship with study treatment. Laboratory value changes that required treatment or adjustment in current therapy were considered adverse events. Each adverse event was graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE), where Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, and Grade 4 = life-threatening AE. A serious adverse event is defined as an adverse event that met at least 1 of the following serious criteria: fatal life threatening required in-patient hospitalization or prolongation of existing hospitalization resulted in persistent or significant disability/incapacity congenital anomaly/birth defect other medically important serious event | From first dose of study drug to 4 weeks after last dose; treatment duration was 7 days in the dose escalation phase. | 
| Expansion Phase: Number of Participants With Treatment-emergent Adverse Events | An adverse event is defined as any untoward medical occurrence in a clinical trial participant, including worsening of a preexisting medical condition. The event does not necessarily have a causal relationship with study treatment. Laboratory value changes that required treatment or adjustment in current therapy were considered adverse events. Each adverse event was graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE), where Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, and Grade 4 = life-threatening AE. A serious adverse event is defined as an adverse event that met at least 1 of the following serious criteria: fatal life threatening required in-patient hospitalization or prolongation of existing hospitalization resulted in persistent or significant disability/incapacity congenital anomaly/birth defect other medically important serious event | From first dose of study drug until 4 weeks after last dose; treatment duration was 20 weeks in the expansion phase. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AMG 423, Pharmacokinetics, Omecamtiv mecarbil, Double-blind, Randomized, Placebo-controlled, Oral forumlation, CK-1827452, Cardiac myosin activator