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

Phase 2

Completed

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

Interventions: Drug: Omecamtiv Mecarbil Swellable Core Technology F2
Drug: Placebo
Drug: Omecamtiv Mecarbil Matrix F1 Formulation
Drug: Omecamtiv Mecarbil Matrix F2 Formulation

Registration Number: NCT01786512

Lead Sponsor: Cytokinetics

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 544

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2	Omecamtiv Mecarbil Swellable Core Technology F2	Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.
Expansion Phase: Placebo	Placebo	Participants received placebo tablets twice a day for 20 weeks.
Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1	Omecamtiv Mecarbil Matrix F1 Formulation	Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days.
Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2	Omecamtiv Mecarbil Matrix F2 Formulation	Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days.
Dose-escalation Cohort 2: Placebo	Placebo	Participants received placebo tablets twice a day for 7 days.
Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2	Omecamtiv Mecarbil Matrix F2 Formulation	Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days.
Expansion Phase: Omecamtiv Mecarbil 25 mg M-F1	Omecamtiv Mecarbil Matrix F1 Formulation	Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks.
Dose-escalation Cohort 1: Placebo	Placebo	Participants received placebo tablets twice a day (BID) for 7 days.
Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1	Omecamtiv Mecarbil Matrix F1 Formulation	Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days.
Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2	Omecamtiv Mecarbil Swellable Core Technology F2	Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days.
Expansion Phase: OM M-F1 PK-based Titration	Omecamtiv Mecarbil Matrix F1 Formulation	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.

Primary Outcome Measures

Name	Time	Method
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: 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
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.
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.
Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing	Predose (before morning dose) at weeks 2, 8, 12, 16, and 20

Secondary Outcome Measures

Name	Time	Method
Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20	Baseline and 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.
Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20	Baseline and 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.
Expansion Phase: Number of Participants With Treatment-emergent Adverse Events	From first dose of study drug until 4 weeks after last dose; treatment duration was 20 weeks in the expansion phase.	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
Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20	Baseline and 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.
Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20	Baseline and 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.
Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events	From first dose of study drug to 4 weeks after last dose; treatment duration was 7 days in the dose escalation phase.	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
Expansion Phase: Change From Baseline in Stroke Volume at Week 20	Baseline and 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.
Expansion Phase: Change From Baseline in Heart Rate at Week 20	Baseline and 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.