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

Cytokinetics

Status and phase: Completed; Phase 2

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

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

Study type: Interventional

Funder types: Industry

Identifiers

NCT01786512

2012-000327-40 (EudraCT Number)

20110151

Details and patient eligibility

About

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.

Full 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.

Enrollment: 544 patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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544 participants in 11 patient groups, including a placebo group

Dose-escalation Cohort 1: Placebo

Placebo Comparator group

Description:

Participants received placebo tablets twice a day (BID) for 7 days.

Treatment:

Drug: Placebo

Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1

Experimental group

Description:

Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days.

Treatment:

Drug: Omecamtiv Mecarbil Matrix F1 Formulation

Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2

Experimental group

Description:

Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days.

Treatment:

Drug: Omecamtiv Mecarbil Matrix F2 Formulation

Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2

Experimental group

Description:

Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days.

Treatment:

Drug: Omecamtiv Mecarbil Swellable Core Technology F2

Dose-escalation Cohort 2: Placebo

Placebo Comparator group

Description:

Participants received placebo tablets twice a day for 7 days.

Treatment:

Drug: Placebo

Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1

Experimental group

Description:

Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days.

Treatment:

Drug: Omecamtiv Mecarbil Matrix F1 Formulation

Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2

Experimental group

Description:

Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days.

Treatment:

Drug: Omecamtiv Mecarbil Matrix F2 Formulation

Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2

Experimental group

Description:

Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.

Treatment:

Drug: Omecamtiv Mecarbil Swellable Core Technology F2

Expansion Phase: Placebo

Placebo Comparator group

Description:

Participants received placebo tablets twice a day for 20 weeks.

Treatment:

Drug: Placebo

Expansion Phase: Omecamtiv Mecarbil 25 mg M-F1

Experimental group

Description:

Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks.

Treatment:

Drug: Omecamtiv Mecarbil Matrix F1 Formulation

Expansion Phase: OM M-F1 PK-based Titration

Experimental group

Description:

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.

Treatment:

Drug: Omecamtiv Mecarbil Matrix F1 Formulation