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

C

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: Placebo
Drug: Omecamtiv Mecarbil Matrix F2 Formulation

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

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

Trial contacts and locations

101

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Data sourced from clinicaltrials.gov

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