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Completed

NCT Number: NCT01786512

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

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.

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Key information

Conditions

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

Age range

18 year–85 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Research Site, Darlinghurst, New South Wales, Australia

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Omecamtiv Mecarbil Matrix F1 Formulation

Drug

Modified release tablets for oral administration

Other names: AMG 423, CK-1827452

Omecamtiv Mecarbil Matrix F2 Formulation

Drug

Modified release tablets for oral administration

Other names: AMG 423, CK-1827452

Placebo

Drug

Modified release tablets matching to omecamtiv mecarbil

Omecamtiv Mecarbil Swellable Core Technology F2

Drug

Modified release tablets for oral administration

Other names: AMG 423, CK-1827452

Primary outcomes

  1. Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)

    Time frame: 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.

  2. Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)

    Time frame: 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.

  3. Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7

    Time frame: Day 7 at predose

  4. Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil

    Time frame: Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose

  5. Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing

    Time frame: Predose (before morning dose) at weeks 2, 8, 12, 16, and 20

  6. Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil

    Time frame: Weeks 2 and 12 at predose and 1, 2, 4, 6, and 8 hours post-dose.

Secondary outcomes

  1. Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20

    Time frame: 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.

  2. Expansion Phase: Change From Baseline in Stroke Volume at Week 20

    Time frame: 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.

  3. Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20

    Time frame: 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.

  4. Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20

    Time frame: 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.

  5. Expansion Phase: Change From Baseline in Heart Rate at Week 20

    Time frame: 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.

  6. Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20

    Time frame: 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.

  7. Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events

    Time frame: 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

  8. Expansion Phase: Number of Participants With Treatment-emergent Adverse Events

    Time frame: 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

Sponsors and collaborators

Lead sponsor

Cytokinetics

Industry

Registry information

Official study title

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

Acronym: COSMIC-HF

Important dates

Study start
2013
Primary completion
2015
Study completion
2015
First posted
Feb 8, 2013
Registry last updated
Aug 12, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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