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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01786512
Recruitment Status : Completed
First Posted : February 8, 2013
Results First Posted : May 17, 2021
Last Update Posted : August 12, 2021
Sponsor:
Information provided by (Responsible Party):
Cytokinetics

Study Description
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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.

Condition or disease Intervention/treatment Phase
Modified Release Oral Formulation Left Ventricular Systolic Dysfunction Chronic Heart Failure History of Chronic Heart Failure Left Ventricular Ejection Fraction Pharmacokinetics Echocardiogram Drug: Omecamtiv Mecarbil Matrix F1 Formulation Drug: Omecamtiv Mecarbil Matrix F2 Formulation Drug: Placebo Drug: Omecamtiv Mecarbil Swellable Core Technology F2 Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 544 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : February 26, 2013
Actual Primary Completion Date : July 22, 2015
Actual Study Completion Date : August 19, 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Dose-escalation Cohort 1: Placebo
Participants received placebo tablets twice a day (BID) for 7 days.
 Drug: Placebo
Modified release tablets matching to omecamtiv mecarbil
Experimental: Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1
Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days.
 Drug: Omecamtiv Mecarbil Matrix F1 Formulation
Modified release tablets for oral administration
Other Names:
  • AMG 423
  • CK-1827452
Experimental: Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2
Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days.
 Drug: Omecamtiv Mecarbil Matrix F2 Formulation
Modified release tablets for oral administration
Other Names:
  • AMG 423
  • CK-1827452
Experimental: Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2
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
Modified release tablets for oral administration
Other Names:
  • AMG 423
  • CK-1827452
Placebo Comparator: Dose-escalation Cohort 2: Placebo
Participants received placebo tablets twice a day for 7 days.
 Drug: Placebo
Modified release tablets matching to omecamtiv mecarbil
Experimental: Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1
Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days.
 Drug: Omecamtiv Mecarbil Matrix F1 Formulation
Modified release tablets for oral administration
Other Names:
  • AMG 423
  • CK-1827452
Experimental: Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2
Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days.
 Drug: Omecamtiv Mecarbil Matrix F2 Formulation
Modified release tablets for oral administration
Other Names:
  • AMG 423
  • CK-1827452
Experimental: Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.
 Drug: Omecamtiv Mecarbil Swellable Core Technology F2
Modified release tablets for oral administration
Other Names:
  • AMG 423
  • CK-1827452
Placebo Comparator: Expansion Phase: Placebo
Participants received placebo tablets twice a day for 20 weeks.
 Drug: Placebo
Modified release tablets matching to omecamtiv mecarbil
Experimental: Expansion Phase: Omecamtiv Mecarbil 25 mg M-F1
Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks.
 Drug: Omecamtiv Mecarbil Matrix F1 Formulation
Modified release tablets for oral administration
Other Names:
  • AMG 423
  • CK-1827452
Experimental: Expansion Phase: OM M-F1 PK-based Titration
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
Modified release tablets for oral administration
Other Names:
  • AMG 423
  • CK-1827452


Outcome Measures
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Primary Outcome Measures :
  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 Outcome Measures :
  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


Eligibility Criteria
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Layout table for eligibility information
Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01786512


Locations
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Sponsors and Collaborators
Cytokinetics
Investigators
Layout table for investigator information
Study Director: MD Amgen
More Information
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Additional Information:

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Cytokinetics
ClinicalTrials.gov Identifier: NCT01786512    
Other Study ID Numbers: 20110151
2012-000327-40 ( EudraCT Number )
First Posted: February 8, 2013    Key Record Dates
Results First Posted: May 17, 2021
Last Update Posted: August 12, 2021
Last Verified: July 2021
Keywords provided by Cytokinetics:
Pharmacokinetics
Omecamtiv mecarbil
AMG 423
Double-blind
Randomized
 Placebo-controlled
Oral forumlation
CK-1827452
Cardiac myosin activator
Additional relevant MeSH terms:
Layout table for MeSH terms
Heart Failure
Ventricular Dysfunction, Left
Systolic Murmurs
Heart Diseases
 Cardiovascular Diseases
Heart Murmurs
Ventricular Dysfunction