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.
Brief Title
COSMIC-HF - Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure
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.
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Modified Release Oral Formulation
Left Ventricular Systolic Dysfunction
Chronic Heart Failure
History of Chronic Heart Failure
Left Ventricular Ejection Fraction
Pharmacokinetics
Echocardiogram
Eligibility 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
* 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
Inclusion 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)
* 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)
Gender
All
Gender Based
false
Keywords
Pharmacokinetics
Omecamtiv mecarbil
AMG 423
Double-blind
Randomized
Placebo-controlled
Oral forumlation
CK-1827452
Cardiac myosin activator
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
85 Years
Minimum Age
18 Years
NCT Id
NCT01786512
Org Class
Industry
Org Full Name
Cytokinetics
Org Study Id
20110151
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome Measure
Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
Outcome 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.
Outcome Measure
Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
Outcome 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.
Outcome Measure
Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7
Outcome Time Frame
Day 7 at predose
Outcome Measure
Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil
Outcome Time Frame
Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose
Outcome Measure
Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing
Outcome Time Frame
Predose (before morning dose) at weeks 2, 8, 12, 16, and 20
Outcome Measure
Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil
Outcome Time Frame
Weeks 2 and 12 at predose and 1, 2, 4, 6, and 8 hours post-dose.
Secondary Ids
Secondary Id
2012-000327-40
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
Baseline and week 20
Outcome Measure
Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20
Outcome Description
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.
Outcome Time Frame
Baseline and week 20
Outcome Measure
Expansion Phase: Change From Baseline in Stroke Volume at Week 20
Outcome Description
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.
Outcome Time Frame
Baseline and week 20
Outcome Measure
Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20
Outcome Description
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.
Outcome Time Frame
Baseline and week 20
Outcome Measure
Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20
Outcome Description
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.
Outcome Time Frame
Baseline and week 20
Outcome Measure
Expansion Phase: Change From Baseline in Heart Rate at Week 20
Outcome Description
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.
Outcome Time Frame
Baseline and week 20
Outcome Measure
Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20
Outcome Description
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
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
Outcome Time Frame
From first dose of study drug to 4 weeks after last dose; treatment duration was 7 days in the dose escalation phase.
Outcome Measure
Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events
Outcome Description
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
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
Outcome Time Frame
From first dose of study drug until 4 weeks after last dose; treatment duration was 20 weeks in the expansion phase.
Outcome Measure
Expansion Phase: Number of Participants With Treatment-emergent Adverse Events
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
85
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Jooyoung Shin
Investigator Email
jushin@montefiore.org
Investigator Phone