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

Pharmacokinetics Clinical Trial

— COSMIC-HF  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01786512
• Other study ID #: 20110151
• Secondary ID: 2012-000327-40
• Status: Completed
• Phase: Phase 2
• Start date: February 26, 2013
• Est. completion date: August 19, 2015

Study information

• Verified date: July 2021
• Source: Cytokinetics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 544
• Est. completion date: August 19, 2015
• Est. primary completion date: July 22, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Omecamtiv Mecarbil Matrix F1 Formulation
Modified release tablets for oral administration
• Omecamtiv Mecarbil Matrix F2 Formulation
Modified release tablets for oral administration
• Placebo
Modified release tablets matching to omecamtiv mecarbil
• Omecamtiv Mecarbil Swellable Core Technology F2
Modified release tablets for oral administration

Locations

Country	Name	City	State
Australia	Research Site	Darlinghurst	New South Wales
Australia	Research Site	Nedlands	Western Australia
Belgium	Research Site	Antwerpen
Belgium	Research Site	Bonheiden
Belgium	Research Site	Gent
Belgium	Research Site	Ieper
Belgium	Research Site	Liege
Bulgaria	Research Site	Kazanlak
Bulgaria	Research Site	Pazardzhik
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Sandanski
Bulgaria	Research Site	Sliven
Bulgaria	Research Site	Smolyan
Bulgaria	Research Site	Sofia
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Halifax	Nova Scotia
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Ottawa	Ontario
Canada	Research Site	Québec	Quebec
Canada	Research Site	Sherbrooke	Quebec
Canada	Research Site	St. Johns	Newfoundland and Labrador
Canada	Research Site	Trois Rivieres	Quebec
Canada	Research Site	Winnipeg	Manitoba
Czechia	Research Site	Brno
Czechia	Research Site	Brno
Czechia	Research Site	Olomouc
Czechia	Research Site	Praha 2
Czechia	Research Site	Praha 4
Czechia	Research Site	Svitavy
Czechia	Research Site	Teplice
Germany	Research Site	Bad Krozingen
Germany	Research Site	Bad Nauheim
Germany	Research Site	Berlin
Germany	Research Site	Dortmund
Germany	Research Site	Greifswald
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Jaszbereny
Hungary	Research Site	Zalaegerszeg
Italy	Research Site	Brescia
Italy	Research Site	Pavia
Italy	Research Site	Verona
Lithuania	Research Site	Kaunas
Lithuania	Research Site	Vilnius
Netherlands	Research Site	Amersfoort
Netherlands	Research Site	Groningen
Netherlands	Research Site	Utrecht
Poland	Research Site	Bialystok
Poland	Research Site	Klodzko
Poland	Research Site	Krakow
Poland	Research Site	Krakow
Poland	Research Site	Lublin
Poland	Research Site	Ruda Slaska
Poland	Research Site	Warszawa
Poland	Research Site	Wroclaw
United Kingdom	Research Site	Dudley
United Kingdom	Research Site	Dundee
United Kingdom	Research Site	Glasgow
United Kingdom	Research Site	Harrow
United Kingdom	Research Site	Leicester
United Kingdom	Research Site	Liverpool
United Kingdom	Research Site	London
United States	Research Site	Atlanta	Georgia
United States	Research Site	Atlantis	Florida
United States	Research Site	Auburn	Maine
United States	Research Site	Aventura	Florida
United States	Research Site	Baltimore	Maryland
United States	Research Site	Bronx	New York
United States	Research Site	Chapel Hill	North Carolina
United States	Research Site	Chicago	Illinois
United States	Research Site	Clearwater	Florida
United States	Research Site	Cortlandt Manor	New York
United States	Research Site	Costa Mesa	California
United States	Research Site	Danbury	Connecticut
United States	Research Site	Detroit	Michigan
United States	Research Site	Durham	North Carolina
United States	Research Site	Fresno	California
United States	Research Site	Greenville	South Carolina
United States	Research Site	Houston	Texas
United States	Research Site	Inglewood	California
United States	Research Site	La Jolla	California
United States	Research Site	Las Vegas	Nevada
United States	Research Site	Los Angeles	California
United States	Research Site	Macon	Georgia
United States	Research Site	Madison	Wisconsin
United States	Research Site	Miami	Florida
United States	Research Site	Minneapolis	Minnesota
United States	Research Site	Minneapolis	Minnesota
United States	Research Site	Mobile	Alabama
United States	Research Site	Nashville	Tennessee
United States	Research Site	Newark	Delaware
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Petoskey	Michigan
United States	Research Site	Portland	Oregon
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Seattle	Washington
United States	Research Site	Tampa	Florida
United States	Research Site	Thousand Oaks	California
United States	Research Site	Tullahoma	Tennessee
United States	Research Site	Tustin	California

Sponsors (1)

Lead Sponsor	Collaborator
Cytokinetics

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Bulgaria,  Canada,  Czechia,  Germany,  Hungary,  Italy,  Lithuania,  Netherlands,  Poland,  United Kingdom, 

References & Publications (1)

Teerlink JR, Felker GM, McMurray JJ, Solomon SD, Adams KF Jr, Cleland JG, Ezekowitz JA, Goudev A, Macdonald P, Metra M, Mitrovic V, Ponikowski P, Serpytis P, Spinar J, Tomcsányi J, Vandekerckhove HJ, Voors AA, Monsalvo ML, Johnston J, Malik FI, Honarpour N; COSMIC-HF Investigators. Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet. 2016 Dec 10;388(10062):2895-2903. doi: 10.1016/S0140-6736(16)32049-9. Epub 2016 Dec 1. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)		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.
Primary	Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)		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.
Primary	Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7		Day 7 at predose
Primary	Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil		Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose
Primary	Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing		Predose (before morning dose) at weeks 2, 8, 12, 16, and 20
Primary	Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil		Weeks 2 and 12 at predose and 1, 2, 4, 6, and 8 hours post-dose.
Secondary	Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at 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.	Baseline and week 20
Secondary	Expansion Phase: Change From Baseline in Stroke Volume at 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.	Baseline and week 20
Secondary	Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at 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.	Baseline and week 20
Secondary	Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at 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.	Baseline and week 20
Secondary	Expansion Phase: Change From Baseline in Heart Rate at 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.	Baseline and week 20
Secondary	Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at 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.	Baseline and week 20
Secondary	Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events	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	From first dose of study drug to 4 weeks after last dose; treatment duration was 7 days in the dose escalation phase.
Secondary	Expansion Phase: Number of Participants With Treatment-emergent Adverse Events	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	From first dose of study drug until 4 weeks after last dose; treatment duration was 20 weeks in the expansion phase.

External Links

•   AmgenTrials clinical trials website