Clinical trial NCT01786512: COSMIC-HF - Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Modified Release Oral Formulation
Left Ventricular Systolic Dysfunction
Chronic Heart Failure
History of Chronic Heart Failure
Left Ventricular Ejection Fraction
Pharmacokinetics
Echocardiogram
Keywords: Pharmacokinetics
Omecamtiv mecarbil
AMG 423
Double-blind
Randomized
Placebo-controlled
Oral forumlation
CK-1827452
Cardiac myosin activator
Lead sponsor: Cytokinetics
Sponsor class: INDUSTRY
First posted: 2013-02-08
Enrollment: 544
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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

Primary outcomes:
measure: Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
timeFrame: 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.
measure: Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
timeFrame: 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.
measure: Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7
timeFrame: Day 7 at predose
measure: Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil
timeFrame: Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose
measure: Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing
timeFrame: Predose (before morning dose) at weeks 2, 8, 12, 16, and 20
measure: Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil
timeFrame: Weeks 2 and 12 at predose and 1, 2, 4, 6, and 8 hours post-dose.
Secondary outcomes:
measure: Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20
timeFrame: Baseline and week 20
measure: Expansion Phase: Change From Baseline in Stroke Volume at Week 20
timeFrame: Baseline and week 20
measure: Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20
timeFrame: Baseline and week 20
measure: Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20
timeFrame: Baseline and week 20
measure: Expansion Phase: Change From Baseline in Heart Rate at Week 20
timeFrame: Baseline and week 20
measure: Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20
timeFrame: Baseline and week 20
measure: Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events
timeFrame: From first dose of study drug to 4 weeks after last dose; treatment duration was 7 days in the dose escalation phase.
measure: Expansion Phase: Number of Participants With Treatment-emergent Adverse Events
timeFrame: From first dose of study drug until 4 weeks after last dose; treatment duration was 20 weeks in the expansion phase.
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Research Site
state: Alabama
city: Costa Mesa
country: United States
facility: Research Site
state: California
city: Fresno
country: United States
facility: Research Site
state: California
city: Inglewood
country: United States
facility: Research Site
state: California
city: La Jolla
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
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state: California
city: Thousand Oaks
country: United States
facility: Research Site
state: California
city: Tustin
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state: California
city: Danbury
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state: Connecticut
city: Newark
country: United States
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state: Delaware
city: Atlantis
country: United States
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state: Florida
city: Aventura
country: United States
facility: Research Site
state: Florida
city: Clearwater
country: United States
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state: Florida
city: Miami
country: United States
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state: Florida
city: Tampa
country: United States
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state: Florida
city: Atlanta
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facility: Research Site
state: Georgia
city: Macon
country: United States
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state: Georgia
city: Chicago
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state: Illinois
city: Auburn
country: United States
facility: Research Site
state: Maine
city: Baltimore
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state: Maryland
city: Detroit
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state: Michigan
city: Petoskey
country: United States
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state: Michigan
city: Minneapolis
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state: Minnesota
city: Minneapolis
country: United States
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state: Minnesota
city: Saint Louis
country: United States
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state: Missouri
city: Las Vegas
country: United States
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state: Nevada
city: Bronx
country: United States
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state: New York
city: Cortlandt Manor
country: United States
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state: New York
city: Chapel Hill
country: United States
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state: North Carolina
city: Durham
country: United States
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state: North Carolina
city: Oklahoma City
country: United States
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state: Oklahoma
city: Portland
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state: Oregon
city: Greenville
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state: South Carolina
city: Nashville
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state: Tennessee
city: Tullahoma
country: United States
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state: Tennessee
city: Houston
country: United States
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state: Texas
city: Seattle
country: United States
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state: Washington
city: Madison
country: United States
facility: Research Site
state: Wisconsin
city: Darlinghurst
country: Australia
facility: Research Site
state: New South Wales
city: Nedlands
country: Australia
facility: Research Site
state: Western Australia
city: Antwerpen
country: Belgium
facility: Research Site
city: Bonheiden
country: Belgium
facility: Research Site
city: Gent
country: Belgium
facility: Research Site
city: Ieper
country: Belgium
facility: Research Site
city: Liege
country: Belgium
facility: Research Site
city: Kazanlak
country: Bulgaria
facility: Research Site
city: Pazardzhik
country: Bulgaria
facility: Research Site
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Sandanski
country: Bulgaria
facility: Research Site
city: Sliven
country: Bulgaria
facility: Research Site
city: Smolyan
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Winnipeg
country: Canada
facility: Research Site
state: Manitoba
city: St. Johns
country: Canada
facility: Research Site
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: Research Site
state: Nova Scotia
city: Ottawa
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Québec
country: Canada
facility: Research Site
state: Quebec
city: Sherbrooke
country: Canada
facility: Research Site
state: Quebec
city: Trois Rivieres
country: Canada
facility: Research Site
state: Quebec
city: Brno
country: Czechia
facility: Research Site
city: Brno
country: Czechia
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Praha 2
country: Czechia
facility: Research Site
city: Praha 4
country: Czechia
facility: Research Site
city: Svitavy
country: Czechia
facility: Research Site
city: Teplice
country: Czechia
facility: Research Site
city: Bad Krozingen
country: Germany
facility: Research Site
city: Bad Nauheim
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Dortmund
country: Germany
facility: Research Site
city: Greifswald
country: Germany
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Jaszbereny
country: Hungary
facility: Research Site
city: Zalaegerszeg
country: Hungary
facility: Research Site
city: Brescia
country: Italy
facility: Research Site
city: Pavia
country: Italy
facility: Research Site
city: Verona
country: Italy
facility: Research Site
city: Kaunas
country: Lithuania
facility: Research Site
city: Vilnius
country: Lithuania
facility: Research Site
city: Amersfoort
country: Netherlands
facility: Research Site
city: Groningen
country: Netherlands
facility: Research Site
city: Utrecht
country: Netherlands
facility: Research Site
city: Bialystok
country: Poland
facility: Research Site
city: Klodzko
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Lublin
country: Poland
facility: Research Site
city: Ruda Slaska
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Wroclaw
country: Poland
facility: Research Site
city: Dudley
country: United Kingdom
facility: Research Site
city: Dundee
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: Harrow
country: United Kingdom
facility: Research Site
city: Leicester
country: United Kingdom
facility: Research Site
city: Liverpool
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: 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, Tomcsanyi 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.
citation: Biering-Sorensen T, Minamisawa M, Liu J, Claggett B, Papolos AI, Felker GM, McMurray JJV, Legg JC, Malik FI, Honarpour N, Kurtz CE, Teerlink JR, Solomon SD. The effect of the cardiac myosin activator, omecamtiv mecarbil, on right ventricular structure and function in chronic systolic heart failure (COSMIC-HF). Eur J Heart Fail. 2021 Jun;23(6):1052-1056. doi: 10.1002/ejhf.2181. Epub 2021 May 5. No abstract available.
citation: Biering-Sorensen T, Minamisawa M, Claggett B, Liu J, Felker GM, McMurray JJV, Malik FI, Abbasi S, Kurtz CE, Teerlink JR, Solomon SD. Cardiac Myosin Activator Omecamtiv Mecarbil Improves Left Ventricular Myocardial Deformation in Chronic Heart Failure: The COSMIC-HF Trial. Circ Heart Fail. 2020 Dec;13(12):e008007. doi: 10.1161/CIRCHEARTFAILURE.120.008007. Epub 2020 Nov 12. No abstract available.
citation: Felker GM, Solomon SD, McMurray JJV, Cleland JGF, Abbasi SA, Malik FI, Zhang H, Globe G, Teerlink JR; COSMIC-HF Investigators. Effects of Omecamtiv Mecarbil on Symptoms and Health-Related Quality of Life in Patients With Chronic Heart Failure: Results From the COSMIC-HF Study. Circ Heart Fail. 2020 Dec;13(12):e007814. doi: 10.1161/CIRCHEARTFAILURE.120.007814. Epub 2020 Nov 12.