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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Heart Failure; Pharmacokinetics; Left Ventricular Systolic Dysfunction; Left Ventricular Ejection Fraction; Modified Release Oral Formulation; History of Chronic Heart Failure; Echocardiogram
• Intervention / Treatment: Drug: Placebo; Drug: Omecamtiv Mecarbil Matrix F1 Formulation; Drug: Omecamtiv Mecarbil Matrix F2 Formulation; Drug: Omecamtiv Mecarbil Swellable Core Technology F2

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 Type: Interventional
• Enrollment (Actual): 544
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • Research Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Research Site
• Belgium
  • Antwerpen, Belgium, 2020
    • Research Site
  • Bonheiden, Belgium, 2820
    • Research Site
  • Gent, Belgium, 9000
    • Research Site
  • Ieper, Belgium, 8900
    • Research Site
  • Liege, Belgium, 4000
    • Research Site
• Bulgaria
  • Kazanlak, Bulgaria, 6100
    • Research Site
  • Pazardzhik, Bulgaria, 4700
    • Research Site
  • Plovdiv, Bulgaria, 4002
    • Research Site
  • Sandanski, Bulgaria, 2800
    • Research Site
  • Sliven, Bulgaria, 8800
    • Research Site
  • Smolyan, Bulgaria, 4400
    • Research Site
  • Sofia, Bulgaria, 1527
    • Research Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • Research Site
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
      • Research Site
  • Newfoundland and Labrador
    • St. Johns, Newfoundland and Labrador, Canada, A1B 3V6
      • Research Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Research Site
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4W7
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H3G 1A4
      • Research Site
    • Québec, Quebec, Canada, G1V 4G5
      • Research Site
    • Sherbrooke, Quebec, Canada, J1G 2E8
      • Research Site
    • Trois Rivieres, Quebec, Canada, G8T 7A1
      • Research Site
• Czechia
  • Brno, Czechia, 625 00
    • Research Site
  • Brno, Czechia, 636 00
    • Research Site
  • Olomouc, Czechia, 771 11
    • Research Site
  • Praha 2, Czechia, 128 08
    • Research Site
  • Praha 4, Czechia, 140 21
    • Research Site
  • Svitavy, Czechia, 568 25
    • Research Site
  • Teplice, Czechia, 415 29
    • Research Site
• Germany
  • Bad Krozingen, Germany, 79189
    • Research Site
  • Bad Nauheim, Germany, 61231
    • Research Site
  • Berlin, Germany, 13353
    • Research Site
  • Dortmund, Germany, 44137
    • Research Site
  • Greifswald, Germany, 17475
    • Research Site
• Hungary
  • Budapest, Hungary, 1125
    • Research Site
  • Budapest, Hungary, 1135
    • Research Site
  • Budapest, Hungary, 1027
    • Research Site
  • Jaszbereny, Hungary, 5100
    • Research Site
  • Zalaegerszeg, Hungary, 8900
    • Research Site
• Italy
  • Brescia, Italy, 25125
    • Research Site
  • Pavia, Italy, 27100
    • Research Site
  • Verona, Italy, 37134
    • Research Site
• Lithuania
  • Kaunas, Lithuania, 50009
    • Research Site
  • Vilnius, Lithuania, 08661
    • Research Site
• Netherlands
  • Amersfoort, Netherlands, 3813 TZ
    • Research Site
  • Groningen, Netherlands, 9713 GZ
    • Research Site
  • Utrecht, Netherlands, 3584 CX
    • Research Site
• Poland
  • Bialystok, Poland, 15-276
    • Research Site
  • Klodzko, Poland, 57-300
    • Research Site
  • Krakow, Poland, 31-501
    • Research Site
  • Krakow, Poland, 31-202
    • Research Site
  • Lublin, Poland, 20-954
    • Research Site
  • Ruda Slaska, Poland, 41-703
    • Research Site
  • Warszawa, Poland, 04-256
    • Research Site
  • Wroclaw, Poland, 50-981
    • Research Site
• United Kingdom
  • Dudley, United Kingdom, DY1 2HQ
    • Research Site
  • Dundee, United Kingdom, DD1 9SY
    • Research Site
  • Glasgow, United Kingdom, G11 6NT
    • Research Site
  • Harrow, United Kingdom, HA1 3UJ
    • Research Site
  • Leicester, United Kingdom, LE3 9QP
    • Research Site
  • Liverpool, United Kingdom, L14 3PE
    • Research Site
  • London, United Kingdom, EC1M 6BQ
    • Research Site
• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Research Site
  • California
    • Costa Mesa, California, United States, 92626
      • Research Site
    • Fresno, California, United States, 93721
      • Research Site
    • Inglewood, California, United States, 90301
      • Research Site
    • La Jolla, California, United States, 92037
      • Research Site
    • Los Angeles, California, United States, 90033
      • Research Site
    • Thousand Oaks, California, United States, 91360
      • Research Site
    • Tustin, California, United States, 92780
      • Research Site
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Research Site
  • Delaware
    • Newark, Delaware, United States, 19718
      • Research Site
  • Florida
    • Atlantis, Florida, United States, 33462
      • Research Site
    • Aventura, Florida, United States, 33180
      • Research Site
    • Clearwater, Florida, United States, 33756
      • Research Site
    • Miami, Florida, United States, 33136
      • Research Site
    • Tampa, Florida, United States, 33606
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Research Site
    • Macon, Georgia, United States, 31201
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Research Site
  • Maine
    • Auburn, Maine, United States, 04210
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Research Site
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Research Site
    • Petoskey, Michigan, United States, 49770
      • Research Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417
      • Research Site
    • Minneapolis, Minnesota, United States, 55415
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
  • Nevada
    • Las Vegas, Nevada, United States, 89128
      • Research Site
  • New York
    • Bronx, New York, United States, 10467
      • Research Site
    • Cortlandt Manor, New York, United States, 10567
      • Research Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Research Site
    • Durham, North Carolina, United States, 27705
      • Research Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
      • Research Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Research Site
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37232-8802
      • Research Site
    • Tullahoma, Tennessee, United States, 37388
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98195
      • Research Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

11

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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.
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.
Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7	Day 7 at predose
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
Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing	Predose (before morning dose) at weeks 2, 8, 12, 16, and 20
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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.
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.

Collaborators and Investigators

• Sponsor: Cytokinetics

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 26, 2013
• Primary Completion (ACTUAL): July 22, 2015
• Study Completion (ACTUAL): August 19, 2015

Study Registration Dates

• First Submitted: January 18, 2013
• First Submitted That Met QC Criteria: February 6, 2013
• First Posted (ESTIMATE): February 8, 2013

Study Record Updates

• Last Update Posted (ACTUAL): August 12, 2021
• Last Update Submitted That Met QC Criteria: July 25, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Placebo-controlled; Randomized; Double-blind; Omecamtiv mecarbil; AMG 423; Oral forumlation; CK-1827452; Cardiac myosin activator
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Murmurs; Ventricular Dysfunction; Heart Failure; Systolic Murmurs; Ventricular Dysfunction, Left
• Other Study ID Numbers: 20110151; 2012-000327-40 (EUDRACT_NUMBER)