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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01786512




Registration number
NCT01786512
Ethics application status
Date submitted
18/01/2013
Date registered
8/02/2013
Date last updated
17/05/2021

Titles & IDs
Public title
COSMIC-HF - Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure
Scientific 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
Secondary ID [1] 0 0
2012-000327-40
Secondary ID [2] 0 0
20110151
Universal Trial Number (UTN)
Trial acronym
COSMIC-HF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Modified Release Oral Formulation 0 0
Left Ventricular Systolic Dysfunction 0 0
Chronic Heart Failure 0 0
History of Chronic Heart Failure 0 0
Left Ventricular Ejection Fraction 0 0
Pharmacokinetics 0 0
Echocardiogram 0 0
Condition category
Condition code
Cardiovascular 0 0 0 0
Coronary heart disease
Cardiovascular 0 0 0 0
Other cardiovascular diseases
Cardiovascular 0 0 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Omecamtiv Mecarbil Matrix F1 Formulation
Treatment: Drugs - Omecamtiv Mecarbil Matrix F2 Formulation
Treatment: Drugs - Placebo
Treatment: Drugs - Omecamtiv Mecarbil Swellable Core Technology F2

Placebo Comparator: Dose-escalation Cohort 1: Placebo - Participants received placebo tablets twice a day (BID) for 7 days.

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.

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.

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.

Placebo Comparator: Dose-escalation Cohort 2: Placebo - Participants received placebo tablets twice a day for 7 days.

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.

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.

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.

Placebo Comparator: Expansion Phase: Placebo - Participants received placebo tablets twice a day for 20 weeks.

Experimental: Expansion Phase: Omecamtiv Mecarbil 25 mg M-F1 - Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks.

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.


Treatment: Drugs: Omecamtiv Mecarbil Matrix F1 Formulation
Modified release tablets for oral administration

Treatment: Drugs: Omecamtiv Mecarbil Matrix F2 Formulation
Modified release tablets for oral administration

Treatment: Drugs: Placebo
Modified release tablets matching to omecamtiv mecarbil

Treatment: Drugs: Omecamtiv Mecarbil Swellable Core Technology F2
Modified release tablets for oral administration

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
Timepoint [1] 0 0
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 outcome [2] 0 0
Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
Timepoint [2] 0 0
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 outcome [3] 0 0
Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7
Timepoint [3] 0 0
Day 7 at predose
Primary outcome [4] 0 0
Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil
Timepoint [4] 0 0
Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose
Primary outcome [5] 0 0
Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing
Timepoint [5] 0 0
Predose (before morning dose) at weeks 2, 8, 12, 16, and 20
Primary outcome [6] 0 0
Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil
Timepoint [6] 0 0
Weeks 2 and 12 at predose and 1, 2, 4, 6, and 8 hours post-dose.
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
Baseline and week 20
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
Baseline and week 20
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
Baseline and week 20
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
Baseline and week 20
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
Baseline and week 20
Secondary outcome [6] 0 0
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.
Timepoint [6] 0 0
Baseline and week 20
Secondary outcome [7] 0 0
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
Timepoint [7] 0 0
From first dose of study drug to 4 weeks after last dose; treatment duration was 7 days in the dose escalation phase.
Secondary outcome [8] 0 0
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
Timepoint [8] 0 0
From first dose of study drug until 4 weeks after last dose; treatment duration was 20 weeks in the expansion phase.

Eligibility
Key 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)
Minimum age
18 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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 design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA
Recruitment hospital [1] 0 0
Research Site - Darlinghurst
Recruitment hospital [2] 0 0
Research Site - Nedlands
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Connecticut
Country [4] 0 0
United States of America
State/province [4] 0 0
Delaware
Country [5] 0 0
United States of America
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Florida
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United States of America
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Georgia
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United States of America
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Illinois
Country [8] 0 0
United States of America
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Maine
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United States of America
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Maryland
Country [10] 0 0
United States of America
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Michigan
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Minnesota
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Missouri
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Nevada
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New York
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North Carolina
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Oklahoma
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Oregon
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South Carolina
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Tennessee
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Antwerpen
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Bonheiden
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Belgium
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Gent
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Belgium
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Ieper
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Belgium
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Liege
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Bulgaria
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Kazanlak
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Pazardzhik
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Bulgaria
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Plovdiv
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Sandanski
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Sliven
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Smolyan
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Sofia
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Svitavy
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Teplice
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Germany
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Brescia
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Italy
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Pavia
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Italy
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Verona
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Lithuania
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Kaunas
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Lithuania
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Vilnius
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Netherlands
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Amersfoort
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Netherlands
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Groningen
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Utrecht
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Poland
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Bialystok
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Klodzko
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Krakow
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Lublin
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Ruda Slaska
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Warszawa
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Wroclaw
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Dudley
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Dundee
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Glasgow
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Harrow
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Leicester
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Liverpool
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London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Amgen
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Cytokinetics
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT01786512
Trial related presentations / 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, 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.
Public notes

Contacts
Principal investigator
Name 0 0
MD
Address 0 0
Amgen
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications