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

Sponsor
Cytokinetics (Industry)
Overall Status
Completed
CT.gov ID
NCT01786512
Collaborator
(none)
544
101
11
29.7
5.4
0.2

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Omecamtiv Mecarbil Matrix F1 Formulation
  • Drug: Omecamtiv Mecarbil Matrix F2 Formulation
  • Drug: Placebo
  • Drug: Omecamtiv Mecarbil Swellable Core Technology F2
Phase 2

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 Design

Study Type:
Interventional
Actual Enrollment :
544 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Feb 26, 2013
Actual Primary Completion Date :
Jul 22, 2015
Actual Study Completion Date :
Aug 19, 2015

Arms and Interventions

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
  • Outcome Measures

    Primary Outcome Measures

    1. 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.]

    2. 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.]

    3. Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7 [Day 7 at predose]

    4. 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]

    5. Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing [Predose (before morning dose) at weeks 2, 8, 12, 16, and 20]

    6. 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

    1. Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20 [Baseline and 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.

    2. Expansion Phase: Change From Baseline in Stroke Volume at Week 20 [Baseline and 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.

    3. Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20 [Baseline and 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.

    4. Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20 [Baseline and 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.

    5. Expansion Phase: Change From Baseline in Heart Rate at Week 20 [Baseline and 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.

    6. Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20 [Baseline and 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.

    7. Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events [From first dose of study drug to 4 weeks after last dose; treatment duration was 7 days in the dose escalation phase.]

      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

    8. Expansion Phase: Number of Participants With Treatment-emergent Adverse Events [From first dose of study drug until 4 weeks after last dose; treatment duration was 20 weeks in the expansion phase.]

      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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 85 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site Mobile Alabama United States 36608
    2 Research Site Costa Mesa California United States 92626
    3 Research Site Fresno California United States 93721
    4 Research Site Inglewood California United States 90301
    5 Research Site La Jolla California United States 92037
    6 Research Site Los Angeles California United States 90033
    7 Research Site Thousand Oaks California United States 91360
    8 Research Site Tustin California United States 92780
    9 Research Site Danbury Connecticut United States 06810
    10 Research Site Newark Delaware United States 19718
    11 Research Site Atlantis Florida United States 33462
    12 Research Site Aventura Florida United States 33180
    13 Research Site Clearwater Florida United States 33756
    14 Research Site Miami Florida United States 33136
    15 Research Site Tampa Florida United States 33606
    16 Research Site Atlanta Georgia United States 30322
    17 Research Site Macon Georgia United States 31201
    18 Research Site Chicago Illinois United States 60612
    19 Research Site Auburn Maine United States 04210
    20 Research Site Baltimore Maryland United States 21201
    21 Research Site Detroit Michigan United States 48202
    22 Research Site Petoskey Michigan United States 49770
    23 Research Site Minneapolis Minnesota United States 55415
    24 Research Site Minneapolis Minnesota United States 55417
    25 Research Site Saint Louis Missouri United States 63110
    26 Research Site Las Vegas Nevada United States 89128
    27 Research Site Bronx New York United States 10467
    28 Research Site Cortlandt Manor New York United States 10567
    29 Research Site Chapel Hill North Carolina United States 27599
    30 Research Site Durham North Carolina United States 27705
    31 Research Site Oklahoma City Oklahoma United States 73120
    32 Research Site Portland Oregon United States 97239
    33 Research Site Greenville South Carolina United States 29605
    34 Research Site Nashville Tennessee United States 37232-8802
    35 Research Site Tullahoma Tennessee United States 37388
    36 Research Site Houston Texas United States 77030
    37 Research Site Seattle Washington United States 98195
    38 Research Site Madison Wisconsin United States 53792
    39 Research Site Darlinghurst New South Wales Australia 2010
    40 Research Site Nedlands Western Australia Australia 6009
    41 Research Site Antwerpen Belgium 2020
    42 Research Site Bonheiden Belgium 2820
    43 Research Site Gent Belgium 9000
    44 Research Site Ieper Belgium 8900
    45 Research Site Liege Belgium 4000
    46 Research Site Kazanlak Bulgaria 6100
    47 Research Site Pazardzhik Bulgaria 4700
    48 Research Site Plovdiv Bulgaria 4002
    49 Research Site Sandanski Bulgaria 2800
    50 Research Site Sliven Bulgaria 8800
    51 Research Site Smolyan Bulgaria 4400
    52 Research Site Sofia Bulgaria 1527
    53 Research Site Edmonton Alberta Canada T6G 2B7
    54 Research Site Winnipeg Manitoba Canada R2H 2A6
    55 Research Site St. Johns Newfoundland and Labrador Canada A1B 3V6
    56 Research Site Halifax Nova Scotia Canada B3H 3A7
    57 Research Site Ottawa Ontario Canada K1Y 4W7
    58 Research Site Montreal Quebec Canada H3G 1A4
    59 Research Site Québec Quebec Canada G1V 4G5
    60 Research Site Sherbrooke Quebec Canada J1G 2E8
    61 Research Site Trois Rivieres Quebec Canada G8T 7A1
    62 Research Site Brno Czechia 625 00
    63 Research Site Brno Czechia 636 00
    64 Research Site Olomouc Czechia 771 11
    65 Research Site Praha 2 Czechia 128 08
    66 Research Site Praha 4 Czechia 140 21
    67 Research Site Svitavy Czechia 568 25
    68 Research Site Teplice Czechia 415 29
    69 Research Site Bad Krozingen Germany 79189
    70 Research Site Bad Nauheim Germany 61231
    71 Research Site Berlin Germany 13353
    72 Research Site Dortmund Germany 44137
    73 Research Site Greifswald Germany 17475
    74 Research Site Budapest Hungary 1027
    75 Research Site Budapest Hungary 1125
    76 Research Site Budapest Hungary 1135
    77 Research Site Jaszbereny Hungary 5100
    78 Research Site Zalaegerszeg Hungary 8900
    79 Research Site Brescia Italy 25125
    80 Research Site Pavia Italy 27100
    81 Research Site Verona Italy 37134
    82 Research Site Kaunas Lithuania 50009
    83 Research Site Vilnius Lithuania 08661
    84 Research Site Amersfoort Netherlands 3813 TZ
    85 Research Site Groningen Netherlands 9713 GZ
    86 Research Site Utrecht Netherlands 3584 CX
    87 Research Site Bialystok Poland 15-276
    88 Research Site Klodzko Poland 57-300
    89 Research Site Krakow Poland 31-202
    90 Research Site Krakow Poland 31-501
    91 Research Site Lublin Poland 20-954
    92 Research Site Ruda Slaska Poland 41-703
    93 Research Site Warszawa Poland 04-256
    94 Research Site Wroclaw Poland 50-981
    95 Research Site Dudley United Kingdom DY1 2HQ
    96 Research Site Dundee United Kingdom DD1 9SY
    97 Research Site Glasgow United Kingdom G11 6NT
    98 Research Site Harrow United Kingdom HA1 3UJ
    99 Research Site Leicester United Kingdom LE3 9QP
    100 Research Site Liverpool United Kingdom L14 3PE
    101 Research Site London United Kingdom EC1M 6BQ

    Sponsors and Collaborators

    • Cytokinetics

    Investigators

    • Study Director: MD, Amgen

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Cytokinetics
    ClinicalTrials.gov Identifier:
    NCT01786512
    Other Study ID Numbers:
    • 20110151
    • 2012-000327-40
    First Posted:
    Feb 8, 2013
    Last Update Posted:
    Aug 12, 2021
    Last Verified:
    Jul 1, 2021

    Study Results

    Participant Flow

    Recruitment Details Participants with chronic heart failure treated with stable, optimal pharmacological therapy for ≥ 4 weeks were enrolled from February 2013 to March 2015 at 86 centers in 13 countries in Europe, Australia, and North America. The study consisted of a dose-escalation phase to select 1 of 3 omecamtiv mecarbil (OM) oral formulations in 2 dose cohorts, and an expansion phase to evaluate 20 weeks of treatment with the selected formulation at 2 target dose levels, compared with placebo.
    Pre-assignment Detail In each of the dose-escalation cohorts participants were randomized equally to receive 1 of the 3 formulations of OM or placebo. In the expansion phase participants were randomized equally to receive 25 mg oral OM twice daily (fixed-dose group), 25 mg oral OM twice daily titrated up to 50 mg twice daily (pharmacokinetic-titration group), or oral placebo. Randomization in both phases was stratified by presence or absence of atrial fibrillation/flutter.
    Arm/Group Title Dose-escalation Cohort 1: Placebo Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Dose-escalation Cohort 2: Placebo Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Arm/Group Description Participants received placebo tablets twice a day (BID) for 7 days. Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days. Participants received placebo tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days. Participants received placebo tablets twice a day for 20 weeks. Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. 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.
    Period Title: Overall Study
    STARTED 11 11 14 13 10 11 12 14 149 150 149
    Received Study Treatment 11 10 14 13 10 11 11 14 149 150 146
    COMPLETED 11 10 14 13 10 11 11 14 145 145 137
    NOT COMPLETED 0 1 0 0 0 0 1 0 4 5 12

    Baseline Characteristics

    Arm/Group Title Dose-escalation Cohort 1: Placebo Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Dose-escalation Cohort 2: Placebo Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration Total
    Arm/Group Description Participants received placebo tablets twice a day (BID) for 7 days. Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days. Participants received placebo tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days. Participants received placebo tablets twice a day for 20 weeks. Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. 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. Total of all reporting groups
    Overall Participants 11 11 14 13 10 11 12 14 149 150 149 544
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    66.5
    (4.6)
    67.7
    (11.4)
    65.3
    (8.8)
    66.7
    (8.7)
    62.1
    (9.3)
    65.1
    (7.0)
    63.8
    (11.6)
    64.3
    (11.5)
    63.7
    (9.7)
    62.8
    (10.2)
    62.7
    (11.7)
    63.4
    (10.4)
    Age, Customized (Count of Participants)
    18 - 64 years
    3
    27.3%
    4
    36.4%
    7
    50%
    5
    38.5%
    5
    50%
    6
    54.5%
    5
    41.7%
    6
    42.9%
    82
    55%
    81
    54%
    76
    51%
    280
    51.5%
    65 - 74 years
    8
    72.7%
    4
    36.4%
    4
    28.6%
    6
    46.2%
    5
    50%
    4
    36.4%
    4
    33.3%
    5
    35.7%
    46
    30.9%
    52
    34.7%
    50
    33.6%
    188
    34.6%
    75 - 84 years
    0
    0%
    3
    27.3%
    3
    21.4%
    2
    15.4%
    0
    0%
    1
    9.1%
    3
    25%
    3
    21.4%
    21
    14.1%
    17
    11.3%
    23
    15.4%
    76
    14%
    Sex: Female, Male (Count of Participants)
    Female
    2
    18.2%
    2
    18.2%
    3
    21.4%
    1
    7.7%
    3
    30%
    3
    27.3%
    4
    33.3%
    2
    14.3%
    30
    20.1%
    23
    15.3%
    24
    16.1%
    97
    17.8%
    Male
    9
    81.8%
    9
    81.8%
    11
    78.6%
    12
    92.3%
    7
    70%
    8
    72.7%
    8
    66.7%
    12
    85.7%
    119
    79.9%
    127
    84.7%
    125
    83.9%
    447
    82.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    1
    9.1%
    0
    0%
    1
    7.7%
    1
    10%
    0
    0%
    1
    8.3%
    0
    0%
    2
    1.3%
    7
    4.7%
    4
    2.7%
    17
    3.1%
    Not Hispanic or Latino
    11
    100%
    10
    90.9%
    14
    100%
    12
    92.3%
    9
    90%
    11
    100%
    11
    91.7%
    14
    100%
    147
    98.7%
    143
    95.3%
    145
    97.3%
    527
    96.9%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    1.3%
    1
    0.7%
    0
    0%
    3
    0.6%
    Black or African American
    3
    27.3%
    1
    9.1%
    0
    0%
    0
    0%
    0
    0%
    3
    27.3%
    1
    8.3%
    2
    14.3%
    11
    7.4%
    5
    3.3%
    8
    5.4%
    34
    6.3%
    Mixed Race
    0
    0%
    0
    0%
    0
    0%
    1
    7.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    0.2%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    0.7%
    0
    0%
    1
    0.2%
    White
    7
    63.6%
    10
    90.9%
    14
    100%
    12
    92.3%
    10
    100%
    8
    72.7%
    11
    91.7%
    12
    85.7%
    136
    91.3%
    142
    94.7%
    140
    94%
    502
    92.3%
    Other
    1
    9.1%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    0.7%
    1
    0.7%
    3
    0.6%
    Stratification Factor - Atrial Fibrillation/Flutter at Randomization (Count of Participants)
    Yes
    0
    0%
    0
    0%
    3
    21.4%
    2
    15.4%
    0
    0%
    1
    9.1%
    2
    16.7%
    3
    21.4%
    32
    21.5%
    32
    21.3%
    32
    21.5%
    107
    19.7%
    No
    11
    100%
    11
    100%
    11
    78.6%
    11
    84.6%
    10
    100%
    10
    90.9%
    10
    83.3%
    11
    78.6%
    117
    78.5%
    118
    78.7%
    117
    78.5%
    437
    80.3%

    Outcome Measures

    1. Primary Outcome
    Title Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
    Description
    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 Data

    Analysis Population Description
    The pharmacokinetic analysis set (PKAS) included all randomized participants who received at least 1 dose of OM and had at least 1 evaluable OM PK parameter.
    Arm/Group Title Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Arm/Group Description Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.
    Measure Participants 10 14 13 10 11 14
    Mean (Standard Deviation) [ng/mL]
    193
    (58.8)
    201
    (94.4)
    171
    (53.8)
    492
    (115)
    502
    (138)
    601
    (204)
    2. Primary Outcome
    Title Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7)
    Description
    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 Data

    Analysis Population Description
    Pharmacokinetic analysis set
    Arm/Group Title Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Arm/Group Description Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.
    Measure Participants 10 14 13 10 11 14
    Mean (Standard Deviation) [hours]
    3.9
    (4.4)
    2.0
    (1.2)
    4.2
    (1.9)
    2.6
    (2.4)
    2.2
    (1.8)
    4.6
    (2.3)
    3. Primary Outcome
    Title Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7
    Description
    Time Frame Day 7 at predose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set
    Arm/Group Title Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Arm/Group Description Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.
    Measure Participants 10 14 13 10 11 14
    Mean (Standard Deviation) [ng/mL]
    157
    (63.7)
    137
    (56.8)
    134
    (54.7)
    376
    (170)
    395
    (108)
    476
    (234)
    4. Primary Outcome
    Title Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil
    Description
    Time Frame Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set
    Arm/Group Title Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Arm/Group Description Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.
    Measure Participants 10 14 13 10 11 14
    Mean (Standard Deviation) [ng*hr/mL]
    2030
    (658)
    2000
    (1020)
    1740
    (586)
    5070
    (1060)
    5010
    (1160)
    6550
    (2340)
    5. Primary Outcome
    Title Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing
    Description
    Time Frame Predose (before morning dose) at weeks 2, 8, 12, 16, and 20

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set with available data at each time point.
    Arm/Group Title Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Arm/Group Description Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. 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.
    Measure Participants 147 141
    Week 2
    174
    (62.2)
    179
    (68.8)
    Week 8
    156
    (69.1)
    161
    (74.4)
    Week 12
    165
    (67.9)
    263
    (116)
    Week 16
    155
    (69.0)
    240
    (120)
    Week 20
    149
    (71.2)
    239
    (118)
    6. Primary Outcome
    Title Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil
    Description
    Time Frame Weeks 2 and 12 at predose and 1, 2, 4, 6, and 8 hours post-dose.

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set with available data at each time point.
    Arm/Group Title Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Arm/Group Description Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. 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.
    Measure Participants 147 141
    Week 2
    212
    (70.4)
    212
    (81.0)
    Week 12
    200
    (71.1)
    318
    (129)
    7. Secondary Outcome
    Title Expansion Phase: Change From Baseline in Systolic Ejection Time (SET) at Week 20
    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.
    Time Frame Baseline and week 20

    Outcome Measure Data

    Analysis Population Description
    The full analysis set (FAS) included all randomized participants who received at least 1 dose of study drug. The repeated-measures model included all observed values.
    Arm/Group Title Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Arm/Group Description Participants received placebo tablets twice a day for 20 weeks. Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. 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.
    Measure Participants 149 150 146
    Least Squares Mean (Standard Error) [seconds]
    0.0000
    (0.0025)
    0.0112
    (0.0024)
    0.0250
    (0.0026)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1, Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0007
    Comments
    Method Repeated Measures
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value 0.0112
    Confidence Interval (2-Sided) 95%
    0.0047 to 0.0176
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.0033
    Estimation Comments Repeated measures model includes treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1, Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Repeated Measures
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value 0.0250
    Confidence Interval (2-Sided) 95%
    0.0184 to 0.0315
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.0033
    Estimation Comments Repeated measures model includes treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    8. Secondary Outcome
    Title Expansion Phase: Change From Baseline in Stroke Volume at Week 20
    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.
    Time Frame Baseline and week 20

    Outcome Measure Data

    Analysis Population Description
    The full analysis set included all randomized participants who received at least 1 dose of study drug. The repeated-measures model included all observed values.
    Arm/Group Title Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Arm/Group Description Participants received placebo tablets twice a day for 20 weeks. Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. 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.
    Measure Participants 149 150 146
    Least Squares Mean (Standard Error) [mL]
    -1.05
    (1.18)
    3.53
    (1.16)
    2.58
    (1.19)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1, Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0036
    Comments
    Method Repeated Measures
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value 4.58
    Confidence Interval (2-Sided) 95%
    1.50 to 7.65
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.56
    Estimation Comments Repeated measures model includes treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1, Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0217
    Comments
    Method Repeated Measures
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value 3.63
    Confidence Interval (2-Sided) 95%
    0.53 to 6.72
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.57
    Estimation Comments Repeated measures model includes treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    9. Secondary Outcome
    Title Expansion Phase: Change From Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20
    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.
    Time Frame Baseline and week 20

    Outcome Measure Data

    Analysis Population Description
    The full analysis set included all randomized participants who received at least 1 dose of study drug. The repeated-measures model included all observed values.
    Arm/Group Title Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Arm/Group Description Participants received placebo tablets twice a day for 20 weeks. Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. 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.
    Measure Participants 149 150 146
    Least Squares Mean (Standard Error) [cm]
    -0.242
    (0.043)
    -0.322
    (0.044)
    -0.421
    (0.045)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1, Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1732
    Comments
    Method Repeated Measures
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value -0.079
    Confidence Interval (2-Sided) 95%
    -0.194 to 0.035
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.058
    Estimation Comments Repeated measures model includes treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1, Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0027
    Comments
    Method Repeated Measures
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value -0.179
    Confidence Interval (2-Sided) 95%
    -0.295 to -0.062
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.059
    Estimation Comments Repeated measures model includes treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    10. Secondary Outcome
    Title Expansion Phase: Change From Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20
    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.
    Time Frame Baseline and week 20

    Outcome Measure Data

    Analysis Population Description
    The full analysis set included all randomized participants who received at least 1 dose of study drug. The repeated-measures model included all observed values.
    Arm/Group Title Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Arm/Group Description Participants received placebo tablets twice a day for 20 weeks. Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. 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.
    Measure Participants 149 150 146
    Least Squares Mean (Standard Error) [cm]
    0.089
    (0.038)
    0.023
    (0.038)
    -0.040
    (0.040)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1, Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1899
    Comments
    Method Repeated Measures
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value -0.067
    Confidence Interval (2-Sided) 95%
    -0.166 to 0.033
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.051
    Estimation Comments Repeated measures model includes treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1, Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0128
    Comments
    Method Repeated Measures
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value -0.129
    Confidence Interval (2-Sided) 95%
    -0.231 to -0.028
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.052
    Estimation Comments Repeated measures model includes treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    11. Secondary Outcome
    Title Expansion Phase: Change From Baseline in Heart Rate at Week 20
    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.
    Time Frame Baseline and week 20

    Outcome Measure Data

    Analysis Population Description
    The full analysis set included all randomized participants who received at least 1 dose of study drug. The repeated-measures model included all observed values.
    Arm/Group Title Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Arm/Group Description Participants received placebo tablets twice a day for 20 weeks. Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. 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.
    Measure Participants 149 150 146
    Least Squares Mean (Standard Error) [bpm]
    0.57
    (0.79)
    -0.77
    (0.79)
    -2.40
    (0.81)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1, Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2177
    Comments
    Method Repeated Measures
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value -1.34
    Confidence Interval (2-Sided) 95%
    -3.47 to 0.79
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.09
    Estimation Comments Repeated measures model includes treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1, Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0070
    Comments
    Method Repeated Measures
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value -2.97
    Confidence Interval (2-Sided) 95%
    -5.12 to -0.81
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.09
    Estimation Comments Repeated measures model includes treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    12. Secondary Outcome
    Title Expansion Phase: Change From Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20
    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.
    Time Frame Baseline and week 20

    Outcome Measure Data

    Analysis Population Description
    The full analysis set included all randomized participants who received at least 1 dose of study drug. The repeated-measures model included all observed values.
    Arm/Group Title Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Arm/Group Description Participants received placebo tablets twice a day for 20 weeks. Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. 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.
    Measure Participants 149 150 146
    Least Squares Mean (Standard Error) [pg/mL]
    502
    (257)
    -319
    (257)
    -468
    (262)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1, Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0205
    Comments
    Method Repeated Measures
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value -822
    Confidence Interval (2-Sided) 95%
    -1516 to -127
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 353
    Estimation Comments Repeated measures model includes treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1, Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0069
    Comments
    Method Repeated Measures
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value -970
    Confidence Interval (2-Sided) 95%
    -1672 to -268
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 357
    Estimation Comments Repeated measures model includes treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    13. Secondary Outcome
    Title Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events
    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
    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 Data

    Analysis Population Description
    Participants randomized in the dose-escalation phase who received at least 1 dose of study drug.
    Arm/Group Title Dose-escalation Cohort 1: Placebo Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Dose-escalation Cohort 2: Placebo Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Arm/Group Description Participants received placebo tablets twice a day (BID) for 7 days. Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days. Participants received placebo tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.
    Measure Participants 11 10 14 13 10 11 11 14
    Any treatment-emergent adverse event (TEAE)
    4
    36.4%
    2
    18.2%
    6
    42.9%
    6
    46.2%
    1
    10%
    9
    81.8%
    3
    25%
    5
    35.7%
    TEAE Grade ≥ 2
    0
    0%
    1
    9.1%
    1
    7.1%
    1
    7.7%
    1
    10%
    5
    45.5%
    1
    8.3%
    1
    7.1%
    TEAE Grade ≥ 3
    0
    0%
    0
    0%
    1
    7.1%
    0
    0%
    0
    0%
    2
    18.2%
    0
    0%
    1
    7.1%
    TEAE Grade ≥ 4
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Serious adverse events
    0
    0%
    0
    0%
    1
    7.1%
    0
    0%
    0
    0%
    2
    18.2%
    0
    0%
    1
    7.1%
    TEAE leading to discontinuation of study drug
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    18.2%
    0
    0%
    0
    0%
    Fatal adverse events
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    14. Secondary Outcome
    Title Expansion Phase: Number of Participants With Treatment-emergent Adverse Events
    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
    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 Data

    Analysis Population Description
    All participants randomized in the expansion phase who received at least 1 dose of study drug.
    Arm/Group Title Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Arm/Group Description Participants received placebo tablets twice a day for 20 weeks. Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. 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.
    Measure Participants 149 150 146
    Any treatment-emergent adverse event (TEAE)
    91
    827.3%
    92
    836.4%
    95
    678.6%
    TEAE Grade ≥ 2
    62
    563.6%
    60
    545.5%
    61
    435.7%
    TEAE Grade ≥ 3
    34
    309.1%
    28
    254.5%
    31
    221.4%
    TEAE Grade ≥ 4
    5
    45.5%
    8
    72.7%
    11
    78.6%
    Serious adverse events
    30
    272.7%
    36
    327.3%
    32
    228.6%
    TEAEs leading to discontinuation of study drug
    12
    109.1%
    8
    72.7%
    12
    85.7%
    Fatal adverse events
    4
    36.4%
    1
    9.1%
    3
    21.4%

    Adverse Events

    Time Frame From first dose of study drug to 4 weeks after last dose; treatment duration was 7 days in the dose escalation phase and 20 weeks in the expansion phase.
    Adverse Event Reporting Description Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
    Arm/Group Title Dose-escalation Cohort 1: Placebo Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Dose-escalation Cohort 2: Placebo Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Arm/Group Description Participants received placebo tablets BID for 7 days. Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days. Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days. Participants received placebo tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days. Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days. Participants received placebo tablets twice a day for 20 weeks. Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks. 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.
    All Cause Mortality
    Dose-escalation Cohort 1: Placebo Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Dose-escalation Cohort 2: Placebo Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Dose-escalation Cohort 1: Placebo Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Dose-escalation Cohort 2: Placebo Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/11 (0%) 0/10 (0%) 1/14 (7.1%) 0/13 (0%) 0/10 (0%) 2/11 (18.2%) 0/11 (0%) 1/14 (7.1%) 30/149 (20.1%) 36/150 (24%) 32/146 (21.9%)
    Blood and lymphatic system disorders
    Anaemia 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Cardiac disorders
    Acute myocardial infarction 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 1/146 (0.7%)
    Angina pectoris 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 3/150 (2%) 1/146 (0.7%)
    Angina unstable 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 1/146 (0.7%)
    Atrial fibrillation 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 2/150 (1.3%) 0/146 (0%)
    Atrial flutter 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Cardiac arrest 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 2/149 (1.3%) 1/150 (0.7%) 0/146 (0%)
    Cardiac asthma 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Cardiac failure 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 4/149 (2.7%) 3/150 (2%) 5/146 (3.4%)
    Cardiac failure acute 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 3/150 (2%) 3/146 (2.1%)
    Cardiac failure chronic 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 3/149 (2%) 0/150 (0%) 0/146 (0%)
    Cardiac failure congestive 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 3/149 (2%) 3/150 (2%) 3/146 (2.1%)
    Cardio-respiratory distress 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Coronary artery disease 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Ischaemic cardiomyopathy 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Left ventricular dysfunction 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Myocardial infarction 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 2/149 (1.3%) 0/150 (0%) 0/146 (0%)
    Myocardial ischaemia 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Palpitations 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Pericardial effusion 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Supraventricular tachycardia 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Ventricular fibrillation 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Ventricular tachycardia 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 2/150 (1.3%) 1/146 (0.7%)
    Ear and labyrinth disorders
    Vertigo positional 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Gastrointestinal disorders
    Gastrointestinal haemorrhage 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Inguinal hernia 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 1/150 (0.7%) 0/146 (0%)
    Pancreatitis acute 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    General disorders
    Cardiac complication associated with device 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Chest discomfort 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Death 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Impaired healing 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Non-cardiac chest pain 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 2/149 (1.3%) 0/150 (0%) 1/146 (0.7%)
    Hepatobiliary disorders
    Cholecystitis acute 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Hepatic congestion 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Hepatic failure 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Infections and infestations
    Abscess limb 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Appendicitis 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Arthritis bacterial 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Bronchitis 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 2/149 (1.3%) 0/150 (0%) 0/146 (0%)
    Bronchopneumonia 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Cellulitis 0/11 (0%) 0/10 (0%) 1/14 (7.1%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 2/146 (1.4%)
    Gangrene 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Klebsiella sepsis 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Pneumonia 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 1/14 (7.1%) 1/149 (0.7%) 1/150 (0.7%) 3/146 (2.1%)
    Pneumonia bacterial 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Prostate infection 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Respiratory tract infection 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Upper respiratory tract infection 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Urinary tract infection bacterial 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Injury, poisoning and procedural complications
    Laceration 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Ulnar nerve injury 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Vascular pseudoaneurysm 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Investigations
    Alanine aminotransferase increased 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Aspartate aminotransferase increased 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Blood creatinine increased 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Troponin I increased 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Troponin increased 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 2/150 (1.3%) 2/146 (1.4%)
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Hypoglycaemia 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Carcinoma in situ of skin 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Lung neoplasm malignant 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Metastases to central nervous system 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Metastatic carcinoma of the bladder 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Tonsil cancer 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Nervous system disorders
    Cerebrovascular accident 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Dizziness 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Epilepsy 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Facial paresis 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Ischaemic cerebral infarction 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Myoclonus 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Transient ischaemic attack 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Psychiatric disorders
    Suicide attempt 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Renal and urinary disorders
    Acute kidney injury 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Chronic kidney disease 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Asthma 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Chronic obstructive pulmonary disease 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 1/146 (0.7%)
    Dyspnoea 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 2/150 (1.3%) 0/146 (0%)
    Pneumonia aspiration 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Pulmonary oedema 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Skin and subcutaneous tissue disorders
    Decubitus ulcer 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Vascular disorders
    Hypertension 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Peripheral arterial occlusive disease 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 1/146 (0.7%)
    Other (Not Including Serious) Adverse Events
    Dose-escalation Cohort 1: Placebo Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Dose-escalation Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Dose-escalation Cohort 2: Placebo Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Dose-escalation Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: OM PK-based Titration
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/11 (36.4%) 2/10 (20%) 5/14 (35.7%) 6/13 (46.2%) 1/10 (10%) 8/11 (72.7%) 3/11 (27.3%) 4/14 (28.6%) 48/149 (32.2%) 51/150 (34%) 48/146 (32.9%)
    Blood and lymphatic system disorders
    Anaemia 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 1/10 (10%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Cardiac disorders
    Bundle branch block left 0/11 (0%) 1/10 (10%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Cardiac failure 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 9/149 (6%) 2/150 (1.3%) 3/146 (2.1%)
    Palpitations 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 3/149 (2%) 3/150 (2%) 4/146 (2.7%)
    Sinus bradycardia 1/11 (9.1%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Sinus tachycardia 0/11 (0%) 1/10 (10%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 0/146 (0%)
    Ear and labyrinth disorders
    Tinnitus 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 0/146 (0%)
    Gastrointestinal disorders
    Abdominal pain 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 1/150 (0.7%) 1/146 (0.7%)
    Abnormal faeces 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 1/14 (7.1%) 0/149 (0%) 0/150 (0%) 0/146 (0%)
    Constipation 1/11 (9.1%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 2/149 (1.3%) 2/150 (1.3%) 1/146 (0.7%)
    Diarrhoea 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 5/149 (3.4%) 5/150 (3.3%) 4/146 (2.7%)
    Dry mouth 0/11 (0%) 0/10 (0%) 0/14 (0%) 1/13 (7.7%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 2/149 (1.3%) 0/150 (0%) 0/146 (0%)
    Flatulence 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 1/14 (7.1%) 0/149 (0%) 0/150 (0%) 0/146 (0%)
    Nausea 1/11 (9.1%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 5/149 (3.4%) 2/150 (1.3%) 8/146 (5.5%)
    General disorders
    Asthenia 0/11 (0%) 1/10 (10%) 3/14 (21.4%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 1/11 (9.1%) 0/14 (0%) 2/149 (1.3%) 2/150 (1.3%) 2/146 (1.4%)
    Fatigue 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 4/149 (2.7%) 14/150 (9.3%) 9/146 (6.2%)
    Feeling hot 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 0/146 (0%)
    Nodule 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 0/146 (0%)
    Infections and infestations
    Nasopharyngitis 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 5/149 (3.4%) 8/150 (5.3%) 5/146 (3.4%)
    Injury, poisoning and procedural complications
    Skin abrasion 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 1/10 (10%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 0/146 (0%)
    Investigations
    Blood alkaline phosphatase increased 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 1/14 (7.1%) 0/149 (0%) 2/150 (1.3%) 0/146 (0%)
    Blood bicarbonate decreased 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 0/146 (0%)
    Carotid bruit 0/11 (0%) 0/10 (0%) 1/14 (7.1%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 0/146 (0%)
    Heart rate increased 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 1/14 (7.1%) 0/149 (0%) 0/150 (0%) 0/146 (0%)
    N-terminal prohormone brain natriuretic peptide increased 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 0/146 (0%)
    Troponin I increased 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 1/150 (0.7%) 1/146 (0.7%)
    Weight increased 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 1/11 (9.1%) 0/14 (0%) 1/149 (0.7%) 1/150 (0.7%) 0/146 (0%)
    Metabolism and nutrition disorders
    Gout 1/11 (9.1%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 6/149 (4%) 3/150 (2%) 2/146 (1.4%)
    Musculoskeletal and connective tissue disorders
    Muscle spasms 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 2/11 (18.2%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 1/146 (0.7%)
    Myalgia 0/11 (0%) 0/10 (0%) 0/14 (0%) 1/13 (7.7%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 3/150 (2%) 0/146 (0%)
    Pain in extremity 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 1/11 (9.1%) 0/14 (0%) 1/149 (0.7%) 2/150 (1.3%) 0/146 (0%)
    Nervous system disorders
    Dizziness 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 6/149 (4%) 8/150 (5.3%) 9/146 (6.2%)
    Headache 0/11 (0%) 0/10 (0%) 1/14 (7.1%) 5/13 (38.5%) 0/10 (0%) 2/11 (18.2%) 0/11 (0%) 0/14 (0%) 5/149 (3.4%) 2/150 (1.3%) 9/146 (6.2%)
    Psychiatric disorders
    Insomnia 1/11 (9.1%) 0/10 (0%) 0/14 (0%) 1/13 (7.7%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 2/150 (1.3%) 1/146 (0.7%)
    Mental status changes 1/11 (9.1%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 0/146 (0%)
    Renal and urinary disorders
    Renal impairment 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 1/11 (9.1%) 0/14 (0%) 1/149 (0.7%) 2/150 (1.3%) 1/146 (0.7%)
    Respiratory, thoracic and mediastinal disorders
    Asthma 0/11 (0%) 1/10 (10%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 0/150 (0%) 0/146 (0%)
    Dyspnoea 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 7/149 (4.7%) 9/150 (6%) 13/146 (8.9%)
    Nasal congestion 1/11 (9.1%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 1/11 (9.1%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Oropharyngeal pain 0/11 (0%) 0/10 (0%) 0/14 (0%) 1/13 (7.7%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 2/149 (1.3%) 2/150 (1.3%) 2/146 (1.4%)
    Pulmonary oedema 1/11 (9.1%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 1/149 (0.7%) 0/150 (0%) 0/146 (0%)
    Vascular disorders
    Hypertension 1/11 (9.1%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 0/11 (0%) 0/11 (0%) 0/14 (0%) 2/149 (1.3%) 3/150 (2%) 1/146 (0.7%)
    Hypotension 0/11 (0%) 1/10 (10%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 1/14 (7.1%) 3/149 (2%) 1/150 (0.7%) 5/146 (3.4%)
    Orthostatic hypotension 0/11 (0%) 0/10 (0%) 0/14 (0%) 0/13 (0%) 0/10 (0%) 1/11 (9.1%) 0/11 (0%) 0/14 (0%) 0/149 (0%) 1/150 (0.7%) 1/146 (0.7%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

    Results Point of Contact

    Name/Title Study Director
    Organization Amgen Inc.
    Phone 866-572-6436
    Email medinfo@amgen.com
    Responsible Party:
    Cytokinetics
    ClinicalTrials.gov Identifier:
    NCT01786512
    Other Study ID Numbers:
    • 20110151
    • 2012-000327-40
    First Posted:
    Feb 8, 2013
    Last Update Posted:
    Aug 12, 2021
    Last Verified:
    Jul 1, 2021