COSMIC-HF - Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure
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 |
---|---|---|
|
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
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
Outcome Measures
Primary Outcome Measures
- Dose Escalation Phase: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) [Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours, and 7 days post-dose.]
- Dose Escalation Phase: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil Following the Last Dose (Day 7) [Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours, and 7 days post-dose.]
- Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing on Day 7 [Day 7 at predose]
- Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil [Day 7 at predose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose]
- Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing [Predose (before morning dose) at weeks 2, 8, 12, 16, and 20]
- Expansion Phase: Maximum Observed Plasma Concentration of Omecamtiv Mecarbil [Weeks 2 and 12 at predose and 1, 2, 4, 6, and 8 hours post-dose.]
Secondary Outcome Measures
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- 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
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
- 20110151
- 2012-000327-40
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
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)
|
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)
|
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)
|
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)
|
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)
|
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)
|
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. |
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. |
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. |
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. |
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. |
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. |
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%
|
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
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 |
medinfo@amgen.com |
- 20110151
- 2012-000327-40