Pharmacokinetics and Safety Study of Omecamtiv Mecarbil in Healthy Japanese Adults

• Sponsor: Cytokinetics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02601001
• Collaborator: (none)
• Enrollment: 50
• Location: 1
• Arms: 3
• Actual Duration (Months): 1.8
• Patients Per Site Per Month: 28.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of omecamtiv mecarbil in healthy volunteers in Japan.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteer	Drug: Omecamtiv mecarbil; Drug: Placebo	Phase 1

Detailed Description

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: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Single Center Double-blind, Randomized, Placebo-controlled Study to Evaluate the Pharmacokinetics and Safety of Omecamtiv Mecarbil in Healthy Japanese Subjects
• Actual Study Start Date: Nov 13, 2015
• Actual Primary Completion Date: Jan 6, 2016
• Actual Study Completion Date: Jan 6, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo tablets twice a day (BID) in dosing period 1 (days 1 to 8) and in dosing period 2 (days 20 to 27).	Drug: Placebo; Matching placebo tablets
Experimental: Omecamtiv mecarbil 25 mg / 37.5 mg Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg or 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 predose omecamtiv mecarbil plasma concentration (Cpredose): If day 8 Cpredose was < 200 ng/mL, participants received 37.5 mg BID; if day 8 Cpredose was ≥ 200 ng/mL or a day 8 PK value was not available participants continued to receive 25 mg BID.	Drug: Omecamtiv mecarbil; Omecamtiv mecarbil tablets for oral administration; Other Names: AMG 423
Experimental: Omecamtiv mecarbil 25 mg / 50 mg Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg or 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 predose omecamtiv mecarbil plasma concentration (Cpredose): If day 8 Cpredose was < 200 ng/mL, participants received 50 mg BID; if day 8 Cpredose was ≥ 200 ng/mL or a day 8 PK value was not available participants continued to receive 25 mg BID.	Drug: Omecamtiv mecarbil; Omecamtiv mecarbil tablets for oral administration; Other Names: AMG 423

Outcome Measures

Primary Outcome Measures

1. Dosing Period 1: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 [Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose.]

2. Dosing Period 1: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1 [Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose.]

3. Dosing Period 1: Area Under the Concentration-time Curve for a Dosing Interval of 12 Hours (AUC0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 1 [Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose.]

4. Dosing Period 1: Predose Omecamtiv Mecarbil Plasma Concentration [Day 8 predose]

5. Dosing Period 1: Accumulation Ratio [Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose.]

   Accumulation ratio calculated as the ratio of day 8 AUC(0-12) / day 1 AUC(0-12)

6. Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 [Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose.]

7. Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2 [Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose.]

8. Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2 [Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose.]

9. Dosing Period 2: Predose Omecamtiv Mecarbil Plasma Concentration [Day 27 predose]

10. Dosing Period 2: Accumulation Ratio [Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose.]

    Accumulation ratio calculated as the ratio of day 27 AUC(0-12) / day 20 AUC(0-12).

Secondary Outcome Measures

1. Number of Participants With Treatment-emergent Adverse Events [35 days]

   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. 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. Adverse events were graded for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

2. Number of Participants With Grade 3 or Higher Laboratory Toxicities [35 days]

   Abnormal laboratory findings were graded for severity according to the NCI CTCAE version 4.0 according to the following guideline: Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE.

3. Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1 [Day 1 predose and day 8]

   QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle as measured by electrocardiogram (ECG). Maximum increase from Period 1 baseline was categorized as: ≤ 30 milliseconds (ms) > 30 to 60 ms > 60 ms

4. Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2 [Day 20 predose and Day 27]

   QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle as measured by ECG. Maximum increase from Period 2 baseline was categorized as: ≤ 30 ms > 30 to 60 ms > 60 ms

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• No history or evidence of clinically relevant medical disorders as determined by the Investigator, and in good health as determined by a pre-study physical examination and medical history with no clinically significant abnormalities, normal vital signs and no history or presence of a clinically significant abnormal electrocardiogram finding

• Subjects' pre-study clinical laboratory findings (including creatine phosphokinase) should be within normal range or if outside of the normal range, are deemed not clinically significant by the Investigator.

Exclusion Criteria:

• A clinically significant disorder/disease, including gastro intestinal abnormalities that might interfere with absorption

• An unstable medical condition, defined as having been hospitalized within 28 days before day 1, major surgery within 6 months before day 1, or otherwise unstable in the judgment of the Investigator

• History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the Investigator or Medical Monitor would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion

• History of malignancy of any type other than surgically excised non-melanomatous skin cancers or in situ cervical cancer within 5 years before the day of dosing

• Use of any prescription or over-the-counter medications within 14 days or 5 half-lives (whichever time period is greater), prior to receiving the first dose of omecamtiv mecarbil (acetaminophen up to 2 grams per day for analgesia and hormone replacement therapy (e.g., estrogen) will be allowed

• Use of any known inhibitors of CYP3A4/p-glycoprotein (P-gp) or CYP2D6 within 14 days or 5 half-lives, whichever is longer; or use of grapefruit juice or grapefruit containing products within 7 days prior to receiving the first dose of omecamtiv mecarbil

• Use of any known CYP3A4 inducers within 30 days or 5 half-lives, whichever is longer, before receiving omecamtiv mecarbil

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Kagoshima-shi	Kagoshima	Japan	890-0081

Sponsors and Collaborators

• Cytokinetics

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

None provided.

• Responsible Party: Cytokinetics
• ClinicalTrials.gov Identifier: NCT02601001
• Other Study ID Numbers: 20150134
• First Posted: Nov 10, 2015
• Last Update Posted: Jul 27, 2021
• Last Verified: Jul 1, 2021

• Keywords provided by Cytokinetics: Heart failure

Study Results

Participant Flow

Recruitment Details	This study was conducted at a single center in Japan. Participants were enrolled from 13 November 2015 to 24 November 2015.
Pre-assignment Detail	Participants were randomly assigned to one of three treatment groups in a 1:2:2 ratio. The study consisted of a screening period, two 8-day treatment periods with an 11-day drug holiday in between, and an end of study (EOS) visit on day 35.

Arm/Group Title	Placebo	Period 1 Group A: Omecamtiv Mecarbil 25 mg	Period 1 Group B: Omecamtiv Mecarbil 25 mg	Period 2 Group A: Omecamtiv Mecarbil 25 mg	Period 2 Group A: Omecamtiv Mecarbil 37.5 mg	Period 2 Group B: Omecamtiv Mecarbil 25 mg	Period 2 Group B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received placebo tablets twice a day (BID) in dosing period 1 (days 1 to 8) and in dosing period 2 (days 20 to 27).	Participants received omecamtiv mecarbil (OM) 25 mg BID in dosing period 1 (days 1 to 8).	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).	Participants who received omecamtiv mecarbil 25 mg BID in dosing period 1 then received omecamtiv mecarbil 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 predose omecamtiv mecarbil plasma concentration (Cpredose).	Participants who received omecamtiv mecarbil 25 mg BID in dosing period 1 then received omecamtiv mecarbil 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants who received omecamtiv mecarbil 25 mg BID in dosing period 1 then received omecamtiv mecarbil 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants who received omecamtiv mecarbil 25 mg BID in dosing period 1 then received omecamtiv mecarbil 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.
Period Title: Dosing Period 1
STARTED	10	20	20	0	0	0	0
COMPLETED	10	20	20	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0
Period Title: Dosing Period 1
STARTED	10	0	0	7	13	7	13
COMPLETED	10	0	0	7	13	7	12
NOT COMPLETED	0	0	0	0	0	0	1

Baseline Characteristics

Arm/Group Title	Placebo	Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg	Group B: Omecamtiv Mecarbil 25 mg / 50 mg	Total
Arm/Group Description	Participants received placebo tablets twice a day (BID) in dosing period 1 (days 1 to 8) and in dosing period 2 (days 20 to 27).	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg or 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 predose omecamtiv mecarbil plasma concentration (Cpredose): If day 8 Cpredose was < 200 ng/mL, participants received 37.5 mg BID; if day 8 Cpredose was ≥ 200 ng/mL participants continued to receive 25 mg BID.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg or 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 predose omecamtiv mecarbil plasma concentration (Cpredose): If day 8 Cpredose was < 200 ng/mL, participants received 50 mg BID; if day 8 Cpredose was ≥ 200 ng/mL participants continued to receive 25 mg BID.	Total of all reporting groups
Overall Participants	10	20	20	50
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.2 (4.2)	35.5 (7.6)	27.3 (4.6)	31.0 (7.0)
Sex: Female, Male (Count of Participants)
Female	3 30%	6 30%	6 30%	15 30%
Male	7 70%	14 70%	14 70%	35 70%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	10 100%	20 100%	20 100%	50 100%
Unknown or Not Reported	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%
Asian	10 100%	20 100%	20 100%	50 100%
Black or African American	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Dosing Period 1: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1
Time Frame	Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) analysis set included all randomized participants who received at least 1 dose of omecamtiv mecarbil and had at least 1 evaluable omecamtiv mecarbil PK parameter.

Arm/Group Title	Group A: Omecamtiv Mecarbil 25 mg	Group B: Omecamtiv Mecarbil 25 mg
Arm/Group Description	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).
Measure Participants	20	20
After first dose on day 1	77.4 (21.6)	79.5 (18.9)
After last dose on day 8	256 (71.2)	259 (59.2)

2. Primary Outcome

Title	Dosing Period 1: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 1
Time Frame	Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose.

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Group A: Omecamtiv Mecarbil 25 mg	Group B: Omecamtiv Mecarbil 25 mg
Arm/Group Description	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).
Measure Participants	20	20
After first dose on day 1	4.0	3.0
After last dose on day 8	2.0	2.0

3. Primary Outcome

Title	Dosing Period 1: Area Under the Concentration-time Curve for a Dosing Interval of 12 Hours (AUC0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 1
Time Frame	Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose.

Outcome Measure Data

Analysis Population Description

The PK analysis set with available AUC data at each time point

Arm/Group Title	Group A: Omecamtiv Mecarbil 25 mg	Group B: Omecamtiv Mecarbil 25 mg
Arm/Group Description	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).
Measure Participants	20	20
After first dose on day 1	687 (210)	677 (163)
After last dose on day 8	2570 (739)	2670 (699)

4. Primary Outcome

Title	Dosing Period 1: Predose Omecamtiv Mecarbil Plasma Concentration
Time Frame	Day 8 predose

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Group A: Omecamtiv Mecarbil 25 mg	Group B: Omecamtiv Mecarbil 25 mg
Arm/Group Description	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).
Measure Participants	20	20
Mean (Standard Deviation) [ng/mL]	190 (58.5)	192 (55.1)

5. Primary Outcome

Title	Dosing Period 1: Accumulation Ratio
Description	Accumulation ratio calculated as the ratio of day 8 AUC(0-12) / day 1 AUC(0-12)
Time Frame	Day 1 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 8 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose.

Outcome Measure Data

Analysis Population Description

The PK analysis set with available AUC data at both time points

Arm/Group Title	Group A: Omecamtiv Mecarbil 25 mg	Group B: Omecamtiv Mecarbil 25 mg
Arm/Group Description	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).
Measure Participants	10	14
Mean (Standard Deviation) [ratio]	3.66 (0.89)	3.79 (0.77)

6. Primary Outcome

Title	Dosing Period 2: Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2
Time Frame	Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set with available data at each time point

Arm/Group Title	Group A: Omecamtiv Mecarbil 25 mg / 25 mg	Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg	Group B: Omecamtiv Mecarbil 25 mg / 25 mg	Group B: Omecamtiv Mecarbil 25 mg / 50 mg
Arm/Group Description	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.
Measure Participants	7	13	7	13
After first dose on day 20	96.5 (27.2)	107 (30.4)	84.9 (30.0)	154 (22.0)
After last dose on day 27	335 (32.0)	341 (48.8)	311 (54.2)	537 (91.7)

7. Primary Outcome

Title	Dosing Period 2: Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil After First and Last Dose in Period 2
Time Frame	Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after the morning dose.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set with available data at each time point

Arm/Group Title	Group A: Omecamtiv Mecarbil 25 mg / 25 mg	Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg	Group B: Omecamtiv Mecarbil 25 mg / 25 mg	Group B: Omecamtiv Mecarbil 25 mg / 50 mg
Arm/Group Description	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.
Measure Participants	7	13	7	13
After first dose on day 20	4.0	2.0	4.0	3.0
After last dose on day 27	2.0	3.0	4.0	3.0

8. Primary Outcome

Title	Dosing Period 2: AUC(0-12) for Omecamtiv Mecarbil After First and Last Dose in Period 2
Time Frame	Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set with available AUC data at each time point

Arm/Group Title	Group A: Omecamtiv Mecarbil 25 mg / 25 mg	Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg	Group B: Omecamtiv Mecarbil 25 mg / 25 mg	Group B: Omecamtiv Mecarbil 25 mg / 50 mg
Arm/Group Description	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.
Measure Participants	7	13	7	13
After first dose on day 20	902 (220)	950 (228)	841 (403)	1330 (217)
After last dose on day 27	3520 (505)	3500 (519)	3290 (662)	5490 (1000)

9. Primary Outcome

Title	Dosing Period 2: Predose Omecamtiv Mecarbil Plasma Concentration
Time Frame	Day 27 predose

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Group A: Omecamtiv Mecarbil 25 mg / 25 mg	Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg	Group B: Omecamtiv Mecarbil 25 mg / 25 mg	Group B: Omecamtiv Mecarbil 25 mg / 50 mg
Arm/Group Description	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.
Measure Participants	7	13	7	12
Mean (Standard Deviation) [ng/mL]	271 (44.8)	256 (42.1)	245 (43.3)	401 (77.8)

10. Primary Outcome

Title	Dosing Period 2: Accumulation Ratio
Description	Accumulation ratio calculated as the ratio of day 27 AUC(0-12) / day 20 AUC(0-12).
Time Frame	Day 20 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Day 27 at 0 hours and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set with available AUC data at both time points

Arm/Group Title	Group A: Omecamtiv Mecarbil 25 mg / 25 mg	Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg	Group B: Omecamtiv Mecarbil 25 mg / 25 mg	Group B: Omecamtiv Mecarbil 25 mg / 50 mg
Arm/Group Description	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.
Measure Participants	4	10	4	9
Mean (Standard Deviation) [ratio]	4.12 (1.28)	3.81 (0.83)	4.53 (1.19)	4.11 (1.15)

11. Secondary Outcome

Title	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. 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. Adverse events were graded for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time Frame	35 days

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study treatment (omecamtiv mecarbil or placebo).

Arm/Group Title	Placebo	Group A: Omecamtiv Mecarbil 25 mg / 25 mg	Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg	Group B: Omecamtiv Mecarbil 25 mg / 25 mg	Group B: Omecamtiv Mecarbil 25 mg / 50 mg
Arm/Group Description	Participants received placebo tablets twice a day (BID) in dosing period 1 (days 1 to 8) and in dosing period 2 (days 20 to 27).	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.
Measure Participants	10	7	13	7	13
Any treatment-emergent adverse event	6 60%	4 20%	7 35%	4 8%	3 NaN
Serious adverse events	0 0%	0 0%	0 0%	0 0%	0 NaN
TEAE leading to discontinuation of study drug	0 0%	0 0%	0 0%	0 0%	1 NaN
Severe adverse events	0 0%	0 0%	0 0%	1 2%	1 NaN
Life-threatening adverse events	0 0%	0 0%	0 0%	0 0%	0 NaN
Fatal adverse events	0 0%	0 0%	0 0%	0 0%	0 NaN

12. Secondary Outcome

Title	Number of Participants With Grade 3 or Higher Laboratory Toxicities
Description	Abnormal laboratory findings were graded for severity according to the NCI CTCAE version 4.0 according to the following guideline: Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE.
Time Frame	35 days

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study treatment (omecamtiv mecarbil or placebo).

Arm/Group Title	Placebo	Group A: Omecamtiv Mecarbil 25 mg / 25 mg	Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg	Group B: Omecamtiv Mecarbil 25 mg / 25 mg	Group B: Omecamtiv Mecarbil 25 mg / 50 mg
Arm/Group Description	Participants received placebo tablets twice a day (BID) in dosing period 1 (days 1 to 8) and in dosing period 2 (days 20 to 27).	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.
Measure Participants	10	7	13	7	13
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 NaN

13. Secondary Outcome

Title	Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 1
Description	QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle as measured by electrocardiogram (ECG). Maximum increase from Period 1 baseline was categorized as: ≤ 30 milliseconds (ms) > 30 to 60 ms > 60 ms
Time Frame	Day 1 predose and day 8

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study treatment (omecamtiv mecarbil or placebo).

Arm/Group Title	Placebo	Group A: Omecamtiv Mecarbil 25 mg / 25 mg	Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg	Group B: Omecamtiv Mecarbil 25 mg / 25 mg	Group B: Omecamtiv Mecarbil 25 mg / 50 mg
Arm/Group Description	Participants received placebo tablets twice a day (BID) in dosing period 1 (days 1 to 8) and in dosing period 2 (days 20 to 27).	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.
Measure Participants	10	7	13	7	13
≤ 30 ms	10 100%	7 35%	13 65%	7 14%	13 NaN
> 30 to 60 ms	0 0%	0 0%	0 0%	0 0%	0 NaN
> 60 ms	0 0%	0 0%	0 0%	0 0%	0 NaN

14. Secondary Outcome

Title	Maximum Increase From Baseline in Fridericia-Corrected QT Interval (QTcF) In Dosing Period 2
Description	QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle as measured by ECG. Maximum increase from Period 2 baseline was categorized as: ≤ 30 ms > 30 to 60 ms > 60 ms
Time Frame	Day 20 predose and Day 27

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least one dose of study treatment (omecamtiv mecarbil or placebo), with available data.

Arm/Group Title	Placebo	Group A: Omecamtiv Mecarbil 25 mg / 25 mg	Group A: Omecamtiv Mecarbil 25 mg / 37.5 mg	Group B: Omecamtiv Mecarbil 25 mg / 25 mg	Group B: Omecamtiv Mecarbil 25 mg / 50 mg
Arm/Group Description	Participants received placebo tablets twice a day (BID) in dosing period 1 (days 1 to 8) and in dosing period 2 (days 20 to 27).	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.	Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8) and 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.
Measure Participants	10	7	13	7	12
≤ 30 ms	10 100%	7 35%	13 65%	7 14%	12 NaN
> 30 to 60 ms	0 0%	0 0%	0 0%	0 0%	0 NaN
> 60 ms	0 0%	0 0%	0 0%	0 0%	0 NaN

Adverse Events

Time Frame	Period 1: Day 1 to day 19 Period 2: Day 20 to day 35
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	Period 1: Placebo		Period 1 Group A: OM 25 mg BID		Period 1 Group B: OM 25 mg BID		Period 2: Placebo		Period 2 Group A: OM 25 mg BID		Period 2 Group A: OM 37.5 mg BID		Period 2 Group B: OM 25 mg BID		Period 2 Group B: OM 50 mg BID
Arm/Group Description	Participants received placebo tablets twice a day (BID) in dosing period 1 (days 1 to 8).		Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).		Participants received omecamtiv mecarbil 25 mg BID in dosing period 1 (days 1 to 8).		Participants received placebo tablets BID in dosing period 2 (days 20 to 27).		Participants received omecamtiv mecarbil 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.		Participants received omecamtiv mecarbil 37.5 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.		Participants received omecamtiv mecarbil 25 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.		Participants received omecamtiv mecarbil 50 mg BID in dosing period 2 (days 20 to 27) based on their day 8 omecamtiv mecarbil Cpredose.
All Cause Mortality
	Period 1: Placebo		Period 1 Group A: OM 25 mg BID		Period 1 Group B: OM 25 mg BID		Period 2: Placebo		Period 2 Group A: OM 25 mg BID		Period 2 Group A: OM 37.5 mg BID		Period 2 Group B: OM 25 mg BID		Period 2 Group B: OM 50 mg BID
	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)
Serious Adverse Events
	Period 1: Placebo		Period 1 Group A: OM 25 mg BID		Period 1 Group B: OM 25 mg BID		Period 2: Placebo		Period 2 Group A: OM 25 mg BID		Period 2 Group A: OM 37.5 mg BID		Period 2 Group B: OM 25 mg BID		Period 2 Group B: OM 50 mg BID
	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	0/10 (0%)		0/20 (0%)		0/20 (0%)		0/10 (0%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Period 1: Placebo		Period 1 Group A: OM 25 mg BID		Period 1 Group B: OM 25 mg BID		Period 2: Placebo		Period 2 Group A: OM 25 mg BID		Period 2 Group A: OM 37.5 mg BID		Period 2 Group B: OM 25 mg BID		Period 2 Group B: OM 50 mg BID
	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	2/10 (20%)		5/20 (25%)		3/20 (15%)		4/10 (40%)		3/7 (42.9%)		3/13 (23.1%)		1/7 (14.3%)		3/13 (23.1%)
Cardiac disorders
Ventricular tachycardia	0/10 (0%)		0/20 (0%)		0/20 (0%)		0/10 (0%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		1/13 (7.7%)
Gastrointestinal disorders
Nausea	1/10 (10%)		0/20 (0%)		0/20 (0%)		0/10 (0%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		0/13 (0%)
General disorders
Chest pain	0/10 (0%)		0/20 (0%)		0/20 (0%)		1/10 (10%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		0/13 (0%)
Injection site nerve damage	0/10 (0%)		0/20 (0%)		0/20 (0%)		0/10 (0%)		0/7 (0%)		0/13 (0%)		1/7 (14.3%)		0/13 (0%)
Infections and infestations
Chronic tonsillitis	0/10 (0%)		0/20 (0%)		0/20 (0%)		0/10 (0%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		1/13 (7.7%)
Herpes zoster	0/10 (0%)		0/20 (0%)		1/20 (5%)		0/10 (0%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		0/13 (0%)
Pharyngitis	0/10 (0%)		0/20 (0%)		0/20 (0%)		0/10 (0%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		1/13 (7.7%)
Investigations
Alanine aminotransferase increased	0/10 (0%)		2/20 (10%)		0/20 (0%)		2/10 (20%)		1/7 (14.3%)		3/13 (23.1%)		0/7 (0%)		1/13 (7.7%)
Aspartate aminotransferase increased	0/10 (0%)		1/20 (5%)		0/20 (0%)		1/10 (10%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		1/13 (7.7%)
Blood bilirubin increased	0/10 (0%)		1/20 (5%)		0/20 (0%)		0/10 (0%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		0/13 (0%)
Protein urine present	0/10 (0%)		0/20 (0%)		0/20 (0%)		0/10 (0%)		1/7 (14.3%)		0/13 (0%)		0/7 (0%)		0/13 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/10 (0%)		0/20 (0%)		0/20 (0%)		1/10 (10%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		0/13 (0%)
Back pain	1/10 (10%)		0/20 (0%)		0/20 (0%)		0/10 (0%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		0/13 (0%)
Nervous system disorders
Headache	0/10 (0%)		0/20 (0%)		1/20 (5%)		0/10 (0%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		0/13 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/10 (10%)		0/20 (0%)		0/20 (0%)		0/10 (0%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		0/13 (0%)
Upper respiratory tract inflammation	0/10 (0%)		2/20 (10%)		0/20 (0%)		0/10 (0%)		1/7 (14.3%)		0/13 (0%)		0/7 (0%)		0/13 (0%)
Skin and subcutaneous tissue disorders
Dermatitis contact	0/10 (0%)		0/20 (0%)		2/20 (10%)		0/10 (0%)		0/7 (0%)		0/13 (0%)		0/7 (0%)		0/13 (0%)
Vascular disorders
Orthostatic hypotension	0/10 (0%)		0/20 (0%)		0/20 (0%)		0/10 (0%)		1/7 (14.3%)		0/13 (0%)		0/7 (0%)		0/13 (0%)

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.