Study to Assess the Effect of Omecamtiv Mecarbil (OM) on QT/QTc Intervals in Healthy Adults

• Sponsor: Cytokinetics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04175808
• Collaborator: (none)
• Enrollment: 70
• Location: 1
• Arms: 2
• Actual Duration (Months): 3.6
• Patients Per Site Per Month: 19.2

Study Details

Study Description

Brief Summary

The primary objective of this study is to assess the effect of a single therapeutic (50 mg) oral dose of omecamtiv mecarbil (OM) on the QT interval / QT interval corrected for heart rate (QTc), relative to placebo, in healthy adults.

The QT interval is the section on an electrocardiogram (ECG) that represents the time it takes for the electrical system to fire an impulse through the ventricles and then recharge, or the time it takes for the heart muscle to contract and then recover.

Condition or Disease	Intervention/Treatment	Phase
QT Intervals Changes; QTc Intervals Changes	Drug: Omecamtiv Mecarbil (OM); Drug: Placebo; Drug: Moxifloxacin	Phase 1

Detailed Description

The study consists of 2 parts: Part A and Part B. Participants are enrolled in Part A to determine eligibility for Part B.

In Part A participants receive a single oral dose of 25 mg omecamtiv mecarbil; participants with a resulting maximum observed OM plasma concentration (Cmax) ≤ 350 ng/mL are eligible to enter Part B.

Part B is a 3-period cross-over study in which participants are randomized to receive 3 treatments in 1 of 6 sequences, each separated by a washout of at least 7 days.

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: 70 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Masking Description: This was a partially double-blind study. In Part B, placebo and OM treatments were double-blinded, moxifloxacin treatment was open-label, and the core ECG laboratory was blinded to all treatment information. Except for the moxifloxacin treatment in 1 of 3 periods in Part B, treatment assignment was blinded to all participants, site personnel, the Medical Monitor, and Clinical Research Associates.
• Primary Purpose: Treatment
• Official Title: Single-dose and Randomized, Single-center, Placebo- and Active-controlled, Crossover Study to Assess the Effect of Omecamtiv Mecarbil (OM) on QT/QTc Intervals in Healthy Subjects
• Actual Study Start Date: Nov 14, 2019
• Actual Primary Completion Date: Mar 4, 2020
• Actual Study Completion Date: Mar 4, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A After an overnight fast of at least 10 hours participants received a single oral dose of 25 mg omecamtiv mecarbil on Day 1.	Drug: Omecamtiv Mecarbil (OM); Oral solution; Other Names: AMG 423
Experimental: Part B Participants with a maximum observed plasma OM concentration ≤ 350 ng/mL in Part A were randomly assigned to receive a single dose of each the following 3 treatments in one of six treatment sequences: Placebo 50 mg omecamtiv mecarbil 400 mg moxifloxacin Each treatment was separated by a washout of at least 7 days.	Drug: Omecamtiv Mecarbil (OM); Oral solution; Other Names: AMG 423 ; Drug: Placebo; Placebo oral solution; Drug: Moxifloxacin; 400 mg moxifloxacin oral tablet

Outcome Measures

Primary Outcome Measures

1. Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Omecamtiv Mecarbil Dosing in Part B [Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose]

   Continuous 12-lead digital ECG recording was performed on day 1 of each period. ECGs were analyzed by a blinded, central reader. At each specified timepoint, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that timepoint. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Change from baseline (ΔQTcF) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QTcF as covariate. Placebo-corrected ΔQTcF (ΔΔQTcF) was calculated as the adjusted mean ΔQTcF after OM dosing minus adjusted mean ΔQTcF after placebo. If the upper bound of the confidence interval of ΔΔQTcF was < 10 ms for all post-dose time points, OM was to be concluded to not have a significant effect on QT interval prolongation.

Secondary Outcome Measures

1. Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil in Part B [Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.]

   Plasma samples at each timepoint were quantified using a validated liquid chromatography-tandem mass spectrometry method. The lower limit of quantification for plasma samples was 1 ng/mL.

2. Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil In Part B [Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.]

3. Apparent Terminal Elimination Half-life (T1/2) of Omecamtiv Mecarbil in Part B [Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.]

4. Apparent Total Plasma Clearance (CL/F) for Omecamtiv Mecarbil in Part B [Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.]

5. Apparent Volume of Distribution (VZ/F) for Omecamtiv Mecarbil in Part B [Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.]

6. Area Under the Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-t) for Omecamtiv Mecarbil in Part B [Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.]

7. AUC From Time 0 to Infinity (AUCinf) for Omecamtiv Mecarbil in Part B [Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.]

8. Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B [Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the moxifloxacin treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.]

   Assay sensitivity was validated by analysis of ∆QTcF of moxifloxacin. Continuous 12-lead digital ECG recording was performed on Day 1 of each period. ECGs were analyzed by a blinded, central reader. At each specified timepoint, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that timepoint. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Change from baseline (ΔQTcF) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QTcF as covariate. Placebo-corrected ΔQTcF (ΔΔQTcF) was calculated as the adjusted mean ΔQTcF after moxifloxacin dosing minus adjusted mean ΔQTcF after placebo. If ∆∆QTcF was larger than 5 ms at 2, 3, or 4 hours, assay sensitivity was considered to be demonstrated.

9. Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B [Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.]

   Change from baseline in heart rate (HR) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline HR as a covariate.

10. Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B [Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.]

    Change from baseline in QTcF was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QTcF as a covariate.

11. Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B [Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.]

    The PR interval is the time from the onset of the P-wave to the start of the next QRS complex. Change from baseline was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline PR interval as covariate.

12. Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B [Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.]

    The QRS complex is a combination of the Q wave, R wave and S wave on an ECG tracing, and represents ventricular depolarization. Change from baseline was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QRS as covariate.

13. Slope of Omecamtiv Mecarbil Plasma Concentration Estimated From Concentration-QTc Analysis in Part B [Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.]

    The relationship between omecamtiv mecarbil plasma concentration and ΔQTcF was investigated by linear mixed-effects modeling with ΔQTcF as the dependent variable, time-matched concentration of OM as the explanatory variable (0 for placebo), centered baseline QTcF (i.e., baseline QTcF for individual subject minus the population mean baseline QTcF for all subjects in the same period) as an additional covariate, study treatment (OM = 1 or placebo = 0) and time (i.e., post-dose time point) as fixed effects, and a random intercept and slope per subject. From the model, the slope (i.e., the regression parameter for the concentration) was estimated together with the 2-sided 90% CI.

14. Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B [Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.]

    Change from baseline in heart rate (ΔHR) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline HR as covariate. Placebo-corrected ΔHR (ΔΔHR) was calculated as the adjusted mean ΔHR after OM dosing minus adjusted mean ΔHR after placebo dosing.

15. Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B [Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.]

    Change from baseline in PR interval (ΔPR) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline PR interval as covariate. Placebo-corrected ΔPR (ΔΔPR) was calculated as the adjusted mean ΔPR after OM dosing minus adjusted mean ΔPR after placebo dosing.

16. Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B [Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.]

    Change from baseline in QRS (ΔQRS) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QRS as covariate. Placebo-corrected ΔQRS (ΔΔQRS) was calculated as the adjusted mean ΔQRS after OM dosing minus adjusted mean ΔQRS after placebo dosing.

17. Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B [Day 1 of the OM treatment period at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.]

    Outliers were predefined according to the following categories: QTcF: Treatment-emergent value of > 450 and ≤ 480 ms when not present at baseline (new onset) Treatment-emergent value of > 480 and ≤ 500 ms when not present at baseline (new onset) Treatment-emergent value of > 500 ms when not present at baseline (new onset) Increase of QTcF from baseline of > 30 and ≤ 60 ms Increase of QTcF from baseline > 60 ms Increase of PR from baseline > 25% resulting in PR > 200 ms Increase of QRS from baseline > 25% resulting in QRS > 120 ms Decrease of HR from baseline > 25% resulting in HR < 50 bpm Increase of HR from baseline > 25% resulting in HR > 100 bpm

18. Number of Participants With Treatment-emergent Changes in T-wave Morphology and U-wave Presence After Omecamtiv Mecarbil Dosing in Part B [Day 1 of the OM treatment period at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.]

    T-wave abnormalities were categorized as follows: Flat T-wave: T amplitude < 1 mm (either positive or negative) including flat isoelectric line Notched T-wave (+): Presence of notch(es) of at least 0.05 mV amplitude on ascending or descending arm of the positive T-wave Biphasic: T-wave that contains a second component with an opposite phase that is at least 0.1 mV deep (both positive/negative and negative/positive and polyphasic T-waves included) Normal T-wave (-): T amplitude that is negative, without biphasic T-wave or notches Notched T-wave (-): Presence of notch(es) of at least 0.05 mV amplitude on descending or ascending arm of the negative T-wave U waves: Presence of abnormal U-waves

19. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [From first dose of study treatment to day 6 of each treatment period]

    A TEAE was defined as an adverse event (AE) that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. A treatment-related TEAE was defined as a TEAE with a relationship of related to the study treatment as determined by the investigator. The Investigator assessed the severity of each AE reported during the study based on the following grading scale: Mild: Aware of sign or symptom, easily tolerated Moderate: Discomfort enough to cause interference with usual activity Severe: Incapacitating, inability to work or do usual activity SAEs were defined as any untoward medical occurrence that met at least 1 of the following serious criteria: Resulted in Death Was life-threatening Required in-patient hospitalization or prolongation of existing hospitalization Resulted in persistent or significant disability/incapacity Was a congenital anomaly/birth defect Other medically important serious event

20. Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings [From first dose up to day 6 of each treatment period]

    Blood and urine samples were collected for clinical laboratory evaluations (including clinical chemistry, hematology, urinalysis, and serology). Vital signs included blood pressure, pulse rate and body temperature. Standard safety 12-lead ECGs were recorded after the subject had been supine or semi-recumbent and at rest for at least 5 minutes to detect any immediate ECG effects for subject safety. These ECGs were viewed locally. The Investigator determined whether an abnormal value in an individual participant represented a clinically significant change from the participant's baseline values.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subject has provided informed consent before initiation of any study-specific activities/procedures.

• Healthy male or healthy female subjects greater than or equal to 18 to less than or equal to 50 years of age.

• No history or evidence of clinically relevant medical disorders as determined by the Investigator at Screening.

• Physical examination at Screening and vital signs, clinical laboratory values, and electrocardiogram (ECG) at Screening and Day -1 of each period are clinically acceptable to the Investigator.

• Body mass index (BMI) greater than, or equal to 18.0 kg/m^{2 and less than, or equal to 30.0 kg/m}2.

• Willing to maintain current general diet and physical activity regimen.

Exclusion Criteria:

• History or evidence of clinically significant disorder, condition, or disease not otherwise excluded that, in the opinion of the Investigator, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.

• Any users of tobacco- or nicotine-containing products within 6 months before Day -1 of Part A.

• History suggestive of esophageal (including esophageal spasm, esophagitis), gastric, or duodenal ulceration or bowel disease (including, but not limited to, peptic ulceration, gastrointestinal bleeding, ulcerative colitis, Crohn's disease, or irritable bowel syndrome); or a history of gastrointestinal surgery other than uncomplicated appendectomy.

• History or current signs or symptoms of cardiovascular disease, including but not limited to myocardial infarction, congenital heart disease, valvular heart disease, coronary revascularization, or angina.

• Known substance abuse (eg, alcohol, licit or illicit drugs) within 1 year prior to Screening.

• Subjects with poor peripheral venous access.

• Use of any medications/substances outside the allowed timeframes as specified in Section 6.1.2.

• Currently receiving treatment in another investigational device or drug study, or less than 3 months, or 5 half-lives if longer, prior to receiving the first dose of study drug. Other investigational procedures while participating in this study are excluded.

• Donated blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening.

• Subjects who were previously exposed to OM.

• Hepatic impairment defined by a total bilirubin (TBL) greater than or equal to 1.2 times the upper limit of normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than ULN (and confirmed upon repeat).

• Systolic blood pressure (BP) greater than 140 mmHg or less than 90 mmHg, or diastolic BP greater than 90 mmHg.

• QTcF interval greater than 450 msec in male or greater than 470 msec in female or history/evidence of long QT syndrome, or PR of greater than or equal to 200 msec; or 2nd degree atrioventricular (AV) block or 3rd degree AV block, or heart rate greater than 100 bpm (and confirmed upon repeat, except 2nd or 3rd degree AV block, which are exclusionary based on a single finding).

• Troponin I or creatine kinase MB fraction (CK-MB) greater than ULN at Screening or Check-in for Part A or B.

• Estimated glomerular filtration rate (eGFR) less than 80 mL/min/1.73 m^2 at Screening as calculated by the Modified Diet in Renal Disease (MDRD) equation;

• Any positive test for drugs, cotinine (tobacco or nicotine use), and/or alcohol use.

• Positive hepatitis panel and/or positive human immunodeficiency virus test. Subjects whose results are compatible with prior immunization may be included.

• Subject has known sensitivity to any of the products or components to be administered during dosing, including history of hypersensitivity to moxifloxacin or any member of the quinolone class of antibacterials.

• History of tendon rupture or connective tissue disorders.

• Female subjects with a positive pregnancy test.

• Female subjects lactating/breastfeeding or who plans to breastfeed during the study through 90 days after the end of study (EOS) visit.

• Unwilling to adhere to contraceptive requirements through 90 days after the EOS visit.

• Unwilling to abstain from sperm and ovum donation through 90 days after the EOS visit.

• Male subjects with a female partner of childbearing potential and not willing to inform his partner of his participation in this clinical study.

• Male subjects with a pregnant partner or partner planning to become pregnant while the subject is on study through 90 days after the EOS visit.

• Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, Clinical Outcome Assessments) to the best of the subject and Investigator's knowledge.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Leeds		United Kingdom	LS2 9LH

Sponsors and Collaborators

• Cytokinetics

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Aug 23, 2019
• Statistical Analysis Plan: SAP Version 1 - Dec 10, 2019
• Statistical Analysis Plan: Supplemental SAP - Apr 15, 2020

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

None provided.

• Responsible Party: Cytokinetics
• ClinicalTrials.gov Identifier: NCT04175808
• Other Study ID Numbers: 20090231; 2018-003157-19
• First Posted: Nov 25, 2019
• Last Update Posted: Nov 4, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Cytokinetics: Thorough QT; QTc study
• Additional relevant MeSH terms: Moxifloxacin

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at a single site in the United Kingdom. The study consisted of 2 parts: Part A and Part B. Part A was a lead-in phase to ensure that omecamtiv mecarbil (OM) plasma concentrations in Part B would not exceed 1000 ng/mL.
Pre-assignment Detail	Participants in Part A received a single oral dose of 25 mg omecamtiv mecarbil; participants with maximum observed OM plasma concentration (Cmax) ≤ 350 ng/mL were eligible to enter Part B. Part B was a 3-period cross-over study in which all participants received a single dose of placebo, omecamtiv mecarbil, and moxifloxacin in 1 of 6 sequences, each separated by a washout of at least 7 days.

Arm/Group Title	Part A	Part B: Placebo/OM/Moxifloxacin	Part B: OM/Moxifloxacin/Placebo	Part B: Moxifloxacin/Placebo/OM	Part B: Placebo/Moxifloxacin/OM	Part B: Moxifloxacin/OM/Placebo	Part B: OM/Placebo/Moxifloxacin
Arm/Group Description	After an overnight fast of at least 10 hours participants received a single oral dose of 25 mg omecamtiv mecarbil on Day 1.	Participants received a single dose of placebo oral solution in Period 1, 50 mg omecamtiv mecarbil oral solution in Period 2 and 400 mg moxifloxacin oral tablet in Period 3. Each treatment was separated by a washout period of at least 7 days.	Participants received a single dose of 50 mg omecamtiv mecarbil oral solution in Period 1, 400 mg moxifloxacin oral tablet in Period 2, and placebo oral solution in Period 3. Each treatment was separated by a washout period of at least 7 days.	Participants received a single dose of 400 mg moxifloxacin oral tablet in Period 1, placebo oral solution in Period 2, and 50 mg omecamtiv mecarbil oral solution in Period 3. Each treatment was separated by a washout period of at least 7 days.	Participants received a single dose of placebo oral solution in Period 1, 400 mg moxifloxacin oral tablet in Period 2, and 50 mg omecamtiv mecarbil oral solution in Period 3. Each treatment was separated by a washout period of at least 7 days.	Participants received a single dose of 400 mg moxifloxacin oral tablet in Period 1, 50 mg omecamtiv mecarbil oral solution in Period 2, and placebo oral solution in Period 3. Each treatment was separated by a washout period of at least 7 days.	Participants received a single dose of 50 mg omecamtiv mecarbil oral solution in Period 1, placebo oral solution in Period 2, and 400 mg moxifloxacin oral tablet in Period 3. Each treatment was separated by a washout period of at least 7 days.
Period Title: Part A
STARTED	70	0	0	0	0	0	0
COMPLETED	68	0	0	0	0	0	0
NOT COMPLETED	2	0	0	0	0	0	0
Period Title: Part A
STARTED	0	10	10	10	10	10	10
COMPLETED	0	10	10	10	10	10	10
NOT COMPLETED	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Part B
Arm/Group Description	Participants with a maximum observed OM plasma concentration ≤ 350 ng/mL in Part A were randomly assigned to receive a single dose of each the following 3 treatments in one of six treatment sequences: Placebo 50 mg omecamtiv mecarbil 400 mg moxifloxacin Each treatment was separated by a washout of at least 7 days.
Overall Participants	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.7 (8.88)
Sex: Female, Male (Count of Participants)
Female	26 43.3%
Male	34 56.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	60 100%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	49 81.7%
Black or African American	6 10%
Asian	4 6.7%
Native Hawaiian or Other Pacific Islander	0 0%
American Indian or Alaska Native	0 0%
Multiple	1 1.7%
QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) (ms) [Mean (Standard Deviation) ]
Prior to OM dose	402.9 (18.27)
Prior to moxifloxacin dose	402.4 (18.38)
Prior to placebo dose	404.1 (19.06)
PR Interval (ms) [Mean (Standard Deviation) ]
Prior to OM dose	151.4 (22.48)
Prior to moxifloxacin dose	150.7 (22.73)
Prior to placebo dose	151.2 (24.20)
QRS (ms) [Mean (Standard Deviation) ]
Prior to OM dose	105.6 (5.74)
Prior to moxifloxacin dose	105.8 (5.36)
Prior to placebo dose	105.8 (5.52)
Heart Rate (beats/minute) [Mean (Standard Deviation) ]
Prior to OM dose	59.2 (7.87)
Prior to moxifloxacin dose	59.5 (7.36)
Prior to placebo dose	58.6 (8.03)

Outcome Measures

1. Primary Outcome

Title	Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Omecamtiv Mecarbil Dosing in Part B
Description	Continuous 12-lead digital ECG recording was performed on day 1 of each period. ECGs were analyzed by a blinded, central reader. At each specified timepoint, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that timepoint. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Change from baseline (ΔQTcF) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QTcF as covariate. Placebo-corrected ΔQTcF (ΔΔQTcF) was calculated as the adjusted mean ΔQTcF after OM dosing minus adjusted mean ΔQTcF after placebo. If the upper bound of the confidence interval of ΔΔQTcF was < 10 ms for all post-dose time points, OM was to be concluded to not have a significant effect on QT interval prolongation.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set included all participants who received at least 1 dose of study treatment with measurements at baseline as well as on-treatment with at least 1 postdose timepoint with a valid ΔQTcF value in Part B.

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
0.25 hours post-dose	-2.6
0.5 hours post-dose	-4.9
0.75 hours post-dose	-5.8
1 hour post-dose	-6.7
1.5 hours post-dose	-4.5
2 hours post-dose	-2.7
3 hours post-dose	-1.5
4 hours post-dose	-0.8
8 hours post-dose	-2.2
12 hours post-dose	-1.9
24 hours post-dose	-1.2

2. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil in Part B
Description	Plasma samples at each timepoint were quantified using a validated liquid chromatography-tandem mass spectrometry method. The lower limit of quantification for plasma samples was 1 ng/mL.
Time Frame	Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) population for Part B consisted of all participants who received OM and had evaluable PK data.

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	416 (33.2)

3. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil In Part B
Time Frame	Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.

Outcome Measure Data

Analysis Population Description

Part B PK population

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
Median (Full Range) [hours]	0.583

4. Secondary Outcome

Title	Apparent Terminal Elimination Half-life (T1/2) of Omecamtiv Mecarbil in Part B
Time Frame	Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.

Outcome Measure Data

Analysis Population Description

Part B PK population

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
Geometric Mean (Geometric Coefficient of Variation) [hours]	20.0 (2.91)

5. Secondary Outcome

Title	Apparent Total Plasma Clearance (CL/F) for Omecamtiv Mecarbil in Part B
Time Frame	Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.

Outcome Measure Data

Analysis Population Description

Part B PK population

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
Geometric Mean (Geometric Coefficient of Variation) [L/h]	10.4 (21.2)

6. Secondary Outcome

Title	Apparent Volume of Distribution (VZ/F) for Omecamtiv Mecarbil in Part B
Time Frame	Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.

Outcome Measure Data

Analysis Population Description

Part B PK population

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
Geometric Mean (Geometric Coefficient of Variation) [liters]	299 (21.5)

7. Secondary Outcome

Title	Area Under the Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-t) for Omecamtiv Mecarbil in Part B
Time Frame	Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.

Outcome Measure Data

Analysis Population Description

Part B PK population

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	4710 (21.0)

8. Secondary Outcome

Title	AUC From Time 0 to Infinity (AUCinf) for Omecamtiv Mecarbil in Part B
Time Frame	Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.

Outcome Measure Data

Analysis Population Description

Part B PK population

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	4790 (21.2)

9. Secondary Outcome

Title	Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B
Description	Assay sensitivity was validated by analysis of ∆QTcF of moxifloxacin. Continuous 12-lead digital ECG recording was performed on Day 1 of each period. ECGs were analyzed by a blinded, central reader. At each specified timepoint, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that timepoint. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Change from baseline (ΔQTcF) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QTcF as covariate. Placebo-corrected ΔQTcF (ΔΔQTcF) was calculated as the adjusted mean ΔQTcF after moxifloxacin dosing minus adjusted mean ΔQTcF after placebo. If ∆∆QTcF was larger than 5 ms at 2, 3, or 4 hours, assay sensitivity was considered to be demonstrated.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the moxifloxacin treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set

Arm/Group Title	Part B: Moxifloxacin 400 mg
Arm/Group Description	Participants received a single dose of 400 mg moxifloxacin on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
0.25 hours post-dose	2.2
0.5 hours post-dose	8.6
0.75 hours post-dose	10.1
1 hour post-dose	10.2
1.5 hours post-dose	11.1
2 hours post-dose	12.7
3 hours post-dose	13.1
4 hours post-dose	12.9
8 hours post-dose	9.7
12 hours post-dose	9.0
24 hours post-dose	5.3

10. Secondary Outcome

Title	Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B
Description	Change from baseline in heart rate (HR) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline HR as a covariate.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
0.25 hours post-dose	1.3
0.5 hours post-dose	1.2
0.75 hours post-dose	1.4
1 hour post-dose	0.2
1.5 hours post-dose	-0.5
2 hours post-dose	-0.2
3 hours post-dose	1.1
4 hours post-dose	1.8
8 hours post-dose	7.8
12 hours post-dose	8.3
24 hours post-dose	2.8

11. Secondary Outcome

Title	Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B
Description	Change from baseline in QTcF was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QTcF as a covariate.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
0.25 hours post-dose	-6.3
0.5 hours post-dose	-9.1
0.75 hours post-dose	-8.6
1 hour post-dose	-8.1
1.5 hours post-dose	-5.5
2 hours post-dose	-5.2
3 hours post-dose	-4.9
4 hours post-dose	-3.3
8 hours post-dose	-7.1
12 hours post-dose	-6.6
24 hours post-dose	-4.1

12. Secondary Outcome

Title	Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B
Description	The PR interval is the time from the onset of the P-wave to the start of the next QRS complex. Change from baseline was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline PR interval as covariate.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
0.25 hours post-dose	-0.5
0.5 hours post-dose	1.0
0.75 hours post-dose	0.4
1 hour post-dose	0.4
1.5 hours post-dose	-1.2
2 hours post-dose	-0.8
3 hours post-dose	-2.0
4 hours post-dose	-3.2
8 hours post-dose	-7.5
12 hours post-dose	-7.8
24 hours post-dose	-2.1

13. Secondary Outcome

Title	Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B
Description	The QRS complex is a combination of the Q wave, R wave and S wave on an ECG tracing, and represents ventricular depolarization. Change from baseline was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QRS as covariate.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
0.25 hours post-dose	-0.2
0.5 hours post-dose	0.0
0.75 hours post-dose	-0.2
1 hour post-dose	0.0
1.5 hours post-dose	-0.2
2 hours post-dose	-0.3
3 hours post-dose	0.00
4 hours post-dose	0.1
8 hours post-dose	-0.4
12 hours post-dose	-0.7
24 hours post-dose	-0.3

14. Secondary Outcome

Title	Slope of Omecamtiv Mecarbil Plasma Concentration Estimated From Concentration-QTc Analysis in Part B
Description	The relationship between omecamtiv mecarbil plasma concentration and ΔQTcF was investigated by linear mixed-effects modeling with ΔQTcF as the dependent variable, time-matched concentration of OM as the explanatory variable (0 for placebo), centered baseline QTcF (i.e., baseline QTcF for individual subject minus the population mean baseline QTcF for all subjects in the same period) as an additional covariate, study treatment (OM = 1 or placebo = 0) and time (i.e., post-dose time point) as fixed effects, and a random intercept and slope per subject. From the model, the slope (i.e., the regression parameter for the concentration) was estimated together with the 2-sided 90% CI.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The PK/QTc analysis set included all participants who were in both the QT/QTc and PK analysis sets with at least 1 pair of post-dose PK and QTcF data from the same timepoint.

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
Number (90% Confidence Interval) [ms per ng/mL]	-0.011

15. Secondary Outcome

Title	Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B
Description	Change from baseline in heart rate (ΔHR) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline HR as covariate. Placebo-corrected ΔHR (ΔΔHR) was calculated as the adjusted mean ΔHR after OM dosing minus adjusted mean ΔHR after placebo dosing.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
0.25 hours post-dose	-0.9
0.5 hours post-dose	-1.3
0.75 hours post-dose	-0.6
1 hour post-dose	-2.3
1.5 hours post-dose	-1.9
2 hours post-dose	-1.5
3 hours post-dose	-0.9
4 hours post-dose	0.5
8 hours post-dose	-0.1
12 hours post-dose	-1.0
24 hours post-dose	-1.7

16. Secondary Outcome

Title	Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B
Description	Change from baseline in PR interval (ΔPR) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline PR interval as covariate. Placebo-corrected ΔPR (ΔΔPR) was calculated as the adjusted mean ΔPR after OM dosing minus adjusted mean ΔPR after placebo dosing.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
0.25 hours post-dose	0.6
0.5 hours post-dose	0.9
0.75 hours post-dose	-0.3
1 hour post-dose	1.0
1.5 hours post-dose	0.1
2 hours post-dose	1.9
3 hours post-dose	0.4
4 hours post-dose	0.1
8 hours post-dose	-1.6
12 hours post-dose	-1.0
24 hours post-dose	-0.1

17. Secondary Outcome

Title	Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B
Description	Change from baseline in QRS (ΔQRS) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QRS as covariate. Placebo-corrected ΔQRS (ΔΔQRS) was calculated as the adjusted mean ΔQRS after OM dosing minus adjusted mean ΔQRS after placebo dosing.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
0.25 hours post-dose	-0.1
0.5 hours post-dose	-0.1
0.75 hours post-dose	-0.1
1 hour post-dose	-0.1
1.5 hours post-dose	0.0
2 hours post-dose	0.1
3 hours post-dose	0.1
4 hours post-dose	0.1
8 hours post-dose	0.3
12 hours post-dose	0.4
24 hours post-dose	-0.1

18. Secondary Outcome

Title	Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B
Description	Outliers were predefined according to the following categories: QTcF: Treatment-emergent value of > 450 and ≤ 480 ms when not present at baseline (new onset) Treatment-emergent value of > 480 and ≤ 500 ms when not present at baseline (new onset) Treatment-emergent value of > 500 ms when not present at baseline (new onset) Increase of QTcF from baseline of > 30 and ≤ 60 ms Increase of QTcF from baseline > 60 ms Increase of PR from baseline > 25% resulting in PR > 200 ms Increase of QRS from baseline > 25% resulting in QRS > 120 ms Decrease of HR from baseline > 25% resulting in HR < 50 bpm Increase of HR from baseline > 25% resulting in HR > 100 bpm
Time Frame	Day 1 of the OM treatment period at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
QTcF > 450 and ≤ 480 ms (new onset)	1 1.7%
QTcF > 480 and ≤ 500 ms (new onset)	0 0%
QTcF > 500 ms (new onset)	0 0%
Increase in ΔQTcF > 30 and ≤ 60 ms	0 0%
Increase in ΔQTcF > 60 ms	0 0%
HR < 50 bpm with a decrease in ΔHR > 25%	0 0%
HR > 100 bpm with an increase in ΔHR > 25%	0 0%
PR > 200 ms with an increase in ΔPR > 25%	0 0%
QRS > 120 ms with an increase in ΔQRS > 25%	0 0%

19. Secondary Outcome

Title	Number of Participants With Treatment-emergent Changes in T-wave Morphology and U-wave Presence After Omecamtiv Mecarbil Dosing in Part B
Description	T-wave abnormalities were categorized as follows: Flat T-wave: T amplitude < 1 mm (either positive or negative) including flat isoelectric line Notched T-wave (+): Presence of notch(es) of at least 0.05 mV amplitude on ascending or descending arm of the positive T-wave Biphasic: T-wave that contains a second component with an opposite phase that is at least 0.1 mV deep (both positive/negative and negative/positive and polyphasic T-waves included) Normal T-wave (-): T amplitude that is negative, without biphasic T-wave or notches Notched T-wave (-): Presence of notch(es) of at least 0.05 mV amplitude on descending or ascending arm of the negative T-wave U waves: Presence of abnormal U-waves
Time Frame	Day 1 of the OM treatment period at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60
Flat T-wave	0 0%
Notched T-wave (+)	0 0%
Biphasic T-wave	0 0%
Normal T-wave (-)	0 0%
Notched T-wave (-)	0 0%
U-Wave presence	0 0%

20. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Description	A TEAE was defined as an adverse event (AE) that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. A treatment-related TEAE was defined as a TEAE with a relationship of related to the study treatment as determined by the investigator. The Investigator assessed the severity of each AE reported during the study based on the following grading scale: Mild: Aware of sign or symptom, easily tolerated Moderate: Discomfort enough to cause interference with usual activity Severe: Incapacitating, inability to work or do usual activity SAEs were defined as any untoward medical occurrence that met at least 1 of the following serious criteria: Resulted in Death Was life-threatening Required in-patient hospitalization or prolongation of existing hospitalization Resulted in persistent or significant disability/incapacity Was a congenital anomaly/birth defect Other medically important serious event
Time Frame	From first dose of study treatment to day 6 of each treatment period

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least 1 dose of study treatment (OM, placebo, or moxifloxacin) and had at least 1 postdose safety assessment.

Arm/Group Title	Part A: Omecamtiv Mecarbil 25 mg	Part B: Placebo	Part B: Omecamtiv Mecarbil 50 mg	Part B: Moxifloxacin 400 mg
Arm/Group Description	After an overnight fast of at least 10 hours participants received a single oral dose of 25 mg omecamtiv mecarbil on Day 1.	Participants received a single oral dose of placebo on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.	Participants received a single dose of 400 mg moxifloxacin on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	70	60	60	60
Any TEAE	20 33.3%	26 NaN	24 NaN	29 NaN
Serious TEAE	0 0%	0 NaN	0 NaN	0 NaN
TEAE leading to discontinuation	0 0%	0 NaN	0 NaN	0 NaN
TEAE leading to death	0 0%	0 NaN	0 NaN	0 NaN
Mild TEAE	19 31.7%	25 NaN	24 NaN	28 NaN
Moderate TEAE	2 3.3%	1 NaN	1 NaN	2 NaN
Severe TEAE	0 0%	0 NaN	0 NaN	0 NaN
Treatment-related TEAE	2 3.3%	0 NaN	4 NaN	2 NaN
Treatment-related serious TEAE	0 0%	0 NaN	0 NaN	0 NaN
Treatment-related TEAE leading to discontinuation	0 0%	0 NaN	0 NaN	0 NaN
Treatment-related TEAE leading to death	0 0%	0 NaN	0 NaN	0 NaN
Treatment-related mild TEAE	2 3.3%	0 NaN	4 NaN	2 NaN
Treatment-related moderate TEAE	0 0%	0 NaN	0 NaN	0 NaN
Treatment-related severe TEAE	0 0%	0 NaN	0 NaN	0 NaN

21. Secondary Outcome

Title	Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings
Description	Blood and urine samples were collected for clinical laboratory evaluations (including clinical chemistry, hematology, urinalysis, and serology). Vital signs included blood pressure, pulse rate and body temperature. Standard safety 12-lead ECGs were recorded after the subject had been supine or semi-recumbent and at rest for at least 5 minutes to detect any immediate ECG effects for subject safety. These ECGs were viewed locally. The Investigator determined whether an abnormal value in an individual participant represented a clinically significant change from the participant's baseline values.
Time Frame	From first dose up to day 6 of each treatment period

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Part A: Omecamtiv Mecarbil 25 mg	Part B: Placebo	Part B: Omecamtiv Mecarbil 50 mg	Part B: Moxifloxacin 400 mg
Arm/Group Description	After an overnight fast of at least 10 hours participants received a single oral dose of 25 mg omecamtiv mecarbil on Day 1.	Participants received a single oral dose of placebo on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.	Participants received a single dose of 400 mg moxifloxacin on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	70	60	60	60
Clinical Laboratory Evaluations	0 0%	0 NaN	0 NaN	0 NaN
Vital Signs	0 0%	0 NaN	0 NaN	0 NaN
12-lead Electrocardiogram	0 0%	0 NaN	0 NaN	0 NaN

22. Post-Hoc Outcome

Title	Change From Baseline in QTcF After Each Treatment In Part 2
Description	Change from baseline in QTcF was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QTcF as a covariate.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg	Part B: Moxifloxacin 400 mg	Part B: Placebo
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.	Participants received a single dose of 400 mg moxifloxacin on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.	Participants received a single oral dose of placebo on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60	60	60
0.25 hours post-dose	-6.3	-1.6	-3.8
0.5 hours post-dose	-9.1	4.4	-4.2
0.75 hours post-dose	-8.6	7.2	-2.8
1 hour post-dose	-8.1	8.8	-1.4
1.5 hours post-dose	-5.5	10.1	-1.0
2 hours post-dose	-5.2	10.1	-2.5
3 hours post-dose	-4.9	9.8	-3.4
4 hours post-dose	-3.3	10.4	-2.5
8 hours post-dose	-7.1	4.8	-4.9
12 hours post-dose	-6.6	4.2	-4.7
24 hours post-dose	-4.1	2.4	-2.9

23. Post-Hoc Outcome

Title	Change From Baseline in Heart Rate After Each Treatment In Part 2
Description	Change from baseline in heart rate (HR) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline HR as a covariate.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg	Part B: Moxifloxacin 400 mg	Part B: Placebo
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.	Participants received a single dose of 400 mg moxifloxacin on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.	Participants received a single oral dose of placebo on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60	60	60
0.25 hours post-dose	1.3	2.1	2.1
0.5 hours post-dose	1.2	4.0	2.6
0.75 hours post-dose	1.4	5.3	2.1
1 hour post-dose	0.2	5.4	2.5
1.5 hours post-dose	-0.5	2.0	1.4
2 hours post-dose	-0.2	2.0	1.4
3 hours post-dose	1.1	3.0	2.0
4 hours post-dose	1.8	2.9	1.3
8 hours post-dose	7.8	9.1	8.0
12 hours post-dose	8.3	9.6	9.3
24 hours post-dose	2.8	3.4	4.5

24. Post-Hoc Outcome

Title	Change From Baseline in PR Interval After Each Treatment In Part 2
Description	The PR interval is the time from the onset of the P-wave to the start of the next QRS complex. Change from baseline was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline PR interval as covariate.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg	Part B: Moxifloxacin 400 mg	Part B: Placebo
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.	Participants received a single dose of 400 mg moxifloxacin on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.	Participants received a single oral dose of placebo on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60	60	60
0.25 hours post-dose	-0.5	-1.6	-1.2
0.5 hours post-dose	1.0	-0.6	0.1
0.75 hours post-dose	0.4	-1.1	0.7
1 hour post-dose	0.4	-1.5	-0.6
1.5 hours post-dose	-1.2	-2.1	-1.3
2 hours post-dose	-0.8	-1.6	-2.6
3 hours post-dose	-2.0	-3.3	-2.5
4 hours post-dose	-3.2	-4.5	-3.3
8 hours post-dose	-7.5	-7.7	-5.8
12 hours post-dose	-7.8	-7.5	-6.8
24 hours post-dose	-2.1	-2.6	-2.1

25. Post-Hoc Outcome

Title	Change From Baseline in QRS After Each Treatment In Part 2
Description	The QRS complex is a combination of the Q wave, R wave and S wave on an ECG tracing, and represents ventricular depolarization. Change from baseline was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QRS as covariate.
Time Frame	Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.

Outcome Measure Data

Analysis Population Description

The QT/QTc analysis set

Arm/Group Title	Part B: Omecamtiv Mecarbil 50 mg	Part B: Moxifloxacin 400 mg	Part B: Placebo
Arm/Group Description	Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.	Participants received a single dose of 400 mg moxifloxacin on day 1 of treatment period 1, 2, or 3, depending on sequence assignment	Participants received a single oral dose of placebo on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.
Measure Participants	60	60	60
0.25 hours post-dose	-0.2	-0.2	-0.2
0.5 hours post-dose	0.0	-0.1	0.0
0.75 hours post-dose	-0.2	0.0	-0.1
1 hour post-dose	0.0	0.1	0.1
1.5 hours post-dose	-0.2	0.0	-0.2
2 hours post-dose	-0.3	0.1	-0.3
3 hours post-dose	0.00	0.1	-0.2
4 hours post-dose	0.1	0.2	0.0
8 hours post-dose	-0.4	-0.3	-0.6
12 hours post-dose	-0.7	-0.7	-1.1
24 hours post-dose	-0.3	0.0	-0.1

Adverse Events

Time Frame	From first dose of study drug to 6 days post-dose in each treatment period.
Arm/Group Title	Part A: Omecamtiv Mecarbil 25 mg		Part B: Placebo		Part B: Omecamtiv Mecarbil 50 mg		Part B: Moxifloxacin 400 mg		Overall
Arm/Group Description	After an overnight fast of at least 10 hours participants received a single oral dose of 25 mg omecamtiv mecarbil on Day 1.		Participants received a single oral dose of placebo on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.		Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.		Participants received a single dose of 400 mg moxifloxacin on day 1 of treatment period 1, 2, or 3, depending on sequence assignment.		ALL TREATED SUBJECTS
All Cause Mortality
	Part A: Omecamtiv Mecarbil 25 mg		Part B: Placebo		Part B: Omecamtiv Mecarbil 50 mg		Part B: Moxifloxacin 400 mg		Overall
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		0/60 (0%)		0/60 (0%)		0/60 (0%)		0/70 (0%)
Serious Adverse Events
	Part A: Omecamtiv Mecarbil 25 mg		Part B: Placebo		Part B: Omecamtiv Mecarbil 50 mg		Part B: Moxifloxacin 400 mg		Overall
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		0/60 (0%)		0/60 (0%)		0/60 (0%)		0/70 (0%)
Other (Not Including Serious) Adverse Events
	Part A: Omecamtiv Mecarbil 25 mg		Part B: Placebo		Part B: Omecamtiv Mecarbil 50 mg		Part B: Moxifloxacin 400 mg		Overall
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/70 (20%)		16/60 (26.7%)		13/60 (21.7%)		18/60 (30%)		39/70 (55.7%)
Gastrointestinal disorders
Nausea	1/70 (1.4%)		4/60 (6.7%)		1/60 (1.7%)		3/60 (5%)		7/70 (10%)
Infections and infestations
Nasopharyngitis	1/70 (1.4%)		1/60 (1.7%)		2/60 (3.3%)		0/60 (0%)		4/70 (5.7%)
Injury, poisoning and procedural complications
Post procedural complication	4/70 (5.7%)		2/60 (3.3%)		3/60 (5%)		1/60 (1.7%)		10/70 (14.3%)
Post procedural erythema	2/70 (2.9%)		6/60 (10%)		5/60 (8.3%)		5/60 (8.3%)		15/70 (21.4%)
Procedural pain	0/70 (0%)		0/60 (0%)		1/60 (1.7%)		3/60 (5%)		4/70 (5.7%)
Musculoskeletal and connective tissue disorders
Pain in extremity	0/70 (0%)		0/60 (0%)		0/60 (0%)		3/60 (5%)		3/70 (4.3%)
Nervous system disorders
Dizziness	1/70 (1.4%)		2/60 (3.3%)		0/60 (0%)		2/60 (3.3%)		5/70 (7.1%)
Headache	1/70 (1.4%)		3/60 (5%)		3/60 (5%)		2/60 (3.3%)		9/70 (12.9%)
Psychiatric disorders
Insomnia	1/70 (1.4%)		2/60 (3.3%)		2/60 (3.3%)		1/60 (1.7%)		6/70 (8.6%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	1/70 (1.4%)		1/60 (1.7%)		0/60 (0%)		2/60 (3.3%)		4/70 (5.7%)
Oropharyngeal pain	3/70 (4.3%)		0/60 (0%)		3/60 (5%)		1/60 (1.7%)		7/70 (10%)
Skin and subcutaneous tissue disorders
Rash	1/70 (1.4%)		2/60 (3.3%)		0/60 (0%)		1/60 (1.7%)		4/70 (5.7%)
Rash papular	2/70 (2.9%)		1/60 (1.7%)		0/60 (0%)		1/60 (1.7%)		4/70 (5.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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