QTc Intervals Changes, QT Intervals Changes
Conditions
Keywords
Thorough QT, QTc study
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.
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.
Interventions
Oral solution
DRUGPlacebo
Placebo oral solution
DRUGMoxifloxacin
400 mg moxifloxacin oral tablet
Sponsors
Cytokinetics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. | — |
| 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. | — |
| 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. | — |
| 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. | — |
| 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. | — |
| 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. |
| 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. |
| 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. |
| 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. | — |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 |
| 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 |
| 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 |
| 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. |
| 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. |
Countries
United Kingdom
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Part B 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. | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Part A | Miscellaneous | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part B |
|---|---|
| Age, Continuous | 32.7 years STANDARD_DEVIATION 8.88 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Heart Rate Prior to moxifloxacin dose | 59.5 beats/minute STANDARD_DEVIATION 7.36 |
| Heart Rate Prior to OM dose | 59.2 beats/minute STANDARD_DEVIATION 7.87 |
| Heart Rate Prior to placebo dose | 58.6 beats/minute STANDARD_DEVIATION 8.03 |
| PR Interval Prior to moxifloxacin dose | 150.7 ms STANDARD_DEVIATION 22.73 |
| PR Interval Prior to OM dose | 151.4 ms STANDARD_DEVIATION 22.48 |
| PR Interval Prior to placebo dose | 151.2 ms STANDARD_DEVIATION 24.2 |
| QRS Prior to moxifloxacin dose | 105.8 ms STANDARD_DEVIATION 5.36 |
| QRS Prior to OM dose | 105.6 ms STANDARD_DEVIATION 5.74 |
| QRS Prior to placebo dose | 105.8 ms STANDARD_DEVIATION 5.52 |
| QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) Prior to moxifloxacin dose | 402.4 ms STANDARD_DEVIATION 18.38 |
| QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) Prior to OM dose | 402.9 ms STANDARD_DEVIATION 18.27 |
| QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) Prior to placebo dose | 404.1 ms STANDARD_DEVIATION 19.06 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 6 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized White | 49 Participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 70 | 0 / 60 | 0 / 60 | 0 / 60 | 0 / 70 |
| other Total, other adverse events | 14 / 70 | 16 / 60 | 13 / 60 | 18 / 60 | 39 / 70 |
| serious Total, serious adverse events | 0 / 70 | 0 / 60 | 0 / 60 | 0 / 60 | 0 / 70 |
Outcome results
Primary
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
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | 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 | 0.5 hours post-dose | -4.9 ms |
| Part B: Omecamtiv Mecarbil 50 mg | 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 | 1 hour post-dose | -6.7 ms |
| Part B: Omecamtiv Mecarbil 50 mg | 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 | 1.5 hours post-dose | -4.5 ms |
| Part B: Omecamtiv Mecarbil 50 mg | 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 | 0.25 hours post-dose | -2.6 ms |
| Part B: Omecamtiv Mecarbil 50 mg | 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 | 0.75 hours post-dose | -5.8 ms |
| Part B: Omecamtiv Mecarbil 50 mg | 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 | 2 hours post-dose | -2.7 ms |
| Part B: Omecamtiv Mecarbil 50 mg | 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 | 3 hours post-dose | -1.5 ms |
| Part B: Omecamtiv Mecarbil 50 mg | 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 | 4 hours post-dose | -0.8 ms |
| Part B: Omecamtiv Mecarbil 50 mg | 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 | 8 hours post-dose | -2.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | 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 | 12 hours post-dose | -1.9 ms |
| Part B: Omecamtiv Mecarbil 50 mg | 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 | 24 hours post-dose | -1.2 ms |
Secondary
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.
Population: Part B PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Apparent Terminal Elimination Half-life (T1/2) of Omecamtiv Mecarbil in Part B | 20.0 hours | Geometric Coefficient of Variation 2.91 |
Secondary
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.
Population: Part B PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Apparent Total Plasma Clearance (CL/F) for Omecamtiv Mecarbil in Part B | 10.4 L/h | Geometric Coefficient of Variation 21.2 |
Secondary
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.
Population: Part B PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Apparent Volume of Distribution (VZ/F) for Omecamtiv Mecarbil in Part B | 299 liters | Geometric Coefficient of Variation 21.5 |
Secondary
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.
Population: Part B PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Area Under the Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-t) for Omecamtiv Mecarbil in Part B | 4710 h*ng/mL | Geometric Coefficient of Variation 21 |
Secondary
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.
Population: Part B PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | AUC From Time 0 to Infinity (AUCinf) for Omecamtiv Mecarbil in Part B | 4790 h*ng/mL | Geometric Coefficient of Variation 21.2 |
Secondary
Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B
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.
Population: The QT/QTc analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 0.25 hours post-dose | 1.3 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 0.5 hours post-dose | 1.2 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 0.75 hours post-dose | 1.4 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 1 hour post-dose | 0.2 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 1.5 hours post-dose | -0.5 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 2 hours post-dose | -0.2 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 3 hours post-dose | 1.1 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 4 hours post-dose | 1.8 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 8 hours post-dose | 7.8 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 12 hours post-dose | 8.3 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 24 hours post-dose | 2.8 bpm |
Secondary
Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B
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.
Population: The QT/QTc analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 0.25 hours post-dose | -0.5 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 0.5 hours post-dose | 1.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 0.75 hours post-dose | 0.4 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 1 hour post-dose | 0.4 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 1.5 hours post-dose | -1.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 2 hours post-dose | -0.8 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 3 hours post-dose | -2.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 4 hours post-dose | -3.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 8 hours post-dose | -7.5 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 12 hours post-dose | -7.8 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 24 hours post-dose | -2.1 ms |
Secondary
Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B
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.
Population: The QT/QTc analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 12 hours post-dose | -0.7 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 24 hours post-dose | -0.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 0.25 hours post-dose | -0.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 0.5 hours post-dose | 0.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 0.75 hours post-dose | -0.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 1 hour post-dose | 0.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 1.5 hours post-dose | -0.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 2 hours post-dose | -0.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 3 hours post-dose | 0.00 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 4 hours post-dose | 0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 8 hours post-dose | -0.4 ms |
Secondary
Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B
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.
Population: The QT/QTc analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B | 0.25 hours post-dose | -6.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B | 0.5 hours post-dose | -9.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B | 0.75 hours post-dose | -8.6 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B | 1 hour post-dose | -8.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B | 1.5 hours post-dose | -5.5 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B | 2 hours post-dose | -5.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B | 3 hours post-dose | -4.9 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B | 8 hours post-dose | -7.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B | 12 hours post-dose | -6.6 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B | 4 hours post-dose | -3.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B | 24 hours post-dose | -4.1 ms |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil in Part B
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.
Population: The pharmacokinetic (PK) population for Part B consisted of all participants who received OM and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil in Part B | 416 ng/mL | Geometric Coefficient of Variation 33.2 |
Secondary
Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings
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
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings | Vital Signs | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings | Clinical Laboratory Evaluations | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings | 12-lead Electrocardiogram | 0 Participants |
| Part B: Placebo | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings | Clinical Laboratory Evaluations | 0 Participants |
| Part B: Placebo | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings | Vital Signs | 0 Participants |
| Part B: Placebo | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings | 12-lead Electrocardiogram | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings | Clinical Laboratory Evaluations | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings | 12-lead Electrocardiogram | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings | Vital Signs | 0 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings | Vital Signs | 0 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings | Clinical Laboratory Evaluations | 0 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Tests, or Electrocardiogram Findings | 12-lead Electrocardiogram | 0 Participants |
Secondary
Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B
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.
Population: QT/QTc analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B | QTcF > 450 and ≤ 480 ms (new onset) | 1 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B | QTcF > 480 and ≤ 500 ms (new onset) | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B | QTcF > 500 ms (new onset) | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B | Increase in ΔQTcF > 30 and ≤ 60 ms | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B | HR < 50 bpm with a decrease in ΔHR > 25% | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B | HR > 100 bpm with an increase in ΔHR > 25% | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B | PR > 200 ms with an increase in ΔPR > 25% | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B | QRS > 120 ms with an increase in ΔQRS > 25% | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B | Increase in ΔQTcF > 60 ms | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 20 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE | 2 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Severe TEAE | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Moderate TEAE | 2 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related severe TEAE | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related mild TEAE | 2 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to discontinuation | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related moderate TEAE | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE leading to death | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to death | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious TEAE | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE leading to discontinuation | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related serious TEAE | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Mild TEAE | 19 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Mild TEAE | 25 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious TEAE | 0 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to discontinuation | 0 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to death | 0 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Severe TEAE | 0 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE | 0 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related serious TEAE | 0 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE leading to death | 0 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related mild TEAE | 0 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related moderate TEAE | 0 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 26 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Moderate TEAE | 1 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE leading to discontinuation | 0 Participants |
| Part B: Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related severe TEAE | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related severe TEAE | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE leading to death | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related moderate TEAE | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 24 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Moderate TEAE | 1 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE leading to discontinuation | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related serious TEAE | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious TEAE | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Severe TEAE | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related mild TEAE | 4 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Mild TEAE | 24 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to discontinuation | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE | 4 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to death | 0 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE | 2 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related severe TEAE | 0 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related serious TEAE | 0 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE leading to discontinuation | 0 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to discontinuation | 0 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious TEAE | 0 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE leading to death | 0 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related mild TEAE | 2 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 29 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related moderate TEAE | 0 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Mild TEAE | 28 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Moderate TEAE | 2 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Severe TEAE | 0 Participants |
| Part B: Moxifloxacin 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE leading to death | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Changes in T-wave Morphology and U-wave Presence After Omecamtiv Mecarbil Dosing in Part B
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.
Population: QT/QTc analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Changes in T-wave Morphology and U-wave Presence After Omecamtiv Mecarbil Dosing in Part B | Flat T-wave | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Changes in T-wave Morphology and U-wave Presence After Omecamtiv Mecarbil Dosing in Part B | Notched T-wave (+) | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Changes in T-wave Morphology and U-wave Presence After Omecamtiv Mecarbil Dosing in Part B | Biphasic T-wave | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Changes in T-wave Morphology and U-wave Presence After Omecamtiv Mecarbil Dosing in Part B | Normal T-wave (-) | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Changes in T-wave Morphology and U-wave Presence After Omecamtiv Mecarbil Dosing in Part B | Notched T-wave (-) | 0 Participants |
| Part B: Omecamtiv Mecarbil 50 mg | Number of Participants With Treatment-emergent Changes in T-wave Morphology and U-wave Presence After Omecamtiv Mecarbil Dosing in Part B | U-Wave presence | 0 Participants |
Secondary
Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B
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.
Population: The QT/QTc analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 0.25 hours post-dose | -0.9 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 0.75 hours post-dose | -0.6 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 1 hour post-dose | -2.3 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 1.5 hours post-dose | -1.9 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 2 hours post-dose | -1.5 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 0.5 hours post-dose | -1.3 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 3 hours post-dose | -0.9 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 4 hours post-dose | 0.5 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 8 hours post-dose | -0.1 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 12 hours post-dose | -1.0 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B | 24 hours post-dose | -1.7 bpm |
Secondary
Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B
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.
Population: The QT/QTc analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 0.75 hours post-dose | -0.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 1 hour post-dose | 1.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 1.5 hours post-dose | 0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 2 hours post-dose | 1.9 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 3 hours post-dose | 0.4 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 4 hours post-dose | 0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 8 hours post-dose | -1.6 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 12 hours post-dose | -1.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 24 hours post-dose | -0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 0.25 hours post-dose | 0.6 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B | 0.5 hours post-dose | 0.9 ms |
Secondary
Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B
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.
Population: The QT/QTc analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 0.25 hours post-dose | -0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 0.5 hours post-dose | -0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 0.75 hours post-dose | -0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 1 hour post-dose | -0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 1.5 hours post-dose | 0.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 2 hours post-dose | 0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 3 hours post-dose | 0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 4 hours post-dose | 0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 8 hours post-dose | 0.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 12 hours post-dose | 0.4 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B | 24 hours post-dose | -0.1 ms |
Secondary
Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B
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.
Population: The QT/QTc analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B | 0.25 hours post-dose | 2.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B | 0.5 hours post-dose | 8.6 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B | 0.75 hours post-dose | 10.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B | 1 hour post-dose | 10.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B | 1.5 hours post-dose | 11.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B | 2 hours post-dose | 12.7 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B | 4 hours post-dose | 12.9 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B | 8 hours post-dose | 9.7 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B | 12 hours post-dose | 9.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B | 24 hours post-dose | 5.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B | 3 hours post-dose | 13.1 ms |
Secondary
Slope of Omecamtiv Mecarbil Plasma Concentration Estimated From Concentration-QTc Analysis in Part B
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.
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Slope of Omecamtiv Mecarbil Plasma Concentration Estimated From Concentration-QTc Analysis in Part B | -0.011 ms per ng/mL |
Secondary
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.
Population: Part B PK population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil In Part B | 0.583 hours |
Post Hoc
Change From Baseline in Heart Rate After Each Treatment In Part 2
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.
Population: The QT/QTc analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 4 hours post-dose | 1.8 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 1.5 hours post-dose | -0.5 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 12 hours post-dose | 8.3 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 3 hours post-dose | 1.1 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 2 hours post-dose | -0.2 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 0.25 hours post-dose | 1.3 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 0.75 hours post-dose | 1.4 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 0.5 hours post-dose | 1.2 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 8 hours post-dose | 7.8 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 1 hour post-dose | 0.2 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 24 hours post-dose | 2.8 bpm |
| Part B: Placebo | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 2 hours post-dose | 2.0 bpm |
| Part B: Placebo | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 0.25 hours post-dose | 2.1 bpm |
| Part B: Placebo | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 0.5 hours post-dose | 4.0 bpm |
| Part B: Placebo | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 0.75 hours post-dose | 5.3 bpm |
| Part B: Placebo | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 1 hour post-dose | 5.4 bpm |
| Part B: Placebo | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 1.5 hours post-dose | 2.0 bpm |
| Part B: Placebo | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 3 hours post-dose | 3.0 bpm |
| Part B: Placebo | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 4 hours post-dose | 2.9 bpm |
| Part B: Placebo | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 8 hours post-dose | 9.1 bpm |
| Part B: Placebo | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 12 hours post-dose | 9.6 bpm |
| Part B: Placebo | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 24 hours post-dose | 3.4 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 12 hours post-dose | 9.3 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 4 hours post-dose | 1.3 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 0.75 hours post-dose | 2.1 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 0.25 hours post-dose | 2.1 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 8 hours post-dose | 8.0 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 0.5 hours post-dose | 2.6 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 2 hours post-dose | 1.4 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 1.5 hours post-dose | 1.4 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 24 hours post-dose | 4.5 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 3 hours post-dose | 2.0 bpm |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in Heart Rate After Each Treatment In Part 2 | 1 hour post-dose | 2.5 bpm |
Post Hoc
Change From Baseline in PR Interval After Each Treatment In Part 2
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.
Population: The QT/QTc analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 2 hours post-dose | -0.8 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 0.25 hours post-dose | -0.5 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 8 hours post-dose | -7.5 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 3 hours post-dose | -2.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 1 hour post-dose | 0.4 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 4 hours post-dose | -3.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 0.75 hours post-dose | 0.4 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 24 hours post-dose | -2.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 1.5 hours post-dose | -1.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 0.5 hours post-dose | 1.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 12 hours post-dose | -7.8 ms |
| Part B: Placebo | Change From Baseline in PR Interval After Each Treatment In Part 2 | 0.5 hours post-dose | -0.6 ms |
| Part B: Placebo | Change From Baseline in PR Interval After Each Treatment In Part 2 | 0.75 hours post-dose | -1.1 ms |
| Part B: Placebo | Change From Baseline in PR Interval After Each Treatment In Part 2 | 1 hour post-dose | -1.5 ms |
| Part B: Placebo | Change From Baseline in PR Interval After Each Treatment In Part 2 | 1.5 hours post-dose | -2.1 ms |
| Part B: Placebo | Change From Baseline in PR Interval After Each Treatment In Part 2 | 2 hours post-dose | -1.6 ms |
| Part B: Placebo | Change From Baseline in PR Interval After Each Treatment In Part 2 | 3 hours post-dose | -3.3 ms |
| Part B: Placebo | Change From Baseline in PR Interval After Each Treatment In Part 2 | 4 hours post-dose | -4.5 ms |
| Part B: Placebo | Change From Baseline in PR Interval After Each Treatment In Part 2 | 8 hours post-dose | -7.7 ms |
| Part B: Placebo | Change From Baseline in PR Interval After Each Treatment In Part 2 | 12 hours post-dose | -7.5 ms |
| Part B: Placebo | Change From Baseline in PR Interval After Each Treatment In Part 2 | 24 hours post-dose | -2.6 ms |
| Part B: Placebo | Change From Baseline in PR Interval After Each Treatment In Part 2 | 0.25 hours post-dose | -1.6 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 1.5 hours post-dose | -1.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 0.25 hours post-dose | -1.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 12 hours post-dose | -6.8 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 1 hour post-dose | -0.6 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 0.5 hours post-dose | 0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 24 hours post-dose | -2.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 0.75 hours post-dose | 0.7 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 4 hours post-dose | -3.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 2 hours post-dose | -2.6 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 3 hours post-dose | -2.5 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in PR Interval After Each Treatment In Part 2 | 8 hours post-dose | -5.8 ms |
Post Hoc
Change From Baseline in QRS After Each Treatment In Part 2
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.
Population: The QT/QTc analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 0.25 hours post-dose | -0.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 24 hours post-dose | -0.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 4 hours post-dose | 0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 12 hours post-dose | -0.7 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 8 hours post-dose | -0.4 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 2 hours post-dose | -0.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 0.75 hours post-dose | -0.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 1 hour post-dose | 0.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 0.5 hours post-dose | 0.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 1.5 hours post-dose | -0.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 3 hours post-dose | 0.00 ms |
| Part B: Placebo | Change From Baseline in QRS After Each Treatment In Part 2 | 4 hours post-dose | 0.2 ms |
| Part B: Placebo | Change From Baseline in QRS After Each Treatment In Part 2 | 0.25 hours post-dose | -0.2 ms |
| Part B: Placebo | Change From Baseline in QRS After Each Treatment In Part 2 | 0.5 hours post-dose | -0.1 ms |
| Part B: Placebo | Change From Baseline in QRS After Each Treatment In Part 2 | 1 hour post-dose | 0.1 ms |
| Part B: Placebo | Change From Baseline in QRS After Each Treatment In Part 2 | 3 hours post-dose | 0.1 ms |
| Part B: Placebo | Change From Baseline in QRS After Each Treatment In Part 2 | 8 hours post-dose | -0.3 ms |
| Part B: Placebo | Change From Baseline in QRS After Each Treatment In Part 2 | 12 hours post-dose | -0.7 ms |
| Part B: Placebo | Change From Baseline in QRS After Each Treatment In Part 2 | 24 hours post-dose | 0.0 ms |
| Part B: Placebo | Change From Baseline in QRS After Each Treatment In Part 2 | 0.75 hours post-dose | 0.0 ms |
| Part B: Placebo | Change From Baseline in QRS After Each Treatment In Part 2 | 1.5 hours post-dose | 0.0 ms |
| Part B: Placebo | Change From Baseline in QRS After Each Treatment In Part 2 | 2 hours post-dose | 0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 1.5 hours post-dose | -0.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 24 hours post-dose | -0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 0.5 hours post-dose | 0.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 0.75 hours post-dose | -0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 1 hour post-dose | 0.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 2 hours post-dose | -0.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 8 hours post-dose | -0.6 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 4 hours post-dose | 0.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 0.25 hours post-dose | -0.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 12 hours post-dose | -1.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QRS After Each Treatment In Part 2 | 3 hours post-dose | -0.2 ms |
Post Hoc
Change From Baseline in QTcF After Each Treatment In Part 2
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.
Population: The QT/QTc analysis set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 4 hours post-dose | -3.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 1.5 hours post-dose | -5.5 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 12 hours post-dose | -6.6 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 3 hours post-dose | -4.9 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 2 hours post-dose | -5.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 0.25 hours post-dose | -6.3 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 0.75 hours post-dose | -8.6 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 0.5 hours post-dose | -9.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 8 hours post-dose | -7.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 1 hour post-dose | -8.1 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 24 hours post-dose | -4.1 ms |
| Part B: Placebo | Change From Baseline in QTcF After Each Treatment In Part 2 | 2 hours post-dose | 10.1 ms |
| Part B: Placebo | Change From Baseline in QTcF After Each Treatment In Part 2 | 0.25 hours post-dose | -1.6 ms |
| Part B: Placebo | Change From Baseline in QTcF After Each Treatment In Part 2 | 0.5 hours post-dose | 4.4 ms |
| Part B: Placebo | Change From Baseline in QTcF After Each Treatment In Part 2 | 0.75 hours post-dose | 7.2 ms |
| Part B: Placebo | Change From Baseline in QTcF After Each Treatment In Part 2 | 1 hour post-dose | 8.8 ms |
| Part B: Placebo | Change From Baseline in QTcF After Each Treatment In Part 2 | 1.5 hours post-dose | 10.1 ms |
| Part B: Placebo | Change From Baseline in QTcF After Each Treatment In Part 2 | 3 hours post-dose | 9.8 ms |
| Part B: Placebo | Change From Baseline in QTcF After Each Treatment In Part 2 | 4 hours post-dose | 10.4 ms |
| Part B: Placebo | Change From Baseline in QTcF After Each Treatment In Part 2 | 8 hours post-dose | 4.8 ms |
| Part B: Placebo | Change From Baseline in QTcF After Each Treatment In Part 2 | 12 hours post-dose | 4.2 ms |
| Part B: Placebo | Change From Baseline in QTcF After Each Treatment In Part 2 | 24 hours post-dose | 2.4 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 12 hours post-dose | -4.7 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 4 hours post-dose | -2.5 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 0.75 hours post-dose | -2.8 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 0.25 hours post-dose | -3.8 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 8 hours post-dose | -4.9 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 0.5 hours post-dose | -4.2 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 2 hours post-dose | -2.5 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 1.5 hours post-dose | -1.0 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 24 hours post-dose | -2.9 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 3 hours post-dose | -3.4 ms |
| Part B: Omecamtiv Mecarbil 50 mg | Change From Baseline in QTcF After Each Treatment In Part 2 | 1 hour post-dose | -1.4 ms |