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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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QT Intervals Changes, QTc Intervals Changes

Intervention / Treatment
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* Drug: Omecamtiv Mecarbil (OM)
* Drug: Placebo
* Drug: Moxifloxacin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>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)<br>* Oral solution<br>* Other names: AMG 423;|
| Experimental: Part B<br>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)<br>* Oral solution<br>* Other names: AMG 423;Drug: Placebo<br>* Placebo oral solution<br>Drug: Moxifloxacin<br>* 400 mg moxifloxacin oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | 
| 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. | 
| 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 | 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. | 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. | 
| 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. | 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 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. | 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 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. | 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 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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 | 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. | 
| 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 | 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. | 
| 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 | From first dose of study treatment to day 6 of each treatment period | 
| 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. | From first dose up to day 6 of each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thorough QT, QTc study