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

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

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.

Study Overview

• Status: Completed
• Conditions: QT Intervals Changes; QTc Intervals Changes
• Intervention / Treatment: Drug: Omecamtiv Mecarbil (OM); Drug: Placebo; Drug: Moxifloxacin

Detailed Description

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

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

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

This study was conducted by Amgen as the IND holder, with Cytokinetics as a collaborator. Due to the termination of the collaboration agreement between Amgen and Cytokinetics in May 2021 and subsequent transfer of the omecamtiv mecarbil IND from Amgen to Cytokinetics, Cytokinetics is now listed as the sponsor.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Leeds, United Kingdom, LS2 9LH
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Cytokinetics

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2019
• Primary Completion (Actual): March 4, 2020
• Study Completion (Actual): March 4, 2020

Study Registration Dates

• First Submitted: November 7, 2019
• First Submitted That Met QC Criteria: November 21, 2019
• First Posted (Actual): November 25, 2019

Study Record Updates

• Last Update Posted (Actual): November 4, 2021
• Last Update Submitted That Met QC Criteria: November 2, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Thorough QT; QTc study
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Moxifloxacin
• Other Study ID Numbers: 20090231; 2018-003157-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No