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| ID | Type | Description | Link |
|---|---|---|---|
| 2018-003157-19 | EudraCT Number |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A | Experimental | After an overnight fast of at least 10 hours participants received a single oral dose of 25 mg omecamtiv mecarbil on Day 1. |
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| Part B | Experimental | 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:
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Omecamtiv Mecarbil (OM) | Drug | Oral solution |
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| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| MD | Amgen | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Leeds | LS2 9LH | United Kingdom |
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| Label | URL |
|---|---|
| AmgenTrials clinical trials website | View source |
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De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
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.
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.
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 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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | Part B: Placebo/OM/Moxifloxacin | Participants received a single dose of placebo oral solution in Period 1, 50 mg omecamtiv mecarbil oral solution in Period 2 and 400 mg moxifloxacin oral tablet in Period 3. Each treatment was separated by a washout period of at least 7 days. |
| FG002 | Part B: OM/Moxifloxacin/Placebo | Participants received a single dose of 50 mg omecamtiv mecarbil oral solution in Period 1, 400 mg moxifloxacin oral tablet in Period 2, and placebo oral solution in Period 3. Each treatment was separated by a washout period of at least 7 days. |
| FG003 | Part B: Moxifloxacin/Placebo/OM | Participants received a single dose of 400 mg moxifloxacin oral tablet in Period 1, placebo oral solution in Period 2, and 50 mg omecamtiv mecarbil oral solution in Period 3. Each treatment was separated by a washout period of at least 7 days. |
| FG004 | Part B: Placebo/Moxifloxacin/OM | Participants received a single dose of placebo oral solution in Period 1, 400 mg moxifloxacin oral tablet in Period 2, and 50 mg omecamtiv mecarbil oral solution in Period 3. Each treatment was separated by a washout period of at least 7 days. |
| FG005 | Part B: Moxifloxacin/OM/Placebo | Participants received a single dose of 400 mg moxifloxacin oral tablet in Period 1, 50 mg omecamtiv mecarbil oral solution in Period 2, and placebo oral solution in Period 3. Each treatment was separated by a washout period of at least 7 days. |
| FG006 | Part B: OM/Placebo/Moxifloxacin | Participants received a single dose of 50 mg omecamtiv mecarbil oral solution in Period 1, placebo oral solution in Period 2, and 400 mg moxifloxacin oral tablet in Period 3. Each treatment was separated by a washout period of at least 7 days. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
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| Part A |
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| Part B |
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Participants randomized in Part B of the study
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| ID | Title | Description |
|---|---|---|
| BG000 | 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:
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| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Least Squares Mean | 90% Confidence Interval | ms | 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 |
From first dose of study drug to 6 days post-dose in each treatment period.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Part A: Omecamtiv Mecarbil 25 mg | After an overnight fast of at least 10 hours participants received a single oral dose of 25 mg omecamtiv mecarbil on Day 1. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA 22.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Amgen Inc. | 866-572-6436 | medinfo@amgen.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Aug 23, 2019 | Apr 23, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan: SAP Version 1 | Dec 10, 2019 | Apr 23, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C547293 | omecamtiv mecarbil |
| D000077266 | Moxifloxacin |
| ID | Term |
|---|---|
| D024841 | Fluoroquinolones |
| D042462 | 4-Quinolones |
| D015363 | Quinolones |
| D011804 | Quinolines |
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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.
| Placebo | Drug | Placebo oral solution |
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| Moxifloxacin | Drug | 400 mg moxifloxacin oral tablet |
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| 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:
| 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 |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) | In Part B, continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1 of each treatment period. Up to 10 digital 12-lead ECG tracings were extracted at -1.25, -1, and -0.75 hours pre-dose. The median QTc value from all beats in each replicate was calculated and then the mean of the available medians was used as the participant's reportable value at that time point. Baseline was the average of the values from the 3 pre-dose time points (-1.25, -1, and -0.75 hours) on Day 1 for the respective treatment period. | Mean | Standard Deviation | ms |
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| PR Interval | The PR interval is the time from the onset of the P-wave to the start of the next QRS complex. | Mean | Standard Deviation | ms |
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| QRS | The QRS complex is a combination of the Q wave, R wave and S wave on an ECG tracing, and represents ventricular depolarization. | Mean | Standard Deviation | ms |
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| Heart Rate | Mean | Standard Deviation | beats/minute |
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| 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. | The pharmacokinetic (PK) population for Part B consisted of all participants who received OM and had evaluable PK data. | Posted | Geometric Mean | Geometric Coefficient of Variation | 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. |
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| Secondary | Time to Maximum Observed Plasma Concentration (Tmax) of Omecamtiv Mecarbil In Part B | Part B PK population | Posted | Median | Full Range | hours | 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. |
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| Secondary | Apparent Terminal Elimination Half-life (T1/2) of Omecamtiv Mecarbil in Part B | Part B PK population | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | 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. |
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| Secondary | Apparent Total Plasma Clearance (CL/F) for Omecamtiv Mecarbil in Part B | Part B PK population | Posted | Geometric Mean | Geometric Coefficient of Variation | L/h | 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. |
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| Secondary | Apparent Volume of Distribution (VZ/F) for Omecamtiv Mecarbil in Part B | Part B PK population | Posted | Geometric Mean | Geometric Coefficient of Variation | liters | 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. |
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| 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 | Part B PK population | Posted | Geometric Mean | Geometric Coefficient of Variation | h*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. |
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| Secondary | AUC From Time 0 to Infinity (AUCinf) for Omecamtiv Mecarbil in Part B | Part B PK population | Posted | Geometric Mean | Geometric Coefficient of Variation | h*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. |
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| 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. | The QT/QTc analysis set | Posted | Least Squares Mean | 90% Confidence Interval | ms | 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. |
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| 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. | The QT/QTc analysis set | Posted | Least Squares Mean | 90% Confidence Interval | bpm | 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. |
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| 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. | The QT/QTc analysis set | Posted | Least Squares Mean | 90% Confidence Interval | ms | 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. |
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| 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. | The QT/QTc analysis set | Posted | Least Squares Mean | 90% Confidence Interval | ms | 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. |
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| 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. | The QT/QTc analysis set | Posted | Least Squares Mean | 90% Confidence Interval | ms | 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. |
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| 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. | 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. | Posted | Number | 90% Confidence Interval | ms per ng/mL | 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. |
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| 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. | The QT/QTc analysis set | Posted | Least Squares Mean | 90% Confidence Interval | bpm | 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. |
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| 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. | The QT/QTc analysis set | Posted | Least Squares Mean | 90% Confidence Interval | ms | 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. |
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| 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. | The QT/QTc analysis set | Posted | Least Squares Mean | 90% Confidence Interval | ms | 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. |
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| 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 | QT/QTc analysis set | Posted | Count of Participants | Participants | 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. |
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| 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 | QT/QTc analysis set | Posted | Count of Participants | Participants | 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. |
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| 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:
| 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. | Posted | Count of Participants | Participants | From first dose of study treatment to day 6 of each treatment period |
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| 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. | Safety population | Posted | Count of Participants | Participants | From first dose up to day 6 of each treatment period |
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| 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. | The QT/QTc analysis set | Posted | Least Squares Mean | 90% Confidence Interval | ms | 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. |
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| 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. | The QT/QTc analysis set | Posted | Least Squares Mean | 90% Confidence Interval | bpm | 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. |
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| 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. | The QT/QTc analysis set | Posted | Least Squares Mean | 90% Confidence Interval | ms | 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. |
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| 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. | The QT/QTc analysis set | Posted | Least Squares Mean | 90% Confidence Interval | ms | 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. |
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|
| 0 |
| 70 |
| 0 |
| 70 |
| 14 |
| 70 |
| EG001 | Part B: Placebo | Participants received a single oral dose of placebo on day 1 of treatment period 1, 2, or 3, depending on sequence assignment. | 0 | 60 | 0 | 60 | 16 | 60 |
| EG002 | Part B: Omecamtiv Mecarbil 50 mg | Participants received a single oral dose of 50 mg OM on day 1 of treatment period 1, 2, or 3, depending on sequence assignment. | 0 | 60 | 0 | 60 | 13 | 60 |
| EG003 | Part B: Moxifloxacin 400 mg | Participants received a single dose of 400 mg moxifloxacin on day 1 of treatment period 1, 2, or 3, depending on sequence assignment. | 0 | 60 | 0 | 60 | 18 | 60 |
| EG004 | Overall | ALL TREATED SUBJECTS | 0 | 70 | 0 | 70 | 39 | 70 |
| Nasopharyngitis | Infections and infestations | MedDRA 22.1 | Systematic Assessment |
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| Post procedural complication | Injury, poisoning and procedural complications | MedDRA 22.1 | Systematic Assessment |
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| Post procedural erythema | Injury, poisoning and procedural complications | MedDRA 22.1 | Systematic Assessment |
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| Procedural pain | Injury, poisoning and procedural complications | MedDRA 22.1 | Systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 22.1 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 22.1 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 22.1 | Systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA 22.1 | Systematic Assessment |
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| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 22.1 | Systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 22.1 | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA 22.1 | Systematic Assessment |
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| Rash papular | Skin and subcutaneous tissue disorders | MedDRA 22.1 | Systematic Assessment |
|
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
| D006574 |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| Title | Measurements |
|---|---|
|
| 1 hour post-dose |
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| 1.5 hours post-dose |
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| 2 hours post-dose |
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| 3 hours post-dose |
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| 4 hours post-dose |
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| 8 hours post-dose |
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| 12 hours post-dose |
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| 24 hours post-dose |
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| Title | Measurements |
|---|---|
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| 1 hour post-dose |
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| 1.5 hours post-dose |
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| 2 hours post-dose |
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| 3 hours post-dose |
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| 4 hours post-dose |
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| 8 hours post-dose |
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| 12 hours post-dose |
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| 24 hours post-dose |
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| Title | Measurements |
|---|---|
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| 1 hour post-dose |
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| 1.5 hours post-dose |
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| 2 hours post-dose |
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| 3 hours post-dose |
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| 4 hours post-dose |
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| 8 hours post-dose |
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| 12 hours post-dose |
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| 24 hours post-dose |
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| Title | Measurements |
|---|---|
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| 1 hour post-dose |
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| 1.5 hours post-dose |
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| 2 hours post-dose |
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| 3 hours post-dose |
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| 4 hours post-dose |
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| 8 hours post-dose |
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| 12 hours post-dose |
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| 24 hours post-dose |
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| Title | Measurements |
|---|---|
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| 1 hour post-dose |
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| 1.5 hours post-dose |
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| 2 hours post-dose |
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| 3 hours post-dose |
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| 4 hours post-dose |
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| 8 hours post-dose |
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| 12 hours post-dose |
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| 24 hours post-dose |
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| Title | Measurements |
|---|---|
|
| 1 hour post-dose |
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| 1.5 hours post-dose |
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| 2 hours post-dose |
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| 3 hours post-dose |
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| 4 hours post-dose |
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| 8 hours post-dose |
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| 12 hours post-dose |
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| 24 hours post-dose |
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| Title | Measurements |
|---|---|
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| 1 hour post-dose |
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| 1.5 hours post-dose |
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| 2 hours post-dose |
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| 3 hours post-dose |
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| 4 hours post-dose |
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| 8 hours post-dose |
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| 12 hours post-dose |
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| 24 hours post-dose |
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| Title | Measurements |
|---|---|
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| 1 hour post-dose |
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| 1.5 hours post-dose |
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| 2 hours post-dose |
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| 3 hours post-dose |
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| 4 hours post-dose |
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| 8 hours post-dose |
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| 12 hours post-dose |
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| 24 hours post-dose |
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| Title | Measurements |
|---|---|
|
| Increase in ΔQTcF > 30 and ≤ 60 ms |
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| Increase in ΔQTcF > 60 ms |
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| HR < 50 bpm with a decrease in ΔHR > 25% |
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| HR > 100 bpm with an increase in ΔHR > 25% |
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| PR > 200 ms with an increase in ΔPR > 25% |
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| QRS > 120 ms with an increase in ΔQRS > 25% |
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| Title | Measurements |
|---|---|
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| Normal T-wave (-) |
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| Notched T-wave (-) |
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| U-Wave presence |
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| Serious TEAE |
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| TEAE leading to discontinuation |
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| TEAE leading to death |
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| Mild TEAE |
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| Moderate TEAE |
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| Severe TEAE |
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| Treatment-related TEAE |
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| Treatment-related serious TEAE |
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| Treatment-related TEAE leading to discontinuation |
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| Treatment-related TEAE leading to death |
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| Treatment-related mild TEAE |
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| Treatment-related moderate TEAE |
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| Treatment-related severe TEAE |
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| Vital Signs |
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| 12-lead Electrocardiogram |
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| 0.5 hours post-dose |
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| 0.75 hours post-dose |
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| 1 hour post-dose |
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| 1.5 hours post-dose |
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| 2 hours post-dose |
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| 3 hours post-dose |
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| 4 hours post-dose |
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| 8 hours post-dose |
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| 12 hours post-dose |
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| 24 hours post-dose |
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| 0.5 hours post-dose |
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| 0.75 hours post-dose |
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| 1 hour post-dose |
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| 1.5 hours post-dose |
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| 2 hours post-dose |
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| 3 hours post-dose |
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| 4 hours post-dose |
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| 8 hours post-dose |
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| 12 hours post-dose |
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| 24 hours post-dose |
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| 0.5 hours post-dose |
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| 0.75 hours post-dose |
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| 1 hour post-dose |
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| 1.5 hours post-dose |
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| 2 hours post-dose |
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| 3 hours post-dose |
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| 4 hours post-dose |
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| 8 hours post-dose |
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| 12 hours post-dose |
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| 24 hours post-dose |
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| 0.5 hours post-dose |
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| 0.75 hours post-dose |
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| 1 hour post-dose |
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| 1.5 hours post-dose |
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| 2 hours post-dose |
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| 3 hours post-dose |
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| 4 hours post-dose |
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| 8 hours post-dose |
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