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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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^
- •Willing to maintain current general diet and physical activity regimen.
排除标准
- •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.
- •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.
研究组 & 干预措施
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.
干预措施: Omecamtiv Mecarbil (OM) (Drug)
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.
干预措施: Omecamtiv Mecarbil (OM) (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: Moxifloxacin (Drug)
结局指标
主要结局
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
时间窗: Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose
Continuous 12-lead digital ECG recording was performed on day 1 of each period. ECGs were analyzed by a blinded, central reader. At each specified timepoint, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that timepoint. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Change from baseline (ΔQTcF) was calculated based on a linear mixed-effects model with period, sequence, time (categorical), treatment, and time-by-treatment interaction as fixed effects and baseline QTcF as covariate. Placebo-corrected ΔQTcF (ΔΔQTcF) was calculated as the adjusted mean ΔQTcF after OM dosing minus adjusted mean ΔQTcF after placebo. If the upper bound of the confidence interval of ΔΔQTcF was \< 10 ms for all post-dose time points, OM was to be concluded to not have a significant effect on QT interval prolongation.
次要结局
- 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 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.)
- Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS After Omecamtiv Mecarbil Dosing in Part B(Day 1 of the OM treatment period at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.)
- Maximum Observed Plasma Concentration (Cmax) of Omecamtiv Mecarbil in Part B(Day 1 of the OM treatment period at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-dose.)
- Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B(Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.)
- 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.)
- Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B(Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.)
- Number of Participants With Treatment-emergent Changes in T-wave Morphology and U-wave Presence After Omecamtiv Mecarbil Dosing in Part B(Day 1 of the OM treatment period at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs)(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(From first dose up to day 6 of each treatment period)
- 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 Heart Rate After Omecamtiv Mecarbil Dosing in Part B(Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.)
- 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.)
- Placebo-corrected Change From Baseline in QT Interval Corrected for Heart Rate Based on the Fridericia Method (QTcF) After Moxifloxacin Dosing in Part B(Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the moxifloxacin treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.)
- Change From Baseline in Heart Rate After Omecamtiv Mecarbil Dosing in Part B(Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.)
- Change From Baseline in QTcF After Omecamtiv Mecarbil Dosing in Part B(Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.)
- Slope of Omecamtiv Mecarbil Plasma Concentration Estimated From Concentration-QTc Analysis in Part B(Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.)
- Placebo-corrected Change From Baseline in PR Interval After Omecamtiv Mecarbil Dosing in Part B(Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.)
- Placebo-corrected Change From Baseline in QRS After Omecamtiv Mecarbil Dosing in Part B(Baseline (average of samples taken at -1.25, -1, and -0.75 hours predose on day 1 of the OM treatment period) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12, and 24 hours post-dose.)