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

Cytokinetics

Status and phase: Completed; Phase 1

Conditions: QTc Intervals Changes; QT Intervals Changes

Treatments: Drug: Omecamtiv Mecarbil (OM); Drug: Placebo; Drug: Moxifloxacin

Study type: Interventional

Funder types: Industry

Identifiers

NCT04175808

2018-003157-19 (EudraCT Number)

20090231

Details and patient eligibility

About

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.

Full 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.

Enrollment: 70 patients

Sex: All

Ages: 18 to 50 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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70 participants in 2 patient groups

Part A

Experimental group

Description:

After an overnight fast of at least 10 hours participants received a single oral dose of 25 mg omecamtiv mecarbil on Day 1.

Treatment:

Drug: Omecamtiv Mecarbil (OM)

Part B

Experimental group

Description:

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.

Treatment:

Drug: Moxifloxacin

Drug: Placebo

Drug: Omecamtiv Mecarbil (OM)