Chronic Heart Failure and Left Ventricular Systolic Dysfunction MedDRA version: 16.1 Level: PT Classification code 10063083 Term: Chronic left ventricular failure System Organ Class: 10007541 - Cardiac disorders
Conditions
Interventions
Product Name: omecamtiv mecarbil
Product Code: AMG423
Pharmaceutical Form: Modified-release tablet
INN or Proposed INN: omecamtiv mecarbil
CAS Number: 873697-71-3
Current Sponsor code: AMG423 Matrix F
Sponsors
Amgen Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Dose Escalation Cohorts: 4.1.1 Subject has provided informed consent. 4.1.2 Male or female = 18 years and = 85 years of age at the time of informed consent. 4.1.3 History of chronic HF, defined as requiring treatment for HF for a minimum of 4 weeks prior to screening. 4.1.4 Treated for HF with stable, optimal pharmacological therapy. In general, optimal treatment will include a beta-blocker and an ACE inhibitor and/or an angiotensin receptor blocker at doses shown to be efficacious in HF trials, unless not tolerated. Stable medical therapy is defined as having no new HF drug class introduced or uptitrated = 4 weeks prior to randomization. 4.1.5 LVEF = 40% (echocardiogram, radionuclide ventriculography, cardiac magnetic resonance imaging, or contrast ventriculography) within 18 months prior to randomization and without an intervening value of > 40%. 4.1.6 NT-proBNP = 200 pg/mL (= 1200 pg/mL if the subject has atrial fibrillation at presentation) at screening; (Note: enrollment of subjects with atrial fibrillation will be limited to up to approximately 20% of planned enrollment in each cohort). Expansion Phase: 4.1.7 Subject has provided informed consent. 4.1.8 Male or female = 18 years and = 85 years of age at the time of informed consent. 4.1.9 History of chronic HF, defined as requiring treatment for HF for a minimum of 4 weeks prior to screening. 4.1.10 Treated for HF with stable, optimal pharmacological therapy. In general, optimal treatment will include a beta-blocker and an ACE inhibitor and/or an angiotensin receptor blocker at doses shown to be efficacious in HF trials, unless not tolerated. Stable medical therapy is defined as having no new HF drug class introduced or uptitrated = 4 weeks prior to randomization. 4.1.11 NYHA class II or III symptoms. 4.1.12 LVEF = 40% by centrally read screening echocardiogram. 4.1.13 Acceptable echocardiographic image quality of screening echocardiogram per central echo core laboratory 4.1.14 NT-proBNP = 200 pg/mL (= 1200 pg/mL if the subject has atrial fibrillation at presentation) at screening; (Note: enrollment of subjects with atrial fibrillation will be limited to up to approximately 20% of planned cohort enrollment). Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 280 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 290
Exclusion criteria
Exclusion criteria: Dose Escalation Cohorts and Expansion Phase: 4.2.1 Cardiac resynchronization therapy (CRT) or ICD implantation within 30 days prior to enrollment. 4.2.2 NYHA class IV. 4.2.3 Hospitalization for any reason within 30 days prior to randomization. 4.2.4 Likely to receive within 3 months after randomization, in the opinion of the Investigator, planned revascularization, implantation of ICD or CRT, ventricular assist device, continuous or intermittent inotropic therapy, hospice care, or cardiac transplant. 4.2.5 Severe uncorrected valvular heart disease. 4.2.6 Hypertrophic obstructive cardiomyopathy, active myocarditis, or constrictive pericarditis, or clinically significant congenital heart disease. 4.2.7 Unstable angina or persistent angina at rest within 30 days prior to randomization . 4.2.8 Chronic antiarrhythmic therapy, with the exception of amiodarone. 4.2.9 Routinely scheduled outpatient IV infusions for HF (eg, inotropes, vasodilators [eg, nesiritide], diuretics) or routinely scheduled ultrafiltration. 4.2.10 Systolic BP > 160 mm Hg or 90 mm Hg, or HR > 110 beats per minute (bpm) or HR < 50 bpm at screening. 4.2.11 Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at screening. 4.2.12 Currently taking, or has taken within 14 days prior to randomization, a potent CYP3A4 inhibitor. 4.2.13 Currently taking, or has taken within 28 days prior to randomization, a potent CYP3A4 inducer. 4.2.14 Severe, concomitant noncardiovascular disease that is expected to reduce life expectancy to less than 1 year. 4.2.15 Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, renal) or receiving renal replacement therapy by dialysis. 4.2.16 Malignancy within 5 years prior to randomization with the following exceptions: localized basal or squamous cell carcinoma of the skin or cervical intraepithelial neoplasia. 4.2.17 Known untreated hypothyroidism or hyperthyroidism, adrenal insufficiency, active vasculitis due to collagen vascular disease. 4.2.18 Hepatic impairment 4.2.19 Any acute or serious co-morbid condition (eg, major infection or hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction) that, in the judgment of the investigator, could lead to premature termination of study participation or interfere with the measurement of, or the interpretation of, the efficacy and safety assessments in the study 4.2.20 Previously received omecamtiv mecarbil. 4.2.21 Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study. 4.2.22 Recent (within 3 months) history of alcohol or illicit drug abuse based on self-report. 4.2.23 Known sensitivity to any of the products to be administered during dosing. 4.2.24 Female subject of childbearing potential who is not willing to inform her partner of her participation in this clinical study and to use at least an acceptable method of effective birth control during treatment with IP (omecamtiv mecarbil or placebo) and for an additional 5 days after the last dose of IP. Male subject with a female partner of childbearing potential and not willing to inform his partner of his participation in this clinical study. 4.2.25 Female subject is pregnant or breastfeeding or is planning to become pregnant during treatment or within 5 days after the end of treatment. (Full list in protocol)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: (i) to select an oral modified release (MR) formulation and dose of omecamtiv mecarbil for chronic twice daily (BID) dosing in subjects with HF and left ventricular systolic dysfunction and (ii) to characterize its pharmacokinetics (PK) over 20 weeks of treatment.;Secondary Objective: to evaluate the safety and tolerability of oral omecamtiv mecarbil to measure changes in systolic ejection time (SET), stroke volume, left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), and heart rate over 20 weeks of oral dosing with omecamtiv mecarbil to evaluate the effect over 20 weeks of oral dosing with omecamtiv mecarbil on N-terminal pro–B-type natriuretic peptide (NT-proBNP) to evaluate the PK of omecamtiv mecarbil metabolites with oral omecamtiv mecarbil dosing ;Primary end point(s): Dose Escalation Phase: Cmax, time at which Cmax is attained (Tmax), Cmin and AUC12h of omecamtiv mecarbil Expansion Phase: Cmax and concentration prior to investigational product administration (Cpredose) of omecamtiv mecarbil;Timepoint(s) of evaluation of this end point: Dose Escalation Phase: following dose on day 7 Expansion Phase: at weeks 2, 8, 12, 16 and 20 following chronic oral BID dosing | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Expansion phase only: changes from baseline in SET, stroke volume, LVESD, LVEDD, and HR change from baseline in NT-proBNP;Timepoint(s) of evaluation of this end point: At week 20 | — |
Countries
Australia, Belgium, Bulgaria, Canada, Czech Republic, Germany, Hungary, Italy, Lithuania, Netherlands, Poland, United Kingdom, United States
Contacts
Public ContactIHQ Medical Info-Clinical Trials
Amgen (Europe) GmbH
Outcome results
None listed