E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Heart Failure and Left Ventricular Systolic Dysfunction |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063083 |
E.1.2 | Term | Chronic left ventricular failure |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
(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. |
|
E.2.2 | Secondary objectives of the trial |
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 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 (≥ 23.60 pmol/L) [≥ 1200 pg/mL (≥ 141.60 pmol/L) 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) |
|
E.4 | Principal 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 Acute myocardial infarction, 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 diastolic BP > 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 two acceptable methods of effective birth control or abstinence or surgical contraceptive methods (vasectomy or bilateral tubal ligation) 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
- A female is considered of chilbearing potential unless she has had a hysterectomy, bilateral oophorectomy, or bilateral salpingectomy or she is postmenopausal. menopause is defined as ≥ 12 months of spontaneous and continous amenorrhea in a female ≥ 55 years old; or 12 months of spontaneous and continous amenorrhea with a follicle-stimulating hormone level > 40 IU/L (or according to the definition of "postmenopausal range" for the laboratory involved) in a female < 55 years old; or no spontaneous menses for at least 2 years in a female < 55 years old.
- Two acceptable methods of effective birth control include the following 2 options:
use of hormonal and barrier combination birth control methods (intrauterine device and barrier method with spermicide, intrauterine device and hormonal birth control method, hormonal birth control method and barrier method with spermicide),
two (2) barrier methods (each partner must use one barrier method exceprt a female condom) with at least one of the barrier methods including spermicide. Hormonal methods of birth control include pills, shots/injections, implants, and patches. barrier methods of birth control include diaphragm with spermicide, cervical cap with spermicide, male or female condom with spermicide, and contraceptive sponge with spermicide.
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) |
|
E.5 End points |
E.5.1 | 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 |
|
E.5.1.1 | 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 with chronic oral BID dosing |
|
E.5.2 | Secondary end point(s) |
Expansion phase only:
changes from baseline in SET, stroke volume, LVESD, LVEDD, and HR
change from baseline in NT-proBNP |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Trial has two phases: a dose escalation phase and an enrollment |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 57 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Bulgaria |
Canada |
Czech Republic |
Germany |
Hungary |
Italy |
Lithuania |
Netherlands |
Poland |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |