E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Heart Failure With Reduced Ejection Fraction |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008908 |
E.1.2 | Term | Chronic heart failure |
E.1.2 | System Organ Class | 100000004849 |
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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 |
To evaluate the effect of treatment with omecamtiv mecarbil compared with placebo on the time to cardiovascular (CV) death or first HF event, whichever occurs first, in subjects with chronic HF with reduced ejection fraction (HFrEF) receiving standard of care (SoC) therapy.
An HF event is defined as presentation of the patient for an urgent, unscheduled clinic/office/ED visit, or hospital admission, with a primary diagnosis of HF, where the patient exhibits new or worsening symptoms of HF on presentation, has objective evidence of new or worsening HF, and receives initiation or intensification of treatment specifically for HF (Hicks et al, 2015). Changes to oral diuretic therapy do not qualify as initiation or intensification of treatment. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effects of OM on time to:
- CV death
- HF hospitalization
- all-cause death
To evaluate the effects of treatment with OM on change in patient-reported outcomes (PROs). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subject has provided informed consent
Male or female, ≥ 18 to ≤ 85 years of age at signing of informed consent
History of chronic HF (defined as requiring treatment for HF for a minimum of 30 days before randomization)
LVEF ≤ 35%, per subject's most recent medical record, within 12 months prior to screening. The most recent qualifying LVEF must be at least 30
days after any of the following, if applicable: 1) an event likely to decrease EF (eg, myocardial infarction, sepsis); 2) an intervention likely to increase EF
(eg, cardiac resynchronization therapy, coronary revascularization); or 3) the first ever presentation for HF.
NYHA class II to IV at most recent screening assessment
Managed with HF SoC therapies consistent with regional clinical practice guidelines according to investigator judgment of subject's clinical status Oral SoC therapies for chronic HF (eg, beta blockers, renin-angiotensin- aldosterone system inhibitors) should be present, if not contraindicated. Subjects enrolled during either HF hospitalization or early after HF hospitalization discharge can be reinitiating or titrating oral SoC chronic HF therapies at the
same time of randomization with the goal of achieving optimized therapy on study.
Currently hospitalized with primary reason of HF OR one of the following events within 1 year to screening: 1) hospitalization with primary reason of
HF; 2) urgent visit to ED with primary reason of HF B-type natriuretic peptide (BNP) level ≥ 125 pg/mL or an NT-proBNP level ≥ 400 pg/mL at most recent screening assessment (subjects receiving angiotensin receptor-neprilysin inhibitor [ARNi] must use NT-proBNP assessment; for subjects in
atrial fibrillation/flutter at screening, the cut off levels are: BNP ≥ 375 pg/mL or NT-proBNP ≥ 1200 pg/mL)
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E.4 | Principal exclusion criteria |
Factors expected to interfere with the subject's availability or ability to complete all protocol-required study visits or procedures, and/or to comply with
all required study procedures to the best of the subject and investigator's knowledge (including ongoing substance abuse).
Inability to swallow study medication tablet (eg, swallowing disorders, feeding tubes)
Receiving mechanical hemodynamic support (eg, intra-aortic balloon pump counterpulsation), or invasive mechanical ventilation ≤ 7 days prior to
randomization
Receiving IV inotropes (eg, dobutamine, milrinone, levosimendan) or IV vasopressors (eg, epinephrine, norepinephrine, dopamine, or vasopressin)
≤ 3 days prior to randomization
Receiving IV diuretics or IV vasodilators, supplemental oxygen therapy, or non-invasive mechanical ventilation (eg, bilevel positive airway pressure
[BiPAP] or continuous positive airway pressure [CPAP] ≤ 12 hours prior to randomization (Note: the use of non-invasive ventilation for sleep
disordered breathing is permitted)
Acute coronary syndrome (ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, unstable angina), stroke, or transient
ischemic attack, major cardiac surgery or cardiac intervention (ie, implantation of cardiac closure devices, cardiac resynchronization therapy, or catheter ablation), percutaneous coronary intervention, or valvuloplasty/other cardiac valve repair or implantation within the 3
months prior to randomization
Insertion of other cardiac devices (eg, implantable cardioverter defibrillator, permanent pacemaker, monitoring devices) within 30 days prior to
randomization
Severe uncorrected valvular heart disease, hypertrophic or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically
significant congenital heart disease |
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E.5 End points |
E.5.1 | Primary end point(s) |
Composite of time to CV death or first HF event, whichever occurs first. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Time to CV death.
Change in Kansas City Cardiomyopathy Questionnaire Total Symptoms Score (KCCQ TSS) from baseline to Week 24.
Time to first HF hospitalization.
Time to all-cause death. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
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 | 2 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 322 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Bulgaria |
Canada |
Chile |
China |
Colombia |
Czech Republic |
Denmark |
France |
Germany |
Greece |
Hungary |
Italy |
Japan |
Mexico |
Netherlands |
New Zealand |
Poland |
Portugal |
Romania |
Russian Federation |
Slovakia |
South Africa |
Spain |
Sweden |
Switzerland |
Turkey |
Ukraine |
United Kingdom |
United States |
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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
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The end of study is when the last subject has completed the end of study assessments. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |