Primary Objective:- to evaluate the effect of treatment with omecamtiv mecarbil (OM) compared with placebo on the time to cardiovascular (CV) death of first HF event, whichever occurs first, in subjects with chronic HF with reduced ejection fraction…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
- composite of time to CV death or first HF event, whichever occurs first
An HF event is defined as the presentation of the subject 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.
Secondary outcome
Secondary Endpoints:
* 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
Background summary
Omecamtiv Mecarbil is a promising new oral therapeutic agent for HFrEF patients
targeting myocardial contractility. Current recommended pharmacological
therapies for chronic HF aim at blocking/controlling the physiological
compensatory mechanism. Therapeutic options to directly improve myocardial
contractility for these patients are lacking.
The early post-discharge period following a HF hospitalization carries
particular high risk for poor clinical outcomes and is known as the *vulnerable
phase* (Greene et al, 2015). To help assess effects of omecamtiv mecarbil
during this period, the study will enroll some subjects that are in the
hospital transitioning from initial treatment to discharge. The total
population in this study allows assessment of omecamtiv mecarbil treatment
effect and safety in a more representative population of chronic HFrEF patients.
Omecamtiv mecarbil is a novel small molecule classified as a cardiac myosin
activator that increases cardiac contractility by selectively and directly
activating the enzymatic domain of the cardiac myosin heavy chain, the
force-generating motor protein of the cardiac sarcomere, without increasing
cardiac myocyte intracellular calcium (Teerlink et al, 2011; Malik et al,
2011). Omecamtiv Mecarbil increases the left ventricular systolic ejection time
(SET) without changing the velocity of contraction (dP/dt) or increasing the
heart rate.
The salutary effects of omecamtiv mecarbil were achieved without noticeable
effect upon myocardial oxygen uptake, blood pressure, or coronary blood flow
(Shen et al, 2010; Malik et al, 2011).
Study objective
Primary Objective:
- to evaluate the effect of treatment with omecamtiv mecarbil (OM) compared
with placebo on the time to cardiovascular (CV) death of first HF event,
whichever occurs first, in subjects with chronic HF with reduced ejection
fraction (HFrEF) receiving standard of care (SoC) therapy
Secondary Objectives:
- 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)
Safety Objective:
- to evaluate the safety of OM as measured by subject incidence of reported
adverse events, including serious adverse events of ventricular arrhythmias
requiring treatment and positively adjudicated major cardiac ischemic events
(fatal and nonfatal myocardial infarction, unstable angina hospitalization, and
coronary revascularization) (Hicks et al, 2015)
Study design
This is a randomized, placebo-controlled, double-blind, parallel group,
multicenter, CV outcomes study for oral omecamtiv mecarbil in subjects with
HFrEF, including subjects with ongoing or history of HF hospitalization.
Approximately 8000 eligible subjects will be randomized in a 1:1 ratio to
receive either omecamtiv mecarbil or placebo.
Randomization will be stratified by randomization setting (currently
hospitalized for HF or recently and not currently hospitalized for HF) and
region (5 strata: US and Canada; Latin America; Western Europe, South Africa,
and Australasia; Eastern Europe including Russia; Asia).
Approximately 25% or more of the total planned enrollment will include subjects
who are hospitalized at randomization. Enrollment of subjects with atrial
fibrillation will be limited to 20% of each enrollment setting.
The study is event-driven and will conclude when approximately 1590 CV death
events have occured.
The primary hypothesis is that when added to Standard of Care, omecamtiv
mecarbil is well tolerated and superior to placebo in reducing the risk of CV
death or HF events in subjects with chronic heartfailure (Outcome study).
Intervention
50% of the patients will be randomized to omecamtiv mecarbil, 50% to placebo
(1:1 ratio).
Omecamtiv mecarbil (OM) or placebo will be administered orally twice a day
(BID) in the morning and evening and can be taken under fasted or fed
conditions. Subjects randomized to OM will initiate administration at 25 mg
BID. At study visit Week 2 (steady-state for initial dose), a blood sample will
be collected from all subjects to determine pharmacokinetic (PK) predose level.
The results will be blinded to investigators.
For subjects randomized to OM, the predose plasma concentration at Week 2 will
guide the dose adjustment at Week 4 as follows:
* Subjects with plasma concentration < 200 ng/mL will start administration of
50 mg BID.
* Subjects with plasma concentration * 200 and < 300 ng/mL will start
administration of 37.5 mg BID.
* Subjects with plasma concentration * 300 and < 1000 ng/mL will maintain the
administration of 25 mg BID.
* Subjects with plasma concentration * 1000 ng/mL will start administration of
placebo BID.
* At study visit Week 6, a predose plasma concentration will be collected from
all subjects to confirm plasma concentration achieved while subjects are
receiving their targeted dose and assess if potential changes to the dose
should be made. The results will be blinded to investigators.
* A new investigational product supply will be provided to all subjects at the
Week 4 and Week 8 study visits regardless of randomized treatment group and
outcome of the PK assessment in order to maintain the blind.
Further tests/procedures (as stated in the 'Schedule of Assessments' (page
38-40 of the protocol):
- Medical/Surgical History: 1 time during screening
- Vital Signs, Weight: 1 time during screening, thereafter at each visit and 1
time at End of Study
- Reporting side (adverse) effects: continuously
- Placebo run-in: 1 time during screening
- Dosing instructions: day 1, week 4, week 8, week 12, week 24, week 36, week
48 en after week 48 every 16 weeks
- Compliance assessment: week 2, week 6, week 24, week 48, week 96
- ECG: 1 time at day 1, 1 time at week 48, 1 time at week 96, 1 time at End of
Study
- Physical Examination: 1 time during screening, 1 time at End of Study
- Pregnancy Exam: 1 time during screening
- Blood tests: during screening, at day 1, week 2, week 6, week 24, week 48,
week 96 and at End of Study
- Urinalysis: 1 time at day 1, 1 time at End of Study
- Biomarker Discovery/Future Research: at day 1, week 6, week 24 and at End of
Study
- Omecamtiv mecarbil level test: week 2, week 6, week 24, week 48, week 96
- Patient reported outcomes: as of day 1 at each visit till (incl.) End of Study
- Omecamtiv mecarbil dispensation and tablet count: at day 1 (dispensation
only), week 4, week 8 and week 12, thereafter at each visit till (incl.) End of
Study (only tablet count)
Study burden and risks
Please see question E9 for risks associated with participation.
Please see question E2 with regard to extent of the burden as well as
'intervention' in section K2.
Minervum 7061
Breda 4817 ZK
NL
Minervum 7061
Breda 4817 ZK
NL
Listed location countries
Age
Inclusion criteria
- Subject has provided informed consent
- Male or female, * 18 to * 85 years of age
- History of chronic HF
- LVEF * 35%
- NYHA class II to IV
- Managed with HF SoC therapies consistent with regional clinical practice
guidelines
- Current hospitalization with primary reason of HF or prior HF
hospitalization, or urgent HF admission to emergency department (ED) within 1
year prior to screening
- BNP level * 125 pg/mL or an NT-proBNP level * 400 pg/mL at most recent
screening assessment (for subjects with atrial fibrillation, the cut off levels
are: BNP * 375 pg/mL or NT proBNP * 1200 pg/mL)
Exclusion criteria
- Inability to swallow study medication tablet
- Receiving mechanical hemodynamic support or mechanical ventilation * 7 days
prior to randomization
- Receiving IV inotropes or IV vasopressors * 3 days prior to randomization
- Receiving IV diuretics or IV vasodilators, or supplemental oxygen therapy *
12 hours prior to randomization
- Acute coronary syndrome, stroke, or transient ischemic attack, major cardiac
surgery, percutaneous coronary intervention, or valvuloplasty within the 3
months prior to randomization
- Severe uncorrected valvular heart disease, or hypertrophic obstructive
cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically
significant congenital heart disease
- Routinely scheduled outpatient intravenous infusions for HF (eg, inotropes,
vasodilators, diuretics) or routinely scheduled ultrafiltration
- Systolic blood pressure > 140 mmHg or < 85 mmHg, or diastolic blood pressure
> 90 mmHg, or heart rate > 110 beats per minute, or < 50 beats per minute at
screening
- Estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-002299-28-NL |
| ClinicalTrials.gov | NCT02929329 |
| CCMO | NL58631.028.16 |