Primary Objective:* To evaluate the effect of treatment with omecamtiv mecarbil (OM) compared with placebo on exercise capacity as determined by cardiopulmonary exercise testing (CPET) following 20 weeks of treatment with OM or placeboSecondary…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The Primary Endpoint is change in peak oxygen uptake (pVO2) on CPET from
baseline to Week 20.
Secondary outcome
Secondary Endpoints:
* Change in total workload during CPET from baseline to Week 20
* Change in ventilatory efficiency (VE/VCO2 slope) during CPET from baseline to
Week 20
* Change in the average daily activity units measured over a 2-week period from
baseline to Week 18-20
Exploratory Endpoints:
* Change from baseline to Week 20 in oxygen uptake efficiency slope (VO2/logVE
slope), ventilatory threshold (by the V-slope method), VO2 recovery kinetics,
percent predicted pVO2, circulatory power (VO2 × systolic blood pressure [BP]),
and exercise duration
* Change from baseline in the average daily activity units at Week 6-8 and at
Week 12-14
* Change from baseline in the KCCQ Total Symptom Score and its sub-domains from
baseline to Week 20
Safety Endpoint:
* Subject incidence of reported adverse events and serious adverse events.
Background summary
Heart failure (HF) affects over 26 million people worldwide, with more than 3.5
million people newly diagnosed every year, and is a final pathway for many
diseases that affect the heart (Hilfiker-Kleiner et al, 2006). Symptoms of
dyspnea, fatigue, increased need to rest, low energy, and difficulty in walking
or climbing, correlate with lower quality of life and higher mortality risk
(Heo, 2008; Flynn, 2009; Malhotra, 2016; Swank, 2012).
Exercise intolerance, typically manifest by dyspnea and fatigue on exertion, is
the predominant chronic symptom of HF and often the first symptom that prompts
patients to seek medical care. Assessment of exercise capacity in daily life is
widely used to classify the severity of HF, for example the New York Heart
Association (NYHA) functional classification and the Canadian Cardiovascular
Society functional classification. These assessments are highly prognostic of
long-term outcomes. Even small improvements in exercise capacity as measured by
CPET correlate with improved survival (Swank, 2012).
Few therapies have demonstrated improvements in exercise capacity. Currently,
only angiotensin-converting-enzyme inhibitors (ACEis) have product labels that
describe a positive effect on exercise capacity in patients with HFrEF.
This study will test the hypothesis that improving cardiac function with the
cardiac myosin activator, OM, a drug therapy that directly increases myocardial
contractility, will improve exercise tolerance.
Study objective
Primary Objective:
* To evaluate the effect of treatment with omecamtiv mecarbil (OM) compared
with placebo on exercise capacity as determined by cardiopulmonary exercise
testing (CPET) following 20 weeks of treatment with OM or placebo
Secondary Objective:
* To evaluate the effect of treatment with OM compared with placebo on daily
activity as determined by accelerometry
Exploratory Objective:
* To evaluate the relationships between exercise capacity (determined by CPET),
daily activity (determined by accelerometry), and symptoms (determined by
Kansas City Cardiomyopathy Questionnaire [KCCQ])
Safety Objective:
* To evaluate the safety and tolerability of OM compared with placebo, as
measured by subject incidence of reported adverse events
Study design
This is a randomized, placebo-controlled, double-blind, parallel group,
multicenter study in subjects with heart failure with reduced ejection fraction
(HFrEF). Approximately 270 eligible subjects will be randomized in a 2:1 ratio
to receive either Omecamtiv Mecarbil or placebo, respectively. Randomization
will be stratified based on the respiratory exchange ratio (RER) on the
baseline CPET (<1.15, *1.15) and persistent atrial fibrillation at screening
(Y/N). The number of patients with persistent atrial fibrillation at screening
will be capped at approximately 20% and patients with paroxysmal atrial
fibrillation will be excluded.
In instances where a subject cannot complete the Week 20 CPET as planned due to
COVID-19, those subjects may continue on IP until the visit can be completed
for up to an additional 12 weeks (total of up to 32 weeks on IP), and only
after approval from the medical monitor. Additionally, the investigator should
attempt to complete the Week 20 visit with the CPET as close as safely possible
to the originally planned date.
Intervention
Investigational product will be started at 25 mg orally (PO) twice a day (BID),
titrated based on the Week 2 and Week 6 predose plasma concentrations to doses
of 25, 37.5, or 50 mg BID and continued for a total of 20 weeks. All subjects
will be managed with standard of care HF therapies consistent with regional
clinical practice guidelines.
Study burden and risks
Subjects will need to visit the hospital 10 times over a period of 26-42 weeks
and will be called for phone follow up three times during this period.
Procedures will include physical exams (3x), recording of vital signs (9x) and
weight (5x), ECG (6x), echocardiogram (1x, if needed), cardiopulmonary exercise
test (2x) and collection of blood (8x) and urine (1x) samples. Subjects will be
asked to complete a questionnaire during 4 visits. During the study will be
asked to wear an Actigraph watch for periods of 2 weeks at a time (4x) to
measure their level of daily activity. If the amount of Omecamtiv Mecarbil (OM)
in the blood reaches a very high level, subjects may develop symptoms of
decreased blood supply to the heart (myocardial ischemia) or heart attack
(myocardial infarction). The side effects of using OM in combination with other
drugs are unknown.
East Grand Avenue 280
South San Francisco CA 94080
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East Grand Avenue 280
South San Francisco CA 94080
US
Listed location countries
Age
Inclusion criteria
* Male or female, * 18 to * 85 years of age
* History of chronic HF, defined as requiring continuous treatment with
medications for HF for a minimum of 3 months before screening
* NYHA class II or III at screening
* Left ventricular ejection fraction * 35%
* On maximally tolerated HF SoC therapies consistent with regional clinical
practice guidelines, if not contraindicated and according to investigator
judgment of the subject*s clinical status. Beta blocker dose must be stable for
30 days prior to randomization.
* NT-proBNP level * 200 pg/mL
* Peak VO2 * 75% of the predicted normal value with RER * 1.05 on a screening
CPET, confirmed by a CPET core laboratory
Exclusion criteria
* Paroxysmal atrial fibrillation or flutter documented within the previous 6
months and requiring treatment, direct-current (DC) cardioversion or ablation
procedure for atrial fibrillation within 6 months, or plan to attempt to
restore sinus rhythm within 6 months of randomization. Subjects with persistent
atrial fibrillation and no sinus rhythm documented in the prior 6 months are
permitted.
* Symptomatic bradycardia, second-degree Mobitz type II, or third-degree heart
block without a pacemaker.
* Ongoing or planned enrollment in cardiac rehabilitation.
* Requires assistance to walk or use of mobility assistive devices such as
motorized devices, wheelchairs, or walkers. The use of canes for stability
while ambulating is acceptable if the subject is deemed capable of performing
CPET.
* Major medical event or procedure within 3 months prior to randomization,
including: hospitalization, surgery, renal replacement therapy or cardiac
procedure. This includes episodes of decompensated HF that require IV HF
treatment.
* At screening: Resting systolic BP > 140 mmHg or < 85 mmHg, or diastolic BP >
90 mmHg (mean of triplicate readings); Resting heart rate > 90 beats per
minute, or < 50 beats per minute (mean of triplicate readings); Room air oxygen
saturation < 90%; Hemoglobin <10.0 g/dL; Estimated glomerular filtration rate
(eGFR) < 30 mL/min/1.73m2 (by the modified Modification of Diet in Renal
Disease equation); Hepatic impairment defined by a total bilirubin (TBL) * 2 ×
the upper limit of normal (ULN), or alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) * 3 × ULN. Patients with documented Gilbert syndrome and
TBL * 2 × ULN due to unconjugated hyperbilirubinemia, without other hepatic
impairment, are permitted.
* Significant adverse finding during CPET at screening that precludes safe
participation in the study, per investigator
* Male subject with a female partner of childbearing potential and not willing
to inform his partner of his participation in this clinical study.
* Female subject is pregnant or breastfeeding or is planning to become pregnant
or planning to breastfeed during treatment with investigational product (IP; OM
or placebo) or within 5 days after the end of treatment with IP.
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 | EUCTRTBC-NL |
| ClinicalTrials.gov | NCT03759392 |
| CCMO | NL67921.100.18 |