Study to Assess the Effect of Omecamtiv Mecarbil on Exercise Capacity in Subjects With Heart Failure
Condition: Heart Failure With Reduced Ejection Fraction
MeSH terms: Heart Failure
Intervention: Omecamtiv Mecarbil; Placebo
Intervention description: Oral omecamtiv mecarbil twice daily for up to 20 weeks with dose level determined by periodic blood testing; Oral placebo twice daily for up to 20 weeks
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 276.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the effect of treatment with omecamtiv mecarbil
      compared with placebo on exercise capacity as determined by cardiopulmonary exercise testing
      following 20 weeks of treatment with omecamtiv mecarbil or placebo
    

Eligibility criteria:

        Inclusion Criteria

          -  Male or female, greater than or equal to 18 to lesser than or equal 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

          -  New York Heart Association (NYHA) class II or III at screening

          -  Left ventricular ejection fraction less than or equal to 35%

          -  On maximally tolerated HF standard of care (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.

          -  N-terminal (NT)-proBNP level greater than or equal to 200 pg/mL

          -  Peak VO2 less than or equal to 75% of the predicted normal value with respiratory
             exchange ratio (RER) greater than or equal to 1.05 on a screening CPET, confirmed by a
             CPET core laboratory

        Exclusion Criteria

          -  Severe uncorrected valvular heart disease

          -  Paroxysmal atrial fibrillation or flutter documented within the previous 6 months,
             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.

          -  History of gastrointestinal bleeding requiring hospitalization, urgent procedure or
             transfusion in the prior year, or received intravenous (IV) iron, blood transfusion,
             or an erythropoiesis-stimulating agent (ESA) within 3 months prior to screening, or
             planned blood transfusion or ESA use during the study screening or treatment period.
             Chronic, stable use of oral iron is permitted.

          -  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 greater than 140 mmHg or less than 85 mmHg, or
             diastolic BP greater than 90 mmHg (mean of triplicate readings); Resting heart rate
             greater than 90 beats per minute, or less than 50 beats per minute (mean of triplicate
             readings); Estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73m2 (by
             the modified Modification of Diet in Renal Disease equation); Hepatic impairment
             defined by a total bilirubin (TBL) greater than or equal to 2 times the upper limit of
             normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
             greater than or equal to 3 times ULN. Patients with documented Gilbert syndrome and
             TBL greater than or equal to 2 times ULN due to unconjugated hyperbilirubinemia,
             without other hepatic impairment, are permitted.

          -  Room air oxygen saturation under 90% at screening

          -  Hemoglobin less than 10.0 g/dL at screening

          -  Significant adverse finding (e.g., exercise-induced early ischemic changes, abnormal
             decrease in BP [systolic BP falls by more than 10 mmHg], unexpected arrhythmia or
             other serious finding) during CPET at screening that precludes safe participation in
             the study, per investigator

          -  Chronotropic incompetence (including inadequate pacemaker rate response) during CPET
             at screening, defined as a maximum heart rate <60% of the maximum predicted heart rate