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 exercise capacity as determined by CPET following 20 weeks of treatment with omecamtiv mecarbil or placebo |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of treatment with omecamtiv mecarbil compared with placebo on daily activity as determined by accelerometry |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal exclusion criteria |
● 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. ● 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in peak VO2 on CPET from baseline to Week 20 |
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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) |
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 (Week -2 to Day 1) to Week 18-20 |
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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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 51 |
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 |
Canada |
France |
Germany |
Hungary |
Italy |
Netherlands |
Poland |
Sweden |
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 (EOS) is when the last subject has completed the EOS assessments (i.e., last subject last visit). If the study concludes prior to the time point originally planned in the protocol (i.e., early termination of the study), then the EOS will be the date when the last subject is assessed or receives an intervention for evaluation in the study. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |