| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of chronic heart failure with reduced ejection fraction (HFrEF) |
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| E.1.1.1 | Medical condition in easily understood language |
| Treatment of chronic heart failure with reduced ejection fraction (HFrEF) |
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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 efficacy of the oral soluble guanylate cyclase (sGC) stimulator MK-1242 (vericiguat) in comparison to placebo on a background of standard of care in increasing the time to first occurrence of the composite of CV death or HF hospitalization in subjects with HFrEF. |
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| E.2.2 | Secondary objectives of the trial |
In subjects with HFrEF on a background of standard of care:
(1) To evaluate the efficacy of MK-1242 (vericiguat) in increasing the time to CV death in comparison to placebo.
(2) To evaluate the efficacy of MK-1242 (vericiguat) in increasing the time to first HF hospitalization in comparison to placebo.
(3) To evaluate the efficacy of MK-1242 (vericiguat) in increasing the time to total HF hospitalizations (first and recurrent) in comparison to placebo.
(4) To evaluate the efficacy of MK-1242 (vericiguat) in increasing the time to the first occurrence of the composite of all-cause mortality or HF hospitalization in comparison to placebo.
(5) To evaluate the efficacy of MK-1242 (vericiguat) in increasing the time to all-cause mortality in comparison to placebo.
(6) To evaluate the safety and tolerability of MK-1242 (vericiguat).
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
There will also be a separate imaging sub-study involving echocardiography and cardiovascular magnetic resonance (CMR), at participating sites. Consenting patients will participate, however participation in the imaging sub-studies is optional and does not impact participation in the main study. The imaging sub-study will be subject to a separate informed consent and ancillary document. |
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| E.3 | Principal inclusion criteria |
In order to be eligible for participation in this trial, the subject must:
1. Provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
2. Be male or female, aged 18 years or older on the day of signing informed consent.
3. Have a history of chronic HF (NYHA class II-IV) on standard therapy before qualifying HF decompensation.
4. Have a previous HF hospitalization within 6 months prior to randomization or IV diuretic treatment for HF (without hospitalization) within 3 months prior to randomization.
5. Have brain natriuretic peptide (BNP) or NT-proBNP levels within 30 days prior to randomization as follows:
NT-proBNP BNP
Sinus Rhythm > or = 1000 pg/mL > or = 300 pg/mL
Atrial Fibrillation > or = 1600 pg/mL > or = 500 pg/mL
6. Have a left ventricular ejection fraction (LVEF) of <45% assessed within 12 months prior to randomization by any method (most recent measurement must be used to determine eligibility).
7. Meet one of the following criteria:
a) The subject is a male.
b) The subject is a female who is not of reproductive potential, or who is of reproductive potential and agrees to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug, by complying with acceptable methods of contraception.
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| E.4 | Principal exclusion criteria |
The subject must be excluded from participating in the trial if the subject:
1. Is clinically unstable at the time of randomization as defined by:
a. Administration of any intravenous treatment within 24 hours prior to randomization, and/or
b. Systolic blood pressure (SBP) <100 mmHg or symptomatic hypotension.
2. Has concurrent or anticipated use of long-acting nitrates or NO donors including isosorbide dinitrate, isosorbide 5-mononitrate, pentaerythritol tetranitrate, nicorandil or transdermal nitroglycerin (NTG) patch, and molsidomine.
3. Has concurrent use or anticipated use of phosphodiesterase type 5 (PDE5) inhibitors such as vardenafil, tadalafil, and sildenafil.
4. Has concurrent use or anticipated use of a sGC stimulator such as riociguat.
5. Has known allergy or sensitivity to any sGC stimulator.
6. Is awaiting heart transplantation (United Network for Organ Sharing Class 1A / 1B or equivalent), receiving continuous IV infusion of an inotrope, or has/anticipates receiving an implanted ventricular assist device.
Cardiac Comorbidity
7. Has primary valvular heart disease requiring surgery or intervention, or is within 3 months after valvular surgery or intervention.
8. Has hypertrophic obstructive cardiomyopathy.
9. Has acute myocarditis, amyloidosis, sarcoidosis, Takotsubo cardiomyopathy.
10. Has post-heart transplant cardiomyopathy.
11. Has tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia.
12. Has acute coronary syndrome (unstable angina, non-ST elevation myocardial infarction [NSTEMI], or ST elevation myocardial infarction [STEMI]) or coronary revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI]) within 60 days prior to randomization, or indication for coronary revascularization at time of randomization.
13. Has symptomatic carotid stenosis, transient ischemic attack (TIA) or stroke within 60 days prior to randomization.
14. Has complex congenital heart disease.
15. Has active endocarditis or constrictive pericarditis.
Non-cardiac comorbidity
16. Has an estimated glomerular filtration rate (eGFR) calculated based on the Modification of Diet in Renal Disease (MDRD) equation <15 mL/min/1.73 m2 or chronic dialysis.
17. Has severe hepatic insufficiency such as with hepatic encephalopathy.
18. Has malignancy or other non-cardiac condition limiting life expectancy to <3 years.
19. Requires continuous home oxygen for severe pulmonary disease.
20. Has current alcohol and/or drug abuse.
21. Has participated in another interventional clinical study and treatment with another investigational product ≤30 days prior to randomization or plans to participate in any other trial/investigation during the duration of this study.
22. Has a mental or legal incapacitation and is unable to provide informed consent.
23. Has a medical disorder, condition, or history thereof that in the opinion of the investigator would impair the subject’s ability to participate or complete the study.
24. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial.
25. Has Interstitial Lung Disease.
26. Is pregnant or breastfeeding or plans to become pregnant or breastfeed during the course of the trial. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is the time-to first occurrence of the composite of CV death or HF hospitalization. This endpoint integrates the cause-specific components CV death and HF hospitalization and is the most frequently used primary endpoint in recent Phase III HFrEF trials. Subjects without a HF hospitalization or CV death at the time of analysis will be censored at the time of a non-CV death or time of last information available for subjects still alive at time of analysis. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Effort will be made to follow-up subjects that prematurely stop study medication to collect at least information for the primary endpoint. The time point of final analysis will be based on number of CV deaths. In addition to the final analysis, an interim analysis for efficacy is planned at the time when approximately 75% of the planned number of CV death events are observed and the median follow up time is at least 10 months. At the interim analysis the primary composite endpoint of time to CV death or HF hospitalization and its component time to CV death will be tested. A futility analysis will be performed with the option to terminate the study early if it is determined at the time of analysis that the study is unlikely to demonstrate the efficacy of vericiguat on the primary endpoint |
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| E.5.2 | Secondary end point(s) |
The secondary study endpoints are:
• Components of the primary composite endpoint:
- Time to CV death
- Time to first HF hospitalization
• Time to total HF hospitalizations (first and recurrent)
• Time to first occurrence of the composite of all-cause mortality or HF hospitalization
• Time to all-cause mortality
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Analogous to the analysis of the primary endpoint, the analysis of the secondary efficacy endpoints will be performed under the intention to treat principle. All subjects randomized will be included in the analysis. Subjects will be analyzed as randomized.
In addition to the final study analyses, at the efficacy interim analysis the primary endpoint and the secondary endpoint of time to CV death will be tested. The study can only be terminated early for success if both the primary endpoint and the CV death endpoint are statistically significant based on the pre-specified interim analysis boundaries. |
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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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | 250 |
| 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 |
| Costa Rica |
| Czech Republic |
| Denmark |
| Estonia |
| Finland |
| France |
| Germany |
| Greece |
| Guatemala |
| Hong Kong |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Malaysia |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Peru |
| Philippines |
| Poland |
| Portugal |
| Puerto Rico |
| Romania |
| Russian Federation |
| Singapore |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
| Vietnam |
| Venezuela, Bolivarian Republic of |
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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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| End of trial is defined as last subject’s last study-related phone call or visit. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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