| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Heart Failure with reduced Ejection Fraction |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Heart Failure with reduced Ejection Fraction (HFrEF) |
|
| 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 | 10078289 |
| E.1.2 | Term | Heart failure with reduced ejection fraction |
| E.1.2 | System Organ Class | 100000004849 |
|
| 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 |
| 1. To evaluate the efficacy of vericiguat compared with placebo on reducing the risk of cardiovascular death or heart failure hospitalization. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of vericiguat compared with placebo on reducing the risk of cardiovascular death.
2. To evaluate the efficacy of vericiguat compared with placebo in reducing the risk of heart failure hospitalization.
3. To evaluate the efficacy of vericiguat compared with placebo in reducing the risk of all-cause mortality or heart failure hospitalization.
4. To evaluate the efficacy of vericiguat compared with placebo in reducing the risk of all-cause mortality.
5. To evaluate the safety and tolerability of vericiguat compared with placebo.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has a history of chronic HF (NYHA Class II to IV) on GDMT with no events of HFH within 6 months or outpatient IV diuretic use within 3 months before randomization.
2. Is male or female, at least 18 years of age, at the time of providing documented informed consent.
3. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP OR
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) during the intervention period and for at least 1 month after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
- A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
- The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
- Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
4. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the study without participating in FBR.
5. Has a screening NT-proBNP level within 30 days before randomization. For participants with multiple NT-proBNP results during screening, the most recent value will be used to determine eligibility at the Randomization Visit.
6. Has an LVEF of ≤40% assessed within 12 months before randomization by any imaging method. The most recent measurement must be used to determine eligibility. |
|
| E.4 | Principal exclusion criteria |
1. Has SBP <100 mm Hg or symptomatic hypotension.
2. Has a known allergy or sensitivity to vericiguat, any of its constituents, or any other sGC stimulator.
3. Is awaiting heart transplantation (United Network for Organ Sharing Class 1A / 1B or equivalent), is receiving continuous IV infusion of an inotrope, or has or anticipates receiving an implanted ventricular assist device.
4. Has amyloidosis or sarcoidosis.
5. Has primary valvular heart disease requiring surgical procedure or intervention or has undergone a vascular surgical procedure or intervention within 3 months before randomization.
6. Has hypertrophic cardiomyopathy.
7. Has acute myocarditis or Takotsubo cardiomyopathy.
8. Has received a heart transplant.
9. Has tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia.
10. Has acute coronary syndrome (unstable angina, NSTEMI, or STEMI), undergone CABG or PCI within 3 months before randomization, or indication for coronary revascularization at the time of randomization.
11. Has symptomatic carotid stenosis, TIA, or stroke within 3 months before randomization.
12. Has a history of repaired or unrepaired simple congenital heart disease (eg, atrial or ventricular septal defects, or patent ductus arteriosus) with ongoing hemodynamically significant residual lesions, or any history of complex congenital heart disease (eg, tetralogy of Fallot, transposition of the great arteries, single ventricle disease) regardless of repair status.
13. Has active endocarditis or constrictive pericarditis.
14. Has an eGFR based on the CKD-EPI Creatinine Equation of <15 mL/min/1.73 m2 within 30 days before randomization or is on chronic dialysis. For participants with multiple eGFR results during screening, the most recent value will be used to determine eligibility at the Randomization Visit.
15. Has severe hepatic insufficiency such as with hepatic encephalopathy, hepatic laboratory abnormalities (ALT or AST ≥3 × ULN or total bilirubin ≥2 × ULN) or ALBI Grade 3. Screening albumin, ALT, AST, and total bilirubin results within 30 days before randomization may be used for assessment of laboratory abnormalities or the calculation of the ALBI score. For participants with multiple albumin and/or total bilirubin results during screening, the most recent value for each test will be used to calculate ALBI score.
16. Has malignancy or other noncardiac condition limiting life expectancy to <3 years.
17. Requires continuous home oxygen for severe pulmonary disease.
18. Has interstitial lung disease.
19. Had any discontinuation or dose modification of GDMT (including beta blockers, ACEI/ARBs, ARNI, MRAs, hydralazine-nitrate combinations, SGLT2is, or ivabradine) or vericiguat within 4 weeks before randomization.
20. Has concurrent or anticipated concomitant use of PDE5 inhibitors such as vardenafil, tadalafil, and sildenafil during the study.
21. Has concurrent use of an sGC stimulator such as riociguat or vericiguat.
22. Has participated in another interventional clinical study or has been treated with another investigational product ≤30 days before randomization or plans to participate in any other study or study intervention during this study.
23. Has a recent history (within the last year) of drug or alcohol abuse or dependence.
24. Is pregnant or breastfeeding or plans to become pregnant or to breastfeed during the study.
25. Has a medical disorder, condition, or history thereof that in the opinion of the investigator would impair the participant’s ability to participate in or complete the study.
26. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Time to First Occurrence of Composite Endpoint of Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. From date of randomization until the date of first occurrence of a primary end point, assessed up to approximately 40 months |
|
| E.5.2 | Secondary end point(s) |
1. Time to First Occurrence of CV Death
2. Time to First Occurrence of HF Hospitalization
3. Time to Total HF Hospitalizations (Including First and Recurrent Events)
4. Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization
5. Time to All-Cause Mortality
6. Percentage of Participants who Experienced One or More Selected Nonserious Adverse Events (NSAE)
7. Percentage of Participants Who Experienced One or More Serious Adverse Events (SAE)
8. Percentage of Participants Who Experienced One or More Events of Clinical Interest (ECI)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From date of randomization until the date of first occurrence of a CV Death, assessed up to approximately 40 months
2. From date of randomization until the date of first occurrence of a HF Hospitalization, assessed up to approximately 40 months
3. Up to approximately 40 months
4. From date of randomization until the date of first occurrence of All-Cause Mortality or HF Hospitalization, assessed up to approximately 40 months
5. From date of randomization until the date of death, assessed up to approximately 40 months
6. Up to approximately 40 months
7. Up to approximately 40 months
8. Up to approximately 40 months
|
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 134 |
| 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 |
| Australia |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Hong Kong |
| Israel |
| Korea, Republic of |
| Malaysia |
| Mexico |
| New Zealand |
| Peru |
| Puerto Rico |
| Russian Federation |
| Singapore |
| South Africa |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
| Austria |
| Denmark |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Poland |
| Spain |
| Sweden |
| United Kingdom |
| Czechia |
| Greece |
|
| 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
|
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 7 |
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