Clinical trial NCT02861534: A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction (HFrEF) (MK-1242-001)
Official title: A Randomized Parallel-Group, Placebo-Controlled, Double-Blind, Event-Driven, Multi-Center Pivotal Phase III Clinical Outcome Trial of Efficacy and Safety of the Oral sGC Stimulator Vericiguat in Subjects With Heart Failure With Reduced Ejection Fraction (HFrEF) - VerICiguaT GlObal Study in Subjects With Heart Failure With Reduced EjectIon FrAction (VICTORIA)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Failure
Chronic Heart Failure With Reduced Ejection Fraction
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
Collaborators: name: Bayer
name: Canadian VIGOUR Centre
name: Duke Clinical Research Institute
First posted: 2016-08-10
Enrollment: 5050
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized, placebo-controlled, parallel-group, multi-center, double-blind, event driven study of vericiguat (MK-1242) in participants with heart failure with reduced ejection fraction (HFrEF). The primary hypothesis is vericiguat (MK-1242) is superior to placebo in increasing the time to first occurrence of the composite of cardiovascular (CV) death or heart failure (HF) hospitalization in participants with HFrEF.


Eligibility criteria: Inclusion Criteria:

* History of chronic HF (New York Heart Association \[NYHA\] Class II-IV) on standard therapy before qualifying HF decompensation
* Previous HF hospitalization within 6 months prior to randomization or intravenous (IV) diuretic treatment for HF (without hospitalization) within 3 months.
* Brain natriuretic peptide (BNP) levels: sinus rhythm-≥ 300 pg/mL; atrial fibrillation-≥ 500 pg/mL and N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) levels: sinus rhythm- ≥ 1000 pg/mL; atrial fibrillation - ≥ 1600 pg/mL within 30 days prior to randomization
* Left ventricular ejection fraction (LVEF) of \<45% assessed within 12 months prior to randomization by any method
* If female, is not of reproductive potential or agrees to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug by complying with one of the following: practice abstinence from heterosexual activity or use (or have her partner use) acceptable contraception during heterosexual activity.

Exclusion Criteria:

* Clinically unstable at the time of randomization as defined by either the administration of any IV treatment within 24 hours prior to randomization, and/or systolic blood pressure (SBP) \<100 mmHg or symptomatic hypotension
* Current or anticipated use of long-acting nitrates or nitric oxide (NO) donors including isosorbide dinitrate, isosorbide 5-mononitrate, pentaerythritol tetranitrate, nicorandil or transdermal nitroglycerin (NTG) patch, and molsidomine
* Current or anticipated use of phosphodiesterase type 5 (PDE5) inhibitors such as vardenafil, tadalafil, and sildenafil
* Current use or anticipated use of a soluble guanylate cyclase (sGC) stimulator such as riociguat
* Known allergy or sensitivity to any sGC stimulator
* 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
* Primary valvular heart disease requiring surgery or intervention, or is within 3 months after valvular surgery or intervention
* Hypertrophic obstructive cardiomyopathy
* Acute myocarditis, amyloidosis, sarcoidosis, Takotsubo cardiomyopathy
* Post-heart transplant cardiomyopathy
* Tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia
* 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, or indication for coronary revascularization at time of randomization
* Symptomatic carotid stenosis, transient ischemic attack (TIA) or stroke within 60 days
* Complex congenital heart disease
* Active endocarditis or constrictive pericarditis
* Estimated glomerular filtration rate (eGFR) \<15 mL/min/1.73 m2 or chronic dialysis
* Severe hepatic insufficiency such as with hepatic encephalopathy
* Malignancy or other non-cardiac condition limiting life expectancy to \<3 years
* Require continuous home oxygen for severe pulmonary disease
* Current alcohol and/or drug abuse
* 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
* Mental or legal incapacitation and is unable to provide informed consent
* Immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is involved with this study
* Interstitial Lung Disease
* Is pregnant or breastfeeding or plans to become pregnant or to breastfeed during the course of the study

Primary outcomes:
measure: Time to First Occurrence of Composite Endpoint of Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization
timeFrame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
Secondary outcomes:
measure: Time to the First Occurrence of CV Death
timeFrame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
measure: Time to the First Occurrence of HF Hospitalization
timeFrame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
measure: Time to Total HF Hospitalizations (Including First and Recurrent Events)
timeFrame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
measure: Time to First Occurrence of Composite Endpoint of All-Cause Mortality or HF Hospitalization
timeFrame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
measure: Time to All-Cause Mortality
timeFrame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
measure: Number of Participants Who Experienced One or More Adverse Events
timeFrame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
measure: Number of Participants Who Discontinued Treatment Due to an Adverse Event
timeFrame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
measure: Percentage of Participants Who Experienced Symptomatic Hypotension
timeFrame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
measure: Percentage of Participants Who Experienced Syncope
timeFrame: Up to approximately 33 months (through primary analysis database cutoff date of 18-June-2019)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Mahesh J. Patel, MD
role: STUDY_DIRECTOR
affiliation: Canadian VIGOUR Centre - University of Alberta
name: Paul W. Armstrong, MD
role: STUDY_CHAIR
affiliation: Inova Heart and Vascular Institute
name: Christopher M. O'Connor, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Charité University Medicine and German Heart Center
name: Burkert Pieske, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pieske B, Patel MJ, Westerhout CM, Anstrom KJ, Butler J, Ezekowitz J, Hernandez AF, Koglin J, Lam CSP, Ponikowski P, Roessig L, Voors AA, O'Connor CM, Armstrong PW; VICTORIA Study Group. Baseline features of the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. Eur J Heart Fail. 2019 Dec;21(12):1596-1604. doi: 10.1002/ejhf.1664. Epub 2019 Dec 9.
citation: Armstrong PW, Zheng Y, Troughton RW, Lund LH, Zhang J, Lam CSP, Westerhout CM, Blaustein RO, Butler J, Hernandez AF, Roessig L, O'Connor CM, Voors AA, Ezekowitz JA; VICTORIA Study Group. Sequential Evaluation of NT-proBNP in Heart Failure: Insights Into Clinical Outcomes and Efficacy of Vericiguat. JACC Heart Fail. 2022 Sep;10(9):677-688. doi: 10.1016/j.jchf.2022.04.015. Epub 2022 Jul 6.
citation: Senni M, Alemayehu WG, Sim D, Edelmann F, Butler J, Ezekowitz J, Hernandez AF, Lam CSP, O'Connor CM, Pieske B, Ponikowski P, Roessig L, Voors AA, Westerhout CM, McMullan C, Armstrong PW; VICTORIA Study Group. Efficacy and safety of vericiguat in patients with heart failure with reduced ejection fraction treated with sacubitril/valsartan: insights from the VICTORIA trial. Eur J Heart Fail. 2022 Sep;24(9):1614-1622. doi: 10.1002/ejhf.2608. Epub 2022 Jul 20.
citation: Butler J, Stebbins A, Melenovsky V, Sweitzer NK, Cowie MR, Stehlik J, Khan MS, Blaustein RO, Ezekowitz JA, Hernandez AF, Lam CSP, Nkulikiyinka R, O'Connor CM, Pieske BM, Ponikowski P, Spertus JA, Voors AA, Anstrom KJ, Armstrong PW; VICTORIA Study Group. Vericiguat and Health-Related Quality of Life in Patients With Heart Failure With Reduced Ejection Fraction: Insights From the VICTORIA Trial. Circ Heart Fail. 2022 Jun;15(6):e009337. doi: 10.1161/CIRCHEARTFAILURE.121.009337. Epub 2022 Jun 3.
citation: Lam CSP, Mulder H, Lopatin Y, Vazquez-Tanus JB, Siu D, Ezekowitz J, Pieske B, O'Connor CM, Roessig L, Patel MJ, Anstrom KJ, Hernandez AF, Armstrong PW; VICTORIA Study Group. Blood Pressure and Safety Events With Vericiguat in the VICTORIA Trial. J Am Heart Assoc. 2021 Nov 16;10(22):e021094. doi: 10.1161/JAHA.121.021094. Epub 2021 Nov 6.
citation: Ezekowitz JA, Zheng Y, Cohen-Solal A, Melenovsky V, Escobedo J, Butler J, Hernandez AF, Lam CSP, O'Connor CM, Pieske B, Ponikowski P, Voors AA, deFilippi C, Westerhout CM, McMullan C, Roessig L, Armstrong PW. Hemoglobin and Clinical Outcomes in the Vericiguat Global Study in Patients With Heart Failure and Reduced Ejection Fraction (VICTORIA). Circulation. 2021 Nov 2;144(18):1489-1499. doi: 10.1161/CIRCULATIONAHA.121.056797. Epub 2021 Aug 25.
citation: Ezekowitz J, Mentz RJ, Westerhout CM, Sweitzer NK, Givertz MM, Pina IL, O'Connor CM, Greene SJ, McMullan C, Roessig L, Hernandez AF, Armstrong PW. Participation in a Heart Failure Clinical Trial: Perspectives and Opportunities From the VICTORIA Trial and VICTORIA Simultaneous Registry. Circ Heart Fail. 2021 Sep;14(9):e008242. doi: 10.1161/CIRCHEARTFAILURE.120.008242. Epub 2021 Aug 19.
citation: Mentz RJ, Mulder H, Mosterd A, Sweitzer NK, Senni M, Butler J, Ezekowitz JA, Lam CSP, Pieske B, Ponikowski P, Voors AA, Anstrom KJ, Armstrong PW, O'connor CM, Hernandez AF; VICTORIA Study Group. Clinical Outcome Predictions for the VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) Trial. J Card Fail. 2021 Jun 24:S1071-9164(21)00206-2. doi: 10.1016/j.cardfail.2021.05.016. Online ahead of print.
citation: Mentz RJ, Mulder H, Mosterd A, Sweitzer NK, Senni M, Butler J, Ezekowitz JA, Lam CSP, Pieske B, Ponikowski P, Voors AA, Anstrom KJ, Armstrong PW, O'Connor CM; VICTORIA Study Group. Clinical Outcome Predictions for the VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) Trial: VICTORIA Outcomes Model. J Card Fail. 2021 May 26:S1071-9164(21)00206-2. doi: 10.1016/j.cardfail.2021.05.016. Online ahead of print.
citation: Lam CSP, Giczewska A, Sliwa K, Edelmann F, Refsgaard J, Bocchi E, Ezekowitz JA, Hernandez AF, O'Connor CM, Roessig L, Patel MJ, Pieske B, Anstrom KJ, Armstrong PW; VICTORIA Study Group. Clinical Outcomes and Response to Vericiguat According to Index Heart Failure Event: Insights From the VICTORIA Trial. JAMA Cardiol. 2021 Jun 1;6(6):706-712. doi: 10.1001/jamacardio.2020.6455.
citation: Ezekowitz JA, O'Connor CM, Troughton RW, Alemayehu WG, Westerhout CM, Voors AA, Butler J, Lam CSP, Ponikowski P, Emdin M, Patel MJ, Pieske B, Roessig L, Hernandez AF, Armstrong PW. N-Terminal Pro-B-Type Natriuretic Peptide and Clinical Outcomes: Vericiguat Heart Failure With Reduced Ejection Fraction Study. JACC Heart Fail. 2020 Nov;8(11):931-939. doi: 10.1016/j.jchf.2020.08.008. Epub 2020 Oct 7.
citation: Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, Lam CSP, Ponikowski P, Voors AA, Jia G, McNulty SE, Patel MJ, Roessig L, Koglin J, O'Connor CM; VICTORIA Study Group. Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2020 May 14;382(20):1883-1893. doi: 10.1056/NEJMoa1915928. Epub 2020 Mar 28.
citation: Armstrong PW, Roessig L, Patel MJ, Anstrom KJ, Butler J, Voors AA, Lam CSP, Ponikowski P, Temple T, Pieske B, Ezekowitz J, Hernandez AF, Koglin J, O'Connor CM. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the Efficacy and Safety of the Oral Soluble Guanylate Cyclase Stimulator: The VICTORIA Trial. JACC Heart Fail. 2018 Feb;6(2):96-104. doi: 10.1016/j.jchf.2017.08.013. Epub 2017 Oct 11.