Clinical trial NCT05714085: Efficacy, Safety, and Pharmacokinetics of Vericiguat in Pediatric Participants With Heart Failure Due to Left Ventricular Systolic Dysfunction (MK-1242-036)
Official title: A Phase 2/3 Randomized, Placebo-Controlled, Double-blind, Clinical Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Vericiguat in Pediatric Participants With Heart Failure Due to Systemic Left Ventricular Systolic Dysfunction (VALOR)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Heart Failure
Left Ventricular Systolic Dysfunction
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2023-02-06
Enrollment: 342
Sex: ALL
Minimum age (years): 29
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study aims to compare the efficacy of vericiguat versus placebo on change in n-terminal pro-brain natriuretic peptide (NTproBNP) from baseline to Week 16 of the Base Period. The primary hypothesis is that vericiguat is superior to placebo in reducing NT-proBNP at Week 16 of the Base Period.

Detailed description: As of Protocol Amendment 2, the separate open-label extension arm of study MK-1242-043 (NCT06428383) will be incorporated into the present MK-1242-036 study as an extension period. Participants from the Base Period will be provided the opportunity to participate in the optional open-label Extension Period if eligible. After all ongoing participants are transferred into the extension period of MK-1242-036, MK-1242-043 (NCT06428383) will be formally closed.

Eligibility criteria: Inclusion Criteria:

* Has symptomatic chronic heart failure (HF) resulting from systemic left ventricular (LV) systolic dysfunction.
* Has biventricular physiology with a morphologic systemic left ventricle.
* Is currently receiving stable medical therapy for HF.
* Has left ventricular ejection fraction (LVEF) \<45% assessed within 3 months before randomization.
* Is of any sex/gender, from \>28 days to \<18 years of age inclusive. Must weigh ≥3 kg to participate.
* Female is eligible to participate if not pregnant or breastfeeding, and at least one of the following: is not a participant of childbearing potential (POCBP); or is a POCBP who uses a highly effective contraceptive method; has a negative highly sensitive pregnancy test; abstains from breastfeeding during the study intervention period and for at least 30 days after study intervention; and their medical history; their menstrual history, and recent sexual activity has been reviewed.
* Extension Period: Was randomized, received at least 1 dose of study intervention (vericiguat or placebo), did not permanently discontinue study intervention, and completed the Week 52 visit and safety follow-up period of the Base Period

Exclusion Criteria:

* Is clinically unstable-with at least one of the following: has symptomatic hypotension or is hypotensive for age, recent use of intravenous (IV) inotrope and/or IV vasodilator, or recent IV diuretic.
* Has a known allergy or sensitivity to vericiguat, any of its constituents, or any other soluble guanylate cyclase (sGC) stimulator.
* Has a history of single ventricle heart disease or has a morphologic systemic right ventricle.
* Has undergone heart transplantation, is awaiting heart transplantation United Network for Organ Sharing (UNOS) Class 1A or equivalent, is receiving continuous IV infusion of an inotrope, or has an implanted ventricular assist device.
* Has sustained or symptomatic dysrhythmia uncontrolled with drug or device therapy.
* Has had recent cardiovascular (CV) surgical procedure or percutaneous intervention to palliate or correct congenital CV malformations.
* Has unoperated or residual hemodynamically significant congenital cardiac malformations.
* Has hypertrophic or restrictive cardiomyopathy.
* Has active myocarditis or has been recently diagnosed with presumed or definitive myocarditis.
* Has acute coronary syndrome, undergone recent coronary intervention, or indication for coronary revascularization.
* Has symptomatic carotid stenosis or other symptomatic cerebrovascular disease
* Has severe pulmonary hypertension.
* Requires continuous home oxygen for significant pulmonary disease and/or has known interstitial lung disease.
* Has severe chronic kidney disease.
* Has hepatic disorder such as hepatic encephalopathy, hepatic laboratory abnormalities or Child Pugh Class C.
* Has a gastrointestinal or biliary disorder that could impair absorption, metabolism, or excretion of medications.
* Has significant bone disease (other than osteopenia) that in the assessment of the investigator can alter bone formation
* Has concurrent or anticipated concomitant use of phosphodiesterase type 5 inhibitors or an sGC stimulator.
* Has received a COVID-19 vaccination within 1 week before randomization.

Primary outcomes:
measure: Base Period: Change from baseline to Week 16 in N-terminal pro-brain natriuretic peptide (NT-proBNP)
timeFrame: Baseline and Week 16 of Base Period
measure: Extension Period: Percentage of participants with one or more adverse events (AEs)
timeFrame: Includes data collected up to a maximum of approximately 8 years
measure: Extension Period: Percentage of participants who discontinued study drug due to an AE
timeFrame: Includes data collected up to a maximum of approximately 8 years
Secondary outcomes:
measure: Base Period: Change from baseline to Week 52 in log-transformed NT-proBNP
timeFrame: Baseline and Week 52 of Base Period
measure: Base Period: First event of cardiovascular (CV) death, heart failure hospitalization (HFH), or worsening of heart failure (HF) without hospitalization
timeFrame: Up to Week 54 of Base Period
measure: Base Period: Percentage of participants with one or more adverse events (AEs)
timeFrame: Up to Week 54 of Base Period
measure: Base Period: Percentage of participants who discontinued study drug due to an AE
timeFrame: Up to Week 52 of Base Period
measure: Base Period: Area under the curve from time 0-24 hours post-dose (AUC0-24) of plasma vericiguat
timeFrame: Pre-dose, 2, 6, 16, 32 and 52 weeks post-dose (Base Period)
measure: Base Period: Half-life (t1/2) of vericiguat in plasma
timeFrame: Pre-dose, 2, 6, 16, 32 and 52 weeks post-dose (Base Period)
measure: Base Period: Oral clearance (CL/F) of plasma vericiguat
timeFrame: Pre-dose, 2, 6, 16, 32 and 52 weeks post-dose (Base Period)
measure: Extension Period: Change from extension period baseline to extension period Week 16 in NT-proBNP
timeFrame: Extension Period Baseline (Study Week 54) and Extension Period Week 16 (Study Week 70)
Other outcomes:
Locations:
city: Loma Linda
country: United States
facility: Loma Linda University Health System ( Site 0008)
state: California
city: Los Angeles
country: United States
facility: The Regents of the University of California - Los Angeles (UCLA Pediatrics) ( Site 0002)
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado ( Site 0012)
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center ( Site 0020)
state: District of Columbia
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital ( Site 0029)
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Arthur M. Blank Hospital ( Site 0001)
state: Georgia
city: Ann Arbor
country: United States
facility: C.S. Mott Children's Hospital ( Site 0033)
state: Michigan
city: Saint Louis
country: United States
facility: Washington University-Pediatric Cardiology/ St. Louis Children's Hospital ( Site 0006)
state: Missouri
city: Bronx
country: United States
facility: The Children's Hospital at Montefiore ( Site 0030)
state: New York
city: New York
country: United States
facility: Columbia University Medical Center-Pediatric Cardiology ( Site 0016)
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center ( Site 0034)
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic-Cleveland Clinic Chidren's ( Site 0022)
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia (CHOP) ( Site 0004)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh ( Site 0010)
state: Pennsylvania
city: Memphis
country: United States
facility: Le Bonheur Children's Hospital ( Site 0007)
state: Tennessee
city: Dallas
country: United States
facility: Children's Health-The Heart Center ( Site 0015)
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital-Cardiology/Fetal Therapy ( Site 0019)
state: Washington
city: Liège
country: Belgium
facility: Centre Hospitalier Régional de la Citadelle ( Site 0302)
state: Liege
city: Gent
country: Belgium
facility: UZ Gent ( Site 0301)
state: Oost-Vlaanderen
city: Leuven
country: Belgium
facility: UZ Leuven ( Site 0300)
state: Vlaams-Brabant
city: São Paulo
country: Brazil
facility: Instituto Dante Pazzanese de Cardiology ( Site 0402)
state: Sao Paulo
city: Sao Paulo
country: Brazil
facility: Incor - Instituto do Coracao ( Site 0400)
city: Edmonton
country: Canada
facility: Stollery Children's Hospital ( Site 0501)
state: Alberta
city: Sherbrooke
country: Canada
facility: Centre intégré universitaire de santé et de services sociaux-Centre de recherche du CHUS ( Site 0502)
state: Quebec
city: Rionegro.
country: Colombia
facility: Clinica Somer ( Site 0607)
state: Antioquia
city: Barranquilla
country: Colombia
facility: Ciensalud Ips S A S ( Site 0608)
state: Atlantico
city: Bogotá
country: Colombia
facility: Fundación Cardioinfantil Instituto de Cardiología ( Site 0603)
state: Distrito Capital De Bogota
city: Cali
country: Colombia
facility: Fundación Valle del Lili ( Site 0604)
state: Valle Del Cauca
city: Cali
country: Colombia
facility: Clínica Imbanaco S.A.S ( Site 0602)
state: Valle Del Cauca
city: Copenhagen
country: Denmark
facility: Rigshospitalet-BørneUngeAfdelingen ( Site 0800)
state: Hovedstaden
city: Tampere
country: Finland
facility: Tampereen yliopistollinen sairaala-Pediatric Early Phase Trials Unit ( Site 0900)
state: Pirkanmaa
city: Pessac
country: France
facility: CHU Bordeaux Haut-Leveque ( Site 1000)
state: Aquitaine
city: Lille Cedex
country: France
facility: CHU Lille - Institut Coeur Poumon ( Site 1005)
state: Nord
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes - Hôpital Femme-Enfant-Adolescent Chu De Nantes ( Site 1002)
state: Pays-de-la-Loire
city: Marseille
country: France
facility: Assistance Publique Hôpitaux de Marseille - Hôpital de la Timone ( Site 1003)
state: Provence-Alpes-Cote-d Azur
city: Paris
country: France
facility: Hôpital Universitaire Necker Enfants Malades ( Site 1001)
city: Paris
country: France
facility: Assistance Publique - Hopitaux de Paris (AP-HP) - Hopital Robert Debre - Centre Hospitalo Universita ( Site 1004)
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg ( Site 1102)
state: Baden-Wurttemberg
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg ( Site 1100)
state: Baden-Wurttemberg
city: Erlangen
country: Germany
facility: Kinderklinik des Uni-Klinikums Erlangen ( Site 1104)
state: Bayern
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover ( Site 1108)
state: Niedersachsen
city: Berlin
country: Germany
facility: Deutsches Herzzentrum Berlin ( Site 1101)
city: Budapest
country: Hungary
facility: Gottsegen György Országos Kardiovaszkuláris Intézet-Gyermeksziv Kozpont ( Site 1300)
city: Dublin
country: Ireland
facility: Children's Health Ireland (CHI) at Crumlin ( Site 1400)
city: Genova
country: Italy
facility: IRCCS Istituto Giannina Gaslini ( Site 1603)
state: Liguria
city: Firenze
country: Italy
facility: A.O.Universitaria Meyer ( Site 1600)
state: Toscana
city: Padova
country: Italy
facility: Azienda Ospedale - Università Padova ( Site 1601)
state: Veneto
city: Pusan
country: Korea, Republic of
facility: Pusan National University Yangsan Hospital ( Site 2802)
state: Kyongsangnam-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital ( Site 2803)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System ( Site 2800)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center ( Site 2801)
city: Kota Bharu
country: Malaysia
facility: Hospital Universiti Sains Malaysia ( Site 1703)
state: Kelantan
city: Lembah Pantai
country: Malaysia
facility: University Malaya Medical Centre ( Site 1701)
state: Kuala Lumpur
city: Kuala Lumpur
country: Malaysia
facility: Hospital Tunku Azizah-Paediatric ( Site 1700)
city: Kuala Lumpur
country: Malaysia
facility: Institut Jantung Negara ( Site 1705)
city: Mexico City
country: Mexico
facility: Instituto Nacional de Pediatria ( Site 1803)
state: Distrito Federal
city: León
country: Mexico
facility: Morales Vargas Centro de Investigacion ( Site 1810)
state: Guanajuato
city: Guadalajara
country: Mexico
facility: CINVEC Medica ( Site 1814)
state: Jalisco
city: Ciudad Madero
country: Mexico
facility: Centro de Estudios de Investigacion Metabolicos y Cardiovasculares ( Site 1800)
state: Tamaulipas
city: Aguascalientes
country: Mexico
facility: Centro de Atención e Investigación Clínica ( Site 1813)
city: Hacienda De Las Palmas
country: Mexico
facility: INVECORDIS S.C. ( Site 1808)
city: Mexico
country: Mexico
facility: Instituto Nacional de Cardiologia Ignacio Chavez ( Site 1804)
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum ( Site 1900)
state: Zuid-Holland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen ( Site 1901)
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht ( Site 1902)
city: Auckland
country: New Zealand
facility: Auckland City Hospital ( Site 2000)
city: Jesús María
country: Peru
facility: Instituto Nacional Cardiovascular INCOR Carlos Peschiera Carrillo - EsSalud ( Site 2100)
state: Lima
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne-Klinika Kardiologii Dziecięcej i Wad Wrodzonych Serca ( Site 2302)
state: Pomorskie
city: Lisbon
country: Portugal
facility: Unidade Local de Saude Lisboa Ocidental - Hospital de Santa Cruz ( Site 2401)
state: Lisboa
city: Lisboa
country: Portugal
facility: Unidade Local de Saude de Santa Maria - Hospital de Santa Maria ( Site 2402)
city: Porto
country: Portugal
facility: Unidade Local de Saúde de São João ( Site 2403)
city: Singapore
country: Singapore
facility: National University Hospital-Paediatrics ( Site 2600)
state: South West
city: Singapore
country: Singapore
facility: KK Women's and Children's Hospital ( Site 2601)
state: South West
city: Cape Town
country: South Africa
facility: TREAD Research ( Site 2700)
state: Western Cape
city: Cape Town
country: South Africa
facility: Children's Heart Disease Research Unit ( Site 2704)
state: Western Cape
city: Esplugues de Llobregat
country: Spain
facility: Hospital Sant Joan de Déu-Pediatric cardiology ( Site 2902)
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron ( Site 2903)
state: Cataluna
city: A Coruna
country: Spain
facility: Hospital Materno-Infantil Teresa Herrera ( Site 2905)
state: La Coruna
city: Madrid
country: Spain
facility: HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑON ( Site 2904)
state: Madrid, Comunidad De
city: Madrid
country: Spain
facility: Hospital Universitario La Paz ( Site 2912)
state: Madrid, Comunidad De
city: Sevilla
country: Spain
facility: HOSPITAL UNIVERSITARIO VIRGEN DEL ROCIO ( Site 2907)
city: Lund
country: Sweden
facility: Skånes Universitetssjukhus Lund ( Site 3000)
state: Skane Lan
city: Stockholm
country: Sweden
facility: Astrid Lindgrens Barnsjukhus ( Site 3001)
state: Stockholms Lan
city: Muang
country: Thailand
facility: Faculty of Medicine - Khon Kaen University ( Site 3202)
state: Khon Kaen
city: Bangkok
country: Thailand
facility: Faculty of Medicine Siriraj Hospital ( Site 3200)
state: Krung Thep Maha Nakhon
city: Chiang Mai
country: Thailand
facility: Maharaj Nakorn Chiang Mai Hospital-Department of Pediatrics ( Site 3201)
city: Ankara
country: Turkey
facility: Hacettepe Universite Hastaneleri ( Site 3304)
city: Ankara
country: Turkey
facility: Baskent Universitesi Ankara Hastanesi ( Site 3301)
city: Ankara
country: Turkey
facility: Ankara Bilkent Şehir Hastanesi. ( Site 3300)
city: Istanbul
country: Turkey
facility: Dr. Siyami Ersek Göğüs Kalp Ve Damar Cerrahisi Eğitim Ve Araştırma Hastanesi ( Site 3302)
city: Izmir
country: Turkey
facility: S.B.Ü. DR. BEHÇET UZ ÇOCUK HASTALIKLARI VE CERRAHİSİ EĞİTİM VE ARAŞTIRMA HASTANESİ ( Site 3303)
city: London
country: United Kingdom
facility: Great Ormond Street Hospital For Children NHS Foundation Trust ( Site 3401)
state: London, City Of
city: Newcastle upon Tyne
country: United Kingdom
facility: Freeman Hospital ( Site 3400)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: