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)

Overview

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.

Interventions

• Drug Vericiguat tablet
  2.5 mg or 5 mg or 10 mg vericiguat administered orally once daily in tablet form
• Drug Vericiguat suspension
  0.2 mg/mL or 1 mg/mL vericiguat administered orally once daily in suspension form
• Drug Placebo tablet
  Placebo for vericiguat administered orally once daily in tablet form
• Drug Placebo suspension
  Placebo for vericiguat administered orally once daily in suspension form

Primary outcome measures

• Base Period: Change from baseline to Week 16 in N-terminal pro-brain natriuretic peptide (NT-proBNP) [Time frame: Baseline and Week 16 of Base Period]
• Extension Period: Percentage of participants with one or more adverse events (AEs) [Time frame: Includes data collected up to a maximum of approximately 8 years]
• Extension Period: Percentage of participants who discontinued study drug due to an AE [Time frame: Includes data collected up to a maximum of approximately 8 years]

Secondary outcome measures (8)

• Base Period: Change from baseline to Week 52 in log-transformed NT-proBNP [Time frame: Baseline and Week 52 of Base Period]
• Base Period: First event of cardiovascular (CV) death, heart failure hospitalization (HFH), or worsening of heart failure (HF) without hospitalization [Time frame: Up to Week 54 of Base Period]
• Base Period: Percentage of participants with one or more adverse events (AEs) [Time frame: Up to Week 54 of Base Period]
• Base Period: Percentage of participants who discontinued study drug due to an AE [Time frame: Up to Week 52 of Base Period]
• Base Period: Area under the curve from time 0-24 hours post-dose (AUC0-24) of plasma vericiguat [Time frame: Pre-dose, 2, 6, 16, 32 and 52 weeks post-dose (Base Period)]
• Base Period: Half-life (t1/2) of vericiguat in plasma [Time frame: Pre-dose, 2, 6, 16, 32 and 52 weeks post-dose (Base Period)]
• Base Period: Oral clearance (CL/F) of plasma vericiguat [Time frame: Pre-dose, 2, 6, 16, 32 and 52 weeks post-dose (Base Period)]
• Extension Period: Change from extension period baseline to extension period Week 16 in NT-proBNP [Time frame: Extension Period Baseline (Study Week 54) and Extension Period Week 16 (Study Week 70)]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 20 centers

• The Regents of the University of California - Los Angeles (UCLA Pediatrics) ( Site 0002) — Los Angeles
• Lucile Packard Children's Hospital ( Site 0040) — Palo Alto
• Loma Linda University Health System ( Site 0008) — San Bernardino
• Children's Hospital Colorado ( Site 0012) — Aurora
• Children's National Medical Center ( Site 0020) — Washington D.C.
• Johns Hopkins All Children's Hospital ( Site 0029) — St. Petersburg
• Children's Healthcare of Atlanta - Arthur M. Blank Hospital ( Site 0001) — Atlanta
• Boston Children's Hospital ( Site 0035) — Boston
• … and 12 more centers

Mexico · 9 centers

• Morales Vargas Centro de Investigacion ( Site 1810) — León
• CINVEC Medica ( Site 1814) — Guadalajara
• Instituto Nacional de Pediatria ( Site 1803) — Mexico City
• Hospital Universitario "Dr. Jose Eleuterio Gonzalez"-Pediatria ( Site 1816) — Monterrey
• INVECORDIS S.C. ( Site 1808) — Hacienda de Las Palmas
• Centro de Estudios de Investigacion Metabolicos y Cardiovasculares ( Site 1800) — Ciudad Madero
• Centro de Atención e Investigación Clínica ( Site 1813) — Aguascalientes
• UROLAP ( Site 1812) — Colima
• … and 1 more center

France · 6 centers

• CHU Bordeaux Haut-Leveque ( Site 1000) — Pessac
• Centre Hospitalier Universitaire de Nantes - Hôpital Femme-Enfant-Adolescent Chu De Nantes — Nantes
• CHU Lille - Institut Coeur Poumon ( Site 1005) — Lille
• Assistance Publique Hôpitaux de Marseille - Hôpital de la Timone ( Site 1003) — Marseille
• Hôpital Universitaire Necker Enfants Malades ( Site 1001) — Paris
• Assistance Publique - Hopitaux de Paris (AP-HP) - Hopital Robert Debre - Centre Hospitalo — Paris

Italy · 6 centers

• IRCCS Istituto Giannina Gaslini ( Site 1603) — Genoa
• Ospedale dei Bambini "Vittore Buzzi" ( Site 1606) — Milan
• Ospedale Infantile Regina Margherita ( Site 1604) — Turin
• Ospedale Pediatrico Bambino Gesù IRCCS ( Site 1602) — Rome
• A.O.Universitaria Meyer ( Site 1600) — Florence
• Azienda Ospedale - Università Padova ( Site 1601) — Padova

Spain · 6 centers

Center list to be confirmed — check the primary protocol.

Colombia · 5 centers

• Clinica Somer ( Site 0607) — Rionegro
• Ciensalud Ips S A S ( Site 0608) — Barranquilla
• Fundación Cardioinfantil Instituto de Cardiología ( Site 0603) — Bogotá
• Fundación Valle del Lili ( Site 0604) — Cali
• Clínica Imbanaco S.A.S ( Site 0602) — Cali

Germany · 5 centers

• Universitaetsklinikum Freiburg ( Site 1102) — Freiburg im Breisgau
• Universitaetsklinikum Heidelberg ( Site 1100) — Heidelberg
• Kinderklinik des Uni-Klinikums Erlangen ( Site 1104) — Erlangen
• Medizinische Hochschule Hannover ( Site 1108) — Hanover
• Deutsches Herzzentrum Berlin ( Site 1101) — Berlin

Malaysia · 5 centers

• Hospital Universiti Sains Malaysia ( Site 1703) — Kota Bharu
• University Malaya Medical Centre ( Site 1701) — Lembah Pantai
• Hospital Queen Elizabeth II ( Site 1706) — Kota Kinabalu
• Hospital Tunku Azizah-Paediatric ( Site 1700) — Kuala Lumpur
• Institut Jantung Negara ( Site 1705) — Kuala Lumpur

Turkey (Türkiye) · 5 centers

Center list to be confirmed — check the primary protocol.

South Korea · 4 centers

Center list to be confirmed — check the primary protocol.

Belgium · 3 centers

• Centre Hospitalier Régional de la Citadelle ( Site 0302) — Liège
• UZ Gent ( Site 0301) — Ghent
• UZ Leuven ( Site 0300) — Leuven

Netherlands · 3 centers

• Erasmus Medisch Centrum ( Site 1900) — Rotterdam
• University Medical Center Groningen ( Site 1901) — Groningen
• Universitair Medisch Centrum Utrecht ( Site 1902) — Utrecht

Portugal · 3 centers

• Unidade Local de Saude Lisboa Ocidental - Hospital de Santa Cruz ( Site 2401) — Lisbon
• Unidade Local de Saude de Santa Maria - Hospital de Santa Maria ( Site 2402) — Lisbon
• Unidade Local de Saúde de São João ( Site 2403) — Porto

Serbia · 3 centers

• Childrens University Hospital ( Site 4200) — Belgrade
• Institut za zdravstvenu zastitu majke i deteta Srbije ( Site 4220) — Belgrade
• … and 1 more center

Thailand · 3 centers

Center list to be confirmed — check the primary protocol.

Brazil · 2 centers

• Instituto Dante Pazzanese de Cardiology ( Site 0402) — São Paulo
• Incor - Instituto do Coracao ( Site 0400) — São Paulo

Canada · 2 centers

• Stollery Children's Hospital ( Site 0501) — Edmonton
• Centre intégré universitaire de santé et de services sociaux-Centre de recherche du CHUS ( — Sherbrooke

Singapore · 2 centers

Center list to be confirmed — check the primary protocol.

South Africa · 2 centers

Center list to be confirmed — check the primary protocol.

Sweden · 2 centers

Center list to be confirmed — check the primary protocol.

United Kingdom · 2 centers

Center list to be confirmed — check the primary protocol.

Croatia · 1 center

• Klinički bolnički centar Zagreb ( Site 3700) — Zagreb

Denmark · 1 center

• Rigshospitalet-BørneUngeAfdelingen ( Site 0800) — Copenhagen

Finland · 1 center

• Tampereen yliopistollinen sairaala-Pediatric Early Phase Trials Unit ( Site 0900) — Tampere

Hungary · 1 center

• Gottsegen György Országos Kardiovaszkuláris Intézet-Gyermeksziv Kozpont ( Site 1300) — Budapest

Ireland · 1 center

• Children's Health Ireland (CHI) at Crumlin ( Site 1400) — Dublin

New Zealand · 1 center

• Auckland City Hospital ( Site 2000) — Auckland

Peru · 1 center

• Instituto Nacional Cardiovascular INCOR Carlos Peschiera Carrillo - EsSalud ( Site 2100) — Jesús María

Poland · 1 center

• Uniwersyteckie Centrum Kliniczne-Klinika Kardiologii Dziecięcej i Wad Wrodzonych Serca ( S — Gdansk

Saudi Arabia · 1 center

• King Faisal Specialist Hospital and Research Center ( Site 4100) — Riyadh

Publications

• Fritsch A, Meyer M, Blaustein RO, Trujillo ME, Kauh E, Roessig L, Boettcher M, Becker C. Clinical Pharmacokinetic and Pharmacodynamic Profile of Vericiguat. Clin Pharmacokinet. 2024 Jun;63(6):751-771. doi: 10.1007/s40262-024-01384-1. Epub 2024 Jun 25. PMID 38916717

Identifiers

NCT: NCT05714085 · 1242-036 · MK-1242-036 · 2022-501238-52-00 · U1111-1275-1768 · MK-1242-043 · 2021-004399-33

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗