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 Left Ventricular Systolic Dysfunction (VALOR)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

23 Mar 2023 → ongoing

Decision date (initial)

2023-07-07

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Bayer AG · Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-501238-52-00

WHO UTN

U1111-1275-1768

ClinicalTrials.gov

NCT05714085

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Pharmacokinetic, Efficacy, Safety, Pharmacogenomic, Pharmacogenetic

1. Base Period: To compare the efficacy of vericiguat versus placebo on change in NT-proBNP from baseline to Week 16.
2. Extension Period: To monitor the safety and tolerability of vericiguat.

Secondary objectives 5

1. Base Period: To evaluate the efficacy of vericiguat compared with placebo on change in NT-proBNP from baseline to Week 52.
2. Base Period: To evaluate the efficacy of vericiguat compared with placebo in reducing the risk of the composite of cardiovascular death, heart failure hospitalization, or worsening of heart failure without hospitalization.
3. Base Period: To assess the safety and tolerability of vericiguat compared with placebo.
4. Base Period: To assess the pharmacokinetics of vericiguat.
5. Extension Period: To evaluate change in NT-proBNP from baseline of the Extension Period to Week 16 of the Extension Period.

Conditions and MedDRA coding

Heart failure due to systemic left ventricular systolic dysfunction

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-001636-PIP01-14

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Has symptomatic chronic heart failure (HF) resulting from systemic left ventricular (LV) systolic dysfunction.
2. Has biventricular physiology with a morphologic systemic left ventricle.
3. Is currently receiving stable medical therapy for HF.
4. Has left ventricular ejection fraction (LVEF) <45% assessed within 3 months before randomization.
5. Is of any sex/gender, from >28 days to <18 years of age inclusive. Must weigh ≥3 kg to participate.
6. 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.
7. 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 19

1. 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
2. Has a known allergy or sensitivity to vericiguat, any of its constituents, or any other soluble guanylate cyclase (sGC) stimulator.
3. Has a history of single ventricle heart disease or has a morphologic systemic right ventricle.
4. 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.
5. Has sustained or symptomatic dysrhythmia uncontrolled with drug or device therapy.
6. Has had recent cardiovascular (CV) surgical procedure or percutaneous intervention to palliate or correct congenital CV malformations.
7. Has unoperated or residual hemodynamically significant congenital cardiac malformations.
8. Has hypertrophic or restrictive cardiomyopathy.
9. Has active myocarditis or has been recently diagnosed with presumed or definitive myocarditis.
10. Has acute coronary syndrome, undergone recent coronary intervention, or indication for coronary revascularization.
11. Has symptomatic carotid stenosis or other symptomatic cerebrovascular disease
12. Has severe pulmonary hypertension.
13. Requires continuous home oxygen for significant pulmonary disease and/or has known interstitial lung disease.
14. Has severe chronic kidney disease.
15. Has hepatic disorder such as hepatic encephalopathy, hepatic laboratory abnormalities or Child Pugh Class C.
16. Has a gastrointestinal or biliary disorder that could impair absorption, metabolism, or excretion of medications.
17. Has significant bone disease (other than osteopenia) that in the assessment of the investigator can alter bone formation
18. Has concurrent or anticipated concomitant use of phosphodiesterase type 5 inhibitors or an sGC stimulator.
19. Has received a COVID-19 vaccination within 1 week before randomization.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Base Period: Change from baseline to Week 16 in log-transformed n-terminal pro-brain natriuretic peptide (NT-proBNP)
2. Extension Period: Percentage of participants with one or more adverse events (AE)
3. Extension Period: Percentage of participants who discontinued study drug due to an AE

Secondary endpoints 8

1. Base Period: Change from baseline to Week 52 in log-transformed NT-proBNP
2. Base Period: Time from randomization to the first event of cardiovascular (CV) death, heart failure hospitalization (HFH), or worsening of heart failure (HF) without hospitalization
3. Base Period: Percentage of participants with one or more adverse events (AE)
4. Base Period: Percentage of participants who discontinued study drug due to an AE
5. Base Period: Area under the curve from time 0-24 hours post-dose (AUC0-24) of plasma vericiguat
6. Base Period: Half-life (t1/2) of vericiguat in plasma
7. Base Period: Oral clearance (CL/F) of plasma vericiguat
8. Extension Period: Change from extension period baseline to extension period Week 16 in NT-proBNP

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Mackenzie Ford

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Mackenzie Ford

Third parties 6

Locations

14 EU/EEA countries · 43 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 2 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 336 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

37 submissions — initial application plus substantial / non-substantial modifications