Study of Verinurad in Heart Failure With Preserved Ejection Fraction

NCT ID: NCT04327024

Last Updated: 2023-06-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 159 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-19
• Study Completion Date: 2022-04-29

Brief Summary

International, Multicenter, Double-Blind, Placebo and Active Control Efficacy and Safety Study to Evaluate Verinurad combined with Allopurinol in Heart Failure with Preserved Ejection Fraction

Detailed Description

Evidence shows independent associations between hyperuricaemia and the risk of cardio-renal conditions, including heart failure (HF). Serum uric acid (sUA) is also a strong prognostic factor and correlates with other markers of poor prognosis in HF patients with preserved ejection fraction (HFpEF), and an estimated 1/2-2/3 of HFpEF patients have hyperuricaemia. HFpEF is a microvascular disease likely partly driven by endothelial dysfunction and inflammation in coronary vessel walls. Uric acid crystals have been identified in coronary vessel walls in some hyperuricaemic patients.

Uric acid transporter 1 (URAT1) is responsible for reabsorption of uric acid (UA) in the proximal tubule. Inhibition of URAT1 results in increased urinary excretion of UA and lowering of uric acid in the blood. Verinurad is a novel URAT1 inhibitor in Phase 2 development for chronic kidney disease (CKD) and HF. Verinurad combined with the xanthine oxidase (XO) inhibitors (XOI) febuxostat or allopurinol has been shown to lower sUA in patients with recurrent gout in Phase 2 studies by up to approximately 80%.

The primary objective of this Phase 2 study is to assess the effect of a combination of verinurad and allopurinol on exercise capacity in patients with HFpEF.

The secondary objectives are to assess effect of combination of verinurad and allopurinol in comparison to allopurinol monotheraphy on excercise capacity dwhich will be measured in peak VO2 as well as effect of verinurad and allopurinol compared to placebo and to allopurinol monotheraphy on Kansas City cardiomyopathy questionnaire (KCCQ)-total symptom score (TSS). A sub-study aims to investigate the relationship between UA crystals and inflammation.

Conditions

Heart Failure With Preserved Ejection Fraction (HFpEF)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Verinurad 12 + allopurinol

Dose [mg] verinurad/allopurinol:

Step 1 - titration_3/100 Step 2 - titration_7.5/200 Step 3 - target dose 12/300

Group Type: EXPERIMENTAL

Verinurad

Intervention Type: DRUG

The treatment will be titrated in 3 steps for target low dose (3 mg), intermediate dose (7.5 mg) and high dose (12mg) of verinurad.

Drug: Allopurinol The treatment will be titrated in 3 steps. Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol.

Allopurinol

Intervention Type: DRUG

Study treatments will be titrated in 3 steps: Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol

Allopurinol alone

Dose [mg] verinurad/allopurinol:

Step 1 - titration_0/100 Step 2 - titration_0/200 Step 3 - target dose 0/300

Group Type: EXPERIMENTAL

Allopurinol

Intervention Type: DRUG

Study treatments will be titrated in 3 steps: Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol

Placebo

Placebo \[mg\] in 3 steps 0/0

Group Type: PLACEBO_COMPARATOR

Placebo for verinurad

Intervention Type: DRUG

Matching Capsule

Placebo for allopurinol

Intervention Type: DRUG

Matching tablet

Interventions

Verinurad

The treatment will be titrated in 3 steps for target low dose (3 mg), intermediate dose (7.5 mg) and high dose (12mg) of verinurad.

Drug: Allopurinol The treatment will be titrated in 3 steps. Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol.

Intervention Type: DRUG

Allopurinol

Study treatments will be titrated in 3 steps: Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol

Intervention Type: DRUG

Placebo for verinurad

Matching Capsule

Intervention Type: DRUG

Placebo for allopurinol

Matching tablet

Intervention Type: DRUG

Other Intervention Names

verinurad titration 3 - 7.5 - 12mg; allopurinol titration 100 - 200 - 300 mg; allopurinol titration 100 - 200 - 300 mg; Placebo; Placebo

Eligibility Criteria

Inclusion Criteria

• Patient must be ≥ 40 years of age at the time of signing the ICF
• Patients with hyperuricaemia defined as sUA level of > 6 mg/dL.
• Patients with documented diagnosis of symptomatic HFpEF according to all of the following criteria:

1. Have NYHA functional class II-III at enrolment

2. Have medical history of typical symptoms/signs of HF > 6 weeks before enrolment

3. LVEF ≥ 45%

4. NT-proBNP ≥ 125 pg/mL (≥ 14.75 pmol/L) at Visit 1 for patients without ongoing atrial fibrillation/flutter.

• Patients able to exercise to near exhaustion during a CPET as exhibited by RER

≥ 1.05 during CPET conducted during screening. If patient does not achieve RER ≥ 1.05 the CPET may be repeated once, at least 48 hours but less than 2 weeks (but before randomisation) after the initial test; in such cases the second test will serve as baseline.

• Male or female

Exclusion Criteria

• eGFR < 30ml/min/1.73m2 (based on CKD-EPI formula)
• Presence of any condition that precludes exercise testing
• Known history of a documented LVEF < 40%
• Probable alternative or concomitant diagnoses which in the opinion of the Investigator could account for the patient's HF symptoms and signs (eg, anaemia, hypothyroidism)
• Known carrier of the Human Leukocyte Antigen-B (HLA-B) *58:01 allele: HLA-B

*58:01 genotyping is mandatory prior to randomization for all patients.

• Patients diagnosed with tumor lysis syndrome or Lesch-Nyhan syndrome
• Patients who are severely physically or mentally incapacitated and who in the opinion of investigator are unable to perform the patients' tasks associated with the protocol
• Presence of any condition which, in the opinion of the investigator, places the patient at undue risk or potentially jeopardises the quality of the data to be generated
• Current acute decompensated HF or hospitalisation due to decompensated HF < 4 weeks prior to enrolment
• Myocardial infarction, unstable angina, coronary revascularisation (percutaneous coronary intervention or coronary artery bypass grafting), ablation of atrial flutter/fibrillation, valve repair/replacement, implantation of a cardiac resynchronisation therapy device, stroke or transient ischemic attack within 6 months prior to enrolment.
• Planned coronary revascularisation, ablation of atrial flutter/fibrillation and/or valve repair/replacement
• Atrial fibrillation with persistent resting heart rate > 110 beats per minute.

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 130 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Dalane Kitzman, MD

Role: PRINCIPAL_INVESTIGATOR

1326 Riverview Road Ext Lexington, NC 27292-1764 USA

Locations

Research Site

Granada Hills, California, United States

Research Site

Northridge, California, United States

Research Site

Torrance, California, United States

Research Site

Miami, Florida, United States

Research Site

Pembroke Pines, Florida, United States

Research Site

Port Orange, Florida, United States

Research Site

Winston-Salem, North Carolina, United States

Research Site

Norfolk, Virginia, United States

Research Site

CABA, , Argentina

Research Site

CABA, , Argentina

Research Site

CABA, , Argentina

Research Site

Mar del Plata, , Argentina

Research Site

Mar del Plata, , Argentina

Research Site

Rosario, , Argentina

Research Site

Bedford Park, , Australia

Research Site

Chermside, , Australia

Research Site

Geelong, , Australia

Research Site

Milton, , Australia

Research Site

Graz, , Austria

Research Site

Vienna, , Austria

Research Site

Plovdiv, , Bulgaria

Research Site

Sofia, , Bulgaria

Research Site

Sofia, , Bulgaria

Research Site

Québec, Quebec, Canada

Research Site

Québec, Quebec, Canada

Research Site

Québec, Quebec, Canada

Research Site

Québec, Quebec, Canada

Research Site

Bad Oeynhausen, , Germany

Research Site

Berlin, , Germany

Research Site

Berlin, , Germany

Research Site

Göttingen, , Germany

Research Site

Regensburg, , Germany

Research Site

Würzburg, , Germany

Research Site

Querétaro, , Mexico

Research Site

Bydgoszcz, , Poland

Research Site

Chojnice, , Poland

Research Site

Chrzanów, , Poland

Research Site

Lublin, , Poland

Research Site

Tychy, , Poland

Research Site

Warsaw, , Poland

Research Site

Warsaw, , Poland

Research Site

Warsaw, , Poland

Research Site

Aramil, , Russia

Research Site

Kemerovo, , Russia

Research Site

Novosibirsk, , Russia

Research Site

Saint Petersburg, , Russia

Research Site

Saint Petersburg, , Russia

Research Site

Tomsk, , Russia

Research Site

Brezno, , Slovakia

Research Site

Lučenec, , Slovakia

Research Site

Prešov, , Slovakia

Research Site

Svidník, , Slovakia

Research Site

Cheongju-si, , South Korea

Research Site

Gangwon-do, , South Korea

Research Site

Seoul, , South Korea

Research Site

Seoul, , South Korea

Research Site

Seoul, , South Korea

Research Site

Seoul, , South Korea

Countries

United States; Argentina; Australia; Austria; Bulgaria; Canada; Germany; Mexico; Poland; Russia; Slovakia; South Korea

References

Kitzman DW, Voors AA, Mentz RJ, Lewis GD, Perl S, Myte R, Kaguthi G, Sjostrom CD, Kallgren C, Shah SJ. Verinurad Plus Allopurinol for Heart Failure With Preserved Ejection Fraction: The AMETHYST Randomized Clinical Trial. JAMA Cardiol. 2024 Oct 1;9(10):892-900. doi: 10.1001/jamacardio.2024.2435.

Reference Type: DERIVED

PMID: 39141378 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

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Clinical Study Protocol Redacted

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CSR\_synopsis\_redacted

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Statistical Analysis Plan-redacted

Other Identifiers

2019-004862-16

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

D5496C00005

Identifier Type: -

Identifier Source: org_study_id