Study of Verinurad in Heart Failure With Preserved Ejection Fraction (AMETHYST)

June 12, 2023 updated by: AstraZeneca

A Phase 2, Multicentre, Double-Blind, Placebo and Active Control Efficacy and Safety Study to Evaluate Verinurad Combined With Allopurinol in Heart Failure With Preserved Ejection Fraction

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

159

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Argentina
      • Caba, Argentina, C1119ACN
        • Research Site
      • Caba, Argentina, C1425AGC
        • Research Site
      • Caba, Argentina, C1006ACC
        • Research Site
      • Mar del Plata, Argentina, 7600
        • Research Site
      • Mar del Plata, Argentina, B7600GNY
        • Research Site
      • Rosario, Argentina, 2000
        • Research Site
  • Australia
      • Bedford Park, Australia, 5042
        • Research Site
      • Chermside, Australia, 4032
        • Research Site
      • Geelong, Australia, 3220
        • Research Site
      • Milton, Australia, 4064
        • Research Site
  • Austria
      • Graz, Austria, 8036
        • Research Site
      • Wien, Austria, 1090
        • Research Site
  • Bulgaria
      • Plovdiv, Bulgaria, 4004
        • Research Site
      • Sofia, Bulgaria, 1000
        • Research Site
      • Sofia, Bulgaria, 1431
        • Research Site
  • Canada
      • Quebec, Canada, G1G 3Y8
        • Research Site
      • Quebec, Canada, G1V 4G5
        • Research Site
      • Quebec, Canada, G3K 2P8
        • Research Site
      • Quebec, Canada, G2J 0C4
        • Research Site
  • Germany
      • Bad Oeynhausen, Germany, 32545
        • Research Site
      • Berlin, Germany, 13353
        • Research Site
      • Berlin, Germany, 10789
        • Research Site
      • Göttingen, Germany, 37075
        • Research Site
      • Regensburg, Germany, 93053
        • Research Site
      • Würzburg, Germany, 97078
        • Research Site
  • Korea, Republic of
      • Cheongju-si, Korea, Republic of, 28644
        • Research Site
      • Gangwon-do, Korea, Republic of, 26426
        • Research Site
      • Seoul, Korea, Republic of, 03722
        • Research Site
      • Seoul, Korea, Republic of, 05505
        • Research Site
      • Seoul, Korea, Republic of, 03080
        • Research Site
      • Seoul, Korea, Republic of, 08308
        • Research Site
  • Mexico
      • Querétaro, Mexico, 76000
        • Research Site
  • Poland
      • Bydgoszcz, Poland, 85-079
        • Research Site
      • Chojnice, Poland, 89-600
        • Research Site
      • Chrzanów, Poland, 32-500
        • Research Site
      • Lublin, Poland, 20-362
        • Research Site
      • Tychy, Poland, 43-100
        • Research Site
      • Warszawa, Poland, 02-097
        • Research Site
      • Warszawa, Poland, 02-637
        • Research Site
      • Warszawa, Poland, 04-628
        • Research Site
  • Russian Federation
      • Aramil, Russian Federation, 624002
        • Research Site
      • Kemerovo, Russian Federation, 650002
        • Research Site
      • Novosibirsk, Russian Federation, 630055
        • Research Site
      • Saint-Petersburg, Russian Federation, 199226
        • Research Site
      • St Petersburg, Russian Federation, 195067
        • Research Site
      • Tomsk, Russian Federation, 634012
        • Research Site
  • Slovakia
      • Brezno, Slovakia, 97742
        • Research Site
      • Lucenec, Slovakia, 984 01
        • Research Site
      • Presov, Slovakia, 080 01
        • Research Site
      • Svidnik, Slovakia, 08901
        • Research Site
  • United States
    • California
      • Granada Hills, California, United States, 91344
        • Research Site
      • Northridge, California, United States, 91324
        • Research Site
      • Torrance, California, United States, 90502
        • Research Site
    • Florida
      • Miami, Florida, United States, 33135
        • Research Site
      • Pembroke Pines, Florida, United States, 33024
        • Research Site
      • Port Orange, Florida, United States, 32127
        • Research Site
    • North Carolina
      • Winston-Salem, North Carolina, United States, 27157
        • Research Site
    • Virginia
      • Norfolk, Virginia, United States, 23510
        • Research Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 130 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Verinurad 12 + allopurinol

Dose [mg] verinurad/allopurinol:

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

Other Names:
  • verinurad titration 3 - 7.5 - 12mg
  • allopurinol titration 100 - 200 - 300 mg
Drug: Allopurinol
Study treatments will be titrated in 3 steps: Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol
Other Names:
  • allopurinol titration 100 - 200 - 300 mg
Experimental: Allopurinol alone

Dose [mg] verinurad/allopurinol:

Step 1 - titration_0/100 Step 2 - titration_0/200 Step 3 - target dose 0/300
Drug: Allopurinol
Study treatments will be titrated in 3 steps: Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol
Other Names:
  • allopurinol titration 100 - 200 - 300 mg
Placebo Comparator: Placebo
Placebo [mg] in 3 steps 0/0
Drug: Placebo for verinurad
Matching Capsule
Other Names:
  • Placebo
Drug: Placebo for allopurinol
Matching tablet
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline at Week 32 in Peak V02 Consumption in Verinurad + Allopurinol Compared to Placebo (ANCOVA Model)
Time Frame: From baseline to Week 32

Mean change from baseline in peak VO2 at Week 32 between the treatment groups was compared using change from baseline (i.e., week 32 value - baseline value) as the dependent variable, treatment as the independent variable and baseline peak VO2 included as covariate.

H0: Difference in mean change from baseline in peak VO2 (verinurad + allopurinol vs placebo) = 0 Ha: Difference in mean change from baseline in peak VO2 (verinurad + allopurinol vs placebo) ≠ 0

A hierarchical test sequence was used for the confirmatory analysis of the primary and secondary objectives in order to address the issue of multiple testing and control the Type I error rate at an overall two-sided 0.05 level.

Since this was the first test in the hierarchical test sequence and endpoint was not rejected at a two-sided 0.05 level, the testing sequence did not continue.
From baseline to Week 32

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline at Week 32 in Peak V02 Consumption in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (ANCOVA Model)
Time Frame: From baseline to Week 32

Mean change from baseline in peak VO2 at Week 32 between the treatment groups was compared using change from baseline (i.e., week 32 value - baseline value) as the dependent variable, treatment as the independent variable and baseline peak VO2 included as covariate.

H0: Difference in mean change from baseline in peak VO2 (verinurad + allopurinol vs allopurinol) = 0 Ha: Difference in mean change from baseline in peak VO2 (verinurad + allopurinol vs allopurinol) ≠ 0

A hierarchical test sequence was used for the confirmatory analysis of the primary and secondary objectives in order to address the issue of multiple testing and control the Type I error rate at an overall two-sided 0.05 level.
From baseline to Week 32
Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Placebo (MMRM)
Time Frame: From baseline to Week 22 and Week 32

The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item assessment that measures the patient's perception of their health status, which includes heart failure-related symptoms (frequency, burden, recent change), impact on physical and social function, self-efficacy and knowledge, and how the patient's heart failure affects their quality of life. The Total Symptom Score (TSS) averages the frequency domain and the symptom burden domain subscales, which each range from 0 to 100. The TSS ranges from 0-100 (higher scores = better health status).

Mean change from baseline in KCCQ-TSS at Week 32 between the treatment groups was compared using MMRM analysis, with change from baseline (i.e., week 32 value - baseline value) as the dependent variable, treatment as the independent variable and visit, visit by treatment, and baseline KCCQ-TSS included as covariates.

The number analyzed at each timepoint represents the number of subjects with data at each visit.
From baseline to Week 22 and Week 32
Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (MMRM)
Time Frame: From baseline to Week 22 and Week 32

The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item assessment that measures the patient's perception of their health status, which includes heart failure-related symptoms (frequency, burden, recent change), impact on physical and social function, self-efficacy and knowledge, and how the patient's heart failure affects their quality of life. The Total Symptom Score (TSS) averages the frequency domain and the symptom burden domain subscales, which each range from 0 to 100. The TSS ranges from 0-100 (higher scores = better health status).

Mean change from baseline in KCCQ-TSS at Week 32 between the treatment groups was compared using MMRM analysis, with change from baseline (i.e., week 32 value - baseline value) as the dependent variable, treatment as the independent variable and visit, visit by treatment, and baseline KCCQ-TSS included as covariates.

The number analyzed at each timepoint represents the number of subjects with data at each visit.
From baseline to Week 22 and Week 32

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

AstraZeneca

Investigators

  • Principal Investigator: Dalane Kitzman, MD, 1326 Riverview Road Ext Lexington, NC 27292-1764 USA

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 19, 2020

Primary Completion (Actual)

April 29, 2022

Study Completion (Actual)

April 29, 2022

Study Registration Dates

First Submitted

March 13, 2020

First Submitted That Met QC Criteria

March 27, 2020

First Posted (Actual)

March 30, 2020

Study Record Updates

Last Update Posted (Actual)

June 29, 2023

Last Update Submitted That Met QC Criteria

June 12, 2023

Last Verified

June 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • D5496C00005
  • 2019-004862-16 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared

IPD Sharing Time Frame

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

IPD Sharing Access Criteria

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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