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

AstraZeneca

Status and phase: Completed; Phase 2

Conditions: Heart Failure With Preserved Ejection Fraction (HFpEF)

Treatments: Drug: Verinurad; Drug: Allopurinol; Drug: Placebo for verinurad; Drug: Placebo for allopurinol

Study type: Interventional

Funder types: Industry

Identifiers

NCT04327024

2019-004862-16 (EudraCT Number)

D5496C00005

Details and patient eligibility

About

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

Full 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.

Enrollment: 159 patients

Sex: All

Ages: 40 to 130 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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159 participants in 3 patient groups, including a placebo group

Verinurad 12 + allopurinol

Experimental group

Description:

Dose \[mg\] verinurad/allopurinol: Step 1 - titration_3/100 Step 2 - titration_7.5/200 Step 3 - target dose 12/300

Treatment:

Drug: Allopurinol

Drug: Verinurad

Allopurinol alone

Experimental group

Description:

Dose \[mg\] verinurad/allopurinol: Step 1 - titration_0/100 Step 2 - titration_0/200 Step 3 - target dose 0/300

Treatment:

Drug: Allopurinol

Placebo

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo for allopurinol

Drug: Placebo for verinurad