Study of Verinurad in Heart Failure With Preserved Ejection Fraction

Inclusion Criteria:

- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the Informed Consent Form and in the protocol.

- Provision of signed and dated, written Informed Consent Form prior to any mandatory study-specific procedures, sampling, and analyses.

- Provision of signed and dated written genetic informed consent prior to collection of

- sample for genetic analysis.

- Patient must be ≥ 40 years of age at the time of signing the Informed Consent Form.

- Patients with hyperuricaemia defined as serum uric acid level of > 6 mg/dL.

- Patients with documented diagnosis of symptomatic heart failure with preserved ventricular ejction faction according to all of the following criteria:

1. Have New York Heart Association functional class II-III at enrolment

2. Have medical history of typical symptoms/signs of Heart Failure > 6 weeks before enrolment, which is stably treated medically, with at least intermittent need for diuretic treatment. Typical symptoms of Heart Failure include breathlessness, orthopnoea, paroxysmal nocturnal dyspnoea, reduced exercise tolerance, fatigue, tiredness, increased time to recover after exercise, ankle swelling. Typical signs associated with Heart Failure include elevated jugular venous pressure, hepatojugular reflex, third heart sound (galop rhythm). Less specific symptoms include: weight gain (> 2 kg/week), weight loss (in advanced Heart Failure), tissue wasting (cachexia), cardiac murmur, peripheral oedema (ankle, sacral, scrotal), pulmonary crepitations, reduced air entry and dullness to percussion at lung bases (pleural effusion), tachycardia, irregular pulse, tachypnoea, Cheyne- Stokes respiration, hepatomegaly, ascites, cold extremities, oliguria, narrow pulse pressure.

3. Left Ventricular Ejection Fraction ≥ 45%

4. N-terminal pro b-type natriuretic peptide ≥ 125 pg/mL (≥ 14.75 pmol/L) at Visit 2 for patients without ongoing atrial fibrillation/flutter. If ongoing atrial fibrillation/flutter at the time of sample collection, N-terminal pro b-type natriuretic peptide must be ≥ 250 pg/mL (≥ 29.51 pmol/L) or patients must have a history of pulmonary capillary wedge pressure ≥ 15 mm Hg during rest or pulmonary capillary wedge pressure ≥ 20 mm Hg during exercise.

- Patients able to exercise to near exhaustion during a cardiopulmonary exercise test as exhibited by respiratory exchange ratio ≥ 1.05 during cardiopulmonary exercise test conducted during screening. If patient does not achieve respiratory exchange ratio ≥ 1.05 the cardiopulmonary exercise test 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.

- Patients with peak volume of oxygen ≤ 75% of expected using treadmill, or peak volume of oxygen ≤ 68% of expected using cycle ergometer, based on normal values.

- Patients treated according to locally recognised guidelines on standard-of-care treatment for patients with heart failure with preserved ventricular ejction faction. Therapy should have been individually optimised and stable for ≥ 4 weeks (except diuretics) and include, unless contraindicated or not tolerated, treatment of high blood pressure (targeting a systolic blood pressure < 130mm Hg as suggested in 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America Heart Failure guidelines), ischaemic heart disease, and atrial fibrillation.

- Patients treated with a sodium-glucose transport protein 2 inhibitor or sacubitril/valsartan must be on stable dose for ≥ 4 weeks before randomisation.

- Male or female

- Negative pregnancy test (urine or serum) for female patients of childbearing potential.Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (with a failure rate of < 1% per year) for the duration of the study (from the time they sign consent) and for 4 weeks after the last dose of study treatment to prevent pregnancy. Patients agreeing to total sexual abstinence can also be included, assuming it is their usual lifestyle.

Exclusion Criteria:

- Estimated Glomerular Filtration Rate < 30ml/min/1.73m2 (based on Chronic Kidney Disease Epidemiology Collaboration formula)

- Severe hepatic impairment (Child-Pugh class C)

- Presence of any condition that precludes exercise testing such as:

1. Claudication that limits exertion

2. Uncontrolled bradyarrhythmia or tachyarrhythmia (according to Investigator judgement, pacemaker treatment is allowed as long as the same pacing mode/activity can be used at baseline and follow-up cardiopulmonary exercise test)

3. Clinically significant musculoskeletal disease or orthopaedic conditions that limit the ability to perform the cardiopulmonary exercise test (eg, arthritis or injury in the foot, leg, knee or hip)

4. Severe obesity (body mass index ≥ 50.0 kg/m2)

5. Amputation with artificial limb without stable prosthesis function for the past 3 months

6. Any condition that, in the opinion of the Investigator, would contraindicate cardiopulmonary exercise test assessment (eg, severe visual impairment)

7. Any condition other than Heart Failure that, in the opinion of the Investigator, is the primary limitation to exercise

- Known history of a documented left ventricular ejection fraction < 40%

- Probable alternative or concomitant diagnoses which in the opinion of the Investigator could account for the patient's Heart Failure symptoms and signs (eg, anaemia, hypothyroidism)

- Known carrier of the human leukocyte antygen HLA-B *58:01 allele. Patients of suspected Han Chinese, Korean or Thai descent, and patients from populations in whom the human leukocyte antygen HLA*B58:01 allele is known to be high shall perform genetical testing, for others the genetic test is at the discretion of the investigator

- 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 Heart Failure or hospitalisation due to decompensated Heart Failure < 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.

- Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary disease including chronic obstructive pulmonary disease (COPD) (ie, requiring home supplemental oxygen, chronic oral steroid therapy use at a dose equivalent to 10 mg prednisone or greater, or hospitalisation for exacerbation of chronic obstructive pulmonary disease COPD requiring ventilatory assist within 12 months prior to enrolment)

- Previous cardiac transplantation, or complex congenital heart disease. Planned cardiac resynchronisation therapy. Prior implantation of a ventricular assistance device or similar device, or implantation expected during the course of the study

- Heart Failure due to known infiltrative cardiomyopathy (eg, amyloid, sarcoid, lymphoma, endomyocardial fibrosis, hemochromatosis), active myocarditis, constrictive pericarditis, cardiac tamponade, known genetic hypertrophic cardiomyopathy or obstructive hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia, or uncorrected severe primary valvular disease

- QT interval corrected by the Fridericia formula (QTcF) > 470 msec; in patients with QRS interval (< 120 ms), patients diagnosed with long QT syndrome; patients with a family history of long QT syndrome

- Uncontrolled hypertension with systolic blood pressure >160 mm Hg and/or diastolic blood pressure >100 mm Hg

- History of blood dyscrasias: Myelosuppression (eg, thrombocytopenia, leukopenia, granulocytopenia, pancytopenia) and aplastic anaemia

- Patients with the following bilateral upper or lower arm pathology can be randomised into the study, but are not allowed to participate in the reactive hyperaemia assessment:

1. Presence of fistula / arteriovenous (AV) Shunt

2. Other structural or vascular abnormality

- Treated with any drug for hyperuricaemia in the 6 months preceding randomisation. Drugs for hyperuricaemia include all xanthine oxidase inhibitors (allopurinol, febuxostat and topiroxostat) and uric acid transporter 1 inhibitors (lesinurad, verinurad, probenecid, and benzbromarone) and urate oxidases (pegloticase, rasburicase).

- Treated with strong or moderate organic anion transporting polypeptide (OATP)

- inhibitors (Entresto is not considered a strong or moderate organic anion transporting polypeptide (OATP) ihibitor).

- Patients treated with strong P-glycoprotein and/or CYP3A4 inhibitors due to the potential drug-drug interaction with colchicine

- Participation in another clinical study with an investigational product administered (currently or within 1 month prior to screening).

- Participating in a structured exercise training programme in the 1 month prior to screening or planned to start during the trial

- Claustrophobia

- Involvement in the planning and/or conduct of the study (applies to both AZ staff and/or staff at the study site).

- Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.

- Screened more than once or previous randomisation in the present study.

- Known hypersensitivity to or previous anaphylactic reaction to allopurinol or any organic anion transporting polypeptide inhibitor, including severe cutaneous adverse reaction triggered by allopurinol

- Patients who are pregnant (confirmed with pregnancy test), lactating, or planning tobecome pregnant.