Clinical trial NCT04327024: Study of Verinurad in Heart Failure With Preserved Ejection Fraction
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure With Preserved Ejection Fraction (HFpEF)
Keywords: Phase 2,
Double-Blind,
Placebo and Active Control,
Verinurad,
Allopurinol,
HFpEF,
Heart Failure
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2020-03-30
Enrollment: 159
Sex: ALL
Minimum age (years): 40
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change From Baseline at Week 32 in Peak V02 Consumption in Verinurad + Allopurinol Compared to Placebo (ANCOVA Model)
timeFrame: From baseline to Week 32
Secondary outcomes:
measure: Change From Baseline at Week 32 in Peak V02 Consumption in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (ANCOVA Model)
timeFrame: From baseline to Week 32
measure: Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Placebo (MMRM)
timeFrame: From baseline to Week 22 and Week 32
measure: Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (MMRM)
timeFrame: From baseline to Week 22 and Week 32
Other outcomes:
Locations:
city: Granada Hills
country: United States
facility: Research Site
state: California
city: Northridge
country: United States
facility: Research Site
state: California
city: Torrance
country: United States
facility: Research Site
state: California
city: Miami
country: United States
facility: Research Site
state: Florida
city: Pembroke Pines
country: United States
facility: Research Site
state: Florida
city: Port Orange
country: United States
facility: Research Site
state: Florida
city: Winston-Salem
country: United States
facility: Research Site
state: North Carolina
city: Norfolk
country: United States
facility: Research Site
state: Virginia
city: Caba
country: Argentina
facility: Research Site
city: Caba
country: Argentina
facility: Research Site
city: Caba
country: Argentina
facility: Research Site
city: Mar del Plata
country: Argentina
facility: Research Site
city: Mar del Plata
country: Argentina
facility: Research Site
city: Rosario
country: Argentina
facility: Research Site
city: Bedford Park
country: Australia
facility: Research Site
city: Chermside
country: Australia
facility: Research Site
city: Geelong
country: Australia
facility: Research Site
city: Milton
country: Australia
facility: Research Site
city: Graz
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Quebec
country: Canada
facility: Research Site
city: Quebec
country: Canada
facility: Research Site
city: Quebec
country: Canada
facility: Research Site
city: Quebec
country: Canada
facility: Research Site
city: Bad Oeynhausen
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Göttingen
country: Germany
facility: Research Site
city: Regensburg
country: Germany
facility: Research Site
city: Würzburg
country: Germany
facility: Research Site
city: Cheongju-si
country: Korea, Republic of
facility: Research Site
city: Gangwon-do
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Querétaro
country: Mexico
facility: Research Site
city: Bydgoszcz
country: Poland
facility: Research Site
city: Chojnice
country: Poland
facility: Research Site
city: Chrzanów
country: Poland
facility: Research Site
city: Lublin
country: Poland
facility: Research Site
city: Tychy
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Aramil
country: Russian Federation
facility: Research Site
city: Kemerovo
country: Russian Federation
facility: Research Site
city: Novosibirsk
country: Russian Federation
facility: Research Site
city: Saint-Petersburg
country: Russian Federation
facility: Research Site
city: St Petersburg
country: Russian Federation
facility: Research Site
city: Tomsk
country: Russian Federation
facility: Research Site
city: Brezno
country: Slovakia
facility: Research Site
city: Lucenec
country: Slovakia
facility: Research Site
city: Presov
country: Slovakia
facility: Research Site
city: Svidnik
country: Slovakia
facility: Research Site
Study officials:
affiliation: 1326 Riverview Road Ext Lexington, NC 27292-1764 USA
name: Dalane Kitzman, MD
role: PRINCIPAL_INVESTIGATOR
References: