Study of Verinurad in Heart Failure With Preserved Ejection Fraction

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Heart Failure With Preserved Ejection Fraction (HFpEF)

Intervention / Treatment
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* Drug: Verinurad
* Drug: Allopurinol
* Drug: Placebo for verinurad
* Drug: Placebo for allopurinol


Participation Criteria
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Eligibility Criteria
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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: Have NYHA functional class II-III at enrolment Have medical history of typical symptoms/signs of HF > 6 weeks before enrolment LVEF ≥ 45% 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Verinurad 12 + allopurinol<br>Dose [mg] verinurad/allopurinol: Step 1 - titration_3/100 Step 2 - titration_7.5/200 Step 3 - target dose 12/300 | Drug: Verinurad<br>* 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.<br>* Other names: allopurinol titration 100 - 200 - 300 mg;Drug: Allopurinol<br>* Study treatments will be titrated in 3 steps: Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol<br>* Other names: allopurinol titration 100 - 200 - 300 mg;|
| Experimental: Allopurinol alone<br>Dose [mg] verinurad/allopurinol: Step 1 - titration_0/100 Step 2 - titration_0/200 Step 3 - target dose 0/300 | Drug: Allopurinol<br>* Study treatments will be titrated in 3 steps: Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol<br>* Other names: allopurinol titration 100 - 200 - 300 mg;|
| Placebo Comparator: Placebo<br>Placebo [mg] in 3 steps 0/0 | Drug: Placebo for verinurad<br>* Matching Capsule<br>* Other names: Placebo;Drug: Placebo for allopurinol<br>* Matching tablet<br>* Other names: Placebo;|

What is the study measuring?
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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) | 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) | 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) | 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) | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 2,, Double-Blind,, Placebo and Active Control,, Verinurad,, Allopurinol,, HFpEF,, Heart Failure