Heart Failure With Preserved Ejection Fraction (HFpEF)
Conditions
Keywords
Phase 2,, Double-Blind,, Placebo and Active Control,, Verinurad,, Allopurinol,, HFpEF,, Heart Failure
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.
Interventions
DRUGVerinurad
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.
DRUGAllopurinol
Study treatments will be titrated in 3 steps: Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol
Matching Capsule
Matching tablet
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 130 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 32 in Peak V02 Consumption in Verinurad + Allopurinol Compared to Placebo (ANCOVA Model) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 32 in Peak V02 Consumption in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (ANCOVA Model) | 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. |
| Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Placebo (MMRM) | 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. |
| Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (MMRM) | 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. |
Countries
Argentina, Australia, Austria, Bulgaria, Canada, Germany, Mexico, Poland, Russia, Slovakia, South Korea, United States
Participant flow
Recruitment details
475 subjects were screened between May 19, 2020, and July 16, 2021, at 59 sites in 12 different countries. Of those screened, 159 were randomized into the study and received treatment, 53 in each arm of the study.
Pre-assignment details
Subjects who met all the of inclusion criteria and none of the exclusion criteria were randomized to a study treatment. Study treatment was titrated over 8 weeks. Colchicine prophylaxis was given during the titration period and during the first 4 weeks of treatment at target dose (12 weeks total) and was distributed as available, currently 500 μg within the European Union (EU) and 600 μg within the United States (US).
Participants by arm
| Arm | Count |
|---|---|
| Verinurad + Allopurinol 12 mg verinurad + 300 mg allopurinol | 53 |
| Allopurinol 300 mg Allopurinol | 53 |
| Placebo 0 mg placebo | 53 |
| Total | 159 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 2 | 1 |
| Overall Study | Non-compliance with study drug | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Verinurad + Allopurinol | Allopurinol | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 69.6 Years STANDARD_DEVIATION 9.04 | 70.6 Years STANDARD_DEVIATION 6.98 | 67.5 Years STANDARD_DEVIATION 9.77 | 69.2 Years STANDARD_DEVIATION 8.72 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 4 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants | 47 Participants | 49 Participants | 146 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants | 3 Participants | 4 Participants | 14 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 46 Participants | 46 Participants | 48 Participants | 140 Participants |
| Sex: Female, Male Female | 21 Participants | 19 Participants | 16 Participants | 56 Participants |
| Sex: Female, Male Male | 32 Participants | 34 Participants | 37 Participants | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 53 | 2 / 53 | 1 / 53 |
| other Total, other adverse events | 24 / 53 | 26 / 53 | 20 / 53 |
| serious Total, serious adverse events | 10 / 53 | 10 / 53 | 9 / 53 |
Outcome results
Primary
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.
Time frame: From baseline to Week 32
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Verinurad + Allopurinol | Change From Baseline at Week 32 in Peak V02 Consumption in Verinurad + Allopurinol Compared to Placebo (ANCOVA Model) | 0.27 mL/kg/min |
| Placebo | Change From Baseline at Week 32 in Peak V02 Consumption in Verinurad + Allopurinol Compared to Placebo (ANCOVA Model) | 0.37 mL/kg/min |
p-value: 0.86295% CI: [-1.28, 1.08]ANCOVA
Secondary
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.
Time frame: From baseline to Week 22 and Week 32
Population: Full Analysis Set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Verinurad + Allopurinol | Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (MMRM) | Week 22 | 0.50 Scores on a scale |
| Verinurad + Allopurinol | Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (MMRM) | Week 32 | 4.31 Scores on a scale |
| Placebo | Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (MMRM) | Week 22 | 2.85 Scores on a scale |
| Placebo | Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (MMRM) | Week 32 | 4.45 Scores on a scale |
Comparison: H0: Difference in mean change from baseline in KCCQ-TSS (verinurad + allopurinol vs allopurinol) = 0 Ha: Difference in mean change from baseline in KCCQ-TSS (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.p-value: 0.9695% CI: [-5.9, 5.61]Mixed Models Analysis
Secondary
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.
Time frame: From baseline to Week 22 and Week 32
Population: Full Analysis Set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Verinurad + Allopurinol | Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Placebo (MMRM) | Week 22 | 0.50 Scores on a scale |
| Verinurad + Allopurinol | Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Placebo (MMRM) | Week 32 | 4.31 Scores on a scale |
| Placebo | Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Placebo (MMRM) | Week 22 | 3.55 Scores on a scale |
| Placebo | Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Placebo (MMRM) | Week 32 | 1.16 Scores on a scale |
Comparison: H0: Difference in mean change from baseline in KCCQ-TSS (verinurad + allopurinol vs placebo) = 0 Ha: Difference in mean change from baseline in KCCQ-TSS (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.p-value: 0.28795% CI: [-2.65, 8.94]Mixed Models Analysis
Secondary
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.
Time frame: From baseline to Week 32
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Verinurad + Allopurinol | Change From Baseline at Week 32 in Peak V02 Consumption in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (ANCOVA Model) | 0.27 mL/Kg/min |
| Placebo | Change From Baseline at Week 32 in Peak V02 Consumption in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (ANCOVA Model) | -0.17 mL/Kg/min |
p-value: 0.47295% CI: [-0.76, 1.64]ANCOVA