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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT04327024
Registration number
NCT04327024
Ethics application status
Date submitted
13/03/2020
Date registered
30/03/2020
Titles & IDs
Public title
Study of Verinurad in Heart Failure With Preserved Ejection Fraction
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Scientific 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
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Secondary ID [1]
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2019-004862-16
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Secondary ID [2]
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D5496C00005
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Universal Trial Number (UTN)
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Trial acronym
AMETHYST
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Heart Failure With Preserved Ejection Fraction (HFpEF)
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Condition category
Condition code
Cardiovascular
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Coronary heart disease
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Cardiovascular
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Other cardiovascular diseases
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Verinurad
Treatment: Drugs - Allopurinol
Treatment: Drugs - Placebo for verinurad
Treatment: Drugs - Placebo for allopurinol
Experimental: Verinurad 12 + allopurinol - Dose \[mg\] verinurad/allopurinol:
Step 1 - titration_3/100 Step 2 - titration_7.5/200 Step 3 - target dose 12/300
Experimental: Allopurinol alone - Dose \[mg\] verinurad/allopurinol:
Step 1 - titration_0/100 Step 2 - titration_0/200 Step 3 - target dose 0/300
Placebo comparator: Placebo - Placebo \[mg\] in 3 steps 0/0
Treatment: Drugs: Verinurad
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.
Treatment: Drugs: Allopurinol
Study treatments will be titrated in 3 steps: Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol
Treatment: Drugs: Placebo for verinurad
Matching Capsule
Treatment: Drugs: Placebo for allopurinol
Matching tablet
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Change From Baseline at Week 32 in Peak V02 Consumption in Verinurad + Allopurinol Compared to Placebo (ANCOVA Model)
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Assessment method [1]
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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.
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Timepoint [1]
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From baseline to Week 32
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Secondary outcome [1]
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Change From Baseline at Week 32 in Peak V02 Consumption in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (ANCOVA Model)
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Assessment method [1]
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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.
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Timepoint [1]
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From baseline to Week 32
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Secondary outcome [2]
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Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Placebo (MMRM)
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Assessment method [2]
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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.
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Timepoint [2]
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From baseline to Week 22 and Week 32
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Secondary outcome [3]
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Change From Baseline at Week 32 in KCCQ-TSS in Verinurad+ Allopurinol Compared to Allopurinol Monotherapy (MMRM)
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Assessment method [3]
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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.
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Timepoint [3]
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From baseline to Week 22 and Week 32
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Eligibility
Key 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
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Minimum age
40
Years
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Maximum age
130
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
19/05/2020
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
29/04/2022
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Sample size
Target
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Accrual to date
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Final
159
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Recruitment in Australia
Recruitment state(s)
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Recruitment hospital [1]
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Research Site - Bedford Park
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Recruitment hospital [2]
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Research Site - Chermside
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Recruitment hospital [3]
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Research Site - Geelong
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Recruitment hospital [4]
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Research Site - Milton
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Recruitment postcode(s) [1]
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5042 - Bedford Park
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Recruitment postcode(s) [2]
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4032 - Chermside
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Recruitment postcode(s) [3]
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3220 - Geelong
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Recruitment postcode(s) [4]
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4064 - Milton
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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United States of America
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Florida
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United States of America
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North Carolina
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United States of America
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Virginia
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Argentina
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Caba
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Argentina
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Mar del Plata
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Argentina
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Rosario
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Austria
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Graz
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Austria
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Wien
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Bulgaria
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Plovdiv
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Bulgaria
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Sofia
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Canada
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Quebec
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Germany
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Germany
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Berlin
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Germany
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Göttingen
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Germany
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Regensburg
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Germany
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Würzburg
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Gangwon-do
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Seoul
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Mexico
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Querétaro
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Bydgoszcz
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Chojnice
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Chrzanów
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Lublin
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Tychy
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Warszawa
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Russian Federation
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Aramil
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Russian Federation
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Kemerovo
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Russian Federation
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Novosibirsk
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Saint-Petersburg
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Russian Federation
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St Petersburg
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Tomsk
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Lucenec
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Presov
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Slovakia
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Svidnik
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
AstraZeneca
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Address
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Ethics approval
Ethics application status
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Summary
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
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Trial website
https://clinicaltrials.gov/study/NCT04327024
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Dalane Kitzman, MD
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Address
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1326 Riverview Road Ext Lexington, NC 27292-1764 USA
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared
Supporting document/s available: Study protocol, Statistical analysis plan (SAP)
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When will data be available (start and end dates)?
AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
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Available to whom?
When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
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Available for what types of analyses?
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How or where can data be obtained?
IPD available at link: https://astrazenecagroup-dt.pharmacm.com/DT/Home
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What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/24/NCT04327024/Prot_000.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/24/NCT04327024/SAP_001.pdf
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results not provided in
https://clinicaltrials.gov/study/NCT04327024