Heart FailurePhase 2/3Re-Prosper HFNCT04551222
The Re-Prosper HF Study
A Phase 2/3 study testing probenecid in people with Heart Failure, run by VA Office of Research and Development at 5 sites in United States.
Trial summary
Heart failure with reduced ejection fraction (HFrEF) is a common cause for admission within the Veterans Affairs (VA) Health Care System. It is associated with severe impairment of physical and mental health status and carries a high risk of mortality. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure
- What is being tested?
- probenecid
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 125 participants
- Where
- 5 sitesUnited States
- Study dates
- 9 Jun 2021to 31 Dec 2025
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Have documented heart failure as a treated inpatient or outpatient diagnosis in the medical record.
- Left ventricular ejection 40% within the past 12 months either by echocardiogram, cardiac MRI, cardiac CT, nuclear imaging or cardiac catheterization.
- NYHA class II-III
- On stable GDMT for at least 2 weeks (including at least an EBM dose of betablocker and RAAS inhibition) consistent with the EPHESUS trial criteria [16] or having a documented allergy or adverse reaction to betablocker and/or RAAS inhibition.
- Age 18 years or older.
Who cannot join
- Acute coronary syndrome or cardiac revascularization within the past 3 months.
- End stage renal disease with renal replacement therapy or creatinine clearance less than 30 ml/min [17].
- Cardiac resynchronization therapy within the past 3 months.
- Constrictive pericarditis or restrictive cardiomyopathy on cardiac imaging study (echocardiogram cardiac MRI, cardiac CT) within the last 12 months.
- Ablation for cardiac arrhythmias within the past month.
- Peripartum cardiomyopathy diagnosed within past 6 months. If LVEF is still 40% after 6 months of diagnosis, they can be enrolled into the study.
Show all 17Show fewer
- Uncorrected cyanotic congenital heart disease.
- Severe right sided valvular disease and/or greater than moderate degree of stenotic or regurgitant left valvular disease.
- Terminal illness with expected survival of less than 12 months.
- Women who are pregnant, breast feeding, or plan to become pregnant during the study. All women in childbearing age will undergo baseline and quarterly urine pregnancy tests to ensure absence of pregnancy since the cardiometabolic assessments will be different during pregnancy.
- Oral therapy with probenecid for any indication during the preceding 3 months.
- Hypersensitivity to probenecid based on prior exposure.
- Inability to provide informed consent or study procedures due to dementia, unstable psychiatric disease, or other cause (e.g. inability to do perform exercise testing).
- Acute gout attack within the previous 3 months.
- History of uric acid kidney stones within the last year. Patient will be removed from the study if they develop urate kidney stones.
- History of blood diseases in the past year: Aplastic anemia, Hemolytic anemia, Leukopenia, Neutropenia, Pancytopenia, Thrombocytopenia or leukemia.
- Creatinine clearance (eGFR) <30 ml/min.
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
United States5 sites
VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
Boston, Massachusetts, 02130-4817
Cincinnati VA Medical Center, Cincinnati, OH
Cincinnati, Ohio, 45220-2213
Louis Stokes VA Medical Center, Cleveland, OH
Cleveland, Ohio, 44106-1702
Providence VA Medical Center, Providence, RI
Providence, Rhode Island, 02908-4734
Hunter Holmes McGuire VA Medical Center, Richmond, VA
Richmond, Virginia, 23249-0001
About this study
Official title: Treatment of Veterans With Heart Failure With Reduced Ejection Fraction With Probenecid
Heart failure with reduced ejection fraction (HFrEF) is a common cause for admission within the Veterans Affairs (VA) Health Care System.
It is associated with severe impairment of physical and mental health status and carries a high risk of mortality. Even though significant progress has been made in understanding the disease process, currently, its management and treatment is limited.
Read more
The investigators have discovered that a commonly used drug for the treatment of gout can be repurposed for the treatment of HFrEF.
The objective of this study is the treatment of outpatient Veterans with HFrEF with probenecid to improve heart and health function. Specifically, the investigators are testing whether oral probenecid administered orally twice per day for 180 days improves heart function as measured via ultrasound of the heart (aim 1); improves exercise capacity (aim 2); and improves self-report heart failure specific health status as measured via questionnaires (aim 3).
Read the detailed description
Heart failure with reduced ejection fraction (HFrEF) is a common cause for admission within the Veterans Affairs (VA) Health Care System. It is associated with severe impairment of physical and mental health status and carries a high 5-yr mortality rate of ~75%. Even though significant progress has been made in understanding its pathophysiology, currently, its management and treatment is based on therapeutic targeting of a limited number of receptors and pathways.
The investigators' team and others have made great progress in the last few years by understanding and harnessing the Transient Potential Receptor superfamily as regulators of cardiovascular function. Specifically, the investigators' laboratory has explored the role the vanilloid 2 (TRPV2) subtype plays in regulating calcium handling and contractility. This work has led researchers to understand that TRPV2 modulates contractility via increasing calcium cycling in myocytes on a beat-to-beat basis.
The investigators have used probenecid, a generic, globally available drug with an extremely safe profile that has been used for decades as a treatment for gout, as a TRPV2 agonist. The investigators' work with this drug has demonstrated it to be a potent inotrope without apoptotic, chronotropic or arrhythmogenic effects in cardiomyocytes in vitro as well as in vivo murine and porcine models. These findings have been taken to the bedside with a recently published small phase 2 study of 20 adult patients with HFrEF (the ReProsper HF pilot study) where the investigators demonstrated a mean improvement in left ventricular systolic and diastolic function with no adverse effects after only 1 week of treatment. The use of probenecid in HFrEF was also indirectly supported by a recent retrospective study of approximately 40,000 patients in the Medicare database that found treatment with probenecid (not specifically for heart disease) was associated with a 9% decreased risk of HF hospitalization. These studies strongly argue for the safety and potential efficacy of probenecid to improve systolic function and the need for a larger study, and of longer duration that also evaluates functional and health status outcomes in addition to systolic function.
The overall objective of this study is the treatment of outpatient Veterans with NYHA II-III heart failure with reduced ejection fraction (HFrEF) with probenecid to improve systolic and health function. Specifically, the investigators are proposing a three-site double-blinded, randomized, placebo-controlled, trial that will assess whether oral probenecid administered at 1 gr. orally twice per day for 180 days in patients with NYHA II-III HFrEF improves systolic function as measured via ejection fraction with echocardiography (aim 1); improves functional status as measured by exercise stress testing (aim 2); and improves self-report heart failure specific health status as measured by Kansas City Cardiomyopathy Questionnaire (KCCQ) and overall health status measured by EQ5D (aim 3).
- Conditions
- Heart Failure
- Being tested
- probenecid, Placebo
- Keywords
- heart failure, probenecid
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
probenecidDrug
1 gr. orally of probenecid twice daily for 180 days
PlaceboDrug
identical tablets to probenecid
| Study group | Role | What they receive |
|---|---|---|
| Probenecid | Active comparator | 1 gr. orally of probenecid twice daily for 180 days Receives: Drug: probenecid |
| Placebo | Placebo comparator | identical placebo (to probenecid tablets) for 180 days Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Echocardiogram-derived EF
The main primary outcome is echocardiogram-derived EF. The investigators will use Definity echo contrast if adequate endocardial border definition cannot be ascertained for EF calculation in apical 4 and apical 2 using volumetric tracing analysis and modified Simpson's. The echo sonographers from all sites will follow the same standard study ECHO procedure to obtain the views.
Measured: 6 months
Secondary outcomes (2)
Change From Baseline in Exercise Tolerance Via a Symptom-limited Exercise Test on a Cycle Ergometer
The investigators will perform a maximal bicycle exercise stress test (BEST) on a cycle ergometer (Ergocard II, Esaote) with 25-W workload increments at 3-minute intervals. To adapt to patients with low functional capacity as previously described and with all the standard precautions. Results will be converted to Metabolic Equivalents of Task using standard formula and compared to baseline.
Measured: Baseline and 6 months
Change From Baseline in The Kansas City Cardiomyopathy Questionnaire (KCCQ) and EQ5D
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23 item instrument validated in stable and decompensated HF patients with HFpEF and HFrEF. The questionnaire takes 4-6 minutes to complete and reflects disease-specific health status over the prior two weeks. Overall health status (EQ5D) (Appendix) is a well-known generic measure of health status. It has 5 questions that address five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety or depression) with five levels ranging from 'no problems' to 'extreme problems' each. Total score ranges from 0 to 100, where higher scores indicate better outcome.
Measured: Baseline and 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Sep 2020
- Study start9 Jun 2021
- Primary completion31 Dec 2025
- Study completion31 Dec 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This is a three-site, double-blinded, randomized, placebo controlled, parallel design, trial in a 1:1 fashion of 1 gr. orally of probenecid twice daily or identical placebo for 180 days. The investigators propose to recruit 120 subjects (power analysis below) with HFrEF (LVEF 40%), NYHA II-III on guideline directed medical therapy.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 125 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Jack Rubinstein, MD, Principal investigator, Cincinnati VA Medical Center, Cincinnati, OH
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04551222
- Sponsor's protocol ID
- CARA-006-19F
- Other IDs
- I01CX001968
- Acronym
- Re-Prosper HF
- Status last verified
- Sep 2026
- First submitted
- 9 Sep 2020
- Last updated
- 14 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Rubinstein J, Robbins N, Evans K, Foster G, Mcconeghy K, Onadeko T, Bunke J, Parent M, Luo X, Joseph J, Wu WC. Repurposing Probenecid for the Treatment of Heart Failure (Re-Prosper-HF): a study protocol for a randomized placebo-controlled clinical trial. Trials. 2022 Apr 7;23(1):266. doi: 10.1186/s13063-022-06214-y.
PubMed 35392963
Study at a glance
From the registry record, last updated by the sponsor on 14 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of Veterans With Heart Failure With Reduced Ejection Fraction With Probenecid
- ClinicalTrials.gov ID
- NCT04551222
- Acronym / sponsor ID
- Re-Prosper HF / CARA-006-19F
- Conditions
- Heart Failure
- Keywords
- heart failure, probenecid
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 125 participants (actual)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- 9 Jun 2021 (actual)
- Primary completion
- 31 Dec 2025 (actual)
- Study completion
- 31 Dec 2025 (actual)
- First posted
- 16 Sep 2020 (actual)
- Results
- Posted 14 Sep 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Heart failure with reduced ejection fraction (HFrEF) is a common cause for admission within the Veterans Affairs (VA) Health Care System.
It is associated with severe impairment of physical and mental health status and carries a high risk of mortality. Even though significant progress has been made in understanding the disease process, currently, its management and treatment is limited.
The investigators have discovered that a commonly used drug for the treatment of gout can be repurposed for the treatment of HFrEF.
The objective of this study is the treatment of outpatient Veterans with HFrEF with probenecid to improve heart and health function. Specifically, the investigators are testing whether oral probenecid administered orally twice per day for 180 days improves heart function as measured via ultrasound of the heart (aim 1); improves exercise capacity (aim 2); and improves self-report heart failure specific health status as measured via questionnaires (aim 3).
Detailed description
Heart failure with reduced ejection fraction (HFrEF) is a common cause for admission within the Veterans Affairs (VA) Health Care System. It is associated with severe impairment of physical and mental health status and carries a high 5-yr mortality rate of ~75%. Even though significant progress has been made in understanding its pathophysiology, currently, its management and treatment is based on therapeutic targeting of a limited number of receptors and pathways.
The investigators' team and others have made great progress in the last few years by understanding and harnessing the Transient Potential Receptor superfamily as regulators of cardiovascular function. Specifically, the investigators' laboratory has explored the role the vanilloid 2 (TRPV2) subtype plays in regulating calcium handling and contractility. This work has led researchers to understand that TRPV2 modulates contractility via increasing calcium cycling in myocytes on a beat-to-beat basis.
The investigators have used probenecid, a generic, globally available drug with an extremely safe profile that has been used for decades as a treatment for gout, as a TRPV2 agonist. The investigators' work with this drug has demonstrated it to be a potent inotrope without apoptotic, chronotropic or arrhythmogenic effects in cardiomyocytes in vitro as well as in vivo murine and porcine models. These findings have been taken to the bedside with a recently published small phase 2 study of 20 adult patients with HFrEF (the ReProsper HF pilot study) where the investigators demonstrated a mean improvement in left ventricular systolic and diastolic function with no adverse effects after only 1 week of treatment. The use of probenecid in HFrEF was also indirectly supported by a recent retrospective study of approximately 40,000 patients in the Medicare database that found treatment with probenecid (not specifically for heart disease) was associated with a 9% decreased risk of HF hospitalization. These studies strongly argue for the safety and potential efficacy of probenecid to improve systolic function and the need for a larger study, and of longer duration that also evaluates functional and health status outcomes in addition to systolic function.
The overall objective of this study is the treatment of outpatient Veterans with NYHA II-III heart failure with reduced ejection fraction (HFrEF) with probenecid to improve systolic and health function. Specifically, the investigators are proposing a three-site double-blinded, randomized, placebo-controlled, trial that will assess whether oral probenecid administered at 1 gr. orally twice per day for 180 days in patients with NYHA II-III HFrEF improves systolic function as measured via ejection fraction with echocardiography (aim 1); improves functional status as measured by exercise stress testing (aim 2); and improves self-report heart failure specific health status as measured by Kansas City Cardiomyopathy Questionnaire (KCCQ) and overall health status measured by EQ5D (aim 3).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- This is a three-site, double-blinded, randomized, placebo controlled, parallel design, trial in a 1:1 fashion of 1 gr. orally of probenecid twice daily or identical placebo for 180 days. The investigators propose to recruit 120 subjects (power analysis below) with HFrEF (LVEF 40%), NYHA II-III on guideline directed medical therapy.
| Arm | Type | Receives |
|---|---|---|
| Probenecid | Active comparator | Drug: probenecid1 gr. orally of probenecid twice daily for 180 days |
| Placebo | Placebo comparator | Drug: Placeboidentical placebo (to probenecid tablets) for 180 days |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Have documented heart failure as a treated inpatient or outpatient diagnosis in the medical record.
- Left ventricular ejection 40% within the past 12 months either by echocardiogram, cardiac MRI, cardiac CT, nuclear imaging or cardiac catheterization.
- NYHA class II-III
- On stable GDMT for at least 2 weeks (including at least an EBM dose of betablocker and RAAS inhibition) consistent with the EPHESUS trial criteria [16] or having a documented allergy or adverse reaction to betablocker and/or RAAS inhibition.
- Age 18 years or older.
Key exclusion criteria (17 listed)
- Acute coronary syndrome or cardiac revascularization within the past 3 months.
- End stage renal disease with renal replacement therapy or creatinine clearance less than 30 ml/min [17].
- Cardiac resynchronization therapy within the past 3 months.
- Constrictive pericarditis or restrictive cardiomyopathy on cardiac imaging study (echocardiogram cardiac MRI, cardiac CT) within the last 12 months.
- Ablation for cardiac arrhythmias within the past month.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| probenecid1 gr. orally of probenecid twice daily for 180 days | Drug | Probenecid |
| Placeboidentical tablets to probenecid | Drug | Placebo |
Primary outcome
Echocardiogram-derived EF
Time frame: 6 months
The main primary outcome is echocardiogram-derived EF. The investigators will use Definity echo contrast if adequate endocardial border definition cannot be ascertained for EF calculation in apical 4 and apical 2 using volumetric tracing analysis and modified Simpson's. The echo sonographers from all sites will follow the same standard study ECHO procedure to obtain the views.
2 secondary outcomes
Change From Baseline in Exercise Tolerance Via a Symptom-limited Exercise Test on a Cycle Ergometer
Time frame: Baseline and 6 months
Change From Baseline in The Kansas City Cardiomyopathy Questionnaire (KCCQ) and EQ5D
Time frame: Baseline and 6 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Sep 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 35392963Rubinstein J, Robbins N, Evans K, Foster G, Mcconeghy K, Onadeko T, Bunke J, Parent M, Luo X, Joseph J, Wu WC. Repurposing Probenecid for the Treatment of Heart Failure (Re-Prosper-HF): a study protocol for a randomized placebo-controlled clinical trial. Trials. 2022 Apr 7;23(1):266. doi: 10.1186/s13063-022-06214-y.
- Individual participant dataSharing planned: No
Related trials for Heart Failure
Enrolling by invitationObservational study
Multi-Scale Analysis of Phenotypes in Heart Failure (MAP-HEART)
Heart Failure
Active, not recruitingObservational study
REdo Transcatheter Aortic VALVE Implantation for the Management of Transcatheter Aortic Valve Failure
Aortic Valve Stenosis
RecruitingPhase 3
Optimal Diuretic Therapies for Acute Heart Failure With Volume Overload
Acute Heart Failure
Recruiting
Renal Denervation in Patients With Atrial Fibrillation and Hypertension
Atrial Fibrillation (Paroxysmal), Hypertension
Recruiting
Laser Acupuncture for Fatigue in Hemodialysis Patients
ESRD (End Stage Renal Disease), Dialysis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jack Rubinstein, MD principal investigator
Cincinnati VA Medical Center, Cincinnati, OH
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing probenecid in people with Heart Failure, run by VA Office of Research and Development at 5 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Sep 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Echocardiogram-derived EF (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04551222, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Sep 2026.