Probenecid for Heart Failure

(Re-Prosper HF Trial)

Not currently recruiting at 4 trial locations

Overseen By Jack Rubinstein, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: VA Office of Research and Development

Must be taking: Betablockers, RAAS inhibitors

Must not be taking: Probenecid

Disqualifiers: Renal disease, Pregnancy, Blood diseases, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 26 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether the gout medication probenecid can help people with heart failure with reduced ejection fraction (HFrEF). Researchers aim to determine if taking probenecid twice daily for six months can improve heart function, increase exercise ability, and enhance overall health. Individuals diagnosed with heart failure and a left ventricular ejection fraction of 40% or less might be suitable candidates. Participants will receive either probenecid or a placebo (a pill with no active medicine) to compare results. As a Phase 2, Phase 3 trial, this study evaluates the treatment's effectiveness in a smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking heart failure treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you must be on stable heart failure treatment for at least 2 weeks before joining. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that probenecid, a drug often used for gout, might help people with heart failure. In earlier studies, heart failure patients who took probenecid showed improved heart function. Importantly, these studies found no major side effects after one week of treatment.

Additionally, research suggests that probenecid might reduce the risk of serious heart problems like heart attacks and strokes. This indicates that the drug is generally well-tolerated and could be a safe choice for those with heart failure.

While these results are promising, it's important to remember that probenecid is still under study for this specific use. However, the current evidence provides a hopeful view of its safety for treating heart failure. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for heart failure?

Probenecid is unique because it offers a fresh approach to treating heart failure by potentially enhancing calcium signaling in heart cells. Unlike standard treatments like beta-blockers and ACE inhibitors, which primarily focus on reducing the workload of the heart or managing blood pressure, probenecid works differently by influencing cellular processes to improve heart function. Researchers are excited about its potential to directly improve cardiac contractility, which could lead to better heart function and possibly improved outcomes for patients with heart failure.

What evidence suggests that probenecid might be an effective treatment for heart failure?

Research has shown that probenecid, a drug often used to treat gout, might help improve heart function in people with heart failure with reduced ejection fraction (HFrEF). Studies have found that probenecid can boost heart function in just one week, with few side effects. Specifically, another study discovered that probenecid improved heart function 14 days after a heart event, such as when the blood supply to the heart is blocked. This trial will compare probenecid, which participants may receive, to a placebo. These findings support the idea that probenecid could be a promising treatment for improving heart health in HFrEF patients. ^{3 6 7 8 9}

Who Is on the Research Team?

Jack Rubinstein, MD

Principal Investigator

Cincinnati VA Medical Center, Cincinnati, OH

Are You a Good Fit for This Trial?

This trial is for Veterans aged 18+ with heart failure (HFrEF) who've been stable on standard treatments for at least two weeks. They must have a left ventricular ejection fraction of ≤40% documented in the past year. Exclusions include recent acute coronary events, severe kidney disease, certain heart procedures or conditions within specific timeframes, pregnancy, and known allergies to probenecid.

Inclusion Criteria

My heart condition limits my physical activity but I can still perform light tasks.

I have been on stable heart medication for 2 weeks or I'm allergic to certain heart medications.

I have been diagnosed and treated for heart failure.

Exclusion Criteria

I was diagnosed with heart muscle weakness during or right after pregnancy within the last 6 months.

I am on dialysis or my kidneys filter less than 30 ml/min.

I have had a heart pacing treatment in the last 3 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 1 gr. of probenecid orally twice daily for 180 days to improve heart function

26 weeks

Regular visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• probenecid

Trial Overview The study tests if probenecid, typically used for gout, can improve heart function in those with HFrEF when taken twice daily over six months. It will be compared against a placebo. Heart function will be measured by ultrasound; exercise capacity and health status through questionnaires are also evaluated.

How Is the Trial Designed?

Group I: Probenecid Active Control 1 Intervention

1 gr. orally of probenecid twice daily for 180 days

Group II: Placebo Placebo Group 1 Intervention

identical placebo (to probenecid tablets) for 180 days

probenecid is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Benemid for:

• Gout
• Hyperuricemia

Approved in Canada as Probalan for:

• Gout
• Hyperuricemia

Approved in European Union as Probenecid for:

• Gout
• Hyperuricemia

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

Probenecid (PROB) is effective in preserving high concentrations of beneficial metabolites in the central nervous system (CNS) and has a relatively low side-effect profile, making it a valuable tool in both clinical and research settings.

Recent research highlights PROB's ability to inhibit glutamate-related excitotoxicity through kynurenic acid accumulation, as well as its potential anti-inflammatory and anti-nociceptive effects by targeting various key proteins in the CNS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Probenecid: an emerging tool for neuroprotection. Colín-González, AL., Santamaría, A.[2019]

Concurrent administration of probenecid with certain cephalosporin antibiotics can significantly alter their pharmacokinetics, leading to increased peak serum concentrations and prolonged presence in the urine, although some cephalosporins like ceftriaxone show no significant changes.

The combination of probenecid and cephalosporins has been effectively used in single-dose treatments for gonorrhea, providing sustained systemic concentrations to eradicate the infection, but for ceftriaxone, the addition of probenecid may not be necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cephalosporin-probenecid drug interactions. Brown, GR.[2018]

In a study of 23 patients with high cholesterol and uric acid levels, halofenate effectively reduced serum uric acid to therapeutic levels (5-6 mg/100 ml) over 36 weeks, outperforming probenecid.

While halofenate was effective in lowering uric acid, it did not consistently reduce serum triglycerides, and it had no significant effect on serum cholesterol levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of hyperlipemia and hyperuricemia with 2-acetamidoethyl-(4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetate (halofenate), a derivative of clofibrate]. Keller, C., Wolfram, G., Zöllner, N.[2013]

Probenecid significantly increased the exposure and half-life of ritobegron, a β3-adrenoceptor agonist, in healthy men, indicating that it can enhance the effectiveness of ritobegron by inhibiting its renal clearance.

Despite the increased levels of ritobegron when combined with probenecid, there were no significant changes in adverse events or vital signs, suggesting that this combination is safe and unlikely to cause clinically significant drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of Drug-Drug Interactions Between Ritobegron, a Selective β3 -Adrenoceptor Agonist, With Probenecid in Healthy Men. Abe, Y., Nakano, Y., Kanazawa, T., et al.[2018]

Probenecid significantly increased the plasma levels of sulfamonomethoxine (SMM) and its acetylated form (AcSMM) in pigs, indicating that probenecid enhances the bioavailability of these compounds by inhibiting their renal clearance.

The study suggests that the active tubular secretion of AcSMM is a key factor in the nonlinear pharmacokinetics of SMM, as probenecid suppressed the renal excretion of AcSMM but not SMM itself.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible active tubular secretion of sulfamonomethoxine and its metabolites in pigs. Shimoda, M., Aihara, E., Koyanagi, M., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5850150/

Probenecid Improves Cardiac Function in Patients With ... Probenecid improves cardiac function with minimal effects on symptomatology and no significant adverse effects after 1 week in patients with ...

2. trialsjournal.biomedcentral.com trialsjournal.biomedcentral.com/articles/10.1186/s13063-022-06214-y

a study protocol for a randomized placebo-controlled clinical trial A three-site double-blinded randomized-controlled trial that will test the hypothesis that probenecid can improve cardiac function in patients with HFrEF.

3. bpspubs.onlinelibrary.wiley.com bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.16001

Drug repurposing for cardiovascular diseases: New targets ... Probenecid improved cardiac function 14 days after coronary ligation, without altering infarct size (Good et al., 2021). We have also ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01814319

Repurposing Probenecid as a Positive Inotrope for the ... The hypothesis of this study is that probenecid can be used to improve the function of the heart and therefore the symptoms in patients with heart failure.

5. onlinejcf.com onlinejcf.com/article/S1071-9164(15)00362-0/pdf

Probenecid Improves Cardiac Function in Patients With ... Introduction: There are limited pharmacologic options that improve cardiac func- tion in outpatients with heart failure with reduced ejection fraction (HFrEF).

6. ahajournals.org ahajournals.org/doi/10.1161/jaha.117.007148

Probenecid Improves Cardiac Function in Patients With ... Probenecid improves cardiac function with minimal effects on symptomatology and no significant adverse effects after 1 week in patients with heart failure with ...

7. jacc.org jacc.org/doi/10.1016/j.jacc.2017.12.052

Cardiovascular Risks of Probenecid Versus Allopurinol in ... In the secondary analyses, probenecid was associated with a decreased risk of MI, stroke, HF exacerbation, and mortality versus allopurinol.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5911395/

Cardiovascular Risks in Older Patients with Gout Initiating ... In this study, use of probenecid appears to be associated with a modestly decreased risk of cardiovascular events including myocardial infarction, stroke and ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S1071916415003620

Probenecid Improves Cardiac Function in Patients With ... Conclusions. This interim analysis demonstrates that treatment with probenecid improves systolic and diastolic function in patients with HFrEF with a trend ...