Probenecid for Heart Failure

(Re-Prosper HF Trial)

Recruiting at 3 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

120 Participants Needed

Trial Summary

What is the purpose of this trial?

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).

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.

What makes the drug probenecid unique for heart failure treatment?

Probenecid is unique for heart failure treatment because it is traditionally used for other conditions like gout and as a coadjutant for antibiotics, and it has properties that help preserve high concentrations of certain metabolites in the body, potentially offering new therapeutic benefits for heart failure. ^{1 2 3 4 5}

Research Team

Jack Rubinstein, MD

Principal Investigator

Cincinnati VA Medical Center, Cincinnati, OH

Eligibility Criteria

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

I am 18 years old or older.

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.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

1. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Probenecid: an emerging tool for neuroprotection. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Investigation of Drug-Drug Interactions Between Ritobegron, a Selective β3 -Adrenoceptor Agonist, With Probenecid in Healthy Men. [2018]

3. Japan pubmed.ncbi.nlm.nih.gov

Possible active tubular secretion of sulfamonomethoxine and its metabolites in pigs. [2019]

4. Germany pubmed.ncbi.nlm.nih.gov

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

5. Switzerland pubmed.ncbi.nlm.nih.gov

Cephalosporin-probenecid drug interactions. [2018]