Probenecid for Male Infertility Due to Spinal Cord Injury

Overseen By Odaro Ugbo, BSc

Age: 18+

Sex: Male

Trial Phase: Phase 3

Sponsor: University of Miami

Must not be taking: Methotrexate, Aspirin, Salicylates, Anti-inflammatories

Disqualifiers: Azoospermia, Foley catheter, Unstable condition, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 12 weeks

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether probenecid can improve sperm motility in men with spinal cord injuries, who often face infertility issues. The research involves taking either varying doses of probenecid or a placebo for 90 days. Men who have had a spinal cord injury for over a year and struggle with infertility might be suitable candidates for this trial. As a Phase 3 trial, it represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking treatment advancements.

Do I need to stop my current medications to join the trial?

Yes, you will need to stop taking methotrexate, aspirin, other salicylates, or anti-inflammatory medicines to participate in the trial.

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

Research has shown that probenecid has been safely used for other health issues. However, specific safety information about using probenecid to treat male infertility caused by spinal cord injury remains limited. Past studies found that probenecid was generally well-tolerated for other uses, suggesting it might be safe for this new purpose as well. The study's advanced stage indicates that the treatment has already passed initial safety checks, which is reassuring. Participants will receive either a full or half dose of probenecid, and researchers will closely monitor any possible side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for male infertility due to spinal cord injury?

Unlike the standard treatments for male infertility due to spinal cord injury, which often involve assisted reproductive techniques like IVF or ICSI, probenecid offers a unique approach. Probenecid is traditionally used to treat gout by enhancing uric acid excretion, but researchers are exploring its potential to improve sperm function and motility in this context. What makes probenecid particularly exciting is its novel mechanism of action—it may enhance cellular signaling pathways that are crucial for sperm's ability to move and fertilize an egg. This could provide a non-invasive alternative to current fertility treatments, offering hope for a more natural reproductive process.

What evidence suggests that probenecid might be an effective treatment for male infertility due to spinal cord injury?

Research has shown that probenecid can improve sperm movement in men with spinal cord injuries. In earlier studies, men who took probenecid experienced better sperm movement after just four weeks. Probenecid enhances sperm motility by affecting a specific part of the cell. Most participants tolerated this medication well, experiencing no major side effects. Overall, evidence suggests that probenecid could be a promising option for improving fertility in men with spinal cord injuries. Participants in this trial will be divided into groups: some will receive a full dose of probenecid, others a half dose, and a control group will receive a placebo. ^{1 2 4 6 7}

Who Is on the Research Team?

Emad Ibrahim, MD

Principal Investigator

University of Miami

Are You a Good Fit for This Trial?

This trial is for men over 18 with traumatic spinal cord injury who have been injured for at least a year. It's not for those with zero sperm count, indwelling catheters, unstable conditions like Crohn's or colon cancer, implanted electrical devices, allergies to probenecid, history of kidney stones/ulcers, recent UTI fever, or taking certain medications.

Inclusion Criteria

I have a spinal cord injury due to trauma.

Exclusion Criteria

I cannot safely undergo the procedure or take the medication.

Subject has hypersensitivity to probenecid

Subject has been injured less than 1 year

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a placebo, full dose, or half dose of probenecid for a total of 90 days

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Probenecid

Trial Overview

The study tests if probenecid can improve the swimming ability of sperm in men with spinal cord injuries. Participants will receive either a placebo (no active ingredient) or probenecid at doses of 250 mg or 500 mg to see which works better.

How Is the Trial Designed?

Group I: Half dose group Experimental Treatment 1 Intervention

Participants in this group will receive half the dose of probenecid for a total of 90 days.

Group II: Full dose group Experimental Treatment 1 Intervention

Participants in this group will receive the full dose of probenecid for a total of 90 days.

Group III: Control-placebo group Placebo Group 1 Intervention

Participants in this group will receive a placebo dose (No active ingredient) for a total of 90 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 Probecid for:

• Gout
• Hyperuricemia

Approved in European Union as Probenecid for:

• Gout
• Hyperuricemia

Who Is Running the Clinical Trial?

University of Miami

Lead Sponsor

Trials

976

Recruited

423,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Published Research Related to This Trial

A study of 34 men exposed to methylene chloride revealed that 8 of them experienced reproductive issues, including testicular and lower abdominal pain, which were linked to prostatic problems.

Semen analysis from four volunteers indicated subfertility, showing reduced sperm motility, morphology, and density, suggesting that methylene chloride exposure may negatively impact male reproductive health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case reports of individuals with oligospermia and methylene chloride exposures. Kelly, M.[2019]

In a review of 113 males with spinal cord injuries, electroejaculation was highly effective for semen retrieval (97%), while vibroejaculation was also successful (67%), demonstrating the efficacy of these methods in managing male infertility.

The overall pregnancy rate per cycle for couples seeking assistance was 18%, with a cumulative pregnancy rate of 55%, indicating that specialized fertility treatments can lead to successful outcomes, including 14 live births from 17 pregnancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comprehensive approach to the management of male infertility following spinal cord injury. Rutkowski, SB., Geraghty, TJ., Hagen, DL., et al.[2019]

Male infertility is increasingly common, particularly among men, with many cases having unknown causes; however, the impact of drugs on male fertility has been under-researched, especially in humans.

The article highlights various drugs known to negatively affect male fertility, emphasizing the need for more research, including clinical trials and post-marketing surveillance, to better understand these risks and their mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug reactions on male fertility. Lacroix, I.[2023]

Most men with spinal cord injury (SCI) experience infertility due to erectile dysfunction and semen abnormalities, but sperm from these men can still lead to successful pregnancies, indicating potential for reproductive success despite challenges.

Penile vibratory stimulation is the first-line treatment for achieving ejaculation in anejaculatory patients, and if unsuccessful, other methods like electroejaculation or surgical sperm retrieval can be considered, with reproductive outcomes comparable to those of men without SCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of infertility in men with spinal cord injury. Brackett, NL., Lynne, CM., Ibrahim, E., et al.[2021]

Benomyl, a widely used fungicide, primarily affects the male reproductive system by disrupting microtubules in Sertoli cells, leading to sloughing of germ cells and abnormal development of sperm, particularly at moderate to low doses.

At higher doses, benomyl causes occlusion of the efferent ducts, which blocks sperm passage and can lead to testicular swelling, tubular atrophy, and infertility, highlighting the need for careful evaluation of long-term testicular health in studies involving toxicants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histopathology of the male reproductive system induced by the fungicide benomyl. Hess, RA., Nakai, M.[2018]

Spinal cord injury (SCI) patients often experience various sexual disorders, including erectile dysfunction, and a structured treatment approach is recommended, starting with lifestyle changes and progressing to medications and surgical options.

For male SCI patients, treatments for erectile dysfunction and anejaculatory dysfunction can involve a combination of methods, including PDE5 inhibitors, penile prostheses, and assisted reproductive techniques, while female patients have similar management strategies without the need for erectile treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of sexual disorders in spinal cord injured patients. Rahimi-Movaghar, V., Vaccaro, AR.[2018]

Men with spinal cord injuries often face infertility due to poor semen quality and ejaculatory dysfunction, with only 5% of those with complete upper motor lesions able to ejaculate, compared to up to 70% of men with incomplete lesions.

Effective methods for inducing ejaculation, such as electroejaculation (85% success) and vibratory stimulation (59% success), are available, but require careful monitoring due to risks like autonomic dysreflexia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infertility in men with spinal cord injury. Linsenmeyer, TA., Perkash, I.[2005]

Men with spinal cord injury (SCI) often face infertility due to erectile dysfunction, ejaculatory dysfunction, and abnormal semen quality, but various management options like PDE-5 inhibitors and assisted ejaculation methods (PVS and EEJ) can help address these issues.

Despite having sufficient motile sperm for less invasive procedures like intrauterine insemination (IUI), many couples are prematurely directed towards more invasive and costly methods like IVF/ICSI, highlighting the need for better education on all available fertility options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Male fertility following spinal cord injury: an update. Ibrahim, E., Lynne, CM., Brackett, NL.[2016]

In a 70-day study with male Wistar rats, high doses of the fungicide benomyl (203 ppm) significantly reduced sperm counts and testicular weights, indicating potential reproductive harm.

However, these negative effects were reversible, as a subsequent 70-day recovery period showed that sperm counts, testicular weights, and fertility indices returned to normal levels, suggesting that the damage caused by benomyl is not permanent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reproductive toxicity of methyl-1-(butylcarbamoyl)-2-benzimidazole carbamate (benomyl) in male Wistar rats. Barnes, TB., Verlangieri, AJ., Wilson, MC.[2019]

Certain cardiovascular and respiratory medications, particularly some α1-adrenergic antagonists and atenolol, have been linked to sexual dysfunction and may impact male reproductive health, including risks of retrograde ejaculation and decreased testosterone levels.

Despite concerns, many commonly used medications like calcium channel blockers show significant effects on sperm function in laboratory settings, but lack strong evidence of negatively affecting semen quality or fertility in real-life scenarios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular/Pulmonary Medications and Male Reproduction. Drobnis, EZ., Nangia, AK.[2018]

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