Allopurinol for Resistant Hypertension

(RESIST Trial)

Overseen By Betty M Pat, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Must be taking: Antihypertensives

Must not be taking: Allopurinol, Steroids

Disqualifiers: Heart failure, Chronic kidney disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether Allopurinol, a medication typically used for gout, can improve heart health and exercise ability in African American Veterans with resistant hypertension (high blood pressure that doesn’t respond to standard treatment). The focus is on this group due to their often higher levels of an enzyme linked to heart problems. Participants will take the medication for 8 weeks to assess its impact on their daily lives. African American Veterans with high blood pressure that remains elevated despite taking three different medications may be suitable for this trial. As a Phase 2 trial, this research aims to measure the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant findings.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, since it involves participants with resistant hypertension already on three antihypertensive medications, it seems likely you will continue your current treatment.

Is there any evidence suggesting that Allopurinol is likely to be safe for humans?

Research shows that allopurinol, a medication commonly used to treat gout, has been tested for its impact on blood pressure. Studies have found that allopurinol can slightly lower blood pressure, suggesting it might help manage high blood pressure.

Allopurinol is already FDA-approved for treating gout, indicating it is generally safe when used as directed. However, individuals may react differently, and some might experience side effects like a rash or an upset stomach. The trial will carefully monitor participants to ensure their safety.

This trial is in Phase 2, focusing on how well allopurinol works and its safety for participants. Phase 2 trials usually indicate that the treatment has shown some safety in earlier studies, and researchers are now examining its effectiveness and side effects more closely. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Allopurinol is unique because it targets uric acid levels, which is different from the typical way most treatments for resistant hypertension work. Standard treatments often include diuretics, ACE inhibitors, or calcium channel blockers that primarily focus on blood pressure regulation. Researchers are excited about Allopurinol because it offers a novel approach by potentially addressing underlying metabolic factors contributing to hypertension. This could provide an alternative for patients who do not respond well to conventional therapies.

What evidence suggests that Allopurinol might be an effective treatment for resistant hypertension?

Research has shown that allopurinol can help lower blood pressure. One review found it reduced the systolic number by 3.3 mm Hg and the diastolic number by 1.3 mm Hg. Another study found that allopurinol helped lower blood pressure in teenagers with newly diagnosed hypertension. Evidence also suggests that high doses of allopurinol can improve blood vessel function, potentially benefiting heart health. This trial will specifically investigate the effects of allopurinol on resistant hypertension in African American veterans, suggesting it could help manage blood pressure issues in this population. ^{1 2 3 4 6}

Who Is on the Research Team?

Louis J Dellitalia, MD

Principal Investigator

Birmingham VA Medical Center, Birmingham, AL

Are You a Good Fit for This Trial?

This trial is for African American veterans in Birmingham, AL with resistant hypertension, which means their blood pressure remains high despite taking three different blood pressure medications. They must not have heart failure, kidney disease, coronary artery disease or be on chronic steroid therapy. Also excluded are those already on Allopurinol or with conditions that prevent safe CMR imaging.

Inclusion Criteria

Criterion: You are of African American descent.

This criterion is very broad and needs more context. "Veteran" could refer to someone who has served in the military, but it's not clear how this relates to a clinical trial exclusion criteria. Can you provide more information or context for this criterion?

My blood pressure remains high despite taking 3 different blood pressure medications.

Exclusion Criteria

I am currently taking Allopurinol.

My kidneys do not work well (poor kidney function).

I am on long-term steroid medication.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Allopurinol (300mg/daily) for 4 weeks, then 600mg/daily for an additional 4 weeks if tolerated

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Allopurinol

Trial Overview The study tests whether Allopurinol can improve heart function and quality of life over an 8-week period in African Americans who have high blood pressure that doesn't respond to standard treatments. It explores if lowering xanthine oxidase levels with this medication used for gout makes a difference.

How Is the Trial Designed?

Group I: Allopurinol - African American Veterans Experimental Treatment 1 Intervention

Subjects will receive Allopurinol (300mg/daily) for 4 weeks. If tolerated, dose may be increased to 600mg/daily for an additional 4 weeks. Subjects will take Allopurinol (300-600mg/daily) for 8 weeks total

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

Approved in United States as Zyloprim for:

• Gout
• Kidney stones
• High uric acid levels after chemotherapy

Approved in European Union as Zyloric for:

• Gout
• Kidney stones
• High uric acid levels after chemotherapy

Approved in Canada as Allopurinol for:

• Gout
• Kidney stones
• High uric acid levels after chemotherapy

Approved in Japan as Allopurinol for:

• Gout
• Kidney stones
• High uric acid levels after chemotherapy

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

For patients allergic to allopurinol, alternative treatments for hyperuricemia include uricosuric drugs like probenecid and sulfinpyrazone, but these are only suitable for those with normal kidney function and no history of kidney stones.

In cases where traditional treatments are ineffective or not tolerated, options like slow oral desensitization to allopurinol or the use of oxipurinol can be beneficial, especially for patients who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Difficult gout and new approaches for control of hyperuricemia in the allopurinol-allergic patient. Fam, AG.[2022]

Allopurinol is generally safe, but there is a risk of serious side effects, including a potentially life-threatening hypersensitivity syndrome, as demonstrated in a case where a patient developed a severe exfoliative rash after taking the drug.

Data from Norway (1973-2003) indicate that allopurinol can cause a variety of side effects, including fatalities, especially in patients with impaired renal function or those taking certain medications like ampicillin and thiazide diuretics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Side effects off allopurinol]. Rødevand, E., Sletvold, O., Kvande, KT.[2013]

In a study of 463 patients with hematologic malignancies, only 2.8% experienced maculopapular eruptions from allopurinol, indicating a relatively low incidence of hypersensitivity reactions in this population.

The study found that HLA-DR9 and DR14 are significantly associated with allopurinol-induced hypersensitivity reactions, while HLA-B58 did not show a significant correlation, suggesting that these HLA subtypes may be important for predicting risk in patients receiving allopurinol before chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA-DR9 and DR14 are associated with the allopurinol-induced hypersensitivity in hematologic malignancy. Jung, JW., Kim, JY., Yoon, SS., et al.[2022]

In a study of 264,614 veterans with gout, factors such as older age, higher body mass index, and a military service connection of 50% or higher were associated with better adherence to allopurinol, a key medication for gout management.

Conversely, lower adherence was linked to being from minority racial groups, receiving care from non-rheumatologists, and higher starting doses of allopurinol, highlighting the need for targeted interventions to improve medication adherence in gout patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allopurinol adherence and its predictors in gout: a national cohort study in US veterans. Singh, JA., Richman, J., Yang, S., et al.[2022]

Febuxostat is associated with a higher risk of cardiovascular adverse events, including heart failure and ischemic heart disease, particularly in elderly gout patients, compared to allopurinol.

The analysis of 64 quarters of data from the FDA Adverse Event Reporting System revealed that febuxostat had 2,939 reports of cardiovascular adverse events, while allopurinol had 25,219, indicating a significant concern for febuxostat's safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Safety Evaluation of Febuxostat and Allopurinol: Findings from the FDA Adverse Event Reporting System. Bai, Y., Wu, B., Gou, L., et al.[2023]

Benzbromarone significantly lowers plasma concentrations of oxypurinol when combined with allopurinol, but does not affect allopurinol levels, indicating a pharmacokinetic interaction.

The combination of allopurinol and benzbromarone (Allomaron) is more effective in lowering serum uric acid levels in gout patients compared to allopurinol alone, likely due to benzbromarone's uricosuric effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of benzbromarone on allopurinol/oxypurinol kinetics in patients with gout. Müller, FO., Schall, R., Groenewoud, G., et al.[2022]

A 75-year-old male with gout and renal insufficiency successfully underwent a modified 2-week desensitization protocol for allopurinol, which is typically associated with hypersensitivity reactions in patients with renal issues.

The desensitization allowed the patient to safely tolerate a full dose of 300 mg/day of allopurinol, leading to normalization of his urate levels without any adverse reactions, demonstrating a safe approach for managing gout in patients with multiple comorbidities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allopurinol desensitization with A 2 weeks modified protocol in an elderly patients with multiple comorbidities: a case report. Dursun, AB., Sahin, OZ.[2020]

Allopurinol is an effective treatment for conditions associated with high uric acid levels, but it should not be the only option considered, as careful selection of therapy can enhance outcomes and minimize side effects.

The use of allopurinol carries risks, including the potentially life-threatening allopurinol hypersensitivity syndrome, highlighting the importance of appropriate dosing and monitoring in both adults and children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Milurit's place in therapy. Gömör, B., Szebenyi, B.[2013]

HLA-B*58:01 genotype is strongly associated with severe cutaneous adverse reactions to allopurinol, with an odds ratio of 44.0, indicating a significant risk for patients carrying this genetic marker.

Patients with both HLA-B*58:01 and renal impairment face an even higher risk of severe reactions, suggesting that those with this genotype and poor kidney function should avoid allopurinol to prevent serious adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of the HLA-B(*)58:01 Allele and Renal Impairment on Allopurinol-Induced Cutaneous Adverse Reactions. Ng, CY., Yeh, YT., Wang, CW., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8033809/

Effect of Allopurinol on Blood Pressure: A Systematic Review ... In our analysis we found that allopurinol use was associated with a small but significant lowering of systolic BP by 3.3 mm Hg and diastolic BP by 1.3 mm Hg.

2. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/182461

Effect of Allopurinol on Blood Pressure of Adolescents With ... In this short-term, crossover study of adolescents with newly diagnosed hypertension, treatment with allopurinol resulted in reduction of BP.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT00639756

The Effect of Allopurinol on Insulin Resistance and Blood ... In this study we test the hypothesis that allopurinol may lower BP, reduce triglycerides, and improve metabolic parameters in subjects placed on a high ...

4. nature.com nature.com/articles/s41371-024-00906-5

Allopurinol and blood pressure variability following ... We did not find evidence of an effect of high dose allopurinol on blood pressure variability in people with previous stroke or transient ...

5. ahajournals.org ahajournals.org/doi/10.1161/circulationaha.106.651117

High-Dose Allopurinol Improves Endothelial Function by ... In this study, Guthikonda et al found that a single dose of 600 mg allopurinol improved endothelial function acutely in heavy smokers. An ...

6. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.122.17956

Uric Acid and Hypertension: a Review of Evidence and ... Pilot studies suggest that lowering uric acid can result in an improvement in BP in obese adolescents with hyperuricemia and prehypertension or ...