Salt Reduction Diet for High Blood Pressure

(PEPC3 Trial)

Overseen By Hossam Shaltout, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Wake Forest University Health Sciences

Must not be taking: Antihypertensives

Disqualifiers: Hypertension, Cancer, Kidney, Heart, Liver, others

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

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

Compensation: Varies

Number of Visits: 1

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how dietary salt affects blood pressure in young adults born prematurely. Participants will be divided into two groups: those born at full term and those born preterm with very low birth weights. The preterm group will receive a dietary intervention with either high or low salt intake and a drug called Allopurinol, which the FDA has approved. Ideal candidates for this trial are young adults born before 34 weeks of pregnancy with no history of high blood pressure or related treatments. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking insights.

Do I have to stop taking my current medications for the trial?

The trial excludes people who are currently using antihypertensive medications, so you would not be able to participate if you are taking those.

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

Research has shown that allopurinol is generally safe for use. Studies have found that it can slightly lower blood pressure, which may benefit those with hypertension. While allopurinol often manages uric acid levels, it is also associated with fewer strokes and heart problems, particularly in older adults with high blood pressure.

Most people taking allopurinol do not experience serious side effects, though some may have mild issues like an upset stomach or a rash. Discussing any health conditions, such as diabetes or heart problems, with a doctor before starting allopurinol is important.

Regarding the dietary aspect of the study, research supports that reducing salt intake can lower blood pressure. Such changes can help control blood pressure and might even reduce the need for medication. Overall, both treatments in the study appear safe and could help manage high blood pressure. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard care for high blood pressure, which typically involves medications like ACE inhibitors or beta-blockers, Allopurinol offers a novel approach by potentially addressing uric acid levels in the blood. Researchers are excited about Allopurinol because it targets a different pathway, possibly reducing blood pressure by lowering uric acid, which is linked to hypertension, especially in individuals with low birth weight. This unique mechanism could provide an alternative for those who don’t respond well to conventional treatments, offering hope for a more tailored management of high blood pressure.

What evidence suggests that this trial's treatments could be effective for high blood pressure?

Research has shown that allopurinol, which participants in the Preterm Group of this trial may receive, can help lower blood pressure. It reduces the systolic number by about 3.3 points and the diastolic number by 1.3 points. Allopurinol is also linked to fewer heart issues, such as strokes, in individuals with high blood pressure. Participants in both the Preterm Group and the Term-born Control Group will receive dietary interventions. Studies indicate that dietary changes can lower systolic blood pressure by about 3.07 points. A low-salt diet can further reduce blood pressure. Both allopurinol and dietary changes have shown promise in effectively managing blood pressure. ^{2 4 5 6 7}

Who Is on the Research Team?

Hossam Shaltout, PhD

Principal Investigator

Wake Forest University Health Sciences

Are You a Good Fit for This Trial?

This trial is for young adults born between 1990-1998, either prematurely (before 34 weeks) or at term (after 36 weeks), who are not twins. Participants should not have high blood pressure, be pregnant or breastfeeding, and must be free of serious conditions like active cancer, chronic kidney disease, liver or heart failure.

Inclusion Criteria

I was born before reaching 34 weeks of pregnancy.

I was born after 36 weeks of pregnancy.

I was born between 1990 and 1998.

Exclusion Criteria

I have a genetic condition or birth defect.

I have heart failure.

My cancer is currently active.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Baseline measurements including blood pressure, serum and urine biomarkers are taken

1 week

1 visit (in-person)

Dietary Intervention

Participants undergo a high/low salt diet intervention with or without allopurinol

7 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for changes in blood pressure and other health markers after the intervention

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Allopurinol
• Dietary Intervention

Trial Overview The study is examining the effects of a drug called Allopurinol and dietary changes on how salt affects blood pressure in young adults who were born preterm. The goal is to understand better ways to manage potential risks associated with premature birth.

How Is the Trial Designed?

Group I: Preterm Group Experimental Treatment 2 Interventions

Subjects with very low birth weight (\<37 completed weeks' gestation and birth weight \<1500 g) will receive a dietary intervention (high/low salt diet) and FDA approved drug, Allopurinol

Group II: Term-born control group Active Control 1 Intervention

Subjects with birth weight ≥2500 g will receive a dietary intervention (high/low salt diet)

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?

Wake Forest University Health Sciences

Lead Sponsor

Trials

1,432

Recruited

2,506,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Moderate dietary salt restriction can enhance the effectiveness of antihypertensive medications, potentially allowing for lower doses or even complete withdrawal of some drugs, based on a review of existing medical literature.

Identifying 'salt sensitive' hypertensive patients is crucial, as they may benefit the most from dietary salt modifications; further clinical studies are needed to explore the relationship between salt intake and kidney health outcomes in various demographic groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salt intake and reductions in arterial pressure and proteinuria. Is there a direct link? Bakris, GL., Weir, MR.[2019]

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]

In a systematic review of 16 randomized clinical trials involving 1,943 patients, urate-lowering therapies (ULT) like febuxostat, allopurinol, and benzbromarone did not show significant renoprotective effects in chronic kidney disease (CKD) patients with hyperuricemia.

Febuxostat was found to be more effective than allopurinol in lowering uric acid levels and also showed better control of blood pressure, making it a potentially preferable option among the ULTs studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of Drug Treatments for Lowering Uric Acid on Renal Function in Patients With Chronic Kidney Disease and Hyperuricemia: A Network Meta-Analysis of Randomized Controlled Trials. Liu, X., Qiu, Y., Li, D., et al.[2021]

In a study of 20 patients with hypertension and hyperuricaemia, captopril significantly reduced blood pressure in those on a low-sodium diet, from 192/119 mmHg to 144/95 mmHg after 4 weeks (P < 0.001).

Captopril also lowered serum urate levels in both dietary groups, indicating its effectiveness in managing uric acid levels independently of sodium intake.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Captopril once daily in patients with essential hypertension and hyperuricaemia. Leary, WP., Reyes, AJ., Acosta-Barrios, T., et al.[2014]

In a study of seven proteinuric patients with non-diabetic renal disease, a high sodium intake increased proteinuria levels, demonstrating the negative impact of sodium on the effectiveness of ACE inhibitors.

The addition of hydrochlorothiazide, a diuretic, successfully reduced proteinuria and restored blood pressure control, indicating it can enhance the therapeutic effects of ACE inhibitors even with high sodium intake.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. Buter, H., Hemmelder, MH., Navis, G., et al.[2019]

Hypersensitivity reactions to allopurinol, a medication for high uric acid levels, can be severe and are associated with a high mortality rate, as seen in a review of 38 patients where 26% died due to complications.

Most patients with hypersensitivity had preexisting renal disease and were often prescribed thiazide diuretics, highlighting the need for careful monitoring and dosage adjustments when initiating allopurinol therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The allopurinol hypersensitivity syndrome. Lupton, GP., Odom, RB.[2019]

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]

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]

In a study of 141 hyperuricemic patients with stage 3 chronic kidney disease (CKD) over an average of nearly 56 months, febuxostat significantly lowered serum uric acid levels compared to allopurinol and conventional management, indicating its efficacy in managing hyperuricemia.

Febuxostat also demonstrated a longer renal survival time and a 74.3% reduced risk of renal disease progression compared to the control group, suggesting it is more effective than allopurinol in protecting kidney function in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of renoprotective effects of febuxostat and allopurinol in hyperuricemic patients with chronic kidney disease. Lee, JW., Lee, KH.[2020]

Allopurinol significantly reduced serum uric acid levels in hyperuricemic patients with chronic kidney disease, demonstrating its efficacy in managing uric acid levels over 12 months.

Patients treated with allopurinol had a lower rate of significant deterioration in renal function compared to the control group, suggesting that allopurinol may help preserve kidney function, although further studies are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Siu, YP., Leung, KT., Tong, MK., et al.[2022]

In a study of 55 hemodialysis patients with high uric acid levels, allopurinol therapy significantly reduced both systolic and diastolic blood pressure after 12 weeks, indicating its potential as a treatment for hypertension in this population.

Allopurinol also led to a significant decrease in uric acid levels and improved the quality of dialysis, suggesting that it may provide additional benefits beyond blood pressure control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of allopurinol on lowering blood pressure in hemodialysis patients with hyperuricemia. Jalalzadeh, M., Nurcheshmeh, Z., Mohammadi, R., et al.[2021]

In a study of 4,064 older adults with hypertension, allopurinol use was linked to a significantly lower risk of stroke (50% reduction) and cardiac events (39% reduction) compared to those not using the medication.

Higher doses of allopurinol (≥300 mg daily) were associated with even greater reductions in the risk of stroke and cardiac events, suggesting that dosage may play a crucial role in its cardiovascular protective effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allopurinol and Cardiovascular Outcomes in Adults With Hypertension. MacIsaac, RL., Salatzki, J., Higgins, P., 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]

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. ahajournals.org ahajournals.org/doi/10.1161/hypertensionaha.115.06344

Allopurinol and Cardiovascular Outcomes in Adults With ... Allopurinol use is associated with lower rates of stroke and cardiac events in older adults with hypertension, particularly at higher doses.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26865199/

Allopurinol and Cardiovascular Outcomes in Adults With ... Allopurinol use is associated with lower rates of stroke and cardiac events in older adults with hypertension, particularly at higher doses.

4. e-century.us e-century.us/files/ijcem/11/3/ijcem0060858.pdf

Allopurinol to influence blood pressure in hypertension ... Low-dose allopurinol (< 300 mg/day) was more effective at reducing DBP than high-dose (> 300 mg/day). Indeed, allopurinol can lower the BP in patients with ...

5. 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.

6. mayoclinic.org mayoclinic.org/drugs-supplements/allopurinol-oral-route/description/drg-20075476

Allopurinol (oral route) - Side effects & dosage Allopurinol is used to prevent or lower high uric acid levels in the blood. ... Hypertension (high blood pressure) or; Hyperuricemia (high uric acid level in ...

7. drugs.com drugs.com/allopurinol.html

Allopurinol: Uses, Dosage, Side Effects To make sure this medicine is safe for you, tell your doctor if you have ever had: diabetes;. congestive heart failure;. high blood pressure;.