Salt Reduction Diet for High Blood Pressure

(PEPC3 Trial)

Overseen by Hossam Shaltout, PhD

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: Wake Forest University Health Sciences

Must not be taking: Antihypertensives

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

No Placebo Group

Approved in 5 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is studying young adults who were born prematurely to understand how salt affects their blood pressure. Researchers will see if stopping the body from making uric acid can help lower their blood pressure and improve heart health. The goal is to find better ways to prevent and treat heart disease in this high-risk group. Uric acid has been suspected to be a risk factor for high blood pressure since the 1870s, and lowering uric acid has shown potential in reducing blood pressure in individuals with high blood pressure.

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.

What data supports the effectiveness of the drug Allopurinol for lowering blood pressure?

Research shows that Allopurinol is associated with a lower risk of stroke and heart problems in older adults with high blood pressure, especially at higher doses. ^{1 2 3 4 5}

Is the salt reduction diet for high blood pressure safe for humans?

Allopurinol, a drug sometimes associated with salt reduction diets, is generally considered safe but can cause serious hypersensitivity reactions, especially in people with kidney issues or those taking certain other medications. These reactions can include severe skin rashes and other complications, so it's important to use it under medical supervision. ^{4 6 7 8 9}

How does the drug allopurinol differ from other treatments for high blood pressure?

Allopurinol is unique because it lowers blood pressure by reducing uric acid levels, which may help slow the progression of kidney disease and improve cardiovascular outcomes, unlike traditional blood pressure medications that primarily target blood vessels or heart function. ^{2 10 11 12 13}

Research Team

Hossam Shaltout, PhD

Principal Investigator

Wake Forest University Health Sciences

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Allopurinol (Xanthine Oxidase Inhibitor)
• Dietary Intervention (Behavioural 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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Dr. L. Ebony Boulware

Wake Forest University Health Sciences

Chief Medical Officer since 2022

MD from Duke University School of Medicine, MPH from Johns Hopkins Bloomberg School of Public Health

Dr. Julie Ann Freischlag

Wake Forest University Health Sciences

Chief Executive Officer since 2020

BS from University of Illinois, MD from Rush University

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Dr. Gary H. Gibbons

National Heart, Lung, and Blood Institute (NHLBI)

Chief Executive Officer since 2012

MD from Harvard Medical School

Dr. James P. Kiley

National Heart, Lung, and Blood Institute (NHLBI)

Chief Medical Officer since 2011

MD from University of California, San Francisco

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

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]

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]

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 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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Allopurinol and Cardiovascular Outcomes in Adults With Hypertension. [2022]

3. Switzerland 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. [2021]

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

The effect of benzbromarone on allopurinol/oxypurinol kinetics in patients with gout. [2022]

5. India pubmed.ncbi.nlm.nih.gov

The effect of allopurinol on lowering blood pressure in hemodialysis patients with hyperuricemia. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Cardiovascular Safety Evaluation of Febuxostat and Allopurinol: Findings from the FDA Adverse Event Reporting System. [2023]

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

The allopurinol hypersensitivity syndrome. [2019]

8. Norway pubmed.ncbi.nlm.nih.gov

[Side effects off allopurinol]. [2013]

9. Hungary pubmed.ncbi.nlm.nih.gov

Milurit's place in therapy. [2013]

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

Salt intake and reductions in arterial pressure and proteinuria. Is there a direct link? [2019]

11. South Africa pubmed.ncbi.nlm.nih.gov

Captopril once daily in patients with essential hypertension and hyperuricaemia. [2014]

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

Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. [2022]

13. England pubmed.ncbi.nlm.nih.gov

The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. [2019]