Tart Cherry Citrate Effervescent Tablet for Urate-Lowering Therapy in Participants With Asymptomatic Hyperuricemia

Tart Cherry Citrate Effervescent Tablet for Urate-Lowering Therapy in Participants With Asymptomatic Hyperuricemia: A Study Protocol for a Single-Center, Randomized, Placebo-Controlled Trial

The goal of this clinical trial is to learn whether tart cherry citrate effervescent tablets can lower uric acid levels in people with asymptomatic hyperuricemia (high uric acid levels without gout symptoms).

The main question it aims to answer is:

Does taking tart cherry citrate effervescent tablets lower uric acid levels more effectively than taking a placebo (inactive) tablet, when both groups also receive lifestyle guidance?

Researchers will compare two groups of participants. Both groups will receive lifestyle guidance (advice on diet and exercise). In addition:

• One group will take the tart cherry citrate effervescent tablets.
• The other group will take a placebo effervescent tablet (looks and tastes the same but contains no active ingredient).

The study will last 24 weeks.

Participants will:

• Take the assigned effervescent tablet twice daily for 24 weeks
• Follow lifestyle guidance for diet and exercise
• Attend scheduled clinic visits for checkups and tests
• Provide blood and urine samples for testing

Background and Rationale Hyperuricemia, a common metabolic disorder characterized by elevated serum urate due to purine metabolism dysfunction, affects 14.0% of Chinese adults (24.5% in men, 3.6% in women). Elevated serum urate leads to crystal deposition in joints, soft tissues, and kidneys, contributing not only to gout flares but also to renal and other organ damage. Although urate-lowering therapies (e.g., febuxostat, benzbromarone) effectively control serum urate, current guidelines do not recommend early pharmacological intervention for asymptomatic hyperuricemia due to safety concerns. Thus, additional strategies beyond lifestyle guidance are needed for this population.

Prior Research A prospective randomized study by the Affiliated Hospital of Qingdao University in 182 gout patients showed that a citrate mixture had comparable urate-lowering and urine alkalinization effects to sodium bicarbonate. After 3 months, the citrate effervescent tablet was superior in reducing hematuria and gout recurrence. Tart cherries, rich in anti-inflammatory and antioxidant anthocyanins, have been shown overseas to improve cardiovascular risk factors (blood pressure, cholesterol, blood glucose). The tart cherry citrate effervescent tablet enhances the original citrate mixture with increased citric acid and added tart cherry components.

A 24-week randomized, open-label, parallel-controlled trial in 282 male gout patients (fasting urine pH ≤6) demonstrated that the tart cherry citrate effervescent tablet had similar efficacy and safety to citrate mixture and sodium bicarbonate for urine alkalinization and serum urate lowering. However, it produced greater improvements in urinary albumin-to-creatinine ratio (UACR) and C-reactive protein (CRP), significantly reduced gout flare frequency, and improved metabolic parameters (systolic/diastolic blood pressure, fasting glucose, homeostasis model assessment-insulin resistance [HOMA-IR], total cholesterol).

Study Objectives To evaluate the efficacy and safety of tart cherry citrate effervescent tablet in participants with asymptomatic hyperuricemia.

Trial Design

• Design: Randomized, placebo-controlled, parallel-group trial.
• Number of participants: 196 (1:1 randomization).
• Randomization method: Block randomization.
• Sample size calculation: Based on a pilot study of tart cherry citrate mixture (mean serum urate changes: 54±65 μmol/L in active group vs. 30±19 μmol/L in lifestyle guidance group), 65 participants per group provided >80% power at α=0.05 to detect the difference. Accounting for a 20-25% dropout rate over 12 weeks and extending observation to 24 weeks, the sample size was increased by 50%, resulting in 196 total participants.
• Study population: Participants with primary asymptomatic hyperuricemia who voluntarily sign informed consent and meet eligibility criteria.

Treatment Regimen

• Experimental group: Lifestyle guidance + tart cherry citrate effervescent tablet 4.0 g twice daily (bid)
• Placebo control group: Lifestyle guidance + matching placebo effervescent tablet
• Daily water intake: 2000-2500 mL. Two effervescent tablets taken morning and evening (with or without meals).
• Lifestyle guidance: face-to-face and WeChat group-based regular dietary advice, exercise guidance, and education on recognizing gout flares.

Details are provided in the study protocol.

Study Duration 24 weeks.

Outcome Measures

Efficacy outcomes:

• Serum uric acid (sUA) at 12 and 24 weeks
• Morning urine pH
• 24-hour urinary uric acid excretion (UUE)
• New-onset gout flares
• Changes in kidney stones
• Urate crystal volume by dual-energy computed tomography (DECT)
• C-reactive protein (CRP)
• Renal function (estimated glomerular filtration rate [eGFR], urinary albumin-to--creatinine ratio [UACR])
• Metabolic syndrome components (fasting blood glucose [FBG], blood pressure, lipid profile)

Safety outcomes:

• Vital signs
• Adverse events (AEs)
• Safety laboratory parameters (routine blood/urine tests, liver/renal function, -electrolytes)

Efficacy Evaluation

Primary outcome:

-Difference in serum urate (sUA) levels between groups at week 24.

Secondary outcomes:

• Differences in sUA at week 12 and week 24
• Change in sUA within experimental group from baseline to week 24
• Differences in morning urine pH at week 12 and week 24
• Changes in urine components (hematuria, UACR, urine crystals) from baseline to week 24
• Changes in 24-hour UUE from baseline to week 24
• Differences in eGFR and UACR between groups at week 12 and week 24
• Changes in eGFR and UACR within groups from baseline to week 24
• Changes in metabolic outcomes (FBG, blood pressure, total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, HOMA-IR) between groups at week 12 and week 24
• Changes in metabolic outcomes within experimental group from baseline to week 24
• Number of participants with new-onset gout flares during the 24-week treatment period
• Changes in kidney stone size (mm) within groups from baseline to week 24

Safety Evaluation Monitoring of vital signs at each visit Clinically significant changes in safety laboratory parameters Documentation and assessment of all adverse events

Conclusion This randomized, placebo-controlled trial will compare the effects of tart cherry citrate effervescent tablet versus placebo plus lifestyle guidance on serum urate reduction in participants with asymptomatic hyperuricemia. The findings will provide new clinical data to support early intervention strategies for this condition.

Inclusion Criteria:

1. Aged 18 to 65 years, regardless of sex;
2. Meet the diagnostic criteria for primary hyperuricemia, with serum urate levels between 420 μmol/L and 540 μmol/L (for those without comorbidities) or between 420 μmol/L and 480 μmol/L (for those with at least one of the following comorbidities: hypertension, dyslipidemia, diabetes mellitus, obesity, stroke, coronary heart disease, heart failure, or CKD stage ≥2);
3. Participants with asymptomatic hyperuricemia who have not previously received urate-lowering therapy and have no history of acute gout flares;
4. Voluntarily participate in the study and provide written informed consent.

Exclusion Criteria:

1. Known allergy to any of the study medications, food products, or their components; current allergies; or known hypersensitivity;
2. Active liver disease or cirrhosis, or liver dysfunction with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels >2 times the upper limit of normal (ULN);
3. Acute infection or active gastrointestinal ulcers;
4. History of thyroid dysfunction;
5. Estimated glomerular filtration rate (eGFR) <60 mL/min;
6. Severe cardiac diseases, such as decompensated heart failure (NYHA class III or IV), unstable angina, or a history of myocardial infarction within the previous 12 months;
7. Renal cysts, medullary sponge kidney, or other obstructive nephropathies;
8. Rheumatoid arthritis requiring treatment or arthropathies due to other causes;
9. Current use of medications that affect urate levels, including febuxostat, allopurinol, benzbromarone, probenecid, azathioprine, 6-mercaptopurine, cyclosporine, cyclophosphamide, pyrazinamide, sulfamethoxazole, trimethoprim, theophylline, thiazide diuretics, aspirin (>325 mg/day) or other salicylates, losartan, or intravenous colchicine;
10. Secondary hyperuricemia due to hematologic disorders, renal diseases, or radiotherapy/chemotherapy for malignancies;
11. Brain disorders with impaired judgment, or mental disorders that preclude cooperation;
12. Alcohol or substance abuse;
13. Participation in another clinical trial within the three months prior to screening;
14. Malignancy or active tuberculosis;
15. Presence of other concurrent conditions that, in the investigator's judgment, may affect the efficacy evaluation or result in poor compliance;
16. Use of glucocorticoids;
17. Any other reason that, in the investigator's judgment, makes the participant unsuitable for enrollment in this trial.