Study design

A multi-center, randomized, double-blind, placebo, parallel-controlled clinical trial will be conducted in four hospitals across the province of Zhejiang, including the First Affiliated Hospital of Zhejiang Chinese Medical University, the Second Affiliated Hospital of Zhejiang Chinese Medical University, Shengzhou People’s Hospital, and Huzhou Hospital of TCM.

This protocol adheres to the SPIRIT 2013 reporting checklist prohibit [23]. The study will also proceed according to the Declaration of Helsinki (as revised in 2013). The entire study flowchart and follow-up procedures are illustrated in Fig 1 and Fig 2, respectively.

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Fig 1. Study procedure.

^aObserve continuously throughout the study and record when it occurs. ^bIncluding the number of acute flares of gouty arthritis, the time span from randomization to the first occurrence of an acute attack, and the duration of recurrent acute gouty arthritis. ^cRed blood cell count (RBC), white blood cell count (WBC), hemoglobin (HGB), neutrophil percentage (NEU), platelet count (PLT). ^dAlanine aminotransferase (ALT), aspartate aminotransferase (AST). ^eBlood urea nitrogen (BUN), creatinine (Cr), serum uric acid (SUA).Qu-zhuo Tong-bi formula(QTF).

https://doi.org/10.1371/journal.pone.0327864.g001

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Fig 2. The flow diagram of the study.

https://doi.org/10.1371/journal.pone.0327864.g002

Participants

Patients’ eligibility and criteria

We will recruit a total of 144 participants aged 18–80. The diagnostic criteria were as follows:

1. Diagnosis of gout: Referring to the 2015 ACR/EULAR classification criteria for gout, with a maximum score of 23 points, a diagnosis of gout can be made when the score is ≥ 8 points [24].
2. The TCM diagnosis of spleen deficiency dampness obstruction syndrome: T/CACM1349–2021- Group standards of China Association of Chinese Medicine. (available in Table 1)

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Table 1. Differential diagnosis criteria for syndrome of spleen deficiency with dampness obstruction.

https://doi.org/10.1371/journal.pone.0327864.t001

Inclusion criteria

All participants must meet the following criteria:

1. Meet the above diagnostic criteria and be in the gout intermission stage;
2. TCM diagnosis indicates syndrome of spleen deficiency with dampness obstruction;
3. Serum urate level ≥7 mg/dL (420μmol/L);
4. Aged between 18 and 80 years (inclusive of boundary values), any gender;
5. Having not received urate-lowering drugs such as allopurinol, benzbromarone, or febuxostat in the past month;
6. Relief of gouty flare symptoms (VAS score = 0) for more than 1 week;
7. Acute gout flare≥2 in the past year;
8. Willing to undergo treatment and sign informed consent.

Exclusion criteria

Patients meeting any of the following criteria will be excluded:

1. Severe liver or kidney dysfunction (AST/ALT ≥ twice the normal level, eGFR < 60ml/min), diabetes with target organ damage, severe cardiovascular or cerebrovascular diseases, history of digestive ulcer bleeding or perforation, and patients with psychiatric disorders;
2. Patients’ intolerance to or with contraindications to the medications used in this study (urate-lowering medications, traditional Chinese medicine, nonsteroidal anti-inflammatory medications);
3. Patients with hyperuricemia caused by myeloproliferative disorders or other conditions with obvious urate overproduction;
4. Pregnant or lactating patients.

Exit criteria

Sample size

The sample size calculation was performed using PASS (version 2021) with the “Comparison of two independent sample rates” calculation module. A power of 80% and an alpha level of 0.025 for a one-sided test and a superiority test were used. Based on a previous study by our team [22], the flare rates of acute gouty arthritis after 12 weeks of placebo treatment were 63.2%, and for the group treated with the QTF was 38.5%. Calculations yielded sample sizes of N1 = N2 = 61 for both the intervention and control groups, considering a dropout rate of 20%. In total, 144 patients with intermittent gout will be included, with 72 patients in both the intervention and control groups.

Ethics, oversight, and dissemination

This trial has received approval from the Ethics Committee of Zhejiang Chinese Medical University, with approval number 20240329−6. All participating centers have obtained approval from their respective local institutional review boards. The Ethics Committee of Zhejiang Chinese Medical University will oversee the entire process of the trial, including assessing the status and quality of the research, such as recruitment rates, dropout rates, and AEs. Researchers will promptly address any AEs reported by patients or their families. The results of the RCT will be published in peer-reviewed journals, ensuring patient anonymity by not disclosing their names unless required by law. Access to patient information will be restricted to authorized individuals who will strictly manage data according to government and legal regulations.

Randomization and blinding

A multi-center competitive stratified block randomization method was utilized. Random numbers for the multi-center group were generated using the corresponding randomization procedure in SAS software (version 9.4). These random numbers, alongside their corresponding drug codes, functioned as unique identifiers for participants. After conducting necessary baseline assessments, all eligible patients who met the inclusion criteria and signed informed consent forms will be randomly assigned to either the intervention or control group in a 1:1 ratio. The randomization design and numbers were provided by Jiangsu Famous Medicine Co., Ltd. The relevant parameters and results of the randomization scheme will be recorded by Zhejiang Chinese Medical University (the research design unit). Apart from the outcome evaluators and staff at the drug production center, all researchers and patients remained unaware of treatment allocation. The QTF granules and placebo granules were identical in odor, color, and packaging, ensuring blinding. Distribution details will be disclosed to researchers only when necessary for drug administration. Products were delivered directly to patients according to their allocation codes. In emergencies, the research design unit will promptly provide researchers with randomized numbers and treatment allocations. All participants will strictly adhere to confidentiality regulations to protect patients’ personal privacy information.

Intervention

The visit schedule is set for weeks 0, 6, 12, 24, and 48. Visits at weeks 0, 6,12, and 24 will be conducted offline, with patients attending the hospital to have relevant information collected by the responsible physician. The visit at week 48 will be conducted online (via phone calls or WeChat).

Conventional treatment: Both groups receive ULT, which in this study is stipulated as febuxostat 40 mg once daily.

TCM Treatment: The intervention group receives QTF granules, while the control group is administered placebo granules, with treatment lasting for 12 weeks. QTF granules constitute a Chinese herbal compound, and the composition of the granules is detailed in Table 2. The placebo granules utilized in this study contain 10% of the same components found in QTF granules. All QTF granules and placebo granules are manufactured and packaged by Jiangyin Tianjiang Pharmaceutical Co., Ltd., located in Jiangsu Province, China. There are no discernible differences in appearance, color, odor, or weight between the QTF granules and placebo granules. The quality of these granules underwent inspection by authorized agencies before declaration, ensuring compliance with specified quality standards. Each dose of QTF granules or placebo granules consists of 9.8g per sachet, to be taken twice daily with 200 ml of warm water, continuously for 5 days followed by a 2-day rest period.

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Table 2. Components of Qu-zhuo Tong-bi formula granules.

https://doi.org/10.1371/journal.pone.0327864.t002

During the treatment period, in the event of gout flares, patients are advised to rest in bed with the affected limb elevated. Within 24 hours, they are required to contact the research personnel for a Visual Analog Scale (VAS) pain assessment: mild (VAS score < 5), moderate (5 < VAS score < 8), severe (VAS score > 8). Early administration of an adequate dose of NSAIDs is recommended within 24 hours. In this study, it is specified as a once-daily administration of 120 mg of etoricoxib (with an onset of action within 1 hour and a half-life of approximately 22 hours), with dosage reduction upon relief of symptoms. Blood and urine samples are collected from patients who consent for further research purposes. In the case of AEs, the use of QTF granules or placebo granules is temporarily suspended until the condition stabilizes.

The observing physician will meticulously record the quantity of medication received, used, and returned by the participants to assess medication adherence and ensure timely documentation in the case report forms. Based on the participant’s adherence, a decision will be made regarding their continued participation in the trial. The exclusion criteria for poor adherence are medication adherence rate = (actual medication amount/ theoretical medication amount) < 80% or > 120%. The medication administrator is responsible for locking the cabinet, sealing the medications, and storing them at room temperature. If a participant withdraws from the study early, any remaining medication should be collected and returned.

Regulations on Concurrent Treatments: During the trial, the use of various anti-rheumatic drugs, muscle relaxants, and analgesics, including both traditional Chinese and Western medicines such as Shenling Baizhu Powder/ Pills and Pingwei Powder, is generally prohibited. Additionally, physical therapies such as massage and acupuncture are not allowed.

If participants need to continue taking other medications or undergoing other treatments due to concurrent diseases, these must be documented in detail in the concurrent medication log.

Outcomes

Data management, monitoring and auditing

Data for this trial will be collected from Case Report Forms (CRFs) at each center, with study monitors reviewing the forms to ensure completeness and quality. Two independent data managers will be responsible for entering the data into the system. Researchers will strictly maintain participant confidentiality, with access granted only by permission from the research design unit. The data management system is provided by Jiangsu Famous Medicine Co., Ltd.

The Data Monitoring Committee (DMC), organized and led by Zhejiang Chinese Medical University, comprises experienced clinical researchers and esteemed academic scholars in the field. The committee will conduct regular audits of the data to ensure the integrity and safety of the study. These audits will adhere to internationally recognized standards for clinical trial inspections, including the examination of clinical trial items, quality, and risk management, to ensure the authenticity and integrity of the research data. Once recruitment reaches 50%, the committee will perform interim analyses of the primary outcomes using Lan-DeMets with O’Brien-Fleming methodology to evaluate the study’s effectiveness and safety.

Statistical analysis

The statistical analysis for this trial will be conducted based on the Per-Protocol (PP) and Intent-to-Treat (ITT) data, conducted by Jiangsu Famous Medicine Co., Ltd., situated in Nanjing, China. Different analysis methods will be employed depending on the type of data measurement or counting.

For the primary outcome, the number of gout flares in each group will be compared using t-tests or Wilcoxon rank-sum tests, with center effects controlled through covariance analysis. For count data, such as time span to the first occurrence of gout flares, duration of acute gouty arthritis recurrence, pain visual analog scale score, HAQ-DI, and safety analysis indicators (like routine blood tests), the same methods will be applied. Measurement data, including the recurrence rate of acute gouty arthritis and the incidence of adverse events, will be analyzed using chi-square tests or Fisher’s exact tests, with center effects controlled through binary or multinomial logistic regression analysis. All hypothesis tests in this study will be two-sided, with a significance level of 0.05. Differences will be considered statistically significant when p < 0.05. SAS version 9.4 will be used for all statistical analyses.