Efficacy and Safety of Qinpi Tongfeng Formula in the Treatment of Acute Gouty Arthritis: A Double-Blind, Double-Dummy, Multicenter, Randomized Controlled Trial

Objective Traditional Chinese medicine (TCM) has certain curative effect against acute gouty arthritis (AGA), but it lacks high-quality evidence-based studies. In this randomized controlled trial, we try to evaluate the clinical efficacy and safety of Qinpi Tongfeng Formula (QPTFF) in the treatment of AGA. Methods One hundred and fourteen patients with AGA (damp heat accumulation syndrome) who met the inclusion and exclusion criteria were randomly divided into treatment group and control group in a ratio of 1 : 1. Patients in the treatment group were treated with QPTFF, and patients in the control group were treated with diclofenac sodium sustained-release tablets for 7 days. The primary outcome measure was the change in visual analog scale (VAS) score for pain from the baseline to day 8. The secondary outcome measures were joint symptom score, TCM syndrome score, total effective rate, pain cure rate, complete pain relief time, patient satisfaction score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum uric acid level. The safety outcome measures were routine blood test, urinalysis, liver function including alanine aminotransferase and aspartate aminotransferase, renal function including blood urea nitrogen and serum creatinine, and the rate of treatment-related adverse events (TRAEs). Results 105 patients with 53 in the treatment group and 52 in the control group completed the 7-day treatment. There was no significant difference between two groups in demographic characteristics, VAS score for pain, joint symptom score, TCM syndrome score, ESR, CRP, and serum uric acid level before enrollment at baseline (based on both the full analysis set (FAS) and per protocol set (PPS), P > 0.05). The 95% confidence interval of the difference between the eighth and first VAS score for pain of the two groups was (−0.57, 0.42) in FAS and (−0.48, 0.47) in PPS. The lower bound of both FAS and PPS is greater than the bound value of −0.7. On day 8, there was no significant difference between the two groups in joint symptom score, TCM syndrome score, total effective rate, pain cure rate, complete pain relief time, patient satisfaction score, ESR, and CRP (FAS and PPS, P > 0.05). The serum uric acid level and TRAEs in the treatment group were significantly lower than those in the control group (FAS and PPS, P < 0.05). Conclusions QPTFF could alleviate the symptoms of patients with AGA, which is not inferior to diclofenac sodium sustained-release tablets in analgesic. Moreover, QPTFF overmatches diclofenac sodium sustained-release tablets in decreasing serum uric acid level and TRAEs. Therefore, the results provide reliable foundation for QPTTF in the treatment of AGA. Trial Registration. This study protocol was registered in Chinese Clinical Trial Registry (registration number: ChiCTR2100050638).


Introduction
Gout is a metabolic rheumatism caused by abnormal purine metabolism, increased synthesis, and/or decreased excretion of uric acid, resulting in increased serum uric acid. With the high serum uric acid level, urate will be deposited into crystals to gather in joints, cartilage, and kidney [1]. Urate crystals in joints can lead to bone injury by repeated inflammation stimulation further to influence the daily activities of gout patients. Urate crystals in kidney can lead to gouty nephropathy which will develop into renal failure and endanger life, once poorly controlled [2]. In addition, longterm high serum uric acid level can increase the risk of cardiovascular events and cerebrovascular diseases [3].
Acute gouty arthritis (AGA) is a common acute arthritis with clinical features of severe arthralgia with swelling, recurrence, and poor prognosis [4]. For AGA, 2021 Asia Pacific League of Associations for Rheumatology [5] recommended anti-inflammatory and analgesic therapy. Colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line drugs for the treatment of AGA. Although colchicine can alleviate the patient's condition in a short time, there will be different adverse reactions such as damage to the liver, kidney, gastrointestinal, and bone marrow suppression after the treatment [6]. NSAIDs can also effectively reduce joint pain, but they are lack in reducing serum uric acid level with certain side effects [7]. Hence, it is important to seek a safe and effective treatment method.
In traditional Chinese medicine (TCM), the clinical manifestations of AGA, such as joint swelling and tenderness and local skin redness, constitute the "damp heat accumulation syndrome" of "Bi syndrome" (joint pain) similar to the acute stage of gouty arthritis. e treatment of AGA with TCM has a history of thousand years in China. A preliminary systematic study [8]found that TCM compound has good curative effect with less adverse reactions in the treatment of AGA. However, the included research studies were lack in strictness and poor in quality. More high-quality randomized controlled trials are needed to furnish evidence for the efficacy of TCM. Qinpi Tongfeng Formula (QPTFF) is a TCM treatment for AGA. It has been used clinically in the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine for at least 12 years. Both QPTFF combined with western medicine or bloodletting therapy have good curative effects in the treatment of gout [9,10]. Nevertheless, rigorous randomized controlled trials have not been carried out to compare the efficacy and safety of QPTFF and NSAIDs. us, the purpose of this study is to evaluate the effects and safety of QPTFF in the treatment of AGA.

Study Design.
is is a double-blind, double-dummy, multicenter, randomized, noninferiority clinical trial. e study was conducted under the Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonization. Meanwhile, the study followed consort (Table S1). e protocol of the study has been approved by the Ethics Committee of the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine (ethics number: TYLL2021[Z] 017), and it has been registered in Chinese Clinical Trial Registry (registration number: ChiCTR2100050638).

Participants.
Men and women aged 18-70 years were considered for enrollment if met the diagnostic criteria of AGA of the American College of Rheumatology in 2015 [11] as well as diagnostic criteria of dampness heat accumulation syndrome in the Guidelines for the Combined Diagnosis and Treatment of Gout and Hyperuricemia [12]. All participants signed informed consent. We conducted this clinical trial in three centers, including the First and were unwilling to continue participating in the study or lost to follow-up. Researchers should try to complete the last laboratory test of all withdrawn or lost cases in order to analyze their efficacy and safety. e reasons for the shedding of all shedding cases in detail and the records of the indicators that met the test requirements should be filled in the case report form (CRF). e unfinished indicators should be also filled in by the last carry forward method.

Exclusion.
During the study period, participants who used a series of combined medications at will, which will affect the assessments of curative effect, should be excluded and recorded in the CRF.

Sample Size.
e primary outcome measure of this study was the change in VAS score for pain from the baseline to day 8. According to the preliminary clinical trial, the mean values of VAS score changes of QPTFF and diclofenac sodium sustained-release tablets were 3.67 and 3.75, with the standard deviation of 1.22 and 0.97. For sample size estimation, PASS 15.0 software was used and noninferiority design was adopted with one-sided test selected, taking α � 0.025, β � 0.2, the ratio of the treatment group and the control group � 1 : 1, and the boundary value � −0.7. e calculated sample size for the two groups was 102 cases. Considering the potential dropout rate of about 10%, a total of 114 cases were finally included, with 57 cases in each group. According to the situation, 114 drug packaging bags were numbered, so that each center could distribute drugs according to the numbers. e study was designed to be double-blinded and double-dummied. e treatment group used the QPTFF granule + diclofenac sodium sustained-release tablets simulant (the color, texture, taste, and smell were the same as the actual drug), while the control group used diclofenac sodium sustained-release tablets + QPTFF granule simulant (the color, texture, taste, and smell were the same as the actual drug): (1) Blinding: a trained statistician not involved with the study completed the blinding of the test medications. is study adopted a two-stage blind design. e first stage was the group code corresponding to each drug number, which was group A or group B, and the second stage was the treatment scheme adopted by group A and group B. e two-stage blind data should be placed in an opaque envelope and should not be opened during the study. All researchers who were responsible for recruiting, distributing drugs, testing indexes, and evaluating efficacy, all participants were blind to the randomization. e expert statisticians who were also blind to the randomization would conduct statistical analysis after completing the study.
(2) Emergency unblinding: each drug with a number had a corresponding emergency letter, so that the patient could carry out emergency unblinding in case of serious adverse reaction events.

Emergency Treatment.
If the pain of participants was severe and intolerable during the study, they would be given colchicine tablets (obtained by Guangdong Pidi Pharmaceutical Company, Kaiping, China, H20113208) to assist in emergency pain relief, 0.5 mg each time, three times a day. At the same time, the medication administration would be recorded in the CRF.

Baseline Demographic Characteristics of Patients.
Record the participant's name, gender, age, height, weight, body mass index (BMI), nationality, course of gout disease, allergy history, smoking history, drinking history, past medical history, and family history of gout.

Safety Indicators
(1) Vital sign: temperature, heart rate, blood pressure, and respiration were recorded on day 1 and day 8 (2) Laboratory examination: routine blood test, urinalysis, liver function including alanine aminotransferase and aspartate aminotransferase, and renal function including blood urea nitrogen and serum creatinine were examined on day 1 and day 8 (3) Treatment-related adverse events (TRAEs): researchers refer to the incidence of Common Terminology Criteria for Adverse Events version 5.0 [14] to record the adverse events and treatment measures in the whole process

Primary Outcome Measure
(1) Changes in VAS Score for Pain. e pain degree of the participant was evaluated by VAS [15]. Researchers should record VAS score for pain before each treatment and the VAS score for final pain on day 8. A total of 8 scores were obtained.

Secondary Efficacy Index
(1) Joint Symptom Score. e participant's joint tenderness, redness, swelling, and mobility were evaluated by Likert scale [16] (Table S2) at the baseline and day 8.
(2) TCM Syndrome Score. Researchers would evaluate the TCM syndrome score, including the main and concurrent symptoms of AGA patients (Table S3), referring to the Guiding Principles for Clinical Research of New Traditional Chinese Medicine [17], the quantitative integral evaluation of TCM syndrome was adopted. e higher the score, the worse the condition of AGA was. e TCM syndrome score would be recorded at the baseline on day 8.
(4) Pain Cure Rate. Definition of pain cure: within 24 hours during the treatment, the VAS score for pain was 0, and the VAS score was still 0 24 hours after the treatment. e pain cure rate refers to the proportion of cured patients in the total number of patients within 7 days of treatment. (6) Patient Satisfaction Score. On day 8, the participant would get an overall evaluation of the treatment, which was rated as 5 points (1 point: poor treatment effect; 2 points: slightly effective; 3 points: acceptable curative effect; 4 points: good; and 5 points: extremely good) [16].
(7) Laboratory Index. e levels of CRP, ESR, and serum uric acid of participants were measured at baseline on day 8.

Statistical Analysis.
All outcome measures in this study were analyzed by the full analysis set (FAS) and per protocol set (PPS). In the FAS, for the indicators with missing data, the last observation value carry forward method was used to fill in the data. Safety indicators were analyzed by a safety set. SPSS 22.0 was used to carry out statistical analysis on the data. e quantitative data were described by mean, standard deviation, or interquartile interval M (P 25 , P 75 ). For normal distributed data, the independent sample t-test or paired ttest was used for comparison between groups or within groups before and after the treatment, while data in skewed distribution nonparametric test should be adopted. e repeated measurement data in this study were skewed distribution, so the mixed linear model was used. e counting data were expressed by frequency and composition ratio, and the chi-square test was used for statistics; the Kaplan-Meier survival curve was used to describe the time of complete pain relief, and the log-rank test was used for comparison between groups. P < 0.05 indicated the difference was statistically significant. e change of VAS score was taken as the main efficacy index, and the noninferiority test was carried out according to the confidence interval method. SAS software was used to calculate the 95% confidence interval (CI) of the difference between the changes value of VAS score for pain between the treatment group and the control group before and after treatment. If the lower limit of the CI was greater than the limit value, the noninferiority was established [20]. GraphPad Prism 8 software was used to make graphics.

Case Collection and Completion.
According to the registered protocol, 114 eligible AGA patients were included in this study from August 2021 to February 2022. In the course of the study, the clinical symptom indexes (VAS score for pain, TCM syndrome score, and joint symptom score) were measured. 105 participants completed the 7-day treatment, and 105 were finally included in the PPS, including 53 in the treatment group and 52 in the control group; 89 participants finally finished the laboratory indexes and were included in the PPS, including 45 in the treatment group and 44 in the control group (Figure 1).

Baseline Characteristic Analysis.
ere was no significant difference between the two groups in gender, age, course of gout disease, weight, height, and BMI (P > 0.05), as shown in Table 1.
ere was no significant difference in allergy history, smoking history, drinking history, past history, and family history of gout between the two groups (P > 0.05). ere was no significant difference in temperature, heart rate, systolic blood pressure, diastolic blood pressure, and respiration between the two groups (P > 0.05).
ere was no significant difference between the two groups in VAS score for pain, joint symptom score, TCM syndrome score, ESR, CRP, and serum uric acid level (P > 0.05), as shown in Table 2, indicating that the two groups were comparable at baseline.

VAS Score for Pain.
e VAS score for pain of the two groups decreased gradually, and the changes are shown in Figures 2 and 3. e mixed linear model was used to compare the measurement results of VAS score at different time points between the two groups. e fixed effect analysis results of mixed linear model showed that there was no interaction effect at group * time point (P > 0.05), and the overall curative effect difference between the two groups was not statistically significant (P > 0.05), as shown in Table 3.
ere was no significant difference in VAS score between the two groups at different time points (P > 0.05), as shown in Table 4. In the FAS, the 95% CI of the difference between the eighth time and baseline VAS scores of the two groups was (−0.57, 0.42), and its lower limit was greater than the boundary value of −0.7, so the noninferiority was established. In the PPS set, the 95% CI of the difference between the eighth time and the baseline VAS scores the two groups was (−0.48, 0.47), and its lower limit was greater than the boundary value of −0.7, so the noninferiority was established. In conclusion, the noninferiority test of this study is qualified.

Joint Symptom Score.
e joint symptom scores of the two groups after the treatment were better than those before the treatment (FAS and PPS, P < 0.05). After the treatment, there was no significant difference in the joint symptom scores between the treatment group and the control group (P > 0.05), as shown in Table 5.

TCM Syndrome Score.
In FAS and PPS, the TCM syndrome scores of the two groups after the treatment were better than those before the treatment and the difference was statistically significant (P < 0.05). After the treatment, there was no statistically significant difference between the TCM syndrome scores of the treatment group and the control group (P > 0.05), as shown in Table 6.

Total Effective Rate.
In FAS, the total effective rate was 89.47% in the treatment group and 87.72% in the control group, and there was no significant difference between the two groups (P > 0.05). In PPS, the total effective rate was 96.23% in the treatment group and 96.15% in the control group, and there was no significant difference between the two groups (P > 0.05), as shown in Table 7.

Pain Cure Rate.
In FAS, the pain cure rate was 35.09% in the treatment group and 38.60% in the control group, and there was no significant difference between the two groups (P > 0.05). In PPS, the pain cure rate was 35.84% in the treatment group and 38.46% in the control group, and there was no significant difference between the two groups (P > 0.05), as shown in Table 8.

Comparison of Complete Pain Relief Time between the
Two Groups. In FAS, the median time of complete pain relief time in both the treatment group and the control group was 7.65 days (Figure 4). Using the log-rank test, there was no significant difference between the two groups (P � 0.701). In PPS, the median time of complete pain relief time in the treatment group and the control group was 7.65 days. e survival curve of the two groups is shown in Figure 5. Using the log-rank test, there was no significant difference between the two groups (P � 0.85).

Patient Satisfaction Score.
e patient satisfaction score adopted PPS. e results showed that there was no statistical difference between the two groups (P > 0.05) (see Table 9).

Laboratory Index.
In FAS and PPS, the levels of ESR and CRP in the two groups after the treatment were lower than those before the treatment and the differences within the two groups were statistically significant (P < 0.001). After the treatment, there was no statistically significant difference in the levels of ESR and CRP between the treatment group and the control group (P > 0.05), as shown in Tables 10 and 11. In FAS and PPS, the level of serum uric acid in the treatment group after the treatment was significantly lower Evidence-Based Complementary and Alternative Medicine than that before the treatment (P < 0.001), and there was no significant difference in the level of serum uric acid in the control group before and after the treatment (P > 0.05). After the treatment, the level of serum uric acid in the treatment group was significantly lower than that in the control group (P < 0.05), as shown in Table 12.

Safety Evaluation.
During the treatment, routine blood test and urinalysis did not show abnormalities in the two groups. Only 23 patients had elevated leukocytes stimulated by inflammation before the treatment, but they all returned to normal level after the treatment. Another 9 patients had elevated platelet count before the treatment, but decreased after the treatment.
ere was no abnormal increase or decrease in vital signs in the two groups after the treatment.
e TRAEs were 7.02% in the treatment group and 26.32% in the control group. e TRAEs of the treatment group were significantly lower than those of the control group (P < 0.05), as shown in Table 13.

Discussion
AGA is caused by the deposition of urate crystals in the articular cavity, manifested as redness, swelling, and severe pain of the joints [21]. International guidelines recommend NSAIDs as the first-line treatment of AGA [22,23], and diclofenac sodium sustained-release tablets are commonly used as positive controlled medicines in the treatment of AGA [24][25][26]. erefore, diclofenac sodium sustained-release tablet was chosen as the controlled medicine in this study. VAS score for pain is the most widely used tool to measure pain intensity in clinic [27,28], which is often used   [17], the TCM syndrome score scale is used to evaluate the TCM syndrome of patients, which is widely used in the efficacy evaluation of TCM therapy [9,19]. ESR and CRP are commonly used as inflammatory indicators in clinic and play an important guiding role in judging the progress of inflammation [30]. Serum uric acid level is not only a diagnostic indicator of AGA but also an indicator of its prognosis. e level of serum uric acid is closely related to the recurrence rate of gouty arthritis [31], so we also listed serum uric acid as the outcome measure. Nevertheless, the main aim of the treatment to AGA is to control inflammation and relieve pain, and serum uric acid was set as the secondary outcome measure. In this study, the improvement of patients' pain is the primary outcome measure of the study. e VAS score for pain of participants on day 8 was significantly lower than that at baseline, indicating that both treatments could effectively reduce the pain of patients. e noninferiority test proved that the lower confidence interval of the difference value of VAS score for pain (from baseline to day 8) between the two groups is greater than the lower limit (FAS and PPS, lower limit >−0.7).
ere was no significant difference in complete pain relief time and pain cure rate between the two groups, which suggested that the analgesic effect of QPTFF was not inferior to that of diclofenac sodium sustained-release tablets. e results of secondary outcome measures showed that both treatments had a great improvement in the joint symptom score, TCM syndrome score, ESR, and CRP, but without significant difference, indicating that QPTFF and diclofenac sodium sustainedrelease tablets could significantly improve the patients' symptoms and inflammatory indicators with equal effects. However, QPTFF had more advantages than diclofenac sodium sustained-release tablets in reducing the serum uric acid level. After the treatment, the satisfaction survey was carried out on the patients, and the results showed that the    Evidence-Based Complementary and Alternative Medicine subjective feeling of the patients in the two groups was equal.
In terms of safety evaluation, the rate of TRAEs in the treatment group was significantly lower than that in the control group and the patients in the treatment group had no liver and kidney function injury, but discomfort in the stomach. To timely monitor the changes of liver and renal function, we set the abnormal liver and renal function as higher than the upper limit of the normal, or abnormal liver and renal function before treatment, while further increased after treatment to protect the patient's health. Although the reported percentage of abnormal liver and renal function     [34]. Cortex Fraxini extract can reduce the level of urate anion transporter 1 (URAT1), so it has the effect of reducing uric acid [35]. Aesculetin B and Aesculetin A can also inhibit the release of inflammatory factors [36]. e components in Rhizoma Smilacis Glabrae, such as colchicine, syringic acid, and catechin, can inhibit the expression of inflammatory factors and have strong anti-inflammatory effects [37]. Rhizoma Smilacis Glabrae can reduce the serum uric acid concentration of mouse hyperuricemia model by inhibiting xanthine oxidase activity [38]. Berberine is an important component of Rhizoma Coptidis, which could inhibit the activation of NLRP3 inflammatory bodies and prevent IL-1β to resist inflammation [39]. Berberine in Rhizoma Coptidis can reduce the serum uric acid level and protect renal function by inhibiting the activation of NLRP3 inflammatory bodies and the abnormal expression of URAT1 [40].
ere are sesquiterpenoids, diterpenoids, flavonoids, and other compounds in Herba Siegesbeckiae, which have antiinflammatory and analgesic effects [41]. e extract of Herba Siegesbeckiae can also inhibit the activity of xanthine oxidase and reduce serum uric acid [42]. Rhizome Dioscoreae Hypoglaucae has anti-inflammatory and analgesic effects    Evidence-Based Complementary and Alternative Medicine [43,44]. e extract of Rhizome Dioscoreae Hypoglaucae can promote the excretion of uric acid by regulating the levels of organic anion transporter 1, murat1, and organic cation transporter 2 and has the effect of reducing uric acid [45].
ere are many components with xanthine oxidase inhibitor effect in Semen Plantaginis, such as luteolin, mullein glycoside, golden sage grass flavin, so it has the effect of reducing uric acid [46]. Plantain polysaccharide may have renal protective effect by downregulating the expression of NLRP3, ASC, and caspase-1 protein and inhibiting the release of downstream inflammatory factors [47]. Radix Clematidis inhibits NF-κB and MAPK pathways in macrophages to reduce the production of proinflammatory factors, to function in anti-inflammatory and analgesic [48]. Polysaccharide of Radix Saposhnikoviae has anti-inflammatory and analgesic effects by regulating the expression of p53 and inhibiting the release of inflammatory factors [49]. e extract of Radix Saposhnikoviae can reduce blood uric    acid by inhibiting the activity of xanthine oxidase [50]. erefore, these drugs can exert the clinical efficacy of antiinflammatory and analgesic, reduce serum uric acid, and improve the symptoms of gout patients.
However, our study still has some limitations. is study only uses common efficacy indicators for observation, without the observation of the changes of immune indicators and images in AGA. Although the sample size of this study was estimated by the PASS 15.0 software, it was only the minimum sample size required by clinical practice, and there were only 3 hospitals in the study. In the future, more highquality multicenter, large-sample randomized controlled trials should be carried out to observe the changes of immune indicators and images with AGA.

Conclusions
QPTFF can improve the symptoms and signs of patients with AGA, as well as the inflammatory indexes and serum uric acid level. Its analgesic effect is not inferior to diclofenac sodium sustained-release tablets, but it has more advantages in reducing the serum uric acid level and the rate of treatment-related adverse events. erefore, QPTFF is an effective clinical treatment for AGA.

TCM:
Traditional Chinese medicine AGA: Acute gouty arthritis QPTFF: Qinpi Tongfeng Formula VAS: Visual analog scale ESR: Erythrocyte sedimentation rate CRP: C-reactive protein TRAEs: Treatment-related adverse events FAS: Full analysis set PPS: Per protocol set NSAIDs: Nonsteroidal anti-inflammatory drugs CRF: Case report form BMI: Body mass index CI: Confidence interval.

Data Availability
e datasets used and analyzed in the current study are available from the corresponding author on reasonable request (Wei Liu: fengshiliuwei@163.com).

Ethical Approval
is study has been approved by the ethics committee of First Teaching Hospital of Tianjin University of Traditional Chinese Medicine (TYLL2021[Z]017).

Disclosure
Yihua Fan, Wei Liu, and Hang Lu are the co-first authors. e funded organization only provided financial support and did not play any role in the design, patient recruitment, data collection, statistical analysis, and paper writing of this study.

Conflicts of Interest
e authors declare that they have no conflicts of interest.