2.1 Research design
This trial was designed as an open-label, randomized, controlled, and parallel-group study that focused on the therapeutic efficacy and safety of CQBG combined with Western-medicine-basic treatment in treating AGA. It was conducted from September 2018 to December 2019 in the Department of TCM, the First Affiliated Hospital of China Medical University, which is the NO.1 comprehensive hospital in China's northeast region with a wide range of patients. The study was approved by the ethics committee of the First Affiliated Hospital of China Medical University and registered in the Chinese Clinical Trial Registry. All patients signed the informed consent form.
2.2 Diagnostic criteria
2.2.1 Diagnostic criteria of AGA
For the diagnosis of primary gout, one can refer to the gout classification criteria in the 2015 American College of Rheumatology (ACR)/European League Against Rheumatism(ULAR) .
Acute attack stage of gout: Signs may not occur before the attack. Typical patients with the acute attack are often awakened by arthralgia, which worsens progressively and reaches the peak about 12h later, with unbearable bursting pain, cutting pain, and gnawing pain. The involved joints present swelling, burning, tight skin, obvious tenderness, and restricted motion. The attack can voluntarily alleviate and return to normal in a few days (up to 2 weeks). The first attack often involves a single joint, with more than 50% in the first metatarsophalangeal joint and 90% in the later course. Besides, joints such as dorsum pedis, heel, ankle, and knees can be involved. Symptoms such as fever, chill, headache, palpitation, and nausea can occur in some patients with an increased number of white blood cells, CRP level, and erythrocyte sedimentation rate, showing urate crystals in ultrasound.
Hyperuricemia: a test of blood UA levels twice on different days: sUA >420 mmol/L.
2.2.2 Differentiated Criteria of the dampness-heat syndrome
The differentiation of the dampness-heat syndrome was confirmed by two TCM professors based on clinical symptoms and signs, as well as pathogen and pathological mechanism, including swelling and heat pain in local single joints or multiple joints, accompanied by fever, fear of cold, thirst, anxiety, headache, sweating, less and yellow urination, red tongue, yellow or greasy tongue coating, and stringy and rapid pulse, which complied with Criteria of Syndrome Differentiation and Therapeutic Effect of Zhuoyubi (gouty arthritis) in TCM published by the State Administration of Traditional Chinese Medicine(2017 edition) and Criteria of Diagnosis and Therapeutic Effect of Internal Diseases and Syndromes in Traditional Chinese Medicine published by the State Administration of Traditional Chinese Medicine of the People’s Republic of China(ZY/T001.1–94).
2.2.3 Recruitment criteria
The inclusion criteria were as follows:
(1) conforming to the diagnostic criteria of AGA and hyperuricemia; (2) diagnosis of dampness-heat syndrome; (3) age 18–70 years and any sex; (4) AGA attacked ≥1 in the previous year; (5) alleviation period in previous AGA attacks, ≤ 14 days; (6) main observed regions including first metatarsophalangeal joint, dorsum pedis, ankle joint, knee joint, and so forth, and only the most severe joint (target joint) observed and recorded for each participant, with no change during the observation; (7) VAS score (evaluation of pain scoring criteria) in the target joint, ≥3; (8) <72 h between the last treatment and the attack; and (9) patients who voluntarily participated and signed the written informed consent form.
2.2.4 Exclusion criteria
The exclusion criteria were as follows:
(1) Secondary gout or arthropathy caused by other diseases (e.g., rheumatic arthritis, pyogenic arthritis, traumatic arthritis, senile osteoarthritis, pseudogout, chemotherapy, radiotherapy, chronic lead poisoning, and acute obstructive nephropathy)
(2) Chronic intermittent gout or chronic tophaceous gout
(3) More than four joints involved in the AGA attack
(4) Patients taking drugs that affected the metabolism of blood UA, for example hydrochlorothiazide, furosemide, low-dose aspirin, and drugs that contained the aforementioned components, such as compound reserpine and hydrochlorothiazide; or patients who stopped taking glucocorticoids less than 1 month before enrollment; or patients using NSAIDs, or other analgesic drugs, or external ointment 24 h before the baseline assessment
(5) Severe malformation because of gouty arthropathy or disability resulting from stiffness
(6) Pregnancy or lactation
(7) Allergic constitution or a history of allergy
(8) Serum creatinine (Scr) exceeding the upper limit of the reference value
(9) Liver function, Alanine aminotransferase(AST) and Aspartate aminotransferase(ALT) levels 1.5 times higher than the normal upper limit
(10) Clinically significant arrhythmia
(11) History of alcohol or drug abuse
(12) Severe cerebrovascular, renal, liver, or hematopoietic comorbidities, cancer, or mental disorders
(13) Participated in other clinical trials in the last 3 months
(14) Referring to the judgment by investigators: some other diseases or situations leading to a lower possibility of recruitment or complicate the enrollment, such as missing visits due to frequent changes in the workplace.
2.3 Randomization, blinding and intervention
Patients with AGA were randomly divided into three groups. Following the distribution sequence, random numbers were created using SAS9.2 edition (Straits Leading Pharmaceutical R&D Co. Ltd., Heping District of Shenyang) by an independent statistician from the CMU1h Clinical Trials (GCP) center. Every random number was put into a serially numbered opaque envelope and screened by clinical coordinators. After screening, the clinical researchers provided patients with treatment according to the randomized serial number.Every eligible patient was given a specific treatment number, which was a fixed number for the whole trial used as the basis of drug allocation.
The blinding method was not suitable for both patients and evaluators due to the obvious difference in pharmaceutical types between CQBG used in the treatment group 2 and diclofenac diethylamine emulgel used in the treatment group 1. However, the statisticians were blinded to the study design.
A total of 90 patients in line with the diagnostic standard of AGA were recruited and divided randomly into control, T1, and T2 groups (30 in each group). The participants in the three groups all received Western-medicine-basic treatment, including low-purine diet, drinking water more than 2000 mL/d, three times loxoprofen (60mg each time) and NAHCO3 (1g each time) per day orally. Besides, the T1 group received an external application of diclofenac diethylamine emulgel which is anti-inflammatory and analgesic drugs commonly used in clinic and produced by Novartis Pharma (Beijing) Stein AG. The T2 group received an external application of CQBG. CQBG were prepared adhering to the national production standard by Jiangyin Tianjiang Pharmaceutical Co. Ltd., Jiangsu province. They have Cortex Phellodendri and Herba tuberculate speranskia as the main components. The components and quality control mapping of CQBG are shown in Supplementary file 1.
External medicine usage: Before application, each pack of CQBG (30 g) was dissolved in 80mL of water, and mixed well to form a paste. Apply CQBG or diclofenac diethylamine emulsifier evenly on the affected area. The dosage of CQBG or diclofenac diethylamine emulsifier was defined (1 cm outside the painful area; local application thickness 1-2 cm , 3 times a day). The participants in the control group received single-use Western-medicine-basic treatment. The total treatment course lasted 7 days and the patients in the three groups were followed up for 7 days..
2.4 Ethics permission and registration
This study was performed following the standard of the International Coordinating Committee on Global Partnerships and the revised edition of the Declaration of Helsinki. It was registered in ChiCTR (ChiCTR1800018020). Every participant endorsed the informed consent voluntarily.
2.5 Observation indicators
2.5.1 Primary clinical outcome indicators
(1) Change in the VAS score in the target joint: 0 for no pain and 10 for unbearable pain. The VAS score was evaluated three times a day with consistency among groups in terms of patients’ feeling of pain, and its mean value was taken as the VAS score of the day.
(2) Onse time of pain improvement in the target joint: VAS <3 was defined as pain improvement.
(3) Change in pain duration in the target joint: The duration of target joint pain was obtained from a daily pain recording card, and the change in pain duration was defined as the pain duration on the testing day minus the pain duration on the previous day. To reduce deviation, the patients were stratified into groups 0–24 h, 24–48 h, and 48–72 h according to the disease course of acute gout. The change in pain duration on days 1–4, 7, 10, and 14 was observed.
(4) Swelling score: 1 for no arthrocele, 2 for palpable arthrocele, 3 for macroscopic arthrocele, and 4 for swelling exceeding the joint edge[23,25]. The swelling change in all groups on days 0, 7, and 14 was observed.
2.5.2 Secondary outcome indicators
UA, CRP, and ultrasound examinations of the thickness of the inflammatory synovium of joints were evaluated once before and after the treatment.
2.6 Safety evaluation
Examinations including physical examination, blood routine, urine routine, and hepatorenal function as well as records of all adverse events, were assessed and analyzed with drug dependency.
2.7 Statistical analysis
Data were analyzed with SPSS 23.0 software, while measurement data were presented with ¯x ± s. Per-protocol analysis(PPS) was used to analyze data in the present study. Some baseline characteristics were assessed by one-way analysis of variance (ANOVA). Mauchly’s test of sphericity should be used to judge whether there were relations among the repeated measured data. If any (P<0.05), repeated measures and multivariate analysis of variance of the general linear model should be taken. When Mauchly’s test of sphericity is P >0.05, univariate ANOVA can be used. Bonferroni, LSD and S-N-K tests were chosen for multiple comparison and multiple correction. While qualitative variables were compared using the Chi-squared test(c2), or the Fisher’s exact test in the case of small sample size. A P value<0.05 indicated a statistically significant difference.