Objective
The main objective of the present study will be to evaluate the effect of Guizhi-Shaoyao-Zhimu decoction on outcome indicators in patients with early rheumatoid arthritis.
Sample size calculation
To determine the sample size, we inquired about the previous research contents. The effective rate of methotrexate in the treatment of rheumatoid arthritis was 40%[8], and that of Guizhi Shaoyao Zhimu decoction was 64%[9]. If α = 0.05 and the test efficacy 1 – β = 0.80, then the sample size, Thus, n = 122, with 61 patients in each treatment group. Considering a 20% dropout rate, the planned sample size for randomization was increased to 152.
Trial design and setting
This study is a randomized, double-blinded, parallel group, placebo-controlled trial. Eligible participants will be randomly assigned to the experimental group (Guizhi-Shaoyao-Zhimu decoction) or the control group with a 1:1 ratio. The subjects will be selected from patients with early active rheumatoid arthritis who visited the Rheumatology Department of ShuGuang Hospital affiliated with Shanghai University of Traditional Chinese Medicine. We plan to recruit patients from participating hospitals via poster, networking, or WeChat. The posters will be placed on bulletin boards or other assigned places in the hospitals. At least one staff member (a postgraduate or doctor) will specialize in patient recruitment. Their contact information and clinic for screening visit will be detailed described in the recruitment advertisement.The design of the study follows a strict scientific clinical research methodology and complies with the principles outlined in the Declaration of Helsinki and the guidelines for good clinical practice. At any stage of the clinical study, a participant can withdraw from the clinical research without discrimination or retaliation. Patient rights and interests are not affected. If harm or injury related to the clinical research occurs, then the subjects can be appropriately compensated. The clinical study can be conducted only after the signature of the subject or legal representative/guardian is received with the date specified. If the subject or legal representative/guardian cannot read, a witness should be present. After a detailed explanation of the informed consent form, the subject or legal representative/guardian can provide consent, and the witness can sign and date the form. The flow chart and trial schedule are shown in Fig. 1 and Table 1, respectively.
Table 1: Schedule of study procedures.
Note: A total of 152 participants will be randomized into the control group or the experimental group. Assessors blinded to the randomization will collect data during the intervention period at baseline and at study months 1, 2, and 3. The peripheral blood levels of matrix metalloproteinase 3 (MMP3), matrix metalloprotease 1 (TIMP1), and soluble cluster of differentiation 14 (sCD14) will be detected before and after treatment to explore the biochemical mechanisms of Guizhi-Shaoyao-Zhimu decoction for the treatment of active RA.
Eligibility criteria
To participate in the trial, potential participants must fulfill all the following criteria:
Diagnostic criteria
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Diagnostic criteria for RA: According to the criteria for the classification of RA proposed by the American College Rheumatology(ACR) and European League against Rheumatism(EUHLAR) in 2010, participants with a score of 6 or above who were diagnosed with RA.[10]
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Diagnostic criteria for active RA: Disease Activity Score (DAS28)༞2.6.DAS28, the most commonly used comprehensive score in RA, is used to evaluate the disease activity of RA patients with scores ranging from 0 to 10[11]. According to EULAR diagnostic criteria for RA activity, DAS28༞2.6.This project aims to study active RA patients, so the participants in this study should have a DAS28 score greater than 2.6.
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Diagnostic criteria for TCM syndrome differentiation: According to the Guidelines for Clinical Research of Chinese Medicine (New Drug) [12], the participants had to present with at least two of the primary symptoms and more than two of the secondary symptoms listed below to be diagnosed with wind dampness heat bi syndrome.
1. Primary signs and symptoms:
2. Secondary symptoms:
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aversion to cold with fever
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thirsty upset
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dry stools and yellow urine
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red tongue with yellow or dry fur
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rapid and slippery pulse
Inclusion criteria
Patients who meet the following criteria will be deemed eligible for the trial:
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Meet the diagnostic criteria for RA; Meet the diagnostic criteria for active RA.
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Aged 18–80 years with a disease course of less than 1 year.
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Disease Activity Score in 28 joints-Erythrocyte Sedimentation Rate (DAS28-ESR) ≥ 2.6 (rounded to 1 decimal place).
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Patients receiving NSAIDs and hormone therapy were given a stable dose for at least 30 days before entering the trial, and remained at the same dose for the rest of the treatment.
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Treatment with other DMARDs must be interrupted for at least 30 days before entering the trial.
Exclusion criteria
Patients who meet the following criteria will be excluded from the trial:
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Patients with interstitial lung disease accompanied by severe elevations of liver enzymes.
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Women who are pregnant, breastfeeding or who have recently prepared for childbirth.
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Persons who are allergic or sensitized to the test drugs.
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Patients with severe primary diseases of the heart, liver, kidneys, brain, endocrine system and hematopoietic system, psychiatric disorders, etc.
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The presence of other rheumatic diseases such as systemic lupus erythematosus, Sjogren's syndrome, and myositis.
Withdrawal and termination criteria
Patients will be terminated or withdrawn from the trial if they encounter any of the following conditions:
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Violation of any of the key inclusion or exclusion criteria.
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Failure to take prescribed drugs during the trial, affecting the efficacy evaluation.
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Taking other TCM that are prohibited by this protocol, so that the efficacy and safety of the treatment cannot be correctly judged.
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Serious adverse reactions to the experimental or control drugs.
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The desire to withdraw from the experiment.
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Loss to follow-up, death, or withdrawal from the trial due to any other reason.
Interventions
TCM Guizhi-Shaoyao-Zhimu decoction preparations and placebo preparation
Traditional Chinese medicine decoctions are made by boiling herbs in boiling water for hours. However, for the convenience of administration,handling, distribution and storage, Guizhi-Shaoyao-Zhimu decoction and placebo granules will be distributed to the participants. The preparation of Guizhi decoction and placebo will be entrusted to Jiangsu Tianyin Pharmaceutical Co, Ltd. and all operations will strictly follow the procedures stipulated in the Chinese National Pharmacopoeia. The placebo is composed of starch, dextrin and bitters, and its smell and taste are similar to those of traditional Chinese medicine granules. The composition and function of all herbs in Guizhi decoction are summarized in Table 2
Table 2
Composition and action of Guizhi-Shaoyao-Zhimu decoction in Chinese herbal medicine.
Ingredient
|
Granule dose
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Action (TCM)
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Cinnamomum cassia(guizhi)
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4.5 g
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1. relieving exterior syndrome by diaphoresis
2. harmonizing yingfen and weifen
3. warming the channel and activating blood circulation warming the meridian torelieve pain
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Radix of Paeonia lactiflora (Shaoyao)
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4.5 g
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1. nourishing the blood
2. reducing yin
3. soothing the liver
4. relieving pain stabilizing yin and yang in the liver
|
Radix and Rhizoma of Glycyrrhiza uralensis (gancao)
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3 g
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1. clearing heat and removing toxicity
2. invigorating spleen and supplementing qi moderating the property of herbs
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Rhizoma of Anemarrhena asphodeloides (Zhimu)
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4.5 g
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1. clearing heat-fire nourishing yin for moistening dryness
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Rhizoma of Atractylodes macrocephala (Baizhu)
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4.5 g
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1. invigorating the spleen replenish qi
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Rhizoma of Zingiber officinale (Shengjiang)
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3 g
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resolve the exterior and dissipate cold
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Radix of Saposhnikovia divaricata (Fangfeng)
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4.5 g
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1. expelling wind to relieve superficies
1. removing dampness to relieve pain
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Processed lateralis Radix of Aconitum carmichaeli (Paofuzhi)
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1.5 g
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2. tonifying fire and helping yang
3. dispelling cold and removing dampness
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Conventional Western medicine preparation
Methotrexate tablets: Specification: 2.5mg × 100 tablets/bottle; Manufacturer: Shanghai Xinyi Pharmaceutical Co., LTD.; National drug approval number: H31020644.
Folic acid tablets: 5mg × 100 tablets/bottle; Manufacturer: Shanghai Xinyi Huanghe Pharmaceutical Co., Ltd.; National Drug approval number: H31020147.
Medication method:
Experimental group (Western medicine + Guizhi-Shaoyao-Zhimu decoction): Guizhi-Shaoyao-Zhimu decoction will be taken twice a day(30 g each time). Combined MTX will be taken orally once a week (10 ~ 15 mg). Folic acid tablets will be taken orally twice a week(5 mg).
Control group (Western medicine + TCM placebo): TCM placebo twice a day, 30 g each time. MTX is taken orally 10 ~ 15 mg once a week. Folic acid tablets should be taken 5 mg orally twice a week.
Combination of drugs:
Combination of drugs: According to ethical requirements, if the patient's pain is unbearable and the doctor considers it necessary to add other drugs to the regimen, drug combinations can be used. The combination of drugs is limited to nonsteroidal anti - inflammatory drugs and low-dose hormones. The dosage, starting and ending time will be recorded in detail.
Measurement items and time points of data collection
Outcome measure
general information (before treatment)
The patients’ general information, including demographic data, general medical examination items, and general clinical data will be collected at baseline.
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Demographic data: The patients’ name, sex, age, nationality, occupation ID number,date of birth, home address, and contact information will be collected.
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General medical examination items will include respiration, body temperature, pulse, blood pressure, tongue coating, pulse measurements.
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General clinical data will include history of present illness, past medical history, family history, personal life history, menstrual history, marital history, allergy history, and social history.
Outcome variables
The primary outcome of this trial will be recorded at baseline and at weeks 1, 2, and 3.
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Laboratory indexes including routine blood examination, ESR, CRP, and hepatic and renal function will be measured.
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The visual analog scale (VAS)[13]: The pain VAS is self-completed by the respondent. Using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the “no pain” anchor and the patient's pain anchor, providing a range of scores from 0-100[14, 15]. A higher score indicates greater pain intensity.
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Disease Activity Score in 28 joints-Erythrocyte Sedimentation Rate (DAS28-ESR): DAS28-ESR was calculated as 0.56×√(Tender joint count) + 0.28×√(Swollen joint count) + 0.7 × ln ESR + 0.014 × VAS-GH[16].
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Measurement scale for TCM symptoms: To facilitate the evaluation of the results, we will use the measurement scale for TCM symptoms recommended by the Guidelines for Clinical Research of Chinese Medicine (New Drug) [12]to score the symptoms of the patients. The scale consists of 4 major symptoms and 7 minor symptoms. Each symptom is graded on 4 levels, ranging from zero, mild, medium and severe, with corresponding scores of 0, 1, 2 and 3. The total score was calculated by adding up each score in the scale and using these scores to calculate an efficacy indicator (EI) for the evaluation of treatment efficacy.
EI=(Total symptom score at baseline − Total symptom score post − treatment)/Total symptom score at baseline × 100%
The degree of symptom improvement will be presented in four categories ranging from full recovery (EI ≥ 90%), good recovery (90% > EI ≥ 70%), modest recovery (70% > EI ≥ 30%) to no recovery (EI < 30%).
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Ultrasonic assessment: The 7-joint ultrasound score (US7)[17] is used to determine the degree of synovitis, synovial hyperplasia and bone erosion. This score examines 7 joints (wrist, MCP2, MCP3, PIP2, PIP3, MTP2, and MTP5 joints) of the clinically dominant hand and foot of the patients. The synovitis, tenosynovitis and bone erosion of each joint will be observed, with the highest score being 94 points according to the following standards.
1.Synovial thickening is graded on four grades according to no, light, medium and heavy, and the corresponding scores are 0, 1, 2 and 3.
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0 points: No synovial thickening.
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1 point: Mild synovial thickening (the thickened synovium is located only in the circumferential triangle of the bone).
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2 point: Moderate synovial thickening (thickened synovial membrane extending from the circumferential triangle to the middle, but not to the epiphysis).
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3 points: Severe synovial thickening (thickened synovial membrane extending from the circumferential triangle to the middle and metaphysis)
2. Synovitis of tenosynovitis is graded on two grades according to no or have, and the corresponding score is 0 and 1.
3. Bone erosion scored 0 or 1 on a no or yes basis.
4. Synovitis: If synovial thickening is present, a color Doppler flow signal (PDUS) is additionally observed with color Doppler. The pulse repetition frequency (PRF) is set to a minimum of 0.7 to 1.0 KHz. The Doppler flow signal is graded on 3 levels.
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0 points: No blood flow signal.
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1 point (mild): A small amount of pitting blood flow signal.
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2 points (moderate): A continuous blood flow signal covering less than 50% of the joint cavity.
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3 points (severe): The area of blood flow signal exceeds 50% of the joint cavity.
Randomization and blinding
Use the online central random system of the Chinese Academy of Chinese Medical Sciences. The drug will be randomly coded according to the clinical trial randomization protocol and used as the subject's unique identification code. Subjects are included in a certain order, and random numbers can obtained online. Subjects are randomly assigned to the experimental group and the placebo group in a 1:1 ratio. A double-blind and placebo-controlled trial design is adopted. The patients are randomly assigned drug A or B, respectively, and sequenced according to maintain blinding. Subjects and researchers are blinded, and drug A and drug B are distributed in the order in which patients visit the clinic. If serious adverse events occur during the test, the emergency envelope should be unsealed immediately and delivered to the researcher of the research unit for storage. A double unblinding method will be used. At the end of the study, after verification of blinding, the data will be locked, and the statistical specialist who maintains the blinding will unblind the first level. Statistical experts will be informed of A/B group assignments corresponding to each case number for statistical analysis of all the data. When the statistical analysis and the summary report are completed, level II unblinding will be conducted at the clinical summary meeting to reveal the subjects in Group A and Group B.
Data dissemination
The study results will be disseminated in Open Access, peer-reviewed journals and shared through oral and poster presentations at international conferences. All resources will be uploaded to an online knowledge management platform.
Data quality control
A training will be done for all participating staff on the trial protocol, usage of the randomization, and data management systems, etc. The principle investigator will supervise the proceed of the trial at least once every month, who collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct. An ethics committee will review conduct especially on safety, rights, and well-being of the participants at the middle and the end of the trial. The auditing will be done by Clinical Evaluation Center of the China Academy of Chinese Medical Sciences at the beginning, middle, and end of the trial.
Data collection and management
Composition of data monitoring committee (DMC) is composed of professional statisticians. They will perform statistical analysis, participating in the entire process from the research design and implementation to the analysis and summary. A statistical analysis plan will be developed after the completion of the study program and completion of the case reporting forms, and the statistical analysis reports will be provided after the necessary modification of the data analysis is performed as necessary during the research process. According to the project of the case report form, EpiData3.1a software will be used to establish the corresponding entry procedure and set the logical examination qualifications at the time of entry, and the database will be piloted to establish a database system dedicated to this experiment. The signed case report form and the audit statement will be given to the data administrator, who will examine the date, group criteria, culling criteria, shedding criteria, and missing values. If there is doubt about "data question form", it will be returned to the monitor, and the researcher will answer and sign the question in writing and return it to the data administrator; "data question form" should be properly stored to protect confidentiality before, during, and after the trial. The data are entered synchronously by the data administrator using a two-person entry method. The database will be checked for each item using the verification function in the EpiData3.1a software; any inconsistent result values will be reported. The original case reporting tables will be checked item by item, and 10 case reporting tables and the data in the database will be randomly selected for manual comparison to ensure that the data in the database are consistent with the results in the case reporting tables. The original CRFs and any other records will be archived for 5 years.
Statistical analysis
An independent statistician will perform statistical analysis according to the statistical analysis plan using SPSS software (version 26; SPSS Inc., Chicago, IL, USA). Continuous variables will be expressed as the mean (standard deviation) if the data are normally distributed; otherwise, they will be expressed as the median (interquartile). Categorical variables will be presented as frequencies (percentages). Baseline analyses will be performed using analysis of variance or nonparametric tests for continuous variables, and chi-squared or Fisher’s exact tests for categorical variables, respectively. Changes from baseline to posttreatment in DAS28, VAS, TCM syndrome scores, and US7 will be analyzed using analysis of covariance with associated 95% confidence intervals. A two-sided P value of 0.05 or less is considered statistically significant. Multiple imputation will be used to handle any missing data.