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Abstract
Introduction Rheumatoid arthritis (RA) is a progressive inflammatory autoimmune disease characterised by chronic systemic inflammation, which can cause swelling, stiffening and destruction of articular cartilage and bone. Early diagnosis and treatment of RA can improve outcomes and slow the progression of joint damage. Preliminary exploratory research had hinted an expected effect of modified Zhiwang decoction (MZWD) in treating early RA. However, few randomised clinical trials have evaluated the effectiveness of MZWD in early RA. Therefore, a parallel-group randomised controlled trial was designed to evaluate the efficacy and safety of MZWD combined with methotrexate (MTX) on early RA.
Methods and analysis This is a prospective, parallel-group, single-centre randomised controlled clinical study. A total of 150 patients will be randomly assigned to either the treatment (n=75) or control group (n=75). The treatment group will receive MZWD and MTX, and the control group will receive MTX for 12 weeks. The primary outcome of this study is Disease Activity Score-28, and the secondary outcomes are Fatigue Scale-14, Visual Analogue Scale pain scores and traditional Chinese medicine symptom scores. Safety outcomes, including adverse events and results of ECG and laboratory tests, will be monitored.
Ethics and dissemination Ethics approval was obtained from the Clinical Research Ethics Committee of the China-Japan Friendship Hospital (no. 2022-KY-124) on 8 July 2022. The findings will be disseminated in peer-reviewed publications.
Trial registration number ClinicalTrials.gov Registry (NCT05508815).
- Randomized Controlled Trial
- Clinical Trial
- Immunology
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This study is a prospective, parallel-group, randomised controlled clinical study, which increases evidence for the clinical use of modified Zhiwang decoction to treat early rheumatoid arthritis.
The limitation of the study is the lack of double-blinding and placebo.
This trial also lacks a multicentre design.
Introduction
Rheumatoid arthritis (RA) is an autoimmune disease characterised by chronic systemic inflammation, which can cause swelling, stiffening and destruction of articular cartilage and bones. RA affects about 1% of the world population.1 Early diagnosis and treatment of RA are related to improved outcomes and are thus a significant overarching principle in its management.2 Therapy with disease-modifying antirheumatic drugs (DMARDs) should be started immediately to achieve low disease activity or complete remission.3 Although DMARDs are effective, there are up to 20% of patients with RA who are difficult to treat.4 Moreover, some side effects, such as cytopenia, transaminase elevation, poor tolerability and liver damage, limit the extensive clinical application of DMARDs.5 Consequently, it is urgently necessary to develop safer and more effective drugs to improve treatment outcomes.
In China, as an integral part of its healthcare system, traditional Chinese medicine (TCM) works in conjunction with modern pharmaceuticals. Due to multitarget and omni-direction properties, TCM plays an indispensable role in the adjuvant treatment of RA.6 TCM formulas, such as Guizhi Shaoyao Zhimu decoction,7 combined with Western medicine, might have equal or superior effectiveness for treating RA. However, few randomised clinical trials (RCTs) evaluated the effectiveness of TCM formulas in early RA, making the exploration of therapeutic strategies using TCM formulas for early RA necessary.
Bushen Quhan Zhiwang decoction (BQZD), including 18 herbs, has been widely used for treating RA in China. Various randomised controlled trials were performed to evaluate the efficiency and safety of BQZD for treating RA, showing that BQZD combined with methotrexate (MTX) significantly decreased morning stiffness, joint tenderness, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and rheumatoid factor compared with MTX treatment alone.8 Targeting patients with early RA, BQZD has been changed to modified Zhiwang decoction (MZWD). MZWD is composed of 10 herbs inclding Curcumae longae rhizoma, Cinnamomi ramulus and Spatholobi caulis. Curcumin is the most abundant constituent and chemical marker for the quality control of Curcumae longae rhizoma. Chandran et al showed that curcumin (500 mg) significantly decreased Disease Activity Score (DAS) and American College of Rheumatology (ACR) scores in patients with active RA.9 Spatholobi caulis methanol extract exerted anti-inflammatory effects by decreasing the production of nitric oxide and proinflammatory cytokines in Raw264.7 cells.10 Cinnamomi ramulus is therapeutic for RA by suppressing the expression of MMP-1, MMP-2 and MMP-3.11 MZWD has been used to treat many patients with early RA in our centre, providing good treatment effects. Meanwhile, compared with BQZD, MZWD contains fewer herbs, reducing medication and economic burdens on patients. However, there is yet no rigorously controlled trial testing the effectiveness of MZWDs for treating early RA. Therefore, we designed a randomised controlled trial with a parallel group to evaluate the effectiveness and safety of MZWD for the treatment of patients with early RA.
Objective
A randomised controlled trial with a parallel group was designed to evaluate the efficacy and safety of MZWD combined with MTX in early RA.
Methods and analysis
Study design and setting
A parallel-group, single-blind, single-centre randomised controlled clinical study was designed. The present study will be conducted in China-Japan Friendship Hospital (Beijing, China). The recruitment began on 29 September 2022. The study protocol conforms to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. The flow chart of this study is shown in figure 1, and the trial schedule is shown in table 1.
The flow diagram of the trial. CG, control group; CRP, C reactive protein; DAS-28, Disease Activity Score-28; ESR, erythrocyte sedimentation rate; FS-14, Fatigue Scale-14; MTX, methotrexate; MZWD, modified Zhiwang decoction; TCM, traditional Chinese medicine; TG, treatment group; VAS, Visual Analogue Scale.
Schedule of study procedures
Eligibility criteria
Patients will be included using the following criteria: (1) patients aged 16–70 years12; (2) patients meeting the ACR/European League against Rheumatism (EULAR) 2010 classification criteria13; (3) patients with disease course ≤3 years12; (4) patients with DAS28 score ≤5.114; (5) patients not receiving treatment or taking MTX only.
Patients will be excluded based on the following criteria: (1) patients with other rheumatic diseases or severe pain due to other medical conditions, such as diabetic pain or post-herpetic neuralgia; (2) patients with joint dysfunction and an X-ray wrist score of grade IV; (3) patients with mental and psychological disorders, such as cognitive impairment, depression, anxiety, physical dysfunction, cerebral infarction, cerebral haemorrhage, epilepsy, transient ischaemic attack, myelitis, demyelinating disease and other central nervous system diseases; (4) patients with organ injury or malignant tumours and disorders of the cardiovascular system, liver (alanine transaminase/aspartate transaminase >3 times higher than the upper normal limit), kidneys (creatinine clearance <60 mL/min), brain or haematopoietic system; (5) pregnant and lactating women; (6) patients participating in any other clinical trials; (7) patients who are allergic to the drugs used in this study.
Patients can withdraw from the trial at any time for whatever reason. When such a case occurs, investigators also ask patients for a reasonable withdrawal from the trial.
Recruitment
A total of 150 patients will be recruited in the China-Japan Friendship Hospital. Informed consent forms will be signed by all study participants.
Intervention
Eligible participants will be randomised to either treatment or control group. Participants in the control group will take MTX (7.5–15 mg once a week) (Shanghai Sine Pharmaceutical, Shanghai, China) orally for 12 weeks. The treatment group will receive MZWD 100 mL (two times per day) and MTX (7.5–15 mg once a week) for 12 weeks. MZWD is composed of 10 herbs: Cinnamomi ramulus (12 g), Paeoniae radix alba (12 g), Anemarrhenae rhizoma (12 g), Glycyrrhizae radix et rhizoma (6 g), Ephedrae herba (6 g), Atractylodes macrocephalae rhizoma (12 g), Saposhnikoviae radix (12 g), Aconiti lateralis radix praeparata (10 g), Curcumae longae rhizoma (12 g) and Spatholobi caulis (20 g). All the botanical drugs are described in table 2. All Chinese herbal medicines in the same batch were supplied by Sinopharm Group Beijing HuaMiao Pharmaceutical Co (Beijing, China) and tested by its quality management department. The result showed that MZWD contained 14 representative components: (1R,2S)-(-)-ephedrine hydrochloride, pseudoephedrine hydrochloride, liquiritin, glycyrrhizic acid, curcumin, cinnamaldehyde, prim-O-glucosylcimifugin, 4-O-β-D-glucosyl-5-O-methylvisamminol, mangiferin, timosaponin BII, paeoniflorin, benzoylmesaconine, benzoylaconine and benzoylhypacoitine, which meet the Pharmacopoeia of China (2020 edition) grade standards. The Chinese herbal medicines were stored in the dispensary of TCM of the China-Japan Friendship Hospital.
Components of MZWD
According to unified standards, the herbs are decocted in the decoction room of the China-Japan Friendship Hospital. After soaking in 10-fold distilled water for 1 hour, MZWD was decocted for 1 hour. For the second decoction, 10-fold water was added once again and decocted for 1 hour. Finally, after combining and concentrating, 0.57 g/mL of MZWD extract was obtained from the filtrate and divided into two packs (100 mL/pack). MZWD extracts were vacuum-packaged and stored in a cold storage dispensary of TCM of the China-Japan Friendship Hospital.
Both orally and in written form, participants will be instructed on the dosage, method and frequency of administration. Drugs for the next intervention will be given to the participants at every visit, and any leftover drugs will be returned. With the exception of experimental drugs, other botanicals, zoological species and Western medicines with immunosuppressive and immunomodulatory effects are prohibited. If pain is unbearable, low-dose non-steroidal anti-inflammatory drugs can be used under the investigator’s supervision, and any medication outside the protocol must be documented. Subject diary forms must be completed daily by participants to keep track of medication intake and adverse events.
Outcome
The primary outcome and secondary outcomes are evaluated at baseline and 12 weeks of treatment.
Primary outcome
The primary outcome of this study is DAS28 based on ESR scores. DAS28 is widely accepted to evaluate RA disease activity and assesses the number of tender joints out of 28, the number of swollen joints out of 28, ESR and the patient’s global assessment of disease activity.
Secondary outcomes
The secondary outcomes include Fatigue Scale-14 (FS-14), Visual Analogue Scale (VAS) pain score, TCM symptom score and laboratory tests, including ESR and CRP. The FS-14 is a standardised questionnaire regarding physical and mental fatigue.15 The higher the score, the greater the fatigue. VAS pain score quantifies the pain level (0–10). A VAS score of 0 indicates no pain, while a score of 10 indicates unbearable pain. Laboratory tests, including ESR and CRP, will be measured. Patients’ symptoms will be scored using the measurement scale recommended by the Guidelines for Clinical Research of Chinese Medicine (New Drug).16 The scale for TCM symptoms consists of 15 symptoms, including joint pain, joint swelling, joint tenderness, joint flexion and extension, joint heat, joint cooling, the number of tender and swollen joints, morning stiffness, sweat, aversion to wind or cold, lack of warmth in the limbs, lumbar pain and knee stiffness, distention and oppression in the gastrointestinal tract, fatigue and lack of strength, and reduced food intake. According to disease severity, clinical symptoms were graded and quantified by four levels (0, 1, 2 and 3 points).
Safety outcomes
Safety outcomes consist of adverse events and results of ECG and laboratory tests. Adverse events during treatment will be recorded based on the Rheumatology Common Toxicity Criteria17 and reported to ethics committees within 24 hours. Laboratory tests include routine blood, routine urine, routine stool, liver function and kidney function tests. Laboratory tests and ECG will be monitored at baseline and 12 weeks of treatment.
Allocation and blinding
All patients will be randomly assigned to either the treatment or control group according to the stratified block randomisation method. After entering the zone group, participants will be randomly allocated. The length of the zone group is set to 6, and the 20 permutations obtained are designated as AAABBB, AABABB, AABBAB, AABBBA, ABAABB, ABABAB, ABABBA, ABBAAB, ABBABA, ABBBAA, BAAABB, BAABAB, BAABBA, BABAAB, BABABA, BABBAA, BBAAAB, BBAABA, BBABAA and BBBAAA, with A and B representing treatment or control group, respectively. Then, an array of random numbers will be generated by SPSS software (V.25.0), and allocation sequences will be determined by selecting random numbers of 1 or 2. Afterwards, district groups will be arranged according to the random number sequence.
Because we cannot achieve a placebo, we are unable to perform blinding between participants and researchers. However, the outcome assessors and the statistician are blinded to the allocation in this study to reduce bias among assessors and statistical analysts in evaluating the effectiveness of interventions.
Participant timeline
In the trial, participants need to be assessed four times, including visits at enrolment, 4 weeks, 8 weeks and 12 weeks after intervention.
Sample size
A superiority design approach was used in this study. The primary outcome of this study is the evaluation of DAS28 between treatment and control groups. Data on DAS28 from a previous study were used to calculate sample size.18 After 12 weeks, DAS28 of the treatment group was decreased by 3.48±1.06, while that of the control group was decreased by 2.77±1.20. In this study, the sample size of treatment and control groups was matched to 1:1. A two-sided test was chosen (α=0.05, β=0.2 and δ=0.5). The calculated sample size of each group is 68. Considering the dropout rate of 10%, 75 patients in each group will be selected, with 150 as the final sample size.
Statistical analysis
All analyses and data visualisation will be conducted by statisticians who are blinded to the allocation using IBM SPSS (V.25.0) and R (V.4.1.1).
For the baseline data, continuous data will be presented as the mean and SD, and categorical data will be reported with a frequency table. Missing data will be adjusted using the last observation carried forward method. Outcomes with continuous normal distribution will be compared using Student’s t-test, while the Wilcoxon rank-sum test will be used for non-normal variables. Pearson’s χ2 test will be used for categorical variables.
Intention-to-treat analysis will be used to analyse the outcome data. Outcome variables, including DAS28, FS-14, VAS, ESR, CRP and symptom score, will be summarised with means and SDs. Analysis of covariance (ANCOVA) will be performed to examine outcome variables between the two groups at four time points. The repeated measures ANCOVA will be used to detect differences between groups at different time points, as well as interactions between groups and time points. A comparison of adverse reactions will be conducted using either χ2 or Fisher’s exact tests.
As a significant part of the statistical analysis, the sensitivity analysis will complement the interpretation of the results. Subgroups will be created based on additional drugs and coexisting medical conditions. In each subgroup, the calculations will be rerun to ensure that the results are valid. Any variable with ≤20% missing values will be interpolated using the MICE package in R. The significant difference will be set at p<0.05.
Practitioner training and quality control
All assessors are required to attend professional training sessions to understand and comply with the research protocol and standards. Two investigators will complete the participant’s rating simultaneously in each follow-up visit, with final records used based on the average, to ensure that the content of the case report format is true and reliable. A third investigator will be involved in the assessment when there is a large difference in results. Meanwhile, paper reports will be retained for future verification of objective indicators.
The principal investigator appoints supervisors to ensure that trial records and reports contain accurate and complete information. On-site supervision will be conducted regularly. Meanwhile, the trial is monitored by the Clinical Research Ethics Committee of the China-Japan Friendship Hospital. Additionally, a third-party independent clinical research department will review data regularly and correct existing problems timely.
Data collection methods and management
Data will be recorded in the paper case report form at the clinic. Double-data entry will be performed using a general data platform for integrated traditional Chinese and Western medicine of China-Japan Friendship Hospital (http://10.200.10.150:8000/loginT).
Patient and public involvement
Patients were not involved in the study design. Researchers will publish the results in academic journals to benefit clinicians and patients.
Discussion
RA is a progressive inflammatory autoimmune disease of unknown aetiology. MTX is the first-line treatment for RA. However, some adverse effects of MTX, such as gastrointestinal and hepatic dysfunction, limit its extensive clinical application.19 Therefore, there is an urgent need to develop better treatment. The present study designed a parallel-group, single-blind, single-centre RCT to evaluate the effectiveness and safety of MZWD for the treatment of patients with early RA.
For the above-presented reasons, this protocol was designed according to the SPIRIT guidelines. The present study will provide high-quality evidence on the efficacy and safety of MZWD for the treatment of early RA. The limitation of the study is the lack of double-blinding and placebo control. Blinding is an important methodological feature of RCTs to minimise bias and maximise the validity of the results.20 However, blinding is not always possible. In trials of different styles of patient management or alternative therapies, full blinding is often impossible.21 Moreover, the herbs in Chinese medicine often have unique colour, taste and smell, making it extremely difficult to create an accurate placebo.22 A placebo for Chinese herbs often contains 5–10% of a standard dose of herb extracts to mimic their scent and taste more accurately.23 However, adding TCM extracts is controversial regarding the pharmacological activity of TCM placebo. Furthermore, the preparation and stability of TCM placebos are affected by their dosage form.24 A placebo in a decoction must meet higher colour and appearance requirements than a capsule.23 There is a high probability that patients will detect the placebo, resulting in the failure of blinding and study design. Therefore, although this study does not have double-blinding and placebo, single blinding is used, where the outcome assessors and the statistician are blinded to the allocation. This study is a single-centre study in Beijing. The regionalisation of the population might have some influence on the result. Hence, it is necessary that the conclusions are verified in multicentre RCTs with a large sample in the future.
Trial status
This study is currently in the recruitment phase. The first patient was randomised on 9 February 2023, and the study is expected to end on 31 December 2024.
Ethics and dissemination
The study scheme is in line with the principles of the Declaration of Helsinki and ethics approval was obtained from the Clinical Research Ethics Committee of the China-Japan Friendship Hospital (no. 2022-KY-124). The findings will be disseminated in peer-reviewed publications.
Ethics statements
Patient consent for publication
Acknowledgments
We appreciate the efforts and cooperation of all research staff and patients involved in this study.
References
Footnotes
NZ and L-bZ are joint first authors.
NZ and L-bZ contributed equally.
Contributors NZ and L-bZ collated documents and wrote the manuscript. T-yL and J-pW polished the language. ZW and CX helped to organise the literature. YX and Q-WT contributed significantly to design and revision of the manuscript.
Funding The work was supported by the National High Level Hospital Clinical Research Funding (no. 2022-NHLHCRF-LX-02-0105).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.