Study design
This clinical trail will be accomplished at Guang’anmen hospital, China academy of Chinese Medical Science in Beijing, China. The current study follows the guidelines of the Declaration of Helsinki for humans and has been approved by the ethic s committee of Guang’anmen Hospital (approval number: 2016–062-KY). Enrolled will be 168 patients with documented moderately active RA who will be randomized (1:1 ratio) to one of two treatment groups: the TwHF gel group and the placebo gel group. Written signed consent will be obtained from each participant before any study-related procedures are initiated.
Participants
Inclusion criteria
Eligible patients, men and women, must age from 18 to 65 years old, and must be clinically diagnosed with RA prior to screening for study entry in accordance with the 1987 revised criteria of the American College of Rheumatology [9]. Their RA disease stage must be in the moderate activity range, as defined by the criteria of the 28-joint count Disease Activity Score (DAS-28 score), ranging between 3.2 to 5.1 [10]. If patients are receiving a disease-modifying, anti-rheumatic drugs (DMARDs), those medications should be continued unchanged throughout this study, but their dosages must have been stable for at least 12 weeks prior to study entry.
Exclusion criteria
Exclusion Criteria will include: ongoing rheumatic or inflammatory joint diseases other than RA; serious medical diseases such as: hyperlipidemia, hyperglycemia, diabetes mellitus, cardiovascular diseases, gastrointestinal disease, liver disease or renal failure; patients with RA who have a prominent component of comorbid fibromyalgia syndrome, prior treatment with TwHF agents, glucocorticoids, or biological agents; skin allergies or broken skin in the areas of planned treatment with topical TwHF gel. Female patients who are pregnant, breast-feeding or who plan to become pregnant will be excluded.
Randomization
Randomization will be controlled by an independent third party, the hospital Clinical Evaluation Center, using the SAS system (Version 8.2 for Windows) to assign the eligible participants at a 1:1 ratio to receive either topical compound TwHF gel or placebo.
Blinding
This study is a double-blind and placebo-controlled design. The blinding will also be accomplished and monitored by the hospital Clinical Evaluation Center. The blinding codes record topical compound TwHF gel and the placebo as A and B, sequentially and the details of the allocation sequence will be put in sealed light-tight envelopes and maintained in the Clinical Evaluation Center. The contents of these envelopes will be unknown to the principal investigator, the study staff, and the participants. Since the packing and labeling of the treatment gels are the same, the topical compound TwHF gel and placebo gel will be masked by numeric codes from 001 to 168, which correspond with each participant’s sequential enrollment number. Thus, the study researchers will enroll and evaluate study subjects but will have no influence on randomization. So the case group division is adapted to a randomized, double-blind study design.
Intervention
The ingredients for the compounding of the topical TwHF gel include: Tripterygium wilfordii Hook F, Mangxiao (Mirabilite), Chuanxiong (Rhizoma Ligustici), Ruling (Olibanum), and Moyao (M yrrh) (proportions: 4:4:2:2:1). The topical placebo gel is made of a viscous agent and sucrose which make it looks like the active preparation. Both of the gels will be prepared by the Pharmaceutical Department of Guang’anmen Hospital, and the herbs will be purchased from Beijing Fengtaijinyuan Pharmaceutical Co., Ltd. Each gel is 20 gram (g) per tube. Both the topical compound TwHF gel and the placebo gel will be applied for 1st to 5th metacarpophalangeal joints, 1st to 5th proximal interphalangeal joints, wrists, knees and ankles 10 g for 1 h, once a day from week 0 through week 4 and 10 g from week 5 through week 8.
Outcome measurements
Outcomes measurements will be assessed at baseline, at week 4, at week 8 and at the 12th week follow-up. The DAS28 joints will be assessed for swelling and tenderness by a trained staff member. All the outcome assessments will be accomplished by the same staff researcher.
The primary outcome measure will be ACR20 criteria [11] by week 8. To achieve ACR20, a patient must have a 20% or greater reduction in the number of both tender and swollen joints and a 20% or more improvement in 3 or more of the following: the physician’s or patient’s assessment of global health status, the patient’s assessment of pain on a visual analogue scale, the patient’s assessment of function using a modified version of the Health Assessment Questionnaire (HAQ), and the erythrocyte sedimentation rate (ESR) or serum C-reactive protein (CRP) level.
Secondary outcome measures will include: ACR20 assessed at week 4, ACR50 criteria assessed at weeks 4 and 8, changes at weeks 4 and 8 in DAS28, and joint synovitis classification. Since the DAS28 is a combined index to measure the disease activity in patients with RA, it can be used in combination with the European League Against Rheumatism response criteria [10]. In the present trial, the DAS28 score will be calculated, based on either the C-reactive protein (DAS28-CRP) or the erythrocyte sedimentation rate (DAS28-ESR) [10]. Changes in joint synovitis classification will be determined by serial musculoskeletal ultrasound (MUSU) focused on the total sum of synovitis classification based on the joint used gels. The MUSU synovitis classification will derive from each MUSU measurement as follows: 0 level, no doppler synovial tissue signal; level 1, three independent points or 2 successive or 1 to 2 independent dot doppler synovial tissue signals; level 2, doppler signal indicating <50% of the area representing synovium; level 3, doppler signal indicating synovium in >50% of the measured area [12].
The safety evaluation will be accomplished by a face-to-face interview at the 4th and 8th weeks and by a a telephone-interview with the remote 12th week follow-up. Adverse experiences of interest will include: manifestations of cutaneous allergy (erythema, edema, itching) and gastrointestinal stimulation due to mucous membrane damage. In addition, because of the high frequency of reproductive system damage, the safety evaluation will focus on changes in menstruation patterns among premenopausal female participants. The relevant female participants will be asked a general question about whether they have observed any change in their menstruation pattern. Irrespective of how they answer that question, a series of follow-up questions will attempt to quantify any change in the menstrual cycle (extension, shortening or no change), or in the quantity of menstrual flow (increased, reduced, or unchanged). Blood and urine routine laboratory examinations, including glutamic-pyruvic transaminase, glutamic oxalacetic transaminase, creatinine and urea nitrogen will be accomplished at baseline and on the 8th week. Quantitative changes will be addressed on the record. Professional judgments regarding the severity of any given adverse effect and any recognized relationship between the adverse effect and the study interventions will be documented if any of the above safety measures are observed to fall beyond normal clinical or laboratory ranges.
Sample size
This study is designed as a superiority trial. A previous findings showed the ACR20 response rates were 34.3% in a topical TwHF group and 12.5% in placebo group in patients with active RA [awaiting publication]. Based on the following calculation: n = 2(uα + uβ)
22P(1-P)/(P1-P0)2 [13], it is predicted that 76 participants in each group will be needed to detect a significant (p < =0.05) with 80% power. Based upon a predicted 10% rate of drop out, we will recruit a total of 168 participants, 84 in each group.
Quality control
The identification, registration, and subsequent flow of participants in the trial will be governed by the trial standard operational protocol. The completion of the Case Report Form and compliance with the standard operation procedures will be audited. At regular intervals, a clinical research associate, will monitor the clinical trial procedures, such as compliance with the study protocol and regulatory policy. In particular, the reasons for withdrawal will be fully documented in the Case Report Form.
Data analysis
The statistical analyses will be performed using the intention to treat analysis (ITT). The safety dataset will also include all patients who received ≥1 week of topical applications. Mean ± Standard Deviation, number and percentage will be used for continuous variables and categorical variables, as appropriate. Patient movement through the study will be documented on a Consort diagram. Patient demographic characteristics will be documented in a by-group comparison table and statistically compared between topical TwHF and placebo groups using a 2-sample t test for continuous variables or Pearson 2 test for categorical variables.
All analyses will be performed using SAS system (Version 5.2.127 8.2 for Windows). P values less than .05 will be considered statistically significant. The primary outcome variable, the ACR20 response rate at week 8, and the secondary outcome measure, ACR20 at week 4 and ACR 50 response rate at weeks 4 and 8, will be compared between the 2 groups using the Pearson 2 test. Two-sample t tests will be performed on DAS28-CRP and DAS28-ESR at baseline and posttreatment, as well as their changes after treatment. Paired t tests will be used to compare the changes of DAS28-CRP and DAS28-ESR from baseline to posttreatment in each group. The joint synovitis classification will be compared between the 2 groups at baseline and posttreatment using Kruskal-Wallis rank sum test. Any by-group changes in the joint synovitis classification will be compared using the paired Kruskal-Wallis rank sum test.
Ethical considerations
This study has been approved by the ethics committee of Guang’anmen Hospital (approval number: 2016–062-KY). Written consent to take part in the study will be obtained from all study participants before any of the study-related procedures are initiated. Each study subject will be provided a witnessed copy of the consent document he or she signed, which also bears the signature a study investigator. They will also receive an information sheet explaining the study.