Efficacy and safety of fire needle therapy for blood stasis syndrome of plaque psoriasis: protocol for a randomized, single-blind, multicenter clinical trial

This is a multicenter, single-blind, randomized controlled trial to investigate the efficacy and safety of fire needle therapy for plaque psoriasis. The study will be performed in five centers in China: Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shaanxi Hospital of Traditional Chinese Medicine, First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, and Traditional Chinese Medicine Hospital of Shijiazhuang. Participants will be assigned to treatment and control groups using a centralized randomization system (implemented by a data network platform designed by Nanjing Ningqi Medical Technology Co., Ltd.). The detailed process is shown in a flowchart in Fig. 1.

This protocol has been developed according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 guidelines [12]. This checklist is described in detail in Additional file 1. The protocol has been approved by the institutional review board (IRB) of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of TCM (ethical approval number: 2019–033), and the study is registered at clinicaltrials.gov (ID: NCT03953885; registration date: May 15, 2019).

In Western medicine, the diagnostic criteria for plaque psoriasis have been formulated in accordance with Guideline for the diagnosis and treatment of psoriasis in China (2018 simplified edition) [13], whereas those for BSS of plaque psoriasis have been drafted according to the Evidence-based clinical practice guide for psoriasis vulgaris by the Dermatology Branch of China Association of Chinese Medicine [14].

Accordingly, participants will be diagnosed with plaque psoriasis based on the following criteria [13]: First, the skin lesions appear as dark red plaques or invasive erythema with clear boundaries showing white or silvery-white scales. Second, features such as the “wax drop phenomenon,” “film phenomenon,” “point bleeding phenomenon” (Auspitz sign), and “bundle hair” can be found during physical examination. Third, the scalp, back, and extremities are the most susceptible areas for skin lesions. Fourth, itching may or may not be present. Fifth, the Koebner phenomenon can be observed in the advanced stage. Finally, the skin lesions are prone to relapse, with the majority alleviated in summer and aggravated in winter.

The main sign of BSS of plaque psoriasis is the prolonged presence of dark red, hypertrophic, infiltrating skin lesions. Minor signs include scaly dry skin, a soot-black facial complexion, cyanosis of the lips and nails, dark menstrual blood or blood clots in female patients, a dark purple tongue with ecchymosis and/or petechiae, an unsmooth pulse, and a thready/moderate pulse. The presence of BSS will be confirmed when patients show the main sign along with more than one minor sign [14, 15].

Participants will be recruited from five hospitals in China: Shaanxi Hospital of Traditional Chinese Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, and Traditional Chinese Medicine Hospital of Shijiazhuang. Each research center has one or two clinical research observers (CRO) who will explain this trial to participants before they voluntarily sign an informed consent form at the beginning of the study. On the consent form, participants will be asked if they agree to the use of their data, should they choose to withdraw from the trial. Participants will also be asked to grant permission for the research team to share relevant data with the universities taking part in the research or regulatory authorities, where relevant. This trial does not involve the collection of biological specimens for storage.

The general inclusion criteria for the study are as follows: (1) compliance with the abovementioned diagnostic criteria for plaque psoriasis and BSS of plaque psoriasis; (2) skin lesions involving ≤ 10% of the body surface area (BSA), with primary involvement of the trunk and/or limbs, palms/soles, and/or face/scalp (vulva not included); (3) aged 18 to 65 years (inclusive of 18 and 65 years); and (4) provision of written informed consent for participation in the study.

Exclusion criteria will be applied as follows: (1) presence of other progressive skin diseases that may affect assessment of the condition; (2) treatment with the research drugs, biological agents, and immunosuppressive agents within 1 month before study initiation; (3) treatment with topical glucocorticoids and/or phototherapy within 2 weeks before study initiation; (4) presence of severe, uncontrolled, local or systemic, acute or chronic infection; (5) presence of severe systemic diseases, elevation of alanine aminotransferase or aspartate aminotransferase levels by > 1.5 times the upper limit of normal, elevation of creatinine by 1.5 times the upper limit of normal, decrease in any main blood test parameters (white blood cell count, red blood cell count, hemoglobin amount, platelet count) to below the lower limit of normal, or abnormalities in other laboratory test parameters; (6) history of malignant neoplasms, primary or secondary immune deficiency, and/or a hypersensitivity reaction; (7) major surgery within 8 weeks before study initiation or scheduled during the study period; (8) pregnancy or lactation; (9) history of alcohol abuse or drug abuse, family history of cancer, personal or family history of a serious mental illness; (10) any other factors considered by the researchers as contraindications for study participation.

Criteria for trial suspension, patient rejection, and patient withdrawal are also set as follows: (1) development of other serious or life-threatening organic lesions during the trial, (2) withdrawal at the individual’s discretion, (3) poor patient adherence to treatment, (4) participation in another trial administering treatment that may interfere with the results of the present study, (5) refusal to take contraceptive measures during the trial period (including both treatment and follow-up periods), (6) loss to follow-up for various reasons, and (7) incorrect application of the inclusion and exclusion criteria.

This trial will follow a randomized, single-blind design. The data management company will use a centralized randomization system to generate random codes, which will be sent to the project lead unit. The project lead unit will prepare a random code table and distribute it to the participating units. The random code will then be distributed to the participants by the CRO of each participating unit. Only the CRO responsible for patient recruitment will be aware of the group allocation until the participants have completed the trial. All other research staff, including the individual responsible for measurements, will remain blinded to the group allocation. If participants know which group they belong to, they will be instructed to refrain from sharing the information with the individual responsible for measurements. The participants will be informed of their results only after completion of recruitment, interventions, and evaluations for all participants.

Patients will be randomly assigned to receive fire needle therapy (intervention group) or fire needle control therapy (control group) once a week for 4 weeks. In addition, all patients will receive basic treatment, including prescription of a moisturizing lotion, instructions to avoid inducing and aggravating factors, instructions to bathe appropriately, and lifestyle recommendations.

In this study, the estimated post-treatment PASI score for all patients will be set at 50% lower than the pre-treatment score, both in the intervention group and the control group. The sample size of the current trial is calculated based on the following formula, and take the cure rate as the primary treatment effect index.

According to a previous study titled “Therapeutic Observation of Fire-needle Acupuncture for Stationary Plaque Psoriasis” [19], the cure rate to achieve this score is 76.8% for the intervention group and 35.3% for the control group. In this study, we set the inspection level (α) as 0.05, and the test power as 0.9, then β = 1–0.9 = 0.1. For two-sided tests, at least 25 participants would be required for each group. Considering the correlation of primary outcomes at different times and multicenter effect, we increase the sample size to 38 participants in each group, Considering a dropout rate of 20%, a total of 94 patients (47 per group) will be required for this study (Table 3).

The steering committee, composed of principal investigators (PI) from each sub-center, is responsible for monitoring the progress of the trial, training researchers before the study begins, reviewing adverse events, and developing statistical analysis programs with a statistician. Each sub-center has a clinical research assistant (CRA), and the five of them form the data monitoring committee. CRAs are responsible for checking all documents, such as case report forms (CRFs), related to this trial and coordinating all aspects of local organization. Each committee meets annually to review the trial process, and the interim analysis will take place in the second year of the study; the five research units will share the analysis results. Monitoring will be conducted independently from the PI and sponsors.

If the protocol is to be revised, it must be approved by the IRB of each research center, and the project lead unit may terminate all studies early due to medical reasons. In addition, if the research cannot be carried out in accordance with the research protocol agreement or if any other reason is found, the project lead unit has the right to terminate the research at any time. If the research is terminated or suspended early, the project lead unit should immediately notify the CRO, medical institution, management department, and IRB of the branch center of the decision and its reasons. All research materials must be returned to the project lead unit.

With the exception of the CRO responsible for the participants, participants’ information will be kept confidential from research staff until publication of the study results. All of their documents related to this trial, such as CRFs, will be represented by the participant’s unique random code. Random codes and CRFs will be sealed and stored in a separate filing cabinet. To facilitate data analysis, CRO will also use a unified data collection system for recording (established by Nanjing Ningqi Medical Technology Co., Ltd. Data Management Center, Nanjing, China). The results of this trial will be published in an international peer-reviewed journal.

A statistician will formulate a plan for statistical analysis in consultation with the PI. All analyses will be conducted using SAS statistical software, and the data network platform will be designed by the data management center of Nanjing Ningqi Medical Technology Co., Ltd., which will be entrusted with the third-party statistical analyses. The measurers will be blinded to the results. The overall principles will be as follows: An intention-to-treat (ITT) and per-protocol analysis will be used for statistical analysis. Quantitative variables (such as PASI, BSA, PGA, DLQI, PRQoL, VAS, and TCM syndrome scores) will be expressed as mean and standard deviation values or as median values with lower (Q1) and upper (Q3) quartiles. If the quantitative variables conform to normal distribution, a t test will be used (The homogeneity test will be performed for the two groups, with 0.05 as the significance level. The Satterthwaite method will be used to correct the t test when the variance is not uniform). If quantitative variables conform to skewed distribution, a nonparametric test will be used. Qualitative variables (such as cure rate, recurrence rate) will be expressed as numbers and percentages or composition ratios. Statistical inference will be performed using chi-square tests, Fisher’s exact tests, and Wilcoxon rank sum tests, among others. Potential confounding factors affecting the main outcome indicators will be adjusted by logistic regression. In this study, a p value of less than 0.05 is considered as statistically significant.

To account for missing data, we considered participants who may not complete the follow-up when calculating the sample size. The reasons, main characteristics, and data of a patient’s failure to follow-up will be recorded. Other types of randomly missing data will be considered unsuccessful according to the principle of ITT analysis.

This is version 3.0, and the protocol was registered at clinicaltrials.gov on May 15, 2019. Participant recruitment was initiated in June 2019 and is scheduled to be completed by the end of December 2020.