Acupuncture for primary fibromyalgia: Study protocol of a randomized controlled trial

This study is a two-center, blinding, randomized, controlled trial with two arms for 8 weeks. A total number of 68 patients with FM who meet the criteria are randomly divided into acupuncture group and sham acupuncture group according to the ratio of 1:1. The intervention will be performed for 8 weeks with a follow-up of 16 weeks. The treatment of acupuncture and placebo is three times a week for the first 4 weeks and twice a week for the next 4 weeks. This clinical trial will be completed at Guang’anmen Hospital of China Academy of Chinese Medical Sciences and Shenzhen Traditional Chinese Medicine Hospital. This study will follow the relevant regulations of the World Medical Congress “Helsinki Declaration” and has been approved by the Ethics Committee of Guang’anmen Hospital and Shenzhen Traditional Chinese Medicine Hospital. All enrolled subjects will be informed with a complete and comprehensive introduction including the purpose, procedure, and possible risks of the study. The informed consent will be obtained before the start of this study.

This randomized, sham-controlled, patient and assessor blinded trial will be conducted in Guang’anmen Hospital and Shenzhen Traditional Chinese Medicine Hospital, which will provide outpatient service for FM. Participants in this study will be recruited from either outpatient clinic or inpatient department via advertisement at hospital-based electronic social media platform and poster distribution in the public areas of hospitals and nearby communities with the details of this study and contact information.

The interested subjects will be advised to contact the research assistants by phone or on site for initial screening. The potential participant is registered and given an appointment with the assigned physician for checking the inclusion and exclusion criteria. Patients who meet all inclusion criteria but no exclusion criteria will be invited to participate in the study and provided with the details of this RCT. All the participants will be asked to sign an informed consent form with their comprehensive information collected. The participants will be randomly assigned into two groups: the acupuncture group and the sham acupuncture group. All patients will not be informed about which group they have been assigned to in order to maintain blinding in this trial. Then, the baseline assessments will be performed by the same physician and recorded in CRF. All participants will undergo 8-week treatment and 16-week follow-up with relevant assessments every month in CRF. Each participant will be given a schedule for the dates of intervention and follow-up appointments performed by a research assistant who is neither involved in the treatment nor in the randomization.

The study is a two-center, double-blind, and placebo-controlled trial. With the block randomization method, the random number table will be generated by an independent third party, the Hospital’s Clinical Evaluation Center, using SAS 9.4 software (SAS Institute, Cary, NC, USA). The randomized assignment sequence is placed in a sealed opaque envelope whereas the blind codes are kept at the department of research management and can be reproduced when needed. All of the patients participated in this study; principal investigators and research staff will remain blinded to all patients’ randomization assignments throughout the duration of this study. Eligible patients will be randomly allocated to either the acupuncture or sham group according to a 1:1 ratio.

All participants will receive either real acupuncture or sham acupuncture for 8 weeks. The frequency of acupuncture intervention is three times per week for the first 4 weeks and twice a week for the following 4 weeks. Every participant will be placed in a separate room to receive the treatment for 30 mins every time. All acupuncturists participating in the study are licensed medical practitioners to ensure the accuracy and consistency of the treatments provided. Meanwhile, adverse reactions that may occur during the study will be recorded.

Acupoints include three on the head, four on the back, two on the upper extremities, and eight on the lower extremities. Before acupuncture treatment, a small pad will be pasted on each acupoint. All the needles will be inserted in the acupoints through these pads (Fig. 1).

The sham needle consists of a needle with a blunt tip and a circle adhesive pad (Fig. 1). The needle is very similar to the real needle, 0.30 mm wide, and 40 mm long. The adhesive pad is made of the sterile cylindrical polyethylene foam (10 mm in diameter and 5 mm in length) with a double-sided adhesive tape at the bottom. The adhesive pad supports the sham needle on the acupoint and ensures the implementation of blinding during the intervention. Thus, the sham needle with a blunt tip only contacts the skin surface but will not penetrate into the skin of the participants during sham acupuncture.

Each participant will be interviewed by an investigator prior to the commence of treatment and fill out the CRF with a series of initial data at baseline of the study. After skin sterilization, an adhesive pad made of aseptic cylindrical polyethylene foam with double-sided tape on the bottom is placed on the acupuncture points for fixing the needle and implementation of blinding. The points and manipulation of acupuncture in both groups are the same, with Baihui (DU20), bilateral Tianzhu (BL10), bilateral Jianjing (GB21), bilateral Quyuan (SI13), bilateral Shousanli (LI10), Ququan (LR8), and bilateral Taichong (LR3) with even method, bilateral Sanyinjiao (SP6), Zusanli (ST36) with reinforcing method (Fig. 2). Needles will be retained for 30 min during treatment. Following needle insertion, the state of “de qi” (feelings of patients including soreness, numbness, heaviness, or tingle at the points) is achieved by twirling, lifting, and thrusting, which is essential for the effective treatment [17].

The calculation for sample size was based on the changes in pain VAS scores. We adopted the method described in previous studies [28, 29] that the changes are − 4.00 in the acupuncture group and − 2.50 in the sham-acupuncture group, respectively, indicating that the mean difference between two group is 1.5 with standard deviations of 2.55 and 1.25. Given that the ratio of the acupuncture group and the control group is 1:1, the required sample size is 29 cases for each group as estimated by SAS 9.4 software using a two-sided test with a significance level (α) of 0.05 and a power (1-β) of 0.80. With a possible dropout rate of around 15%, the acupuncture group and control group require a total of 68 cases.

The standard operation procedure (SOP) for the acupuncture operation method is established. The identification, registration, and treatment of participants will be managed by the SOP. Training of acupuncture theory and surgical aseptic operation for acupuncturist with certain clinical experience will be conducted to ensure the consistency of repeated operations of acupuncture. A corresponding data security monitoring plan will be developed. All adverse events are recorded in detail, properly processed, and tracked until properly resolved or the condition is stable, and reported to the Ethics Committee in a timely manner.

The Trial Steering Committee is established for monitoring the trial conduct and ensuring the safety and quality of the data, which consists of three members including a senior rheumatologist, an acupuncturist, and a statistician. The committee is independent from the study group and has no conflict of interest with the investigators. They will provide regular supervision and hold monthly meetings (either face to face or online) to ensure that the trial is conducted smoothly and ethically. The committee will also be responsible for monitoring data collection to ensure the authenticity and integrity of the data. They will conduct at least one on-site visit every 6 months during the process of the trial. During the visit, they will interview investigators, examine the original research documents, check the participant enrollment, and confirm the compliance of clinical centers with the trial protocol. Moreover, they will identify the problems in the trial and provide recommendations on the amendment of the protocol. If any decisions on changes of the protocol were to be made, they would notify the funder first. Subsequently, the PI will apply for approval from the Ethics Review Board with written application and notify the investigators with written notice upon receiving the approval from the ethics committee. Any deviations from the protocol will be fully documented using a breach report form. In addition, the protocol will be updated immediately in the clinical trial registry.

The data of this clinical trial is managed by Beijing CreateMed Medicine Technology Co., LTD, which ensures the authenticity, integrity, and privacy of clinical test data during the research process. The clinical trial database is structured with EpiData 3.1 (Chinese version) by the appointed data manager who is responsible for the regular database management and maintenance. All of the data from the research centers will be imported into the clinical trial database by two research assistants. Any missing or incorrect data will be detected by software system. In such case, the original CRFS will be checked to correct or complete every piece of data.

To assess the effect of acupuncture therapy for fibromyalgia, intention-to-treat (ITT) [30] analysis will be performed for statistical analysis. A value of P < 0.05 with two-tailed test will be considered statistically significant.

The results will be released by the study group after the data analysis. All presentations and publications are expected to protect the integrity of the major objectives of the study. Any data that break the blind will not be presented prior to the release of mainline results. Recommendations as to the timing of presentation of such endpoint data and the meetings at which they might be presented will be discussed by the Steering Committee. The primary outcomes will be presented via publications including papers, abstracts in the meetings, and announcement in the clinical trial registry. The datasets analyzed during the current study are available from the corresponding author upon request.

The protocol has been approved by the Institutional Ethics Committee of Guang’anmen Hospital (approval number: 2018–060-KY) and Shenzhen Chinese Medicine Hospital (approval number: Shenzhen TCM Hospital Ethical Review for Scientific Research-2018-54). All subjects will be required to sign the informed consent form. The consent form is available from the corresponding author upon request. In the consent form, participants will be asked if they agree to use of their data should they choose to withdraw from the trial. Participants will also be asked for permission for the research team to share relevant data with members from the universities involved in the research. This trial does not involve collecting biological specimens for storage. Personal information of the enrolled participants will be maintained properly in order to protect confidentiality before, during, and after the trial.

This protocol version No. A001 revised on Mar 1, 2018 has been approved by the Institutional Ethics Committee of Guang’anmen Hospital and Shenzhen Chinese Medicine Hospital. The date of recruitment began in July 2018 and will be completed in August 2020. This study will be finished in December 2020.