Jin’s three-needle acupuncture technique for chronic fatigue syndrome: a study protocol for a multicentre, randomized, controlled trial

The sample size was calculated via the effective rate based on the FS-14. In some previous acupuncture studies for CFS, researchers adopted the FS-14 score as one of the primary endpoints. The FS-14 score was applied with the formula:

to calculate the effective rate [26]. Thus, based on this method and data from our preliminary study, we assumed the effective rate for the control group to be approximately 64% and the effective rate of JTN treatment to be approximately 86%. Therefore, based upon a two independent proportions power analysis conducted by an independent statistician via PASS 11.0, approximately 80 participants in each group will be needed to detect a statistically significant difference, with a significance level of 5% and a power of 90%. To allow for a predicted dropout rate of 15%, a sample size of 188 participants in total will be sufficient to detect a clinically important difference in this trial.

Inclusion criteria:(1) patients who meet the diagnostic criteria of CFS (published in 1994, by the Centers for Disease Control) [1]; (2) patients aged between 20 and 55 years; (3) patients who volunteered to participate in the study and signed Informed Consent Forms; (4) patients who did not receive any related therapy, such as pharmacotherapy and psychotherapy within 1 month; and (5) patients who had at least a high-school diploma and had the ability to understand the scale.

Exclusion criteria:(1) pregnant and lactating women, and women who have fertility intention within 3 months; (2) patients who have contagious disease, mental illness, cardiovascular diseases, or primary diseases of the liver, kidney, and haematopoietic and endocrine systems; (3) patients with haemorrhagic disease or a bleeding tendency; (4) patients who experienced trauma, fever, or allergic history in the recent 2 weeks; (5) patients who faint during acupuncture or from the sight of blood; and (6) patients who are participating in other clinical trials concurrently.

The study centres will recruit participants via advertisements on the Internet and posters on bulletin boards at the hospitals. The contents of the recruitment advertisement include a brief introduction to CFS, the inclusion criteria, the intervention, and the contact information of the researchers. If a patient is interested in participating in the trial, then they will be invited to consult the researchers. Once the patient signs the Informed Consent Form, they will be screened. Patients who match the diagnostic and inclusive standards will formally enter the study. The following basic personal information will be collected: sex, age, Body Mass Index (BMI), educational background, occupation, marital status, related past health history, etc. These details about the participants will be maintained by the Data Monitoring Committee (DMC) and will never be revealed to any individual or organisation relevant to the study.

The study protocol was approved by all relevant Institutional Review Boards: the First Affiliated Hospital of Guangzhou University of TCM, the Third Affiliated Hospital of Sun Yat-sen University, and Guangzhou Dongsheng Hospital. The researchers will obtain written informed consent from each participant before screening. The informed consent form (in Chinese) is given in Additional file 2.

Both treatments will be conducted for five consecutive days per week and last for 2 weeks. We will use No. 30 disposable acupuncture needles (size: 0.32 × 40 mm, 0.30 × 25 mm; Suzhou Tianxie Acupuncture Instruments Co., Ltd., HuangqiaoQingtai, Suzhou, China) for the intervention. The quality of the needles will be checked before conducting the treatment to ensure safety.

The practitioners of this trial have more than 3 years of clinical experience and have participated in a training session to ensure that the treatments will be administered consistently. The patient may make an appointment with the physician before starting the treatment, and confirmation will be made by a phone call to enhance compliance.

According to the JTN theory, every point group is compatible with some kind of disease or a series of symptoms. Thus, in the treatment group, two groups of points are chosen: ‘the group for fatigue’ and the ‘three-foot-point group’. The former consists of the ‘Sishen points’ (also named ‘Sishen zhen’, a special point), PC6, and ST36, and the latter consists of ST36, SP6, and LR3 [27, 28]. Based on the evaluation of acupuncture literature, the final point prescription is the combination of the two groups plus another three points: GV20, RN4, and BL23.

During the course, patients randomly assigned to the treatment group will be treated while in the lateral position. The patients may lie on their left side in the first week; then, they will turn to the right lateral position in the second week, or vice versa. The position of the patients will be recorded during the course.

Among the selected points, PC6, ST36, SP6, and LR3 will be needled unilaterally based on the position of the patient. PC6 and LR3 will be needled at 45–90° to the body surface and inserted at a depth of 1.0 cun. ST36 and SP6 will be needled at 90° to the body surface and inserted at a depth of 1.5 cun. RN4 will be needled at 45–90° towards the bottom and inserted at a depth of 1 cun. BL23 will be needled 45–90° downward at a depth of 1–1.5 cun. On the head, GV20 will be needled at 15–30° to the body surface and inserted at a depth of 0.5 to 1.5 cun.

Finally, at the Sishen points, the needles will be inserted 1 cun from the four sites obliquely sideways from GV20 at an angle of 15–30° to the body surface. The needling sensations felt by the patient, ‘Deqi’, will be achieved by lifting, thrusting, and twirling the needles during the needling the points. The needles will be retained for 30 min for each treatment session. The needles at the Sishen points, PC6 and ST36, will be gently twirled every 10 min to achieve and enhance the sensation according to the JTN theory.

In the first 20 min, the participants appointed to the control group will be treated in the supine position. At RN4 in the abdominal region, the needle will be tilted at 90° to body surface and inserted 1.5 cun. At bilateral LR3 in the foot region, the needle will be tilted 45 to 90° and inserted 0.5–1 cun. At bilateral ST36 and SP6, the needle will be tilted 90° to the body surface and inserted 1–1.5 cun. Then, in the next 10 min, the participants will be treated in a prone position. For GV20 on the head, the needle will be tilted anterior to the body and inserted 0.5 to 1 cun. At bilateral BL23 in the back region, the needle will be tilted 45 to 90° towards the bottom and inserted 1 to 1.5 cun. The needles will be twirled to enhance the sensation during treatment. If a patient feels pain, then we will slightly change the depth or angle of the needle.

The patients in the two groups will be discouraged from any additional specific complementary treatments related to CFS throughout the trial, including moxibustion, herbal medicine, massage, etc. If a patient needs medications, such as antidepressant drugs and anxiolytics, or to undertake mind-cure, then the relevant information will be recorded in the Case Report Form for that patient. Two researchers, blinded to the treatment, will assess whether to adopt the data.

As the CFS diagnostic criteria are mainly based on the patient’s symptoms, we considered symptom improvement as the primary outcome. Thus, the patient-reported outcome (PRO) method was adopted in this trial. The primary outcome was the effective rate based on the FS-14 score. The FS-14, which is used to evaluate the fatigue level of the patient, reflects the severity of fatigue from two different angles: physical fatigue and mental fatigue [29, 30]. A higher score suggests more serious fatigue. The FS-14 score will be applied with a formula, namely:

to calculate the effective rate. If the integral is reduced by ≥ 60% after treatment, then the treatment will be marked as a notable effective. If the integral is reduced by < 60% but ≥ 30%, then the treatment will be considered as effective. If the integral is reduced by < 30%, then the treatment will be regarded as ineffective [26].

The secondary outcomes include the Fatigue Assessment Scale (FAI), Depression Status Inventory (DSI), and Self-rating Anxiety Scale (SAS): (1) The FAI, a 29-item scale, with scores ranging from 1 to 7 for each choice, evaluates four dimensions of fatigue: fatigue severity (11 items), the sensitivity of fatigue under particular circumstances (six items), associated consequences of fatigue (three items), and the response to sleep (two items). A higher score indicates greater problems with fatigue [31, 32]; (2) The DSI, consisting of 20 questions, is used to evaluate the depressive state of the patient in the past week. This assessment reflects the emotional, somatic, psychomotor retardation, and mental disorders of depression. The DSI is especially suitable for general hospitals to find patients with depression [33]; and (3) The SAS, containing 20 questions, is used to evaluate the level of anxiety of a patient at 1 or 2 weeks before taking the test. The assessment is based on scoring in four groups of manifestations: cognitive, autonomic, motor, and central nervous system symptoms [34].With scores ranging from 1 to 4, a higher SAS or DSI score indicates a higher risk of developing anxiety and depression.

In addition, plasma adrenocorticotropic hormone (ACTH), plasma cortisol, and serum levels of interleukin-2 (IL-2) and interferon-gamma (IFN-γ) will be examined to determine whether the immune and hypothalamic-pituitary-adrenal axis (HPA) functions of CFS patients will be changed by JTN treatment.

Previous studies have indicated the hypoactivity of the HPA axis in CFS [35]. In a study focusing on basal circadian ACTH and cortisol secretion in patients with CFS, the mean basal level of plasma ACTH in the patients was 1.8 ± 0.2 pM, while that in the controls was 2.4 ± 0.5 pM. The average baseline cortisol secretion was 3.1 ± 0.5 μg/dl in patients with CFS and 2.7 ± 0.4 μg/dl in the controls. Researchers have considered that basal hypercortisolaemia results from the resiliency of the HPA axis [36]. In this study, we will measure plasma ACTH and cortisol levels to study changes in HPA function after acupuncture treatment. We assume that the basal level of the two indicators will be increased after treatment.

Previous studies have reported Th1 cytokine abnormalities in CFS, and IFN-γ was found to be increased in CFS patients, while IL-2 was reported with mixed findings [37‐39]. According to Fletcher [39], plasma concentration of IFN-γ in CFS cases was 3.1 (0.1–11.8) pg/ml, while that in controls was 2.6 (1.2–10.6) pg/ml. Plasma IL-2 was 2.3 (1.4–5.4) pg/ml in CFS cases and 2.5 (2.1–3.5) pg/ml in the controls. In this study, IL-2 and IFN-γ will be measured to detect whether the level of the two indicators will be reduced after treatment.

All scale and plasma indicators will be assessed before treatment and immediately after treatment.

Adverse events will be recorded and managed by researchers within 24 h. There will be at least one physician to evaluate and manage the adverse events at each centre. Serious adverse and unexpected events will be reported to the Ethics Committee and other supervising departments. The subjects may leave the trial at their own discretion, or the physicians will determine whether the patient will continue or terminate the study. However, the patient will be followed up until they are in a stable condition following the adverse event.

The primary investigator will review all adverse events periodically, and the Ethics Committee and DMC will have access to the interim results. If necessary, a meeting will be held to reappraise the benefits and risk of this trial.

The possible adverse events related to acupuncture treatment include fainting during acupuncture treatment, nausea, haematoma formation, local infection, injury to the viscera or the peripheral nerves, stuck needle, and needle breakage. Adverse events will be evaluated based on the frequency, severity and symptoms of the patients throughout the trials. Patients who are intolerant to the acupuncture treatment should be removed from the trial.

A total of 188 participants who meet the selection criteria will be randomly allocated into the JTN group and the basic acupuncture group. A statistician blinded to the treatment and data collection will use Strategic Applications Software (SAS, version 9.1.3, SAS Institute Inc., Cary, NC, USA) to generate the random allocation sequence. The group name will be written on a card and sealed in an opaque envelope. The sequence numbers will be written on the envelopes, and the envelopes will be numbered sequentially. Random allocation will be performed for participants who meet all selection standards and signed the Consent Form. The research coordinator will allot participant identification codes and record the codes in the Case Report Forms. The acupuncturists will sequentially open random-allocation envelopes and allocate the participants accordingly. The details (such as name, date of birth, date of inclusion, etc.) of newly included participants will be recorded before randomisation. The opened envelopes will be stored separately in locked cabinets.

The participants will be blinded in this trial. The coordinator will send the study number and group allocation to the acupuncturist via Email. The records of the acupuncturist will be stored in a locked briefcase that will only be available for the acupuncturists and cooperative researchers. Only the acupuncturists and the coordinators will know the group allocation of each participant. The researchers and acupuncturists must not discuss related information with the participants. As patients in the two groups will adopt different positions, these individuals will not be treated in the same place after randomisation. Acupuncturists will inform the patients about the location of the treatment rooms prior to each treatment session. Therefore, the chance of acquaintance between patients in the two groups will be reduced as much as possible.

Unblinding is permissible when a participant leaves the trial at their own discretion or the physicians determine that they should terminate the trial. The blinding will be monitored and assessed by independent statisticians responsible for data monitoring and by the Ethics Committee of the study centre. After receiving permission from the supervisors, the acupuncturists may reveal the allocated intervention to the patient who dropped out.

Acupuncturists will collect the data using Case Report Forms. Two independent researchers will then input the data into the database. All analyses will be carried out under the guidance of independent data monitors to ensure the safety and reliability of the data. For participants who drop out, we will record their number and the reason for termination, especially for adverse events.

All enrolled patients will be included in the primary analysis conducted in accordance with the intention-to-treat (ITT) principle. The data will be analyzed by SPSS for Windows version 19.0. The statistical significance is defined as a two-sided P value of ≤ 0.05. The baseline characteristics will be reported as the means ± standard deviation (SD). For comparison of baseline materials, a chi-squared or Fisher’s exact test will be used for categorical variables, Student’s t test will be used for normally distributed data and the Mann-Whitney U test will be used for non-normally distributed data. The scores of each rating scale and laboratory index before the intervention will be compared between the groups via Student’s t test or the Mann-Whitney U test. For the comparison within groups, the changes in the scores and indexes from baseline to endpoint will be assessed by a paired t test or the Wilcoxon rank-sum test. For the difference between groups, we will use Student’s t test or the Mann-Whitney U test. For the safety analysis, the adverse events will be listed and analyzed using a chi-squared or Fisher’s exact test. For participants who discontinue or deviate from intervention, listwise deletion or multiple imputation will be used.

The DMC of the study centre comprises experienced experts on experimental statistics in the Guangzhou University of Traditional Chinese Medicine (GZUTCM). The DMC periodically reviews the trial on issues such as the execution of the trial, collection of the data, allocation concealment and personal privacy protection. This committee will also provide advice on the modification or termination of the trial. The DMC is independent from the sponsor and has no competing interests.

In accordance with the data-sharing policy of CHICTR (http://​www.​chictr.​org.​cn), the data from this study will be uploaded to the ResMan database within 6 months after the trial is completed. The data will become available to outside researchers at the conclusion of the trial and following the publication of the main study findings as a limited-use dataset with documentation. The study participants were informed about data sharing with external investigators in the Consent Forms. All outside investigators will be asked to sign a data-use agreement to protect study participant confidentiality.