2.1 study design
The present study is a randomized controlled trial with three parallel groups: HC group and two treatment groups including PLWNT and CBT groups. All participant were recruited from December, 2018 to September, 2019 at the Shanghai University of Traditional Chinese Medicine and Yueyang Hospital of Integrated Traditional Chinese and Western Medicine in Shanghai, China. The statistician who did not participate in the recruitment randomly divided the eligible CFS patients into two groups using sealed envelope randomization. by a computer software (Strategic Applications Software, version 9.1.3; SAS Institute Inc., Cary, NC, USA) to create a random number table, and then compiled a set of sealed envelopes on the basis of the random sequence, put the patient's information, treatment method, time and location in an opaque envelope according to random numbers. Finally hand it over to the research team. The study was conducted in accordance with the Declaration of Helsinki and the International Code of Ethics for Biomedical Research Involving Human Subjects, which was approved by the Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine (Ethics Approval Number: 2018-043), and registered on 4 November 2018 in the American Clinical Trial Registry (Registration Number:NCT03496961).
2.2 Sample size calculation
According to our recently published protocol (32), the efficacy of the PLWNT group is assumed to be better than that of the CBT group. With reference to the studies on the efficacy of CFS on the FSS scale (42, 43), it is calculated that the final difference between the two three groups of FSS average scores is 0.915 and the standard deviation is 1.147. The conservative comparison method Bonferroni was used and the sample size of this trial was calculated using the following formula:
Taking into account the allowable 10% dropout rate, the sample size of each group in this experiment is 45. Therefore, this randomized controlled trial (RCT) needs to recruit 135 participants in total.
2.3 Subjects
135 participants were recruited on WeChat (Tencent co., LTD, China) or posters at the Shanghai University of Traditional Chinese Medicine and Yueyang Hospital of Integrated Traditional Chinese and Western Medicine in Shanghai, China. Hospitalized patients were also included with a preliminary diagnosis of CFS, according to the latest Revise Guidelines for Treatment of Chronic Fatigue Syndrome in 2021(44).
The inclusion criteria were as follows: (1) age between 20 and 60 years; no gender requirement; (2) severe chronic fatigue of no less than 6 months, unexplained after clinical evaluation; fatigue not caused by work performed during the trial and unable to be alleviated after rest; and (3) at least four of these eight symptoms (memory or concentration decline, failure to regain energy after sleep, sore throat, headache, lymph node tenderness, muscle pain, multiple joint pain, and myalgia after exertion for more than 24 hours).
The exclusion criteria were as follows: severe cardiovascular and cerebrovascular diseases, endocrine system diseases, motor system diseases, autoimmune diseases, infectious diseases, use of medications that may affect the judgment of the results.
Patients who meet the inclusion and exclusion criteria would have a baseline measurement (T0) and be randomly assigned to the PLWNT group or CBT group. The clinical scale evaluation would be conducted at the end of the intervention (T1). All of the patients involved in the study would be required to sign an informed consent. A more detailed fundamental information of CFS patients is provided in our previously published protocol(32).
2.4 Intervention
PLWNT group
The PLWNT intervention program and operating standards refer to the Chinese general higher TCM compiled college textbook of Tuina and Qigong. Experienced Qigong teachers at Shanghai University of Traditional Chinese Medicine, who have been teaching Qigong for at least 5 years, were in charge of the supervision of the exercise and corrected the exercise posture during the entire intervention period for one hour every Sunday. The first 10 minutes is used to perform stretching and relaxation exercises, as well as movement introductions and demonstrations. In addition, precautions were mentioned and participants’ questions were answered. The subsequent 20 minutes is for individual guidance and correction of actions. Finally, all of the participants practiced PLWNT for 30 minutes together. For the remaining 6 days of the week, all the participants had to practice by themselves for 30 minutes at 6 o'clock every day at home, which is under the supervision of one of the directors . Their practice videos were required to be posted in a Wechat group including all participants. If some of the participants found it inconvenient, videos can be sent privately. All participants are asked to writing down their feelings in the practice recording notebook after every exercise. The entire practice process lasted for 12 weeks. The content of PLWNT Qigong intervention was the same as in our previous research(32). The nine specific forms of manipulations are shown in Figure 1.
Step 1. Preparatory position.
First, relax the whole body, concentrate your thoughts, breathe evenly, put your tongue against the upper jaw, hold your dantian with your mind, and operate step by step
Step 2. PLWNT's first eight types of abdominal massage
- Press the Danzhong acupoint (under the xiphoid process) with the middle three fingers in both hands, make a circle 21 times from the left, within 3 minutes.
- With three fingers of both hands, rub down from Danzhong acupoint and move to the pubic symphysis below the umbilicus, repeated 21 times, within 3 minutes.
- With three fingers in both hands, rub up from the pubic symphysis from two sides back to Danzhong acupoint until the hands were handed over, repeated 21 times, within 3 minutes.
- With three fingers of both hands, push down from Danzhong acupoint and push it straight to the pubic symphysis, repeated 21 times within 3 minutes.
- Rub the abdomen with the right hand from the left 21 times within 3 minutes.
- Rub the abdomen with the left hand from the right 21 times, within 3 minutes.
- Place the left hand on the left side of the lower waist and kidney, with the thumb forward, and the four fingers supporting the back, gently pinch it; With three fingers on the right hand, push straight from the bottom of the left breast to the groin, repeated 21 times in 3 minutes.
- Place the right hand on the right side of the lower waist and kidney, with the thumb forward, and the four fingers supporting the back, gently pinch it; With three fingers on the left hand, push straight from the bottom of the right breast to the groin, repeated 21 times in 3 minutes.
Step 3. Seated rocking method
Sit cross-legged, hold your hands up slightly, and press the hands on your knees. The toes of both feet are slightly bent. Revolve the upper body clockwise 21 times and then revolve it counterclockwise 21 times.
CBT group
Qualified CBT therapists [e.g., diploma in CBT, or other professionally accredited qualifications involving CBT as a major part of training (e.g., a clinical or counseling psychologist degree)] were invited to conduct CBT by giving lectures or psychological consultations on the prevention and treatment of CFS for one hour, once a week. For the remaining 6 days of the week, all the participants are required to listen to lectures on Wechat for 30 minutes every day. If some of the participants found it inconvenient, they are allowed to learn by their own with the given powerpoints. Each participant was asked to write down their feelings in the practice recording notebook after each online study to ensure that the other conditions were the same as those of the PLWNT group. The entire practice process lasted for 12 weeks. The detailed information is available in the previously published protocol(32).
HC group
Healthy participants did not receive any treatment after the beginning of the study and maintained their daily lives. However, it is necessary to receive a doctor’s health review on a regular basis and fill in a health status form every week. If participants have any health problems during the progress of the study, you need to contact the doctor immediately to ensure that the data is scientific and reliable.
2.5 Outcomes
Outcomes evaluation included the basic characteristics of personal information, the detection of peripheral blood of CFS, the quality of sleep, mental and physical fatigue, anxiety and depression symptoms. Evaluate the patient’s basic information at baseline, use the relevant self-assessment scale and peripheral blood concentration to evaluate the primary and secondary outcomes after 12 weeks of intervention, including the Multidimensional Fatigue Inventory-20 (MFI-20), Pittsburgh Sleep Quality Index (PSQI) , and Hospital Anxiety and Depression Scale (HADS).
Primary outcomes
MFI-20
Multi-dimensional Fatigue Inventory-20 (MFI-20) is widely used for CFS measurement of mental and physical fatigue (45), a total of 20 items, including five dimensions of general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. Each item can be scored on a scale of 0-5. The total score was 0-100 points. The higher the score is, the severer the fatigue is.
Secondary outcomes
Overall efficacy evaluation
The overall efficacy evaluation was formulated with reference to the efficacy standard established by "Discussion on the Curative Effect Standards for Diagnosis and Treatment of Chronic Fatigue Syndrome"(46, 47) and combined with the MFI-20 score. Full recovery was defined as the complete disappearance of the main clinical symptoms and concurrent symptoms, and a reduction of MFI-20 score by more than 95%. Markedly effective is defined as the disappearance of more than 2/3 main clinical symptoms and concurrent symptoms, and a reduction of MFI-20 score by more than 70%. Effective as the disappearance of more than 1/3 main clinical symptoms and concurrent symptoms, and a reduction of MFI-20 score by more than 30%. Ineffectiveness as the disappearance of the main clinical symptoms and concurrent symptoms <1/3 or no improvement, and a reduction of MFI-20 score by less than 30%. The total effective rate is the sum of the recovery rate, the markedly effective rate, and the effective rate.
PSQI
PSQI is a self-assessment questionnaire used to evaluate sleep quality. The scale consists of 24 items, with 19 self-reported items and 5 additional items rated by the director but not scored. The 19 items belong to one to the seven subcategories: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction(48). The score range for each dimension is from 0 to 3 points, and the total score range is 0-21 points. The higher the score is, the worse the sleep quality is.
HADS
Hospital Anxiety and Depression Scale (HADS) is used to evaluate the degree of anxiety and depression of patients. The scale consists of 14 items, of which 7 items assess anxiety and the other 7 items assess depression. The score for each item, ranges from 0 point (nothing at all) to 3 points (the extreme form of each symptom)(49). The higher the score is, the severer the degree of anxiety and depression is.
2.6 Correlations
Possible determinants are investigated of the total score of fatigue, sleep quality, and anxiety and depression at the end of treatment (T1). The linear relationship among them has been further explored.
2.7 Adverse event
We did our best to prevent and treat the damage that may be caused by this research. If there was an adverse event in the clinical trial, including any discomfort, or new changes in the condition, or any unexpected situation, it would be sent to the nearby Yueyang Hospital of Integrated Traditional Chinese and Western Medicine for review in time, and the Medical Expert Committee determined whether it was related to treatment. The expert committee has determined that the adverse event was related to treatment, and the cost of treatment and corresponding financial compensation was provided for the damage related to the trial. All unexpected and unexpected reactions reported by each participant was recorded on the adverse event report form. Follow up all adverse events until resolved. Using 1 to 4 to indicate continuous increase in severity degree between PLWNT treatment and adverse events(1= Definitely not related, 2= Probably not related, 3= Probably related,4= Definitely related).
2.8 Statistical analysis
SPSS 25.0 (SPSS version 25.0, SPSS Inc. Chicago, IL, USA) was used for statistical analysis. For measurement data such as age and scale score, the average value ± standard deviation (S) was used. For measurement data conforming to normal distribution and homogeneity of variance test, One-way analysis of variance was used for the comparison between the three groups, two independent sample T test was used for comparison between groups. For non-normally distributed measurement data, Kruskal-Wallis nonparametric test was used for comparison between the three groups, two independent samples of Mann-Whitney non-parametric test were used between groups, and P<0.05 indicated that the difference was statistically significant. The Spearman correlation analysis was used to study the possible relationship between the MFI-20 and the clinical features of the PSQI and HADS scale scores.