We proposed this study is a multi-center, randomized, sham-controlled, patient and assessor blind trial. The trial will be commenced in 4 centers, after ethical approval has been obtained from the Institutional Review Board. The clinical trial is designed and reported following the Consolidated Standards of Reporting Trials and Standards for Reporting Interventions in Clinical Trials of Acupuncture guidelines. Eligible patients will be randomly divided into the acupuncture group and the sham acupuncture group in a 1:1 allocation ratio. All participants will sign the informed consent before proceeding with the trial. The flow chart of the study process is as follows in Fig.1.
The sample size calculation was based on the change of BFI-C scores. According to previous studies, we assume the change is -2.35 in acupuncture group, while -2.0 in sham-acupuncture group; therefore, the mean difference between two group is 0.35 with standard deviations of 1.03 and 1, a sample size of 133 per group can provide 80% power to reject the null hypothesis with a significance level of 0.05 using a 2-sided, 2-sample, unequal-variance t test. Considering the dropout rate of 20%, a total of 320 participants should be recruited for this trial.
This multi-center, randomized, sham-controlled, patient and assessor blind trial will be conducted in the Shanghai Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai Chest Hospital and LongHua Hospital Shanghai University of Traditional Chinese Medicine. Participants of the study will be recruited through the outpatient clinic or inpatient, hospital-based Wechat advertising, and posters in the hospital. Any interested patients will be screened either via telephone or on-site and consented for the study. After being informed of the details of this RCT, participants will be asked to sign the informed consent, and deliver it to an independent research assistant. Patients will be randomly divided into two groups: acupuncture group (n=160) and sham acupuncture group (n=160). All participants will undergo six-week treatment of acupuncture (or sham-acupuncture) and a series of assessments on CRF free of charge. Timing of treatment assessments and data collection are as follows in Table 1.
Inclusion Criteria: Participants with the following conditions will be included:
(1) Participants in line with Interpretation of Chinese lung cancer treatment guidelines (2015 edition) for the diagnosis of lung cancer;
(2) Participants who have imaging evidence that supports Lung adenocarcinoma diagnosis;
(3) Participants whose resection surgery took place within the last 3-6 months and did not receive chemotherapy;
(4) Participants who meets the diagnostic criteria of CRF, and BFI-C score is higher than 4;
(5) Participants aged 18-75 years old;
(6) Participants whose KPS (Karnofsky Performance Status) score is higher than 80;
(7) Participants with the ability to understand the nature of the study and willing to give informed consent;
(8) Participants capable of providing responses during outcome measurement.
Exclusion Criteria: Participants with the following conditions will be excluded:
(1) Participants with comorbidities such as serious heart, kidney or liver disease;
(2) Participants who have severe mental disorders such as cognitive impairment;
(3) Participants with other physiological or pathological fatigue such as chronic fatigue syndrome (CFS);
(4) Participants who have received acupuncture within the past 6 months;
(5) Participants who are pregnant or currently lactating.
Randomization and Allocation concealment：
Stratified block randomization will be used in this experiment. The randomization sequence will be generated by an independent statistician using SPSS 23.0. The participants who meet the criteria will be randomly assigned to 1 of the 2 groups in 1:1 ratio by computer-generated random sequences after completion of baseline assessment. Block randomization with a random bock size ranging from 4-8 will be applied in each center. Randomization concealment is realized by opaque envelope method. The treatment allocation codes will not be revealed until the participants have finished all baseline assessments and before the first acupuncture treatment. In order to minimize breaks in coding, the principal investigator (PI) who designed the trial and research personnel who perform the outcome assessments will be blinded to the treatment assignment. Only the acupuncturists will know which participants belong to which groups.
Participants will be informed that they will be randomly assigned to either acupuncture treatment or acupuncture-like simulation treatment. Participants will be asked to wear an eye-patch when they receive treatment, the 2 groups will receive identical treatment except no skin penetration will be involved in the sham acupuncture group. Therefore, Participants and other researchers (the principal investigator, the data analysts, the outcome assessors and statistician) will be blinded to the group allocation. To ensure the successful implementation of the blinding method, all researchers will be trained before the trial begins.
The acupuncture treatment will be conducted after all participants have given informed consent. All patients will receive 12 treatments, either acupuncture or sham acupuncture treatment twice times per week for 6 weeks. In each treatment session, every patient will be placed in a separate space and asked to wear an eye-patch. Each procedure will be 30 minutes and performed by a trained acupuncturist who will be a registered practitioner with more than 3 years of experience in clinical practice. The acupuncturist will confirm that the participant has undergone the assigned procedure. To improve patients’ compliance, all patients will receive the intervention and assessments by telephone reservation.
The acupuncture procedure will be performed following the Guidance of Clinical Practice of Acupuncture. Before the treatment, all patients will be skin sterilization with alcohol wipes, then the experienced acupuncturists will begin to treat. In the treatment group, acupuncture needles will be standard stainless steel, sterile, and disposable (0.25 × 40 mm and 0.30×40mm in length; Jia Jian, China). The control group will use the Streitberger Placebo-needle at the same acupoints. Each session treatment will last for 30-min. The treatment methods of acupuncture and acupoints are shown in Table 2. Any concomitant care or intervention which has the effect of supplementing Qi (Traditional Chinese Medicine term) is not allowed to be use during the treatment and follow up period, including using some special herbs and exercising Qi-Gong et al.
The acupuncture group:
The acupuncture group will receive a real acupuncture treatment throughout the 6 weeks. According to our previous experience, Baihui (GV20), Yintang (GV29), Zhongwan (CV12), Qihai (CV6), Guanyuan (CV4), bilateral Hegu (LI4), bilateral Taichong (LR3), bilateral Sanyinjiao (SP6), bilateral Zusanli (ST36) will be used as the acupoints for treatment. Patients in the supine position, GV20, CV12, CV6, CV4 and LI4 (with the needle tip pointing towards the ground), CV29 and LR3 (with the needle tip pointing towards the feet), while SP6 and ST36 (with the needle tip pointing towards the limb extremities), all the points will be punctured perpendicularly to the respective depth 10-30mm. Manipulating manually (including lifting, thrusting, and rotating) until the patient reports needling sensations (Deqi sensation). The needles on the bilateral Zusanli (ST36) will be connected to an SDZ-III Electronic Acupuncture Treatment Instrument (Hwato, China), using continuous wave type stimulation, with a frequency of 2Hz, and intensity of 2~3 mA. Needles will be retained for 30 minutes.
The control group:
The control group will undergo treatment with a special sham acupuncture. We will use a non-invasive placebo control, the Streitberger Placebo-needle. Acupoints are the same as with acupuncture group, without insertion. Similarly, the electroacupuncture apparatus (SDZ-III Electronic Acupuncture Treatment Instrument) will be set beside the patients and connected to the bilateral Zusanli (ST36), without electrical pulse. This set up will remain in place for the next 30 minutes.
We will assess the primary outcome at baseline, week 3, post-treatment (week 6), and with follow-ups at the 4th and 12th weeks after the end of treatment. Secondary outcomes will be assessed at baseline and week 6.
Brief Fatigue Inventory-Chinese version (BFI-C):
The change of BFI-C scores will be used to evaluate the degree and impact of fatigue. The Brief Fatigue Inventory scale is designed by Mendoza and translated by Wang, and it is comprised of 2 parts, (the first part consists of 1-3 items, the second part consists 4-9 items), questionnaire items 1-3 are used to assess the individual’s overall fatigue level over the past 24 hours. The items 4-9 are designed to evaluate the effects of fatigue on general activities, emotions, walking ability, normal work (including work and housework), relationship with others and enjoyment of life. The scale uses the 10-point scoring method, 0 points means no fatigue, 10 points for the most severe fatigue. A higher score indicates more severe fatigue. According to the average score, it could be divided into 4 grades, that is no fatigue (score 0), mild fatigue (score 1-3), moderate fatigue (score 4-6), and severe fatigue (score 7-10). The BFI scale has been validated in different cancer patients all over the world[19-21], the structural validity is 0.81-0.92, and the Cronbach’s coefficient of the total scale is 0.96. The Chinese version of BFI has been proven to have good reliability and validity. The mean of the changed score in BFI-C at week 6 will be analyzed as a primary outcome.
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30):
EORTC QLQ-30 is a core scale for the determination of quality of life in all cancer patients by the European Organization for Research and Treatment (EO RTC). It includes a total of 30 entries, which are divided into 15 domains. Of those are 5 functional domains (body, role, cognition, mood and social function), 3 symptom domains (fatigue, pain, nausea and vomiting), 1 overall health status / quality of life area and 6 single entries (each as a domain). The higher the score for the functional domains and overall health status, the better the functional status and quality of life. The higher the score for the symptom domains, the worse the quality of life. The mean of any changed score at week 6 will be analyzed.
Hamilton Rating Scale for Depression (HAMD):
The HAMD developed in 1960[23, 24], is the questionnaire used to describe the severity of cognitive and bodily symptoms of depressive disorders.
Each item is rated in 3- or 5- point scales. According to the total score, the depression could be divided into 4 grades: normal (total score <7); may be depression (total score 7-17); depressed (total score 17-24); severe depression (total score >24). The higher the total score, the more significant the depression tendency. The mean of any changed score at week 6 will be analyzed.
Any adverse events occurring during the trial will be recorded by the patients and doctors. Any discomfort, symptoms or any other diseases will be assessed. All details of adverse events will be reported in the Case Report Form. The researcher will interview participants and write an adverse event report after treatment. The Data and Safety Monitoring Board and ethic review board will assess its correlation with the intervention, and make the final decision as to whether to continue the study or not. We will analyze the influence of all events at the end of the trial.
Credibility of Treatment Rating Scale (CTRS) ：
The CTRS is a scale for assessing the credibility of the acupuncture treatments. It consists 4 items and is used to assess the participants as “perceived logic of the treatment,” “confidence in recommending the treatment to their friends who have similar complaints, “confidence in the treatment to alleviate their complaint,” and “likelihood that the treatment would alleviate their other complaints.” A lower score indicates a greater confidence toward the received treatment [25, 26].
Blinding success assessment：
After the final treatment session, the success of blinding will be tested by asking the participants the following question “When you volunteered for the study, you were informed that you had an equal chance of receiving traditional acupuncture or acupuncture-like simulation treatment. Our study is finished now, which style acupuncture do you think you are received?” The participants will be provided with 3 choices: acupuncture treatment group, acupuncture-like simulation treatment group and uncertain group. If participants do not chose uncertain, we will ask the reason why they have made that assumption .
The Clinical Research Center of Drugs of Shanghai University of Traditional Chinese Medicine will response for the data monitoring team to control bias and identify problems in the project. In order to guarantee the quality of this study, every acupuncturist in this trial will be registered practitioners with 3-5 years of clinical experience in acupuncture practice. Meanwhile, a qualified clinical trial expert will monitor every trial center, and regular board meetings will be held to ensure the study process.
According to the National Institutes of Health (NIH) to monitor the trial progress and review safety and quality of data, A Data and Safety Monitoring Board (DSMB) will be formed. The committee consists of 3 members, including a senior acupuncturist, an oncologist and a statistician. The DMSB is independent of the proposed trial and all members will have to declare any conflict of interest in the trial. Regular meetings will be held during the trial, to ensure the data are collected scientifically and ethically. Moreover, DSMB could avoid participants exposure to by unnecessary risks, it has the right to unblinding if serious adverse events related to the intervention occur. The DSMB committee will provide data monitoring with access to any interim results and will make the final decision to terminate the trial if necessary. It also will identify problems in the project, if any, will make decisions to change the details of this protocol, apply for approval from ethics review board by written application, and announce the persons conducting the trial by written notice after approval is received from the ethics committee. Besides this, a qualified clinical trial expert will be invited to monitor this study, and the PI will take full responsibility and make any final decisions.
Clinical trial registration:
This RCT was registered in the Chinese Clinical Trial Registry (ChiCTR1900022831), Date: 2019-04-27.
The participant will be interviewed at each time point, and further cancer care advice will be given at the interview. This procedure will promote retention and completion of follow-up assessments. All the original data will be collected by blinded assessors and double-entered into the Electronic Data Capture System (EDC). The system will be tested before it is officially launched to ensure that system meets the trial requirements. The original data recorded in case report forms will be entered within 1 week when the participants finished the all treatment and follow-ups. In case report forms, the codes and initials will be used instead of the participant's information to protect the participant's privacy. If the data is found to be uncertain, the data supervisor will notify the researcher to respond with a data question form. If necessary, the statistician will send a data question form to the researcher and the researcher's answer should be filled in the form. The question form is then returned to the statistician by the inspector.
Statistical analysis of data will be carried out by SPSS 23.0 software. We will use multiple imputation to address any missing data. All data including the data from any participants who drop out of the RCT during the trial will be analyzed by Intention-to-Treat (ITT) analysis by an independent statistician who will be blinded to group allocation. Descriptive analyses will be done on baseline demographics. To compare changes in BFI-C between 2 groups as the primary analysis, a repeated measure ANOVA (General Linear Model) will be used. For the secondary outcomes, scores in QLQ-C30, HAMD and CTRS between the two groups will be compared with Student’s t test or the Wilcoxon rank-sum test. All reported P values will be 2-sided, and a P value of less than 0.05 is considered statistically significant. The mean difference and confidence intervals at the 95% level will also be calculated using SPSS.