Shenmai injection for the treatment of cancer-related fatigue in advanced non-small cell lung cancer patients undergoing chemotherapy: study protocol for a randomized controlled trial

This study is registered on chictr.​org.​cn (ChiCTR-INR-17013737). A brief flowchart of the entire study is shown in Fig. 1, and the schedule of events is provided in Fig. 2. This will be a two-group, prospective, randomized controlled trial (RCT) to evaluate the efficacy and safety of SMI for CRF NSCLC patients undergoing chemotherapy. Eligible participants will be randomized to either a treatment group receiving a 5-day SMI regimen plus conventional therapy or a control group receiving only the conventional therapy. The protocol includes the recommended elements elaborated upon in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) [31] checklist (Additional file 1).

The study will be conducted in Guangzhou, the third largest city in southeastern China. Patients will be recruited from the oncology inpatient department at each of the three GPHCM branch hospitals in the different urban districts of Guangzhou. A complete list of inclusion and exclusion criteria is provided in the following section.

Patients who provide informed consent will be randomized into either a treatment group receiving a 5-day SMI regimen plus conventional therapy or a control group receiving only the conventional therapy. A block randomization sequence will be generated by SAS 9.2 (SAS Institute Inc., Cary, NC, USA) in a 1:1 ratio. Treatment assignments will be conducted using a web-based allocation system. Given the nature of the intervention, it is impossible to blind the patients and personnel involved in conducting the programs. Outcome assessors, laboratory technicians, data managers, and statisticians will be unaware of the treatment allocations.

The diagnosis as described in TCM, deficiency of qi syndrome pattern, will be based on guidelines delineated in the Clinical Research of New Investigational Drugs in Traditional Chinese Medicine [32]. The diagnostic criteria are as follows: 1) primary signs and symptoms include fatigue, listlessness, shortness of breath and weak pulse; and 2) secondary signs and symptoms include soreness of the lower back and knees, spontaneous perspiration, and pale lips.

Participants will be diagnosed with deficiency of qi syndrome if they have two or more of the primary signs or symptoms, at least one of the secondary signs or symptoms, and examination of the tongue and pulse indicates deficiency of qi. After being screened for inclusion and exclusion criteria, eligible patients will be entered into the trial.

The treatment delivery processes for both the intervention and control groups are outlined in Fig. 2.

The study data collection process is outlined in Fig. 2.

The following baseline data will be collected using questionnaires and a review of medical charts: 1) sociodemographics; 2) medical history; and 3) anthropometric variables.

Each participant will be asked to attend an in-person assessment appointment at the GPHCM Oncology Department at two time points: baseline and day 5 (the end of the intervention). During each assessment, participants will be asked to complete specified physiological tests and self-reported questionnaires. All tests will be administered by one of two trained independent assessors.

CRF most commonly occurs with other symptoms, such as depression, anxiety, pain, sleep disorder, and loss of functional status [7]. CRF profoundly impacts on a person’s physical, emotional, and mental well-being [11]. The secondary outcomes are listed below.

An independent Data and Safety Monitoring Committee will evaluate the progress of the study and assess the safety data, as requested during the study. Adverse events (AEs) will be defined as any undesirable experience participants endure during the trial period, regardless of whether or not it is associated with the intervention. Participants will be instructed to report AEs to the research team, and a research nurse will monitor participants for potential occurrences of AEs. All details of AEs, such as time of occurrence, severity, management, and causality to the intervention, will be recorded on case report forms. All AEs will be followed up from the date they are brought to the investigator’s attention until resolution. Severe AEs must be reported to both the GPHCM Data and Safety Monitoring Committee and the GPHCM Ethics Committee within 24 h. Severe AEs will be defined according to the International Conference on Harmonization guidelines [41]; any adverse event will be regarded as serious if it results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, or results in persistent or significant disability or incapacity.

To assess safety, we will perform the following tests on participants at the screening phase (baseline) and on day 5 (the end of the intervention): routine blood, routine feces, routine urine, liver, and kidney function, and electrocardiography. Safety will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

In particular, we will pay attention to adverse drug reactions (ADRs) associated with SMI. Because of its effectiveness, the scope of diseases treated with SMI has gradually broadened, and reports of associated adverse reactions have increased correspondingly. The number of published literatures has ranked SMI ninth for ADRs in 33 varieties of Traditional Chinese Medicine injections in the 2004 edition of the National Essential Drugs List (2004 edition) in China [42].

Current evidence shows that SMI has a lower rate of ADRs. However, a systematic review of ADRs associated with SMI since 1995 showed that ADR cases were mainly systemic reactions (allergic shock), skin lesions (urticaria and pruritus), and local pain [43]. Because most ADRs occurred in the first 30 min of the first SMI administration, we suggest that patients should be closely observed during this period. Meanwhile, for patients who had continuous treatment with SMI, there is a need for close attention. ADR severity for each event as classified according to World Health Organization guidelines is shown in Table 1 [44].

The primary endpoint is the fatigue severity self-assessed using the FACIT-F subscale. The sample size is calculated based on the primary endpoint. Previous clinical practice suggests a mean difference (MD) of 4.95 between groups, and the same standard deviation (SD) of 7.28 for each group. Using a superiority test, it is estimated that 38 participants per group are needed to achieve 90% power and a (two-sided) 5% significance level in detecting treatment differences. Thus, the final sample size has been set at a total of 94 patients (47 in each group), assuming a 20% dropout rate.

Efficacy and safety analyses will be conducted according to the intention-to-treat principle. All statistical analyses will be performed using Statistical Packages of Social Sciences software (SPSS; version 19.0). All results made in this study are based on two-sided tests. A P value < 0.05 will be considered statistically significant. Continuous data will be presented as means and standard deviations and compared using the independent t test or Wilcoxon’s rank sum test, while categorical data will be presented as percentages or frequencies and compared using the chi-square or Fisher’s exact test. Data for subjects who meet the dropout criteria (i.e., incidence of serious AEs, < 80% compliance with the protocol, incomplete data that could influence the trial, reluctance to continue the study, large error in protocol, or deviation from the protocol) will be excluded. Missing values will be implemented by multiple imputations.

The management structure comprises principle investigators (PI), a Trial Management Group, a Data Monitoring Committee, and a Trial Steering Committee. The Trial Management Group is responsible for the day-to-day delivery and for conducting the trial. It will comprise a project manager and investigators from the GPHCM. The Trial Management Group will meet weekly to discuss trial progress. The project manager will have a face-to-face meeting with the PI every other week. The role of the Data Monitoring Committee is to review safety and efficacy data and to make recommendations to the Trial Steering Committee. It will comprise four fully independent members: one chairman, one oncologist, one senior biostatistician, and one clinical pharmacology expert from the GPHCM. The Data Monitoring Committee will meet once, prior to the start of patient recruitment, and at least once a year for those years in which patients are involved in exercise sessions. The Trial Steering Committee is responsible for approval of any amendments to the main study protocol and, to monitor the trial, steering it towards its overall objectives, to approve and comment on project deliverables, to consider the recommendations of the Data Monitoring Committee, and to resolve any problems brought up by the Trial Management Group. It will comprise one independent chairman, Dr. Wanyin Wu, Dr. Xiaobing Yang, Dr. Hong Deng, and two other independent members including at least one patient and a public involvement representative. Responsibility for calling and organizing the Trial Steering Committee meetings lies with the PI. The Trial Steering Committee will meet at least annually, more frequently if needed. Representatives of the Data Monitoring Committee are to be invited to all Trial Steering Committee meetings. Before recruitment, the whole research team, including investigators, research assistants, and research nurses will be required to attend a training workshop. This will be done before the trial to ensure their strict adherence to the study protocol and familiarity with the trial administration process. The data collected in this trial will comprise information recorded in case report forms and questionnaires.

Data will be entered using the double-entry method. Data quality will be checked regularly by research assistants and overseen by monitors. Data monitoring will be conducted regularly with standard operation procedures by a team from the GPHCM Key Unit of Methodology in Clinical Research. Inspections will be performed regularly by the GPHCM Department of Science Research. All modifications are to be marked on the case report forms. Data managers will then recheck the data before logging it. The database will be locked after all data have been cleaned. If participants withdraw from the trial during the study period the reasons must be documented, and the dropout rate is to be statistically analyzed.

Recruitment started in December 2017, and it is expected to finish in April 2019.