This study is registered on chictr.org.cn (ChiCTR1900022712). A program summary of the whole experiment is shown in Fig.1, and the test flow chart is provided in Fig.2. The single center clinical study is a two-group, double-blind, prospective, placebo-controlled, RCT to evaluate the efficacy and safety of Zhengyuan capsule for CRF in lung cancer patients undergoing operation. Eligible participants will be randomized to either a treatment group receiving a 8-week Zhengyuan capsule regimen or a control group receiving a 8-week placebo capsule regimen. The protocol include clinical research directory and Additional files (the CFS checklist, the MFSI-SF checklist and the evaluation scale of TCM qi syndrome pattern).
Setting and participants
The study will be conducted in Shanghai. Patients will be recruited from the department of integrated Chinese and western medicine in Shanghai Chest Hospital. Patients who meet all inclusion criteria are eligible for inclusion. At the same time, patients meeting the exclusion criteria must be screened out.
Randomization, allocation concealment, and blinding
After screening, patients should sign and provide informed consent. They will be randomized into either a treatment group receiving a 8-week Zhengyuan capsule regimen or a control group receiving a 8-week placebo capsule regimen. A block randomization sequence will be generated by SAS 9.4(SAS Institute Inc., Cary, NC, USA) in a 1:1 ratio.
The clinician and relevant medical staff obtained the random number set by statistics and filled in ‘the random number’ of the study cases. Then the drug distributor applied for a trial drug based based on a random number. The web-based allocation system would display the drug number to be issued. Because of giving simulated and real capsules having the same size, color and smell, it is possible to blind the patients and clinicians and relevant medical staffs. Project sponsor, experimental technicians, outcome analysts, data managers and statisticians will be unaware of the treatment allocations.
Diagnostic criteria for CRF
Refer to the diagnostic criteria of CRF in the tenth conference for the revision of International Classification of Diseases (ICD–10), fatigue symptoms recur for more than two weeks and concomitant with five or more of the following symptoms: 1.weakness or heaviness in the body; 2.attention can’t concentrate; 3.lack of enthusiasm, depression and decreased interest; 4.insomnia or lethargy; 5.both sleep and rest are fine, but don’t feel refreshed; 6.difficulty in movement; 7. There are emotional responses, such as sadness and frustration; 8.inability to perform routine activities that were previously adequate; 9.short-term memory loss; 10.fatigue symptoms persist for hours without relief
Participants who meet the following criteria are eligible:
- Histologically or cytologically confirmed lung cancer; Clinical confirmed cancer related fatigue, and Chinese version of Cancer Fatigue Scale(CFS) score of≥40 and ＜60;
- Age＞18 and ≤75 years, male or female;
- With Stage I lung cancer, status-post surgery with R0-resection between 3 weeks and 1 month, and chemoradiotherapy is not required;
- The Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of≤2 points;
- Life expectancy ≥6 months;
- Informed consent form signed voluntarily.
Exclusion criteria are as follows:
- Pregnant, breastfeeding or plan to pregnant;
- Allergic constitution or allergic to the ingredients of this preparation;
- Cognitive impairments or verbal expression defects, which are difficult to cooperate with the investigator;
- Suspected or confirmed drug abuse or alcoholism;
- Combined severe cardiovascular, digestive, renal, endocrine, hematopoietic, neurological or chronic disease, which may affect effect judgment;
- Abnormal liver function (ALT or AST≥2 times Upper limits of normal); abnormal renal function (serum creatinine level is above upper limits of normal);
- Participated in other clinical trials within three months;
- The investigators considered that inappropriate for inclusion
- Erythropoietin(EPO), methyl ester, selective serotonin reuptake inhibitor(Ssri), amantadine(AMA), glucocorticoid, melatonin and octreotide.
- Immunotherapy, including mycobacterium vaccine, staph vaccine, sizofiran and cytokine antagonists.
- Except for experimental drugs, it is forbidden to use TCM decoction or proprietary chinese medicine with therapeutic effect on CRF, including oral and external dosage forms.
Combined medication requirements
Person’s underlying diseases and combined medications should be recorded in the chart. Keep detailed records of reasons for combination therapy, drug name, the dose and frequency of taking the medicine, total daily dose, start date, end date and medication at last visit.
Interventions and control
The treatment delivery processes for both the intervention and control groups are outlined in Fig. 2.
Patients in the control group will receive a 8-week placebo capsule regimen. Placebo capsule, as Zhengyuan simulated capsule, will be manufactured by Guangzhou Hairun Pharmaceutical Co., Ltd., based on good manufacturing practice (GMP) standards. It will be administered at a dose of 1.8g (4 capsules) by peros thrice daily for 8 weeks as a period.
Patients in the treatment group will receive a 8-week Zhengyuan capsule regimen. Zhengyuan capsule will be manufactured by Guangzhou Hairun Pharmaceutical Co., Ltd., based on good manufacturing practice (GMP) standards. Each capsule contains epimedium, dried raw ginseng, honey-fried astragalus, atractylodes macrocephala, tortoise shell powder, turtle shell powder, wine-processed glossy privet fruit and dried orange peel. It will be administered at a dose of 1.8g (4 capsules) by peros thrice daily for 8 weeks as a period.
The study data collection process is outlined in Fig.2. The investigator participating in the clinical trial must be qualified, and have the professional background and ability to conduct the clinical trial.
Patient background and medical history
the screening period, that three weeks to one month after the surgery: (1)demographic data; (2)combination therapy and medical history; (3)specified physiological tests; (4)laboratory tests
Outcome measures and assessments
Each participant will be asked to attend an in-person assessment appointment at the department of integrated Chinese and western medicine in Shanghai Chest Hospital at four time points: day–7~0(the screening period), day 0(baseline), day 28±2(the middle of the intervention) and day 56±2(the end of the intervention). During each evaluation, participants will be asked to complete specified physiological tests, self-reported questionnaires, laboratory examinations or tests. Patients will fill in self-reported questionnaires under the guidance of clinicians or relevant medical staffs. And all reports will be administered by outcome analysts.
Fatigue severity on CFS Chinese version grading
Fatigue severity will be self-assessed using the CFS Chinese version at the screening period, baseline, the middle of the intervention and the end of the intervention. CFS has good validity and reliability. It is easy to perform and should be a good instrument for the evaluation of the cancer-related fatigue in the Chinese cancer patients. The total score for CFS is the sum of three domains (physical, emotional and cognitive). Its related symptoms on a scale of 1 to 5 (1, no; 5, very much).
Secondary outcomes include the total score for MFSI-SF Chinese version grading, TCM syndrome pattern differentiation, levels of immunologic indicators(TNF-α, IL–6, IL–1, T lymphocytes subsets and B lymphocyte subsets), patient’s pulmonary functionality and adverse events (AEs). The secondary outcomes are listed below.
Fatigue severity on MFSI-SF Chinese version grading
Fatigue severity will be self-assessed using the MFSI-SF Chinese version at the screening period, baseline, the middle of the intervention and the end of the intervention. MFSI-SF has good validity and reliability. It is easy to perform and should be a good instrument for the evaluation of the cancer-related fatigue in the Chinese cancer patients. The total score for MFSI-SF is the sum of the four domains (conventional, physical, emotional and mental) minus the value of the energic domain. MFSI-SF is a six-item subscale to measure the subjective experience of fatigue. Answers are on a 5-point scale, ranging from 0, ‘not at all’, to 4, ‘extremely’.
TCM syndrome pattern differentiation
TCM believes that CRF belongs to the category of ‘consumptive disease’. Ancient sages and saints consider the depletion of essence causing deficiency as principle of treatment. 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 . The total score for TCM syndrome pattern differentiation is the sum of two domains (primary and secondary signs and symptoms). Primary signs and symptoms including fatigue, listlessness and shortness of breath. Secondary signs and symptoms including laziness to speak and spontaneous perspiration. The evaluation scale of deficiency of qi syndrome pattern is on a 4-point scale, ranging from 0, ‘not at all’, to 3, ‘severity’.
Levels of immunologic indicators
Blood samples will be collected to measure the levels of immunologic indicators. TNF-α, IL–6, IL–1, T lymphocytes subsets, B lymphocyte subsets and NK cell subsets will be analyzed at the department of integrated Chinese and western medicine in Shanghai Chest Hospital. These are associated with cancer-related fatigue in lung cancer patients undergoing operation.
PE include lung volume and pulmonary ventilation function. Lung cancer operation involves the removal of part or all of the lung. As a result, both lung volume and pulmonary ventilation function are significantly reduced. The patient may feel flustered and breathe hard after the operation. So they reduce the frequency of aerobic exercises, which has a intimate relationship with CRF.
Adverse events (AEs)
During this research, Data Safety Monitoring Committee will assess the progress and security data of this experiment. In order to assess security, we will perform the following tests on the baseline and the end of the intervention: vital signs, blood routine, urine routine, microscopic examination of urinary sediment, liver function, kidney function and electrocardiogram.
In particular, we will pay attention to adverse drug reactions (ADRs) and AEs associated with Zhengyuan capsule.
The prescription contains eight traditional Chinese medicines. Most of them belong to Chinese medicinal materials of tonic type, and part of them are combination of medicine and food. Single Chinese medicine has advantages of safe, effective and less toxic side effects, but some herbs have been listed as certain toxic and side effects in experimental research and clinical application, including jaundice, abnormal liver function, allergic diarrhea, skin rash, insomnia nervousness, high blood pressure, hypersexuality and hypofunction, headache, palpitations and bleeding.
AEs will be defined as any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment. Participants will be instructed to report AEs to the research scholar and the research scholar will monitor participants for potential occurrences of AEs. Patients should fill in the adverse event record form truthfully. AEs recorded include time of occurrence, severity, duration, effective measures taken and outcomes. All AEs will be followed up from the date they are brought to the researcher’s attention until resolution. The severity of adverse events will be judged by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 4.03.)
In case of serious adverse events(SAEs), researchers must report to the sponsor, medical ethics committee, local drug administration and national drug administration within 24 hours. SAEs will be defined according to the International Conference on Harmonization guidelines: 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.
Sample size estimation
The primary endpoint is the fatigue severity self-assessed using the CFS Chinese version grading scales. According to the literature, compared with the baseline, the change of CFS was 14 points in the intervention group and 10 points in the control group. The standard deviation of both groups was 7 points. The test effectiveness(1-β) was set at 0.8, the inspection level α was set at 0.05. The two-sample t test process of PASS was used for calculation, then a sample size of 100 was required. Considering the 15% shedding rate, the final sample size has been calculate and expand at a total of 120 patients(60 in each group).
According to the intention-to-treat principle, the whole experimental analyses will be divided into enrolled cases, demographic date and baseline, medication compliance and combination, efficacy and safety. All statistical analyses will be performed using Statistical Analysis System software (SAS, version 9.4). All results made in this study are based on two-sided tests, and α = 0.05. A P value≤0.05 will be considered statistically significant. The confidence levels for all confidence intervals are 95%. Categorical data will be presented as percentages or frequencies and compared using the chi-square or Fisher’s exact test, while Continuous data will be presented as means and standard deviations and compared using the independent t test or Wilcoxon’s rank sum test. Data for subjects who meet the dropout criteria (i.e., incidence of serious AEs, < 80% or 120% 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.
Quality control and trial management
The following must be done in this experimental research:
- The investigator participating in the clinical trial must be qualified, and have the professional background and ability to conduct the clinical trial. The whole research team, including research investigators and assistants will be required to attend unified training and good command of research procedures. Researcher is fixed and do not change easily.
- The original medical records collected must be complete and true.
- All capsules are kept in the Good Clinical Practice (GCP) pharmacy, and a research assistant is responsible for distribution. To establish clinical trial drug use archives, including drug release date, Pinyin abbreviation of the subject’s name, number of pills issued and recovered.
- Investigators will enter data using the double-entry method. All observations are verified to ensure date reliability.
- Laboratory quality control procedures and standard operating procedures(SOPs) will be checked regularly by research assistants.
- Inspections of the whole experiment will be performed regularly by the Department of Integrated Chinese and Western Medicine of Shanghai Chest Hospital. The unit hold regular meetings on issues arising from work and feedback information in the form of reports.
- Research investigators should improve patient compliance, conduct regular follow-up and control the subject withdrawal rate less than 20%.