Efficacy and Safety of Sipjeondaebo-Tang (Shi-Quan-Da-Bu-Tang) for Chronic Fatigue Syndrome: Study Protocol for a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea Medical & Oriental Comprehensive Healthcare Center, Kyung Hee University Hospital, Seoul 02447, Republic of Korea Department of Biofunctional Medicine and Diagnosis, College of Korean Medicine, Sangji University, Wonju 26339, Republic of Korea Department of Sasang Constitutional Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea


Introduction
Chronic fatigue syndrome (CFS), which is synonymous with myalgic encephalomyelitis, is a condition characterized by pervasive fatigue (particularly after minimal exertion), chronic pain, and impaired concentration and memory [1]. It is assumed that CFS involves false fatigue alarms generated by predisposing and precipitating factors, which subsequently perpetuate stress responses [2].
ere are no established biomarkers for CFS; therefore, the diagnosis must be based on a patient's description of the symptoms [3]. e most widely used diagnostic criteria are those published by the Centers for Disease Control and Prevention (CDC) in 1994. e diagnosis is made on the basis of prolonged (>6 months), unexplained, and incapacitating fatigue and fulfilling at least four of eight accompanying criteria [4]. e overall incidence rate of diagnosed CFS has been shown to range from 14.8 to 25.8 per 100,000 person-years, peaking in teenagers and adults in their thirties [5,6]. e prevalence of self-reported CFS has been reported to be 3.28% [7]. e prevalence of diagnosed CFS ranges from 0.083% to 2.3% in males and from 0.37% to 1.8% in females [8,9]. In Korea, the prevalence of chronic fatigue that is physically or psychologically explained is 8.4%, whereas the prevalence of medically unexplained chronic fatigue, including CFS and idiopathic chronic fatigue, is 0.6% [10].
Currently, there is no cure or approved treatment for CFS. However, patients may find some symptom relief through nutritional supplements, exercise, rehabilitation programs, and cognitive behavioral therapy [11][12][13][14]. Intravenous injection of rituximab has been used to treat CFS in the past decade; however, a recent study showed that rituximab had no effect on CFS [15]. Research on herbal medications in East Asia has been conducted to find a curative treatment for CFS because some medications from the region are thought to be effective for fatigue and weariness. In previous studies, traditional Chinese medicine (TCM) has been proven effective for chronic fatigue [16][17][18][19][20][21][22][23][24]. However, according to a recent systematic review, previous studies evaluating the efficacy of TCM on CFS have not provided enough evidence or lacked methodological rigorousness to draw firm conclusions [25,26]. In traditional Korean medicine (TKM), there have been some randomized controlled trials (RCTs) evaluating the efficacy of some herbal medications on CFS [27][28][29]. However, no study up to now has focused on the efficacy of traditional herbal formulas used clinically for patients with chronic fatigue. erefore, well-designed RCTs evaluating the efficacy of herbal TCM and TKM medications for CFS are needed.
Sipjeondaebo-tang (SDT), also called Shi-Quan-Da-Bu-Tang in China and Juzen-taiho-to in Japan [30], is one of the most popular TKM formulas for the treatment of chronic fatigue. It is approved by the Ministry of Food and Drug Safety to treat weakness after illness, anorexia, abnormal sweating, peripheral coldness, and anemia [31]. Previous clinical trials have shown that it alleviates hematotoxicity, activates an anti-inflammatory effect, and promotes hematopoiesis [32][33][34][35][36]. In TKM, the main contributors to CFS are considered to be qi and blood deficiencies; if the flow of blood or qi is not smooth, fatigue may occur. SDT is used to treat chronic illnesses, including CFS, caused by both qi and blood deficiencies by balancing yin and yang. is is known to restore the deterioration of physiological function and activate immune function [37]. Although SDT is generally used to treat CFS clinically, no RCT has examined the efficacy of SDT for CFS. erefore, in this study, we aim to assess the efficacy and safety of SDTfor the treatment of CFS.

Study Design and Setting.
is clinical trial will be conducted as a randomized, double-blind, placebo-controlled, parallel-group, multicenter study within 12-14 weeks at the Kyung Hee University Korean Medicine Hospital at Gangdong and the Woosuk University Korean Medicine Medical Center, both of which are clinical centers in the Republic of Korea. e study was designed in accordance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. e principal investigator or researcher will obtain written informed consent from all participants after they have received a sufficient explanation of the study and made a thoughtful, voluntary decision. Each subject will be screened up to 7 days prior to randomization to avoid changes in subjects' health conditions. Once participants pass the eligibility assessment and receive a trial subject identifier, they will be randomly assigned to either the treatment group or the control group in a 1 : 1 ratio. e treatment group will be prescribed SDT, and the control group will be prescribed a placebo for 8 weeks after attending an educational session regarding the clinical trial. Participants will visit the study site every 4 weeks during the treatment period to allow researchers to evaluate their compliance and the efficacy and safety of the treatment. A follow-up will be completed by phone 4-6 weeks after the completion of the drug administration to evaluate safety. Any medication not consumed by the participants will be returned at visits 2 and 3 to allow us to calculate drug compliance. e evaluation of participants and analysis of the results will be performed by professionals blinded to the group allocation. Figure 1 shows a schematic flow diagram of the study. e schedule of enrollment, intervention, and assessment is presented in Table 1.

Patient Involvement.
Patients were not involved in the research design process. e study is expected to run from May 2018 to December 2020.

Inclusion Criteria.
A total of 96 patients will be recruited via outdoor advertisements or from the outpatient clinics of the two hospitals. Participants must meet all of the following criteria: (1) Male or female older than 19 years of age (2) ose with 76 points or more on the Korean Checklist Individual Strength questionnaire (CIS) [38,39]. (a) e individual who has severe chronic fatigue for 6 or more consecutive months that is not due to ongoing exertion or other medical conditions associated with fatigue (these other conditions need to be ruled out by a doctor after diagnostic tests have been conducted) (b) e fatigue that significantly interferes with daily activities and work    Evidence-Based Complementary and Alternative Medicine 3 (vii) Tender cervical or axillary lymph nodes (viii) A sore throat that is frequent or recurring

Exclusion Criteria.
Participants who meet any of the following conditions will not be able to participate in this study: (1) ose with a medical history of hypersensitivity to the investigational drugs or any herbal ingredients (2) ose who have or are suspected of having anorexia or bulimia (3) ose with a body mass index greater than 45 kg/m 2 (4) ose who present with at least moderate levels of liver dysfunction (e.g., alanine aminotransferase and aspartate aminotransferase levels > 100 IU/L or serum bilirubin level > 3.0 mg/dL) or who have hepatitis, liver cirrhosis, or fatty liver and need medical attention (5) ose with signs of active hepatitis and whose HBsAg and HCV-Ab rapid tests are positive (6) ose with a positive HIV test (7)

Participant Withdrawal Criteria.
Participants who meet any of the following criteria will be removed from the trial: (1) ose with acute reactions to the investigational drugs (2) ose who have received prohibited medications or therapies (3) ose who need surgery or inpatient treatment due to emergencies such as accidents or unexpected diseases (4) ose who become pregnant during the trial period (5) e subject or his or her representative who withdraws consent (6) Occurrence of a serious adverse reaction (7) Researchers' decision to terminate an individual's participation in the trial due to the judgment that the participant's continuation is inappropriate Reasons for withdrawal will be documented in case report forms (CRFs), and data will be analyzed using the intention-to-treat (ITT) principle.

Randomization.
Study patients who meet the eligibility criteria will be randomly assigned to a treatment group (SDT) or a control group (placebo) in a 1 : 1 ratio through hospital-stratified randomization. Randomization will be conducted by a statistician using a computer-generated random allocation sequence in a SAS system through a predefined block randomization list with random block sizes. Doctors will allocate a number in the order of random assignment to each participant. Allocation concealment will be ensured; the randomization code will be released after the end of the trial.

2.6.
Blinding. Both researchers and participants will be blinded to the allocation. e randomization code number on the investigational drugs will be labeled by a staff member of the pharmaceutical company producing the investigational drugs. e labeled trial products will be administered and provided to each participant by independent research pharmacists in each hospital who are also blinded to the randomization. e researchers may reveal blinded information only in the event of urgent medical conditions such as serious adverse events or voluntary withdrawals, in accordance with the standard operating procedures (SOPs). Any unblinding will be documented.

2.7.
Interventions. Participants will be prescribed SDT or a placebo at a dose of 3 g three times a day for 8 weeks. Each dose will be recommended to be taken before or between meals with warm water. Both SDT and the placebo will be manufactured at a factory belonging to Hanpoong Pharm & Foods Co. in Seoul, Republic of Korea, certified for Good Manufacturing Practice. Granulated SDT extract contains 1.0 g each of Poria sclerotium, Cnidii rhizoma, Cinnamomi ramulus, Rehmanniae radix preparata, Astragali radix, Paeoniae radix, Atractylodis rhizoma alba, Ginseng radix alba, and Angelicae gigantis radix and 0.5 g of Glycyrrhizae radix. e SDT will be extracted from these raw materials and concentrated to 3 g per dose. e granulated placebo extract will contain 1.5 g of corn starch, 1.5 g of lactose, 0.05 g of citric acid, 0.06 g of caramel coloring, and 0.002 g of Ginseng radix alba herbal flavor per dose. Placebo pills will have a similar appearance, shape, weight, taste, and flavor as those of SDT.
During the trial, participants will be prohibited from receiving any other medications or therapies that may influence the study outcomes. ese medications and therapies include antipsychotics, antidepressants, dementia drugs, systemic steroids, immunomodulators, immunosuppressants, transfusions, other herbal medicines, and exercise therapy. Short-term use (i.e., ≤5 days) of nonsteroidal antiinflammatory drugs will be allowed, but such drugs must not be taken within the 3 days preceding the efficacy evaluation for SDT and the placebo treatment. Detailed lists of prohibited and allowed medications will be made available to the participants.

Data Collection and Management.
Outcome measurements will be collected, and data on the identification of participants, allocation of random assignments, and health assessments will be written on the CRF by a certified clinical research coordinator (CRC). Data entry and coding of all identifying participant information will also be performed by the CRC. Research data will be permanently stored on the researcher's computer, and documents will be kept in secured locations for more than three years.

Outcomes
2.9.1. Primary Outcome Measurement. Participants with total CIS scores ≤76 will be rated as "responders," and the percentage of participants assessed as "responders" will be defined as the response rate for fatigue. e change in the response rate for fatigue between visit 1 (i.e., baseline) and visits 2 and 3 (i.e., posttreatment assessments) will be used as the primary outcome measure.

Secondary Outcome Measurements.
Changes in the scores of the CIS; Visual Analogue Scale (VAS) for fatigue, happiness, and CDC criteria; Fatigue Severity Scale; EuroQol 5-dimensions, 5-level questionnaire; Korean version of Pittsburgh Sleep Quality Index; Chalder Fatigue Scale; and qi blood Yin Yang deficiency questionnaire between visit 1 and visits 2 and 3 will be used as the secondary outcome measures. All questionnaires will be used in their Korean-validated form [40][41][42][43][44][45][46][47][48]. e VAS will represent the participant's current status on a scale ranging from 0 cm (no symptoms) to 10 cm (maximum symptoms).

Safety Outcome Measurement.
For the safety assessment, participants' vital signs will be documented, and general examinations will be performed at every visit. e occurrence of any adverse events (AEs) will be checked at visits 2 and 3 and during follow-up.

Compliance Calculation.
To calculate drug compliance, participants will be asked to return any remaining investigational drugs at visits 2 and 3. e rate of compliance will be calculated as follows: compliance (%) � (expected intake -remaining products/expected intake) × 100.

AE Reporting.
e researchers will report any AEs that occur after administration. All AEs will be recorded in the CRF and evaluated for causal relationships. If AEs occur, an independent data monitoring committee will decide whether the study should continue. If serious AEs occur, the researchers must notify the institutional review board within 24 hours.

Sample
Size. Based on a previous study, a sample-size calculation was completed to estimate the minimal number of patients required to detect a clinically significant difference of 17% in the primary outcome measure [49]. It is assumed that the response rates at both week 4 and week 8 will be similar. Seventy-eight patients are required to detect such a difference with 80% certainty using a double-sided significance level of 5%. Anticipating a dropout rate of 20%, 96 participants are needed.

Statistical Analyses
2.12.1. Efficacy Assessment. Efficacy evaluation will be carried out on the basis of the full analysis set, with additional analysis performed on the per-protocol set. Adjustments will be made for missing data using the last-observation-carriedforward imputation method. Continuous variables will be reported as the mean ± standard deviation if normally distributed or the median and interquartile range if not normally distributed, and nominal variables will be reported as absolute numbers and percentages. To assess the primary outcome, a superiority test will be conducted. To assess secondary outcomes, an independent two-sample t-test or Wilcoxon test will be conducted on continuous variables and a chi-square test or Fisher's exact test will be conducted on nominal variables. Statistical analysis will be undertaken using the ITT principle with a 95% confidence interval. All analyses will be performed using SPSS (V.19.0; IBM, Chicago, IL, USA). Significance for all tests will be set at P < 0.05 in a two-tailed test.

Safety Assessment.
A safety assessment will be carried out on the safety set.
e safety data will be stratified according to symptoms, and a chi-square test or Fisher's exact test will be conducted.
Evidence-Based Complementary and Alternative Medicine 2.13. Monitoring. Monitoring will be performed by the contracted research organization. All hospitals conducting trials will be monitored during trials in accordance with the SOPs.

Discussion
To the best of our knowledge, this study is the first that aims to provide accurate information regarding the efficacy of SDT for CFS in adults. ough it has limitations, such as the possibility of measurement bias (participant self-rating scales may exaggerate the severity of CFS) and the limitation of the race (all participants will be Korean), it will demonstrate the effect of traditional herbal medication on CFS.
ere is still a lack of research on the effect of medications treating CFS; this study will help identify and expand our knowledge of potential medications for CFS treatment.

Data Availability
Data and materials are available upon request from the corresponding author.
Ethical Approval e protocol design is based on the Consolidated Standards of Reporting Trials (CONSORT) guidelines and the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 statement [50]. e protocol and informed consent guidelines were reviewed and approved by the institutional review board of Kyung Hee University Korean Medicine Hospital at Gangdong in the Republic of Korea (KHNMCOH 2017-06-004-001).
e protocol was registered on the Clinical Research Information Service, which is a registry in the World Health Organization Registry Network (KCT0002684). Important, unavoidable protocol modifications will be reported directly by the researchers to the institutional review board. Only the researchers and the requested statistician have access to the final dataset.

Consent
Written informed consent was obtained from all study participants prior to enrollment.

Conflicts of Interest
e authors declare that they have no conflicts of interest.

Authors' Contributions
HO drafted this manuscript. HO and MH participated in the conception and design of the trial, developed the criteria, and created the CRF. DHN and MH contributed to quality control. MH registered the study. HO and DHN designed the statistical analysis, sample-size calculation, and randomization. All authors read and approved the final manuscript.