Assessment of Management and Anti-inflammatory Therapy Effectiveness in Colorectal cancer: Randomized Assessment of Supplemental Hochuekkito Therapy: Study protocol for a multicenter randomized controlled trial (AMATERAS study)

Assessment of Management and Anti-inflammatory Therapy Effectiveness in Colorectal cancer: Randomized Assessment of Supplemental Hochuekkito Therapy: Study protocol for a multicenter randomized controlled trial (AMATERAS study) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Assessment of Management and Anti-inflammatory Therapy Effectiveness in Colorectal cancer: Randomized Assessment of Supplemental Hochuekkito Therapy: Study protocol for a multicenter randomized controlled trial (AMATERAS study) Yoshinaga Okugawa, Takahito Kitajima, Tadanobu Shimura, Hiroki Imaoka, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8885578/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background Systemic inflammation, a hallmark of cancer, is recognized as a key mechanism underlying malnutrition, sarcopenia, and cancer cachexia. Hochuekkito (TJ-41) is a traditional Japanese Kampo formula composed of ten medicinal plants, and several studies have suggested its anti-inflammatory effects in various diseases. Our recent retrospective study, supported by in vitro experiments, was the first to demonstrate an anti-inflammatory effect of TJ-41 in patients with unresectable or metastatic gastrointestinal cancer, including colorectal cancer (CRC). However, no prospective randomized multicenter clinical trial has evaluated TJ-41 in the palliative setting of malignancies, including CRC. Methods Patients with unresectable or metastatic CRC who have received at least two prior systemic regimens or are intolerant to standard therapy, and who show an elevated C-reactive protein (CRP) level > 0.5 mg/dL on two consecutive occasions within two months before enrollment, will be eligible. After providing written informed consent, patients will be randomly assigned to Treatment group (standard treatment plus TJ-41) or Control Group (standard treatment alone). Patients in Treatment Group will receive oral TJ-41 (Tsumura & Co., Tokyo, Japan) at 7.5 g/day, divided into three doses (2.5 g per dose), before or between meals for 12 weeks. The primary endpoint is the difference in anti-inflammatory effect between groups, assessed by the change in CRP from baseline to 12 weeks. Secondary endpoints include the effects of TJ-41 on other inflammatory and nutritional parameters; patient-reported symptoms and quality of life (QOL) using QOL-ACD and EORTC QLQ-C30; cytokine-based anti-inflammatory and anti-cachectic effects using serial blood specimens; interactions with other appetite-stimulating agents or nutritional products; and effects on antitumor efficacy and adverse events. Each group will include 44 patients, with recruitment planned from July 1, 2024, to December 31, 2026. Discussion This trial will evaluate whether TJ-41 can attenuate systemic inflammation related to host–tumor interactions in patients with unresectable or metastatic CRC. Trial registration: This study was registered in the Japan Registry of Clinical Trials on June 26, 2024 (jRCTs041240051). Hochuekkito TJ-41 systemic inflammation colorectal cancer Figures Figure 1 Figure 2 BACKGROUND Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide[ 1 ]. Furthermore, more than half of CRC cases are diagnosed at an advanced stage. By this time, tumor cell dissemination has already occurred, despite recent advances in screening protocols[ 2 ]. Although treatment options have improved substantially, including the development of novel chemotherapeutic and molecular agents, as well as technical advances in invasive treatment for metastatic lesions, recurrence and metastasis remain leading causes of death in CRC patients[ 1 ]. In addition, effective delivery of novel anticancer drug therapies for unresectable or metastatic CRC requires supportive care to maintain the patient’s general condition. Malnutrition and cancer cachexia, in particular, are associated with increased treatment-related toxicities and reduced ability to continue such therapies[ 3 ]. Based on these standpoints, there is an urgent need to develop a different treatment approach to improve clinical outcomes in these patients. Systemic inflammation via host-tumor interaction, one of the hallmarks of cancer[ 4 ], has long been recognized as a trigger of cancer cachexia and is also gradually recognized as the cause of impaired body composition, including skeletal muscle loss, and malnutrition[ 5 – 8 ]. Our group has also previously revealed that elevated C-reactive protein (CRP) levels was an independent risk factor for the presence of preoperative myopenia in 308 CRC patients[ 9 ]. In fact, international consensus on the diagnostic criteria for malnutrition, which was established by the Global Leadership Initiative on Malnutrition (GLIM) consortium, explicitly states that a systemic inflammation is one etiological factor in malnutrition diagnosis[ 10 ]. Additionally, the Asian Wasting and Cachexia Diagnosis Criteria (AWGC) list elevated CRP as a diagnostic criterion and specify an optimal cutoff value greater than 0.5[ 11 ]. In light of these backgrounds, it is essential to consider developing supportive therapies that suppress systemic inflammation caused by cancer-host interactions. Such therapies could address malnutrition, sarcopenia, and cachexia, thereby improving continuity of cancer treatment, enhancing quality of life, and improving prognosis. We previously reported that immunonutrition containing fish oil had anti-inflammatory effects in patients with unresectable or metastatic gastrointestinal cancer, including CRC[ 12 , 13 ], who were undergoing systemic chemotherapy. This led to improvements in skeletal muscle mass, treatment continuity, and survival, particularly in patients with elevate CRP levels. However, adherence was poor; 51 out of 88 patients discontinued intake within intervention period during six months[ 13 ]. Thus, we have continued to pursue the development of novel supportive therapies. Hochuekkito (TJ-41) is a traditional Japanese Kampo medicine made from ten medicinal plants. It is commonly prescribed in Japan for anorexia and general fatigue. Clinical trials show that TJ-41 improves quality of life and immunological status in older adults[ 14 – 16 ], and in patients with chronic obstructive pulmonary disease, it mitigates systemic inflammation, prevents weight loss, and enhances nutritional status[ 17 ]. Additionally, several studies have revealed the anti-inflammatory effects of TJ-41 through in vitro and in vivo experiments[ 18 – 21 ]. We also recently assessed clinical data from 99 patients including CRC who received TJ-41 treatment for more than 3 months and in vivo experiments[ 22 ]. This study demonstrated that treatment with TJ-41 induced a significant, time-dependent decline in serum CRP levels, with the effect being particularly evident in patients with metastatic malignancies. During TJ-41 therapy, muscle mass was significantly better preserved in the subgroup with decreased CRP levels than in those with increased levels. Consistent with these clinical observations, in vivo experiments using a Colon-26 syngeneic mouse model showed that plasma levels of CRP, serum amyloid A, and interleukin-6 were significantly reduced in mice receiving TJ-41 compared with levels in controls. However, because this study is retrospective and lacks a control group, prospective interventional studies are needed to clarify the anti-inflammatory effects of TJ-41 and its associated outcomes in relation to malnutrition, sarcopenia, and cachexia. This prospective interventional study aims to investigate whether the administration of TJ-41 contributes to an anti-inflammatory effect and maintenance of nutritional status in a palliative setting for patients with unresectable or metastatic CRC and systemic inflammation. METHODS The authors adhered to the SPIRIT recommendations when drafting this protocol (Fig. 1 )[ 23 ]. The protocol is version 1.2, dated April 30, 2024. The CONSORT flowchart is shown in Fig. 2 . Trial design This open-label, multicenter, randomized trial with a 1:1 allocation ratio is designed to evaluate TJ-41's efficacy and safety for treating the anti-inflammatory effects of unresectable or metastatic CRC cancer (Fig. 2 ). This study is registered with the Japan Registry of Clinical Trials (jRCTs041240051). Ethical approval was obtained from the Mie University Hospital ethics committee and subsequently from the institutional review boards of all participating centers. Patients will be recruited from six hospitals across Japan, as listed in Table 1 . The enrollment period is planned to last 2 years and 6 months, followed by a 3-month follow-up period. The maximum follow-up duration is 2 years and 9 months. This trial will be conducted in accordance with the ordinance of the Ministry of Health, Labour and Welfare in Japan, Declaration of Helsinki, Ethical Guidelines for Medical and Biological Research Involving Human Subjects, Clinical Trials Act, and the guideline “Statistical Principles for Clinical Trials”[ 24 ]. The trial was also designed based on the guideline “Structure and Content of Clinical Study Reports”[25]. Table 1 The six participating institutes for AMATERAS study Number Center Department Investigator 1* Mie University Hospital Department of Gastrointestinal and Pediatric Surgery Yuji Toiyama 2 Mie Prefectural General Medical Center Department of Gastrointestinal and General Surgery Yasuhiko Mohri 3 Kuwana City Medical Center Department of Surgery Kosuke Mizukoshi 4 Iga Municipal Ueno General Citizen's Hospital Department of Surgery Susumu Saigusa 5 Aichi Medical University School of Medicine and Hospital Oncology Center Takashi Iwata 6 Doshinkai Tohyama Hospital Department of Surgery Yasuhiro Inoue * Sponsor Investigator Trial eligibility Patients with unresectable or metastatic CRC will be screened for eligibility. The inclusion criteria are as follows: Patients must be at least 20 years old at the time of consent. Patients who provided written consent to participate in this study. Patients must have received at least two prior systemic treatment regimens as adjuvant therapy and/or for metastatic disease (including at least one regimen for which disease progression was documented in the metastatic setting) or be intolerant to standard therapy. Patients with a confirmed CRP level greater than 0.5 mg/dL on two consecutive occasions within two months prior to enrollment based on routine clinical laboratory testing. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and be expected to be followed for at least 12 weeks after study enrollment (Fig. 2 ). The exclusion criteria are as follows: Patients with MSI-high or TMB-high colorectal cancer for whom immune checkpoint inhibitors are or have been used as standard therapy. Patients with comorbidities that may affect nutritional or inflammatory status, such as chronic kidney disease or an autoimmune disease, are also excluded. Patients with infectious diseases requiring antibiotic therapy. Patients with a stoma who have diarrhea interfering with activities of daily living. Patients who have undergone surgical procedures within the past four weeks, or who are scheduled to undergo surgery during the study period. Patients with a history of gastrectomy. Patients who have taken Kampo medicines within two weeks prior to the scheduled date of Visit 1. Patients for whom oral food intake is difficult owing to gastrointestinal disorders, such as intestinal obstruction, or dysphagia. Patients who have difficulty taking Kampo medicine. Patients with moderate or severe hepatic impairment (Child–Pugh class B or C) are also excluded. Patients whose routine clinical laboratory test results from the two months prior to enrollment meet any of the following criteria: AST, ALT, or γ-GTP greater than five times the institutional upper limit of normal (ULN), Total bilirubin or creatinine greater than three times the institutional ULN, Potassium 5.5 mmol/L, Patients with pleural effusion or ascites, Patients with synchronous or metachronous double (multiple) cancers, Patients with serious comorbid conditions (e.g., cardiac, hematologic, or metabolic diseases), Patients with a history of severe drug hypersensitivity or allergy, particularly to TJ-41, Pregnant or breastfeeding women; women who may be pregnant; and patients who wish to become pregnant during the study period, and Patients who, at the discretion of the principal investigator or co-investigator, are deemed otherwise ineligible to participate in this study. Patients at the 6 participating hospitals will be screened. Those who meet all the eligibility criteria will be asked to participate in the study. After receiving sufficient information about the study, patients will decide whether to participate. Written informed consent will then be obtained from all those who agree to enroll. Registration The central registration office at WDB COCO Co., Ltd. will receive an eligibility report form. (Tokyo, Japan). Patients who meet all the inclusion criteria and none of the exclusion criteria will be randomized in a 1:1 ratio to either Treatment Group (standard therapy plus TJ-41) or Control Group (standard therapy alone). Randomization will be performed using a minimization method with stratification by treatment course at the time of enrollment (receiving at least two prior systemic treatment regimens as adjuvant therapy and/or for metastatic disease or be intolerant to standard therapy), and the institution (Mie university hospital or other hospitals) as variables before intervention. Investigators will not be informed of the details of the randomization program. After randomization, the registration center at WDB COCO will provide each investigator with information on the required follow-up assessments. This trial will be conducted at academic or general hospitals in Japan, and the list of participating sites will be available from the AMATERAS study office at Mie University Hospital. Interventions Protocol treatment must be initiated within 21 days of case registration. If initiation cannot occur within 21 days, informed consent must be re-obtained, eligibility must be reconfirmed, and specified tests must be performed. Patients in the Treatment Group will receive TJ-41 (Tsumura & Co., Tokyo, Japan) orally at 7.5g per day, divided into 3 doses (2.5g/dose per packet), before or between meals for 12 weeks of standard treatment. TJ-41 is a powdered hot water-extract consisting of the following 10 components: Astragalus root (Astragali radix), 4.0 g; Atractylodes lancea rhizome (Atractylodis lanceae rhizoma), 4.0 g; Ginseng (Ginseng radix), 4.0 g; Japanese Angelica root (Angelicae radix), 3.0 g; Bupleurum root (Bupleuri radix), 2.0 g; Jujube (Zizyphi fructus), 2.0 g; Citrus unshiu peel (Aurantii nobilis pericarpium), 2.0 g; Glycyrrhiza (Glycyrrhizae radix), 1.5 g; Cimicifuga rhizome (Cimicifugae rhizoma), 1.0 g; and Ginger (Zingiberis rhizoma), 0.5 g, as previously described[ 22 ]. TJ-41 is manufactured by Tsumura & Co. If a dose is missed, the patient may take it as soon as they remember. However, if the next scheduled dose is imminent, skip the missed dose and take the next dose at the regular time. Participant adherence will be monitored by having participants return unused medication and through questionnaires based on their self-reported medication status at each visit. Patients in Control Group will receive standard cancer treatment only, without TJ-41, for 12 weeks. Regarding concomitant therapy and supportive care, prohibited concomitant medications include Kampo preparations other than the investigational product, immune checkpoint inhibitors, and antibacterial agents. There are no restricted concomitant medications, and no concomitant therapies are either prohibited or restricted beyond those specified above. There are no specific provisions defined regarding follow-up treatment after this study is completed. The principal investigator or co-investigator will discuss subsequent treatment options with each study participant and determine the appropriate course of care. Primary and secondary endpoints The primary endpoint is the comparison of the anti-inflammatory effect between the TJ-41 administration group (Treatment Group) and the non-administration, as assessed by the change in CRP levels from baseline to 12 weeks after initiation of treatment. The CRP change rate at 12 weeks is defined as the CRP value at 12 weeks divided by the CRP value at treatment initiation. The date of treatment initiation is used as the baseline for this calculation (change rate = CRP at 12 weeks after treatment initiation / CRP at treatment initiation). The secondary outcome measures the following: the effects of TJ-41 on other inflammatory and nutritional parameters; the effects of TJ-41 on patient-reported symptoms and QOL; the anti-inflammatory and anti-cachectic effects of TJ-41 at the cytokine level; the combined effects of TJ-41 and other appetite-stimulating agents or nutritional products; and the effects of TJ-41 on antitumor efficacy and the occurrence of adverse events. Changes in inflammatory and nutritional parameters before and after TJ-41 administration were assessed using results from routine clinical examinations. Blood tests (RBC, WBC, Hb, Ht, PLT, TP, Alb, TLC, T-bil, AST, ALT, ALP, γ-GTP, K, Cr, and CRP); physical findings (body weight and BMI); nutritional and inflammatory indices (prognostic nutrition index and lymphocyte-CRP ratio); CT-based assessments (myopenia [psoas mass index] and myosteatosis [intramuscular adipose tissue content and modified intramuscular adipose tissue content]); and handgrip strength. Changes in symptoms and QOL were assessed using QOL questionnaires such as QOL-ACD and EORTC QLQ-C30 before and after treatment in the TJ-41 administration group versus the non-administration group. Changes in blood cytokine levels related to anti-inflammatory and anti-cachectic effects were assessed using research blood tests for serum amyloid A, interleukin-6, transthyretin, transferrin, retinol-binding protein, lactate, pyruvate, and growth differentiation factor-15 before and after treatment in the TJ-41 administration versus non-administration groups. The impact of anamorelin and nutritional products on anti-inflammatory and nutritional improvement in the TJ-41 administration versus non-administration groups will be assessed using agents with nutritional or anti-inflammatory effects, such as steroids, non-steroidal anti-inflammatory drugs, anamorelin, and nutritional products covered by the Japanese government's insurance program. We will evaluate tumor status and adverse events before and after treatment in the TJ-41 administration group versus the non-administration group by assessing parameters including tumor markers (CEA, CA19-9), use of anticancer agents, relative dose intensity, cancer/chemotherapy-related adverse events, and tumor response by using image analysis. Adverse events related to cancer or chemotherapy will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0[26]. Tumor response to standard concomitant treatment will be evaluated using RECIST guidelines (v1.1)[27]. Criteria for Discontinuation of Study Drug and Observation Termination The principal investigator or co-investigator shall discontinue administration of the study drug if they determine that continued administration is impossible for any of the following reasons: 1) When the research subject requests discontinuation of the study drug administration, 2) When continuation of the study drug administration is deemed undesirable owing to worsening of the underlying disease, 3) When continuation of the study drug administration is difficult owing to worsening of a complication, 4) When continuation of study drug administration is difficult owing to disease or other reasons, 5) When the principal investigator or sub-investigator deems it appropriate to discontinue study drug administration for other reasons. If discontinuation occurs owing to the onset of a disease or other condition, follow-up shall be conducted until the subject recovers to their original condition as much as possible. In contrast, observation will be terminated in the following cases: (1) If the research subject requests to withdraw from the study or withdraws consent, (2) If, after enrollment, it is found that the subject does not meet the eligibility criteria, (3) If pregnancy is confirmed, (4) If the subject ceases to visit the study site because of relocation or other reasons, (5) If the entire study is discontinued, and (6) If the principal investigator or co-investigator considers it appropriate to discontinue the study for any other reason. The date, reason, and course of discontinuation shall be recorded in the medical record and the electronic data capture (EDC) system. Necessary tests shall be performed at the time of discontinuation or withdrawal to evaluate efficacy and safety. Sample size A prior study[ 22 ] reported that the standard deviation of the log-transformed CRP change rate was 1.5 three months after TJ-41 administration in patients with unresectable CRC receiving cancer drug therapy. Based on this result, the present study used the log-transformed CRP change rate at three months as the primary endpoint to determine the sample size. The CRP change rate is defined as follows: CRP change rate = CRP (3 months)/CRP (0 months). For the TJ-41 combination group (Treatment Group), the outcome measure is defined as log (CRP change rate) = log (CRP (3 months)/CRP (0 months)). In the standard treatment-only group (Control Group), the outcome measure is defined as follows, assuming an additional effect on the actual CRP value at three months: log ([CRP (3 months) + effect size]/CRP (0 months)). Based on the prior study's results and clinical considerations, the effect size for the difference in actual CRP values between the two groups at 3 months was assumed to be 0.3. Under this assumption, the corresponding difference in the mean log-transformed CRP change rate between the two groups was estimated to be approximately 1. Assuming equal variances between the two groups and a common standard deviation of 1.5, as well as a 1:1 allocation ratio, the required sample size to detect a mean difference of 1 between groups was calculated using an unpaired two-sample t-test with a two-sided significance level of 5% and 80% power. Under these assumptions, the required sample size was estimated to be 35 patients per group. Furthermore, accounting for a potential dropout rate of approximately 20% during the observation period, the total target sample size was increased accordingly. The final planned sample size was set at 88 patients, with 44 in the TJ-41 combination group (Treatment Group) and 44 in the standard treatment-only group (Control Group). Safety Adverse events (AEs) are defined as any undesirable event occurring to a subject during the study, regardless of whether they are related to the investigational intervention. AEs of all grades to CTCAE v5.0[26], reported either spontaneously by the subject or observed by the investigator or study staff, will be systematically recorded. Serious adverse events (SAEs) are defined as any of the following: death; a life-threatening event (at the time of occurrence); an event requiring hospitalization or prolongation of existing hospitalization; an event resulting in permanent or significant disability or incapacity; an event causing a congenital anomaly or birth defect in offspring; or any other medically important event or effect judged to be serious by the principal investigator or a sub-investigator. However, this definition excludes adverse events that are known symptoms, signs, or diseases attributable to the underlying cancer; known adverse drug reactions to the anticancer agents currently being administered and listed as expected adverse events in the latest package insert or Drug Information Form for the relevant anticancer drug; and abnormal laboratory values that fall within the expected range of side effects of the anticancer agents currently being administered and are listed in the latest package insert or Drug Information Form for the relevant anticancer drug. Such events shall be classified as non-serious adverse events. SAEs will be reported to the accredited Medical Ethics Review Committee via a website within 15 days. This includes SAEs resulting in death or life-threatening events, as well as all other SAEs suspected to be related to the conduct of clinical research. Reporting will continue for the duration of the study. All AEs will be monitored until they are resolved or stabilized. An independent Data Safety Monitoring Board will oversee safety data throughout the study. Data management, monitoring and auditing In accordance with Good Clinical Practice, the investigators and clinical research coordinators will maintain individual source documents for each participant. These documents will include informed consent forms, medical records, laboratory reports, and case report forms (CRFs). All adverse events will be documented in the CRFs and followed up on prospectively until they are resolved or stabilized. The investigators will oversee all aspects of trial data management. Instead of convening a formal independent data monitoring committee, an independent medical advisor has been appointed to periodically review safety, feasibility, and any emerging issues. All trial data and relevant source documents will be archived for at least five years after the study's completion. A Efficacy and Safety Evaluation Committee (ESEC), composed of clinicians, statisticians and ethics experts, has been established to enhance the quality of this trial. The ESEC maintains independence from the research team and objectively evaluates efficacy and safety. Conducted annually, it leads to critical decisions: “Continue the trial,” “Continue the trial with protocol modifications,” or “Discontinue the trial.” Monitoring is performed by the WDB COCO based on the CRF and EDC system. Statistical analysis. Statistical analyses, including the creation of tables and figures for the study report, will be conducted by the study statistician under blinded conditions, when feasible. The primary and secondary endpoint analyses will primarily be based on the full analysis set (FAS). To confirm the robustness of the results, additional analyses will be performed using the per-protocol set (PPS). Safety endpoint analyses will be conducted using the safety analysis set (SAS). The FAS includes all enrolled participants except those for whom the primary endpoint was not evaluated and those who did not attend any post-baseline visits after the start of treatment. The PPS is defined as the subset of participants who meet all of the following criteria: (1) no major protocol deviations, (2) receipt of at least two-thirds of the prescribed total dose of TJ-41 in the Treatment Group, and (3) no use of prohibited concomitant medications. The SAS for adverse events excludes participants who did not visit the clinic after registration and for whom no analyzable safety data are available. For the analysis of TJ-41–related adverse reactions, the analysis population excludes the following: (1) participants assigned to the TJ-41 group who did not attend any visits after the start of treatment and for whom no analyzable data are available, and (2) participants assigned to the TJ-41 group for whom it was subsequently confirmed that TJ-41 was never administered. For the primary endpoint, the CRP change rate will be log-transformed. The mean and standard deviation will be calculated for each group, and a Student's t-test will be applied. Categorical variables will be analyzed using cross-tabulation and Fisher's exact test. For safety evaluation items (e.g., incidence of diseases or adverse events), cross-tabulations by group will be prepared, and Fisher's exact test will be performed. The significance level for all statistical tests will be set at 5% (two-sided). All statistical analyses will be performed using validated statistical software. Protocol amendments Any modifications to the study protocol made during the trial must be submitted to the Certified Review Board of Mie University Hospital for approval by the principal investigator. After approval is granted, the principal investigator will promptly notify the lead investigators at each participating site of the changes and their rationale. The lead investigators will then submit the approved amendments to their respective institutional authorities for final approval. Dissemination The findings of this study will be disseminated through publication in peer-reviewed journals and presentation at scientific conferences. This ensures that no information identifying individual participants is disclosed. Authorship will be determined according to the criteria established by the International Committee of Medical Journal Editors (ICMJE). Trial status This study was approved by the Mie University Hospital Clinical Research Review Board based on Clinical Trials Act on January 22, 2024 (S2023-004) and was registered with the Japan Registry of Clinical Trials on June 26, 2024 (jRCTs041240051). Participant recruitment began on July 1, 2024, and is ongoing as of January 1, 2026. Role of the funding source The funding agency was provided with the protocol and manuscript prior to submission for review of factual accuracy and funding-related information only and had no authority over study design, data analysis, manuscript content, or the decision to submit for publication. DISCUSSION This AMATERAS study is a multicenter, randomized controlled clinical trial to clarify anti-inflammatory effect of cancer-harboring patients with unresectable or metastatic CRC. To date, no clinical trials have investigated orally administered agents, including Kampo medicines, that may alleviate systemic inflammation by modulating host–tumor interactions at the palliative setting of malignancies, including CRC. Furthermore, this study included several secondary endpoints based on additional clinical data, handgrip strength, quality-of-life questionnaires, and translational research using serial blood samples to elucidate the clinical and biological impact of TJ-41 administration in these patients. This study's results will be published as a research article and will provide novel evidence of the beneficial effects of TJ-41 in patients with unresectable or metastatic CRC. Systemic inflammation resulting from host–tumor interactions has been recognized as one of the hallmarks of cancer[ 4 ], and accumulating evidence indicates that systemic inflammation plays a critical role in tumor initiation, proliferation, progression, and metastasis in malignant diseases[28–30]. In addition, systemic inflammation is closely associated with clinical outcomes in various malignancies including CRC[31–33]. Our previous work also demonstrated that multiple cytokines and serum biomarkers of systemic inflammation—including IL-1β, IL-1ra, IL-6, IL-10 are differentially expressed in the sera of patients with advanced or metastatic CRC[34–38]. In clinical practice, serum CRP is one of the most widely used indicators of systemic inflammation. Multiple retrospective studies have reported that elevated CRP levels are associated with an unfavorable prognosis in patients with CRC[36, 37, 39–41]. Systemic inflammation have been shown to lead to a reduction in muscle mass through the suppression of appetite and an increase in resting energy expenditure, which is mediated by IL-6, TNF-α, IL-1β, and other factors. Emerging evidence revealed that growth differentiation factor 15 (GDF-15) can cause sarcopenia and cachexia by suppressing appetite and altering metabolism[42, 43]. A recent clinical trial showed that ponsegromab, a humanized monoclonal antibody that inhibits GDF-15, increased weight gain and overall activity levels while reducing cachexia symptoms in patients with cancer cachexia and elevated GDF-15 levels, including those with CRC[44]. Our recent study further revealed the significant positive correlation between preoperative serum GDF-15 level and CRP levels, and suggested the additional pathogenesis of systemic inflammation for appetite loss, malnutrition, and sarcopenia/cachexia via circulating GDF-15[45]. In line with these evidences, this prospective intervention study will collect serial blood samples during the observation period to evaluate the effects of TJ-41 administration on CRP and GDF-15 levels in these patients. Hochuekkito (TJ-41), traditional Japanese Kampo medicine made from ten medicinal plants, have several evidence for anti-inflammatory biological effect from several studies. Sekiya and colleagues reported that TJ-41 administration enhances the production of chemokines such as CCL20 in the Peyer's patches of the intestinal mucosa, suppresses TNF-α production, and inhibits intestinal mucosal inflammatory responses[ 18 ]. Other study showed that TJ-41 could inhibit the secretion of inflammatory cytokines (IL-6, TNF-α, IL-1, and IL-8) induced by rhinovirus in human tracheal epithelial cells[ 19 ], Isago and colleagues conducted a series of in vivo studies using a lung emphysema model that mimics the chronic pulmonary inflammation seen in COPD[ 20 ]. They demonstrated that administration of TJ-41 reduced the number of inflammatory cells in bronchoalveolar lavage fluid and attenuated lung inflammation in histopathological analyses. In malignancies, Yae and his colleagues investigated the potential anti-tumor effects of TJ-41 using a mouse cancer model[ 21 ]. Their study showed that TJ-41 treatment led to a significant decrease in circulating IL-6 levels and reduced IL-6 expression by macrophages in the peritumoral tissues. In line with this evidence, our study also demonstrated the anti-inflammatory effects of TJ-41 in patients with cancer using clinical data and a series of in vivo experiments[ 22 ]. Considering these standpoints, the anti-inflammatory effects of TJ-41 in cancer hosts are highly promising. Furthermore, given its potential as a novel supportive therapy for malnutrition, sarcopenia, and cachexia, we are planning this prospective randomized controlled intervention trial. Furthermore, another recent study also clearly revealed that TJ-41 administration could Improve in liver autophagy and maintain energy homeostasis in the elderly mice model[46]. In this prospective study, circulating factors related to mitochondrial function will also be evaluated by collecting serial blood samples during the observation period. In conclusion, this study provides an integrated approach using Kampo medicine, enabling the simultaneous clarification of its clinical significance and biological significance. Abbreviations TJ-41 Hochuekkito CRC Colorectal cancer CRP C-reactive protein QOL quality of life GLIM Global Leadership Initiative on Malnutrition AWGC Asian Wasting and Cachexia Diagnosis Criteria ECOG Eastern Cooperative Oncology Group ULN Upper limit of normal CTCAE Common Terminology Criteria for Adverse Events EDC Electronic data capture AEs Adverse events SAEs Serious adverse events CRFs Case report forms ESEC Efficacy and Safety Evaluation Committee FAS Full analysis set PPS Per-protocol set SAS Safety analysis set ICMJE International Committee of Medical Journal Editors GDF-15 Growth differentiation factor 15 jRCT Japan Registry of Clinical Trials Declarations ACKNOWLEDGEMENTS The authors express their gratitude to all medical and co-medical staff at the participating institutions in the AMATERAS study for their dedicated cooperation. We thank J. Ludovic Croxford, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. FUNDING This study is supported by a research grant from Tsumura & Co., Tokyo, Japan. AUTHOR CONTRIBUTIONS All authors participated in the conceptualization of the study and prepared the study protocol. YO, KJ, and YT coordinated the study process. KJ, ST, HI, MK, AY, AK, KM, HF, TI, SS, EO, YI, and YM supported the development of this protocol. YO, and YT devised the statistical analysis. YO and YT drafted the study protocol. ST, HI, MK, AY, AK, KM, HF, TI, SS, EO, YI, and YM revised the study protocol. ST, HI, MK, AY, AK, KM, HF, TI, SS, EO, YI, and YM read and approved the final version. DATA AVAILABILITY The datasets generated and analyzed during the AMATERAS study are not publicly accessible, but they are available upon reasonable request to the corresponding author. ETHICS APPROVAL AND CONSENT TO PARTICIPATE Ethical approval was granted by the review committee at the Mie University Hospital and was approved and overseen by the institutional review boards of each participating hospital. If deemed eligible, informed consent will be obtained from the patients by the attending physicians at the participating institutes. The study will be conducted in accordance with the World Medical Association Declaration of Helsinki of 1996. The study results will be published in a peer reviewed journal and be presented at national and international conferences. COMPETEING INTERESTS The authors declare that this work was supported by research funding from Tsumura & Co. Tsumura & Co. had no role in the study design or data collection and analysis of the clinical research. YO and YT received a consulting fee from Tsumura& Co for conference attendance as ad hoc advisor regarding the basic research. YO received a speaking honoraria from Tsumura & Co. The other authors have no conflicts of interest to declare. PARTICIPATING INSTITUTIONS Department of Gastrointestinal and Pediatric Surgery, Mie University Hospital; Department of Gastrointestinal and General Surgery, Mie Prefectural General Medical Center; Department of Surgery, Kuwana City Medical Center; Department of Surgery, Iga Municipal Ueno General Citizen's Hospital; Oncology Center, Aichi Medical University School of Medicine and Hospital; Department of Surgery, Doshinkai Tohyama Hospital CONSENT FOR PUBLICATION Not applicable References Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries . CA Cancer J Clin 2024, 74 (3):229-263. Andre N, Schmiegel W: Chemoradiotherapy for colorectal cancer . Gut 2005, 54 (8):1194-1202. 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Arai H, Maeda K, Wakabayashi H, Naito T, Konishi M, Assantachai P, Auyeung WT, Chalermsri C, Chen W, Chew J et al : Diagnosis and outcomes of cachexia in Asia: Working Consensus Report from the Asian Working Group for Cachexia . J Cachexia Sarcopenia Muscle 2023, 14 (5):1949-1958. Okugawa Y, Shirai Y, Toiyama Y, Saigusa S, Hishida A, Yokoe T, Tanaka K, Tanaka M, Yasuda H, Fujikawa H et al : Clinical Burden of Modified Glasgow Prognostic Scale in Colorectal Cancer . Anticancer Res 2018, 38 (3):1599-1610. Shirai Y, Okugawa Y, Hishida A, Ogawa A, Okamoto K, Shintani M, Morimoto Y, Nishikawa R, Yokoe T, Tanaka K et al : Fish oil-enriched nutrition combined with systemic chemotherapy for gastrointestinal cancer patients with cancer cachexia . Sci Rep 2017, 7 (1):4826. Kuroiwa A, Liou S, Yan H, Eshita A, Naitoh S, Nagayama A: Effect of a traditional Japanese herbal medicine, hochu-ekki-to (Bu-Zhong-Yi-Qi Tang), on immunity in elderly persons . Int Immunopharmacol 2004, 4 (2):317-324. 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Okugawa Y, Shirai Y, Fukumori K, Kitajima T, Shimura T, Imaoka H, Kawamura M, Yasuda H, Morimoto Y, Fujiwara T et al : Effect of the Japanese herbal medicine Hochuekkito for systemic inflammation, prognostic nutrition index, and body composition status in patients with gastrointestinal cancer . Clin Nutr ESPEN 2024, 63 :757-767. Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, Hróbjartsson A, Mann H, Dickersin K, Berlin JA et al : SPIRIT 2013 statement: defining standard protocol items for clinical trials . Ann Intern Med 2013, 158 (3):200-207. Statistical principles for clinical trials. https://www.pmda.go.jp/int-activities/int-harmony/ich/0031.html. Accessed 15 Dec 2014 . Structure and content of clinical study reports. https://www.pmda.go.jp/intactivities/int-harmony/ich/0025.html. Accessed 15 Dec 2014 . CTCAE v5.0 URL ： https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50） . Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M et al : New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) . Eur J Cancer 2009, 45 (2):228-247. Grivennikov SI, Greten FR, Karin M: Immunity, inflammation, and cancer . Cell 2010, 140 (6):883-899. Diakos CI, Charles KA, McMillan DC, Clarke SJ: Cancer-related inflammation and treatment effectiveness . Lancet Oncol 2014, 15 (11):e493-503. Toiyama Y, Okugawa Y, Tanaka K, Araki T, Uchida K, Hishida A, Uchino M, Ikeuchi H, Hirota S, Kusunoki M et al : A Panel of Methylated MicroRNA Biomarkers for Identifying High-Risk Patients With Ulcerative Colitis-Associated Colorectal Cancer . Gastroenterology 2017, 153 (6):1634-1646 e1638. Okugawa Y, Toiyama Y, Yamamoto A, Shigemori T, Ide S, Kitajima T, Fujikawa H, Yasuda H, Hiro J, Yoshiyama S et al : Lymphocyte-C-reactive Protein Ratio as Promising New Marker for Predicting Surgical and Oncological Outcomes in Colorectal Cancer . Ann Surg 2020, 272 (2):342-351. Okugawa Y, Toiyama Y, Yamamoto A, Shigemori T, Ichikawa T, Yin C, Suzuki A, Fujikawa H, Yasuda H, Hiro J et al : Lymphocyte-to-C-reactive protein ratio and score are clinically feasible nutrition-inflammation markers of outcome in patients with gastric cancer . Clin Nutr 2020, 39 (4):1209-1217. Yin C, Toiyama Y, Okugawa Y, Omura Y, Kusunoki Y, Kusunoki K, Imaoka Y, Yasuda H, Ohi M, Kusunoki M: Clinical significance of advanced lung cancer inflammation index, a nutritional and inflammation index, in gastric cancer patients after surgical resection: A propensity score matching analysis . Clin Nutr 2021, 40 (3):1130-1136. Miki C, Tonouchi H, Wakuda R, Hatada T, Inoue Y, Minato E, Kobayashi M, Kusunoki M: Intra-tumoral interleukin-6 down-regulation system and genetic mutations of tumor suppressor genes in colorectal carcinoma . Cancer 2002, 94 (5):1584-1592. Okugawa Y, Miki C, Toiyama Y, Yasuda H, Yokoe T, Saigusa S, Hiro J, Tanaka K, Inoue Y, Kusunoki M: Loss of tumoral expression of soluble IL-6 receptor is associated with disease progression in colorectal cancer . British journal of cancer 2010, 103 (6):787-795. Koike Y, Miki C, Okugawa Y, Yokoe T, Toiyama Y, Tanaka K, Inoue Y, Kusunoki M: Preoperative C-reactive protein as a prognostic and therapeutic marker for colorectal cancer . Journal of surgical oncology 2008, 98 (7):540-544. Toiyama Y, Fujikawa H, Koike Y, Saigusa S, Inoue Y, Tanaka K, Mohri Y, Miki C, Kusunoki M: Evaluation of preoperative C-reactive protein aids in predicting poor survival in patients with curative colorectal cancer with poor lymph node assessment . Oncology letters 2013, 5 (6):1881-1888. Toiyama Y, Miki C, Inoue Y, Minobe S, Urano H, Kusunoki M: Loss of tissue expression of interleukin-10 promotes the disease progression of colorectal carcinoma . Surgery today 2010, 40 (1):46-53. Nozoe T, Matsumata T, Kitamura M, Sugimachi K: Significance of preoperative elevation of serum C-reactive protein as an indicator for prognosis in colorectal cancer . American journal of surgery 1998, 176 (4):335-338. Nozoe T, Matsumata T, Sugimachi K: Preoperative elevation of serum C-reactive protein is related to impaired immunity in patients with colorectal cancer . American journal of clinical oncology 2000, 23 (3):263-266. Gunter MJ, Stolzenberg-Solomon R, Cross AJ, Leitzmann MF, Weinstein S, Wood RJ, Virtamo J, Taylor PR, Albanes D, Sinha R: A prospective study of serum C-reactive protein and colorectal cancer risk in men . Cancer research 2006, 66 (4):2483-2487. Mullican SE, Lin-Schmidt X, Chin CN, Chavez JA, Furman JL, Armstrong AA, Beck SC, South VJ, Dinh TQ, Cash-Mason TD et al : GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates . Nat Med 2017, 23 (10):1150-1157. Ling T, Zhang J, Ding F, Ma L: Role of growth differentiation factor 15 in cancer cachexia (Review) . Oncol Lett 2023, 26 (5):462. Groarke JD, Crawford J, Collins SM, Lubaczewski S, Roeland EJ, Naito T, Hendifar AE, Fallon M, Takayama K, Asmis T et al : Ponsegromab for the Treatment of Cancer Cachexia . N Engl J Med 2024, 391 (24):2291-2303. Yamashita S, Okugawa Y, Higashi K, Sato Y, Ichikawa T, Uratani R, Kitajima T, Shimura T, Imaoka H, Kawamura M et al : Direct triangular comparison of tissue and serum growth differentiation factor 15 with host factors in colorectal cancer . Am J Cancer Res 2025, 15 (3):1174-1188. Nahata M, Mogami S, Sekine H, Iizuka S, Okubo N, Fujitsuka N, Takeda H: Bcl-2-dependent autophagy disruption during aging impairs amino acid utilization that is restored by hochuekkito . NPJ Aging Mech Dis 2021, 7 (1):13. Additional Declarations Competing interest reported. The authors declare that this work was supported by research funding from Tsumura & Co. Tsumura & Co. had no role in the study design or data collection and analysis of the clinical research. YO and YT received a consulting fee from Tsumura& Co for conference attendance as ad hoc advisor regarding the basic research. YO received a speaking honoraria from Tsumura & Co. The other authors have no conflicts of interest to declare. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 13 Apr, 2026 Reviews received at journal 08 Apr, 2026 Reviewers agreed at journal 08 Apr, 2026 Reviews received at journal 08 Apr, 2026 Reviews received at journal 23 Mar, 2026 Reviewers agreed at journal 16 Mar, 2026 Reviewers agreed at journal 13 Mar, 2026 Reviewers invited by journal 11 Mar, 2026 Editor assigned by journal 22 Feb, 2026 Submission checks completed at journal 22 Feb, 2026 First submitted to journal 15 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8885578","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":604754453,"identity":"72d3ab5e-9408-4aad-b491-108f19f26c78","order_by":0,"name":"Yoshinaga Okugawa","email":"","orcid":"","institution":"Mie University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yoshinaga","middleName":"","lastName":"Okugawa","suffix":""},{"id":604754454,"identity":"2c7c325d-00c5-4f21-8014-35c36258798f","order_by":1,"name":"Takahito Kitajima","email":"","orcid":"","institution":"Mie University 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11:23:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8885578/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8885578/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104690345,"identity":"2c802119-75e4-4438-91b0-2b59708a12f7","added_by":"auto","created_at":"2026-03-16 06:06:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1989465,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe schedule of enrolment, interventions, and assessments in the AMATERAS study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e#1 RBC, WBC, Hb, Ht, PLT, TP, Alb, TLC, T-bil, AST, ALT, ALP, γ-GTP, K, Cr, and CRP; #2 SAA, IL-6, transthyretin, transferrin, RBP, lactate, pyruvate, and GDF-15; #3:CT-based assessments for myopenia (psoas mass index) and myosteatosis (intramuscular adipose tissue content and modified intramuscular adipose tissue content); ##1 Do not take the medication of the treatment start date; begin taking the medication the following morning; ##2 Only the Hochuekkito administration group will be investigated.;##3 At the start of treatment and 12 weeks after treatment initiation (or at discontinuation), confirm changes in body weight.; ##4 CRP must be confirmed to be greater than 0.5 mg/dL on two consecutive occasions during routine clinical examinations within the past two months prior to registration.; ##5: Imaging test results obtained within two weeks before or after the baseline date (the start of treatment, 12 weeks after the start of treatment, or discontinuation) are acceptable as substitutes. However, imaging tests should be performed on the day of the relevant visit whenever possible.;△: Disease assessment may be added as part of routine care during cancer treatment if deemed necessary by the attending physician.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8885578/v1/5dc06e2dd762d28516acdb76.png"},{"id":104690344,"identity":"57027a51-829f-40c2-8e13-98e8c0574a73","added_by":"auto","created_at":"2026-03-16 06:06:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1466399,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow diagram of the AMATERAS study.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eECOG: Eastern Cooperative Oncology Group\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8885578/v1/7ee57e7a7934b20dee7243b4.png"},{"id":104782117,"identity":"3f66497e-7008-4760-ae2c-3784dad33f06","added_by":"auto","created_at":"2026-03-17 07:56:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6568159,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8885578/v1/3162dd45-12cf-449a-8fb3-e4e0122a216f.pdf"}],"financialInterests":"Competing interest reported. The authors declare that this work was supported by research funding from Tsumura \u0026 Co. Tsumura \u0026 Co. had no role in the study design or data collection and analysis of the clinical research. YO and YT received a consulting fee from Tsumura\u0026 Co for conference attendance as ad hoc advisor regarding the basic research. YO received a speaking honoraria from Tsumura \u0026 Co. The other authors have no conflicts of interest to declare.","formattedTitle":"Assessment of Management and Anti-inflammatory Therapy Effectiveness in Colorectal cancer: Randomized Assessment of Supplemental Hochuekkito Therapy: Study protocol for a multicenter randomized controlled trial (AMATERAS study)","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eColorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Furthermore, more than half of CRC cases are diagnosed at an advanced stage. By this time, tumor cell dissemination has already occurred, despite recent advances in screening protocols[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although treatment options have improved substantially, including the development of novel chemotherapeutic and molecular agents, as well as technical advances in invasive treatment for metastatic lesions, recurrence and metastasis remain leading causes of death in CRC patients[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In addition, effective delivery of novel anticancer drug therapies for unresectable or metastatic CRC requires supportive care to maintain the patient\u0026rsquo;s general condition. Malnutrition and cancer cachexia, in particular, are associated with increased treatment-related toxicities and reduced ability to continue such therapies[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Based on these standpoints, there is an urgent need to develop a different treatment approach to improve clinical outcomes in these patients.\u003c/p\u003e \u003cp\u003eSystemic inflammation via host-tumor interaction, one of the hallmarks of cancer[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], has long been recognized as a trigger of cancer cachexia and is also gradually recognized as the cause of impaired body composition, including skeletal muscle loss, and malnutrition[\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Our group has also previously revealed that elevated C-reactive protein (CRP) levels was an independent risk factor for the presence of preoperative myopenia in 308 CRC patients[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In fact, international consensus on the diagnostic criteria for malnutrition, which was established by the Global Leadership Initiative on Malnutrition (GLIM) consortium, explicitly states that a systemic inflammation is one etiological factor in malnutrition diagnosis[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Additionally, the Asian Wasting and Cachexia Diagnosis Criteria (AWGC) list elevated CRP as a diagnostic criterion and specify an optimal cutoff value greater than 0.5[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In light of these backgrounds, it is essential to consider developing supportive therapies that suppress systemic inflammation caused by cancer-host interactions. Such therapies could address malnutrition, sarcopenia, and cachexia, thereby improving continuity of cancer treatment, enhancing quality of life, and improving prognosis.\u003c/p\u003e \u003cp\u003eWe previously reported that immunonutrition containing fish oil had anti-inflammatory effects in patients with unresectable or metastatic gastrointestinal cancer, including CRC[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], who were undergoing systemic chemotherapy. This led to improvements in skeletal muscle mass, treatment continuity, and survival, particularly in patients with elevate CRP levels. However, adherence was poor; 51 out of 88 patients discontinued intake within intervention period during six months[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Thus, we have continued to pursue the development of novel supportive therapies.\u003c/p\u003e \u003cp\u003eHochuekkito (TJ-41) is a traditional Japanese Kampo medicine made from ten medicinal plants. It is commonly prescribed in Japan for anorexia and general fatigue. Clinical trials show that TJ-41 improves quality of life and immunological status in older adults[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and in patients with chronic obstructive pulmonary disease, it mitigates systemic inflammation, prevents weight loss, and enhances nutritional status[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Additionally, several studies have revealed the anti-inflammatory effects of TJ-41 through in vitro and in vivo experiments[\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. We also recently assessed clinical data from 99 patients including CRC who received TJ-41 treatment for more than 3 months and in vivo experiments[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. This study demonstrated that treatment with TJ-41 induced a significant, time-dependent decline in serum CRP levels, with the effect being particularly evident in patients with metastatic malignancies. During TJ-41 therapy, muscle mass was significantly better preserved in the subgroup with decreased CRP levels than in those with increased levels. Consistent with these clinical observations, in vivo experiments using a Colon-26 syngeneic mouse model showed that plasma levels of CRP, serum amyloid A, and interleukin-6 were significantly reduced in mice receiving TJ-41 compared with levels in controls. However, because this study is retrospective and lacks a control group, prospective interventional studies are needed to clarify the anti-inflammatory effects of TJ-41 and its associated outcomes in relation to malnutrition, sarcopenia, and cachexia.\u003c/p\u003e \u003cp\u003eThis prospective interventional study aims to investigate whether the administration of TJ-41 contributes to an anti-inflammatory effect and maintenance of nutritional status in a palliative setting for patients with unresectable or metastatic CRC and systemic inflammation.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThe authors adhered to the SPIRIT recommendations when drafting this protocol (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The protocol is version 1.2, dated April 30, 2024. The CONSORT flowchart is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTrial design\u003c/h2\u003e \u003cp\u003eThis open-label, multicenter, randomized trial with a 1:1 allocation ratio is designed to evaluate TJ-41's efficacy and safety for treating the anti-inflammatory effects of unresectable or metastatic CRC cancer (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This study is registered with the Japan Registry of Clinical Trials (jRCTs041240051). Ethical approval was obtained from the Mie University Hospital ethics committee and subsequently from the institutional review boards of all participating centers. Patients will be recruited from six hospitals across Japan, as listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The enrollment period is planned to last 2 years and 6 months, followed by a 3-month follow-up period. The maximum follow-up duration is 2 years and 9 months. This trial will be conducted in accordance with the ordinance of the Ministry of Health, Labour and Welfare in Japan, Declaration of Helsinki, Ethical Guidelines for Medical and Biological Research Involving Human Subjects, Clinical Trials Act, and the guideline \u0026ldquo;Statistical Principles for Clinical Trials\u0026rdquo;[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The trial was also designed based on the guideline \u0026ldquo;Structure and Content of Clinical Study Reports\u0026rdquo;[25].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe six participating institutes for AMATERAS study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCenter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDepartment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInvestigator\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMie University Hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDepartment of Gastrointestinal and Pediatric Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYuji Toiyama\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMie Prefectural General Medical Center\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDepartment of Gastrointestinal and General Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYasuhiko Mohri\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKuwana City Medical Center\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDepartment of Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKosuke Mizukoshi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIga Municipal Ueno General Citizen's Hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDepartment of Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSusumu Saigusa\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAichi Medical University School of Medicine and Hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOncology Center\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTakashi Iwata\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDoshinkai Tohyama Hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDepartment of Surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYasuhiro Inoue\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e* Sponsor Investigator\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTrial eligibility\u003c/h3\u003e\n\u003cp\u003ePatients with unresectable or metastatic CRC will be screened for eligibility. The inclusion criteria are as follows: Patients must be at least 20 years old at the time of consent. Patients who provided written consent to participate in this study. Patients must have received at least two prior systemic treatment regimens as adjuvant therapy and/or for metastatic disease (including at least one regimen for which disease progression was documented in the metastatic setting) or be intolerant to standard therapy. Patients with a confirmed CRP level greater than 0.5 mg/dL on two consecutive occasions within two months prior to enrollment based on routine clinical laboratory testing. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and be expected to be followed for at least 12 weeks after study enrollment (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe exclusion criteria are as follows: Patients with MSI-high or TMB-high colorectal cancer for whom immune checkpoint inhibitors are or have been used as standard therapy. Patients with comorbidities that may affect nutritional or inflammatory status, such as chronic kidney disease or an autoimmune disease, are also excluded. Patients with infectious diseases requiring antibiotic therapy. Patients with a stoma who have diarrhea interfering with activities of daily living. Patients who have undergone surgical procedures within the past four weeks, or who are scheduled to undergo surgery during the study period.\u003c/p\u003e \u003cp\u003ePatients with a history of gastrectomy. Patients who have taken Kampo medicines within two weeks prior to the scheduled date of Visit 1. Patients for whom oral food intake is difficult owing to gastrointestinal disorders, such as intestinal obstruction, or dysphagia. Patients who have difficulty taking Kampo medicine. Patients with moderate or severe hepatic impairment (Child\u0026ndash;Pugh class B or C) are also excluded. Patients whose routine clinical laboratory test results from the two months prior to enrollment meet any of the following criteria: AST, ALT, or γ-GTP greater than five times the institutional upper limit of normal (ULN), Total bilirubin or creatinine greater than three times the institutional ULN, Potassium\u0026thinsp;\u0026lt;\u0026thinsp;3.0 mmol/L or \u0026gt;\u0026thinsp;5.5 mmol/L, Patients with pleural effusion or ascites, Patients with synchronous or metachronous double (multiple) cancers, Patients with serious comorbid conditions (e.g., cardiac, hematologic, or metabolic diseases), Patients with a history of severe drug hypersensitivity or allergy, particularly to TJ-41, Pregnant or breastfeeding women; women who may be pregnant; and patients who wish to become pregnant during the study period, and Patients who, at the discretion of the principal investigator or co-investigator, are deemed otherwise ineligible to participate in this study.\u003c/p\u003e \u003cp\u003ePatients at the 6 participating hospitals will be screened. Those who meet all the eligibility criteria will be asked to participate in the study. After receiving sufficient information about the study, patients will decide whether to participate. Written informed consent will then be obtained from all those who agree to enroll.\u003c/p\u003e\n\u003ch3\u003eRegistration\u003c/h3\u003e\n\u003cp\u003eThe central registration office at WDB COCO Co., Ltd. will receive an eligibility report form. (Tokyo, Japan). Patients who meet all the inclusion criteria and none of the exclusion criteria will be randomized in a 1:1 ratio to either Treatment Group (standard therapy plus TJ-41) or Control Group (standard therapy alone). Randomization will be performed using a minimization method with stratification by treatment course at the time of enrollment (receiving at least two prior systemic treatment regimens as adjuvant therapy and/or for metastatic disease or be intolerant to standard therapy), and the institution (Mie university hospital or other hospitals) as variables before intervention. Investigators will not be informed of the details of the randomization program. After randomization, the registration center at WDB COCO will provide each investigator with information on the required follow-up assessments. This trial will be conducted at academic or general hospitals in Japan, and the list of participating sites will be available from the AMATERAS study office at Mie University Hospital.\u003c/p\u003e\n\u003ch3\u003eInterventions\u003c/h3\u003e\n\u003cp\u003eProtocol treatment must be initiated within 21 days of case registration. If initiation cannot occur within 21 days, informed consent must be re-obtained, eligibility must be reconfirmed, and specified tests must be performed. Patients in the Treatment Group will receive TJ-41 (Tsumura \u0026amp; Co., Tokyo, Japan) orally at 7.5g per day, divided into 3 doses (2.5g/dose per packet), before or between meals for 12 weeks of standard treatment. TJ-41 is a powdered hot water-extract consisting of the following 10 components: Astragalus root (Astragali radix), 4.0 g; Atractylodes lancea rhizome (Atractylodis lanceae rhizoma), 4.0 g; Ginseng (Ginseng radix), 4.0 g; Japanese Angelica root (Angelicae radix), 3.0 g; Bupleurum root (Bupleuri radix), 2.0 g; Jujube (Zizyphi fructus), 2.0 g; Citrus unshiu peel (Aurantii nobilis pericarpium), 2.0 g; Glycyrrhiza (Glycyrrhizae radix), 1.5 g; Cimicifuga rhizome (Cimicifugae rhizoma), 1.0 g; and Ginger (Zingiberis rhizoma), 0.5 g, as previously described[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. TJ-41 is manufactured by Tsumura \u0026amp; Co. If a dose is missed, the patient may take it as soon as they remember. However, if the next scheduled dose is imminent, skip the missed dose and take the next dose at the regular time. Participant adherence will be monitored by having participants return unused medication and through questionnaires based on their self-reported medication status at each visit. Patients in Control Group will receive standard cancer treatment only, without TJ-41, for 12 weeks.\u003c/p\u003e \u003cp\u003eRegarding concomitant therapy and supportive care, prohibited concomitant medications include Kampo preparations other than the investigational product, immune checkpoint inhibitors, and antibacterial agents. There are no restricted concomitant medications, and no concomitant therapies are either prohibited or restricted beyond those specified above.\u003c/p\u003e \u003cp\u003eThere are no specific provisions defined regarding follow-up treatment after this study is completed. The principal investigator or co-investigator will discuss subsequent treatment options with each study participant and determine the appropriate course of care.\u003c/p\u003e\n\u003ch3\u003ePrimary and secondary endpoints\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint is the comparison of the anti-inflammatory effect between the TJ-41 administration group (Treatment Group) and the non-administration, as assessed by the change in CRP levels from baseline to 12 weeks after initiation of treatment. The CRP change rate at 12 weeks is defined as the CRP value at 12 weeks divided by the CRP value at treatment initiation. The date of treatment initiation is used as the baseline for this calculation (change rate\u0026thinsp;=\u0026thinsp;CRP at 12 weeks after treatment initiation / CRP at treatment initiation).\u003c/p\u003e \u003cp\u003eThe secondary outcome measures the following: the effects of TJ-41 on other inflammatory and nutritional parameters; the effects of TJ-41 on patient-reported symptoms and QOL; the anti-inflammatory and anti-cachectic effects of TJ-41 at the cytokine level; the combined effects of TJ-41 and other appetite-stimulating agents or nutritional products; and the effects of TJ-41 on antitumor efficacy and the occurrence of adverse events. Changes in inflammatory and nutritional parameters before and after TJ-41 administration were assessed using results from routine clinical examinations. Blood tests (RBC, WBC, Hb, Ht, PLT, TP, Alb, TLC, T-bil, AST, ALT, ALP, γ-GTP, K, Cr, and CRP); physical findings (body weight and BMI); nutritional and inflammatory indices (prognostic nutrition index and lymphocyte-CRP ratio); CT-based assessments (myopenia [psoas mass index] and myosteatosis [intramuscular adipose tissue content and modified intramuscular adipose tissue content]); and handgrip strength. Changes in symptoms and QOL were assessed using QOL questionnaires such as QOL-ACD and EORTC QLQ-C30 before and after treatment in the TJ-41 administration group versus the non-administration group. Changes in blood cytokine levels related to anti-inflammatory and anti-cachectic effects were assessed using research blood tests for serum amyloid A, interleukin-6, transthyretin, transferrin, retinol-binding protein, lactate, pyruvate, and growth differentiation factor-15 before and after treatment in the TJ-41 administration versus non-administration groups. The impact of anamorelin and nutritional products on anti-inflammatory and nutritional improvement in the TJ-41 administration versus non-administration groups will be assessed using agents with nutritional or anti-inflammatory effects, such as steroids, non-steroidal anti-inflammatory drugs, anamorelin, and nutritional products covered by the Japanese government's insurance program. We will evaluate tumor status and adverse events before and after treatment in the TJ-41 administration group versus the non-administration group by assessing parameters including tumor markers (CEA, CA19-9), use of anticancer agents, relative dose intensity, cancer/chemotherapy-related adverse events, and tumor response by using image analysis. Adverse events related to cancer or chemotherapy will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0[26]. Tumor response to standard concomitant treatment will be evaluated using RECIST guidelines (v1.1)[27].\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCriteria for Discontinuation of Study Drug and Observation Termination\u003c/h2\u003e \u003cp\u003eThe principal investigator or co-investigator shall discontinue administration of the study drug if they determine that continued administration is impossible for any of the following reasons: 1) When the research subject requests discontinuation of the study drug administration, 2) When continuation of the study drug administration is deemed undesirable owing to worsening of the underlying disease, 3) When continuation of the study drug administration is difficult owing to worsening of a complication, 4) When continuation of study drug administration is difficult owing to disease or other reasons, 5) When the principal investigator or sub-investigator deems it appropriate to discontinue study drug administration for other reasons. If discontinuation occurs owing to the onset of a disease or other condition, follow-up shall be conducted until the subject recovers to their original condition as much as possible.\u003c/p\u003e \u003cp\u003eIn contrast, observation will be terminated in the following cases: (1) If the research subject requests to withdraw from the study or withdraws consent, (2) If, after enrollment, it is found that the subject does not meet the eligibility criteria, (3) If pregnancy is confirmed, (4) If the subject ceases to visit the study site because of relocation or other reasons, (5) If the entire study is discontinued, and (6) If the principal investigator or co-investigator considers it appropriate to discontinue the study for any other reason.\u003c/p\u003e \u003cp\u003eThe date, reason, and course of discontinuation shall be recorded in the medical record and the electronic data capture (EDC) system. Necessary tests shall be performed at the time of discontinuation or withdrawal to evaluate efficacy and safety.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSample size\u003c/h3\u003e\n\u003cp\u003eA prior study[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] reported that the standard deviation of the log-transformed CRP change rate was 1.5 three months after TJ-41 administration in patients with unresectable CRC receiving cancer drug therapy. Based on this result, the present study used the log-transformed CRP change rate at three months as the primary endpoint to determine the sample size. The CRP change rate is defined as follows: CRP change rate\u0026thinsp;=\u0026thinsp;CRP (3 months)/CRP (0 months). For the TJ-41 combination group (Treatment Group), the outcome measure is defined as log (CRP change rate)\u0026thinsp;=\u0026thinsp;log (CRP (3 months)/CRP (0 months)). In the standard treatment-only group (Control Group), the outcome measure is defined as follows, assuming an additional effect on the actual CRP value at three months: log ([CRP (3 months) + effect size]/CRP (0 months)). Based on the prior study's results and clinical considerations, the effect size for the difference in actual CRP values between the two groups at 3 months was assumed to be 0.3. Under this assumption, the corresponding difference in the mean log-transformed CRP change rate between the two groups was estimated to be approximately 1. Assuming equal variances between the two groups and a common standard deviation of 1.5, as well as a 1:1 allocation ratio, the required sample size to detect a mean difference of 1 between groups was calculated using an unpaired two-sample t-test with a two-sided significance level of 5% and 80% power. Under these assumptions, the required sample size was estimated to be 35 patients per group. Furthermore, accounting for a potential dropout rate of approximately 20% during the observation period, the total target sample size was increased accordingly. The final planned sample size was set at 88 patients, with 44 in the TJ-41 combination group (Treatment Group) and 44 in the standard treatment-only group (Control Group).\u003c/p\u003e\n\u003ch3\u003eSafety\u003c/h3\u003e\n\u003cp\u003eAdverse events (AEs) are defined as any undesirable event occurring to a subject during the study, regardless of whether they are related to the investigational intervention. AEs of all grades to CTCAE v5.0[26], reported either spontaneously by the subject or observed by the investigator or study staff, will be systematically recorded.\u003c/p\u003e \u003cp\u003eSerious adverse events (SAEs) are defined as any of the following: death; a life-threatening event (at the time of occurrence); an event requiring hospitalization or prolongation of existing hospitalization; an event resulting in permanent or significant disability or incapacity; an event causing a congenital anomaly or birth defect in offspring; or any other medically important event or effect judged to be serious by the principal investigator or a sub-investigator. However, this definition excludes adverse events that are known symptoms, signs, or diseases attributable to the underlying cancer; known adverse drug reactions to the anticancer agents currently being administered and listed as expected adverse events in the latest package insert or Drug Information Form for the relevant anticancer drug; and abnormal laboratory values that fall within the expected range of side effects of the anticancer agents currently being administered and are listed in the latest package insert or Drug Information Form for the relevant anticancer drug. Such events shall be classified as non-serious adverse events. SAEs will be reported to the accredited Medical Ethics Review Committee via a website within 15 days. This includes SAEs resulting in death or life-threatening events, as well as all other SAEs suspected to be related to the conduct of clinical research. Reporting will continue for the duration of the study. All AEs will be monitored until they are resolved or stabilized. An independent Data Safety Monitoring Board will oversee safety data throughout the study.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eData management, monitoring and auditing\u003c/h2\u003e \u003cp\u003eIn accordance with Good Clinical Practice, the investigators and clinical research coordinators will maintain individual source documents for each participant. These documents will include informed consent forms, medical records, laboratory reports, and case report forms (CRFs). All adverse events will be documented in the CRFs and followed up on prospectively until they are resolved or stabilized. The investigators will oversee all aspects of trial data management. Instead of convening a formal independent data monitoring committee, an independent medical advisor has been appointed to periodically review safety, feasibility, and any emerging issues. All trial data and relevant source documents will be archived for at least five years after the study's completion.\u003c/p\u003e \u003cp\u003eA Efficacy and Safety Evaluation Committee (ESEC), composed of clinicians, statisticians and ethics experts, has been established to enhance the quality of this trial. The ESEC maintains independence from the research team and objectively evaluates efficacy and safety. Conducted annually, it leads to critical decisions: \u0026ldquo;Continue the trial,\u0026rdquo; \u0026ldquo;Continue the trial with protocol modifications,\u0026rdquo; or \u0026ldquo;Discontinue the trial.\u0026rdquo; Monitoring is performed by the WDB COCO based on the CRF and EDC system.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis.\u003c/h2\u003e \u003cp\u003eStatistical analyses, including the creation of tables and figures for the study report, will be conducted by the study statistician under blinded conditions, when feasible. The primary and secondary endpoint analyses will primarily be based on the full analysis set (FAS). To confirm the robustness of the results, additional analyses will be performed using the per-protocol set (PPS). Safety endpoint analyses will be conducted using the safety analysis set (SAS). The FAS includes all enrolled participants except those for whom the primary endpoint was not evaluated and those who did not attend any post-baseline visits after the start of treatment. The PPS is defined as the subset of participants who meet all of the following criteria: (1) no major protocol deviations, (2) receipt of at least two-thirds of the prescribed total dose of TJ-41 in the Treatment Group, and (3) no use of prohibited concomitant medications. The SAS for adverse events excludes participants who did not visit the clinic after registration and for whom no analyzable safety data are available. For the analysis of TJ-41\u0026ndash;related adverse reactions, the analysis population excludes the following: (1) participants assigned to the TJ-41 group who did not attend any visits after the start of treatment and for whom no analyzable data are available, and (2) participants assigned to the TJ-41 group for whom it was subsequently confirmed that TJ-41 was never administered.\u003c/p\u003e \u003cp\u003eFor the primary endpoint, the CRP change rate will be log-transformed. The mean and standard deviation will be calculated for each group, and a Student's t-test will be applied. Categorical variables will be analyzed using cross-tabulation and Fisher's exact test. For safety evaluation items (e.g., incidence of diseases or adverse events), cross-tabulations by group will be prepared, and Fisher's exact test will be performed. The significance level for all statistical tests will be set at 5% (two-sided). All statistical analyses will be performed using validated statistical software.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eProtocol amendments\u003c/h2\u003e \u003cp\u003eAny modifications to the study protocol made during the trial must be submitted to the Certified Review Board of Mie University Hospital for approval by the principal investigator. After approval is granted, the principal investigator will promptly notify the lead investigators at each participating site of the changes and their rationale. The lead investigators will then submit the approved amendments to their respective institutional authorities for final approval.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eDissemination\u003c/h2\u003e \u003cp\u003eThe findings of this study will be disseminated through publication in peer-reviewed journals and presentation at scientific conferences. This ensures that no information identifying individual participants is disclosed. Authorship will be determined according to the criteria established by the International Committee of Medical Journal Editors (ICMJE).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eTrial status\u003c/h2\u003e \u003cp\u003e This study was approved by the Mie University Hospital Clinical Research Review Board based on Clinical Trials Act on January 22, 2024 (S2023-004) and was registered with the Japan Registry of Clinical Trials on June 26, 2024 (jRCTs041240051). Participant recruitment began on July 1, 2024, and is ongoing as of January 1, 2026.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eRole of the funding source\u003c/h2\u003e \u003cp\u003eThe funding agency was provided with the protocol and manuscript prior to submission for review of factual accuracy and funding-related information only and had no authority over study design, data analysis, manuscript content, or the decision to submit for publication.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis AMATERAS study is a multicenter, randomized controlled clinical trial to clarify anti-inflammatory effect of cancer-harboring patients with unresectable or metastatic CRC.\u003c/p\u003e \u003cp\u003eTo date, no clinical trials have investigated orally administered agents, including Kampo medicines, that may alleviate systemic inflammation by modulating host\u0026ndash;tumor interactions at the palliative setting of malignancies, including CRC. Furthermore, this study included several secondary endpoints based on additional clinical data, handgrip strength, quality-of-life questionnaires, and translational research using serial blood samples to elucidate the clinical and biological impact of TJ-41 administration in these patients. This study's results will be published as a research article and will provide novel evidence of the beneficial effects of TJ-41 in patients with unresectable or metastatic CRC.\u003c/p\u003e \u003cp\u003eSystemic inflammation resulting from host\u0026ndash;tumor interactions has been recognized as one of the hallmarks of cancer[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], and accumulating evidence indicates that systemic inflammation plays a critical role in tumor initiation, proliferation, progression, and metastasis in malignant diseases[28\u0026ndash;30]. In addition, systemic inflammation is closely associated with clinical outcomes in various malignancies including CRC[31\u0026ndash;33]. Our previous work also demonstrated that multiple cytokines and serum biomarkers of systemic inflammation\u0026mdash;including IL-1β, IL-1ra, IL-6, IL-10 are differentially expressed in the sera of patients with advanced or metastatic CRC[34\u0026ndash;38]. In clinical practice, serum CRP is one of the most widely used indicators of systemic inflammation. Multiple retrospective studies have reported that elevated CRP levels are associated with an unfavorable prognosis in patients with CRC[36, 37, 39\u0026ndash;41].\u003c/p\u003e \u003cp\u003eSystemic inflammation have been shown to lead to a reduction in muscle mass through the suppression of appetite and an increase in resting energy expenditure, which is mediated by IL-6, TNF-α, IL-1β, and other factors. Emerging evidence revealed that growth differentiation factor 15 (GDF-15) can cause sarcopenia and cachexia by suppressing appetite and altering metabolism[42, 43]. A recent clinical trial showed that ponsegromab, a humanized monoclonal antibody that inhibits GDF-15, increased weight gain and overall activity levels while reducing cachexia symptoms in patients with cancer cachexia and elevated GDF-15 levels, including those with CRC[44]. Our recent study further revealed the significant positive correlation between preoperative serum GDF-15 level and CRP levels, and suggested the additional pathogenesis of systemic inflammation for appetite loss, malnutrition, and sarcopenia/cachexia via circulating GDF-15[45]. In line with these evidences, this prospective intervention study will collect serial blood samples during the observation period to evaluate the effects of TJ-41 administration on CRP and GDF-15 levels in these patients.\u003c/p\u003e \u003cp\u003eHochuekkito (TJ-41), traditional Japanese Kampo medicine made from ten medicinal plants, have several evidence for anti-inflammatory biological effect from several studies. Sekiya and colleagues reported that TJ-41 administration enhances the production of chemokines such as CCL20 in the Peyer's patches of the intestinal mucosa, suppresses TNF-α production, and inhibits intestinal mucosal inflammatory responses[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Other study showed that TJ-41 could inhibit the secretion of inflammatory cytokines (IL-6, TNF-α, IL-1, and IL-8) induced by rhinovirus in human tracheal epithelial cells[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], Isago and colleagues conducted a series of in vivo studies using a lung emphysema model that mimics the chronic pulmonary inflammation seen in COPD[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. They demonstrated that administration of TJ-41 reduced the number of inflammatory cells in bronchoalveolar lavage fluid and attenuated lung inflammation in histopathological analyses. In malignancies, Yae and his colleagues investigated the potential anti-tumor effects of TJ-41 using a mouse cancer model[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Their study showed that TJ-41 treatment led to a significant decrease in circulating IL-6 levels and reduced IL-6 expression by macrophages in the peritumoral tissues. In line with this evidence, our study also demonstrated the anti-inflammatory effects of TJ-41 in patients with cancer using clinical data and a series of in vivo experiments[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Considering these standpoints, the anti-inflammatory effects of TJ-41 in cancer hosts are highly promising. Furthermore, given its potential as a novel supportive therapy for malnutrition, sarcopenia, and cachexia, we are planning this prospective randomized controlled intervention trial. Furthermore, another recent study also clearly revealed that TJ-41 administration could Improve in liver autophagy and maintain energy homeostasis in the elderly mice model[46]. In this prospective study, circulating factors related to mitochondrial function will also be evaluated by collecting serial blood samples during the observation period.\u003c/p\u003e \u003cp\u003eIn conclusion, this study provides an integrated approach using Kampo medicine, enabling the simultaneous clarification of its clinical significance and biological significance.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTJ-41\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHochuekkito\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eColorectal cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eC-reactive protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eQOL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003equality of life\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGLIM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlobal Leadership Initiative on Malnutrition\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAWGC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAsian Wasting and Cachexia Diagnosis Criteria\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECOG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEastern Cooperative Oncology Group\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eULN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUpper limit of normal\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTCAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCommon Terminology Criteria for Adverse Events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEDC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eElectronic data capture\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSerious adverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRFs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCase report forms\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eESEC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEfficacy and Safety Evaluation Committee\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFull analysis set\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePer-protocol set\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSafety analysis set\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICMJE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Committee of Medical Journal Editors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGDF-15\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGrowth differentiation factor 15\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ejRCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eJapan Registry of Clinical Trials\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors express their gratitude to all medical and co-medical staff at the participating institutions in the AMATERAS study for their dedicated cooperation. We thank J. Ludovic Croxford, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is supported by a research grant from Tsumura \u0026amp; Co., Tokyo, Japan.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors participated in the conceptualization of the study and prepared the study protocol. YO, KJ, and YT coordinated the study process. KJ, ST, HI, MK, AY, AK, KM, HF, TI, SS, EO, YI, and YM supported the development of this protocol. YO, and YT devised the statistical analysis. YO and YT drafted the study protocol. ST, HI, MK, AY, AK, KM, HF, TI, SS, EO, YI, and YM revised the study protocol. ST, HI, MK, AY, AK, KM, HF, TI, SS, EO, YI, and YM read and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the AMATERAS study are not publicly accessible, but they are available upon reasonable request to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICS APPROVAL AND CONSENT TO PARTICIPATE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was granted by the review committee at the Mie University Hospital and was approved and overseen by the institutional review boards of each participating hospital. If deemed eligible, informed consent will be obtained from the patients by the attending physicians at the participating institutes. The study will be conducted in accordance with the World Medical Association Declaration of Helsinki of 1996. The study results will be published in a peer reviewed journal and be presented at national and international conferences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETEING INTERESTS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that this work was supported by research funding from Tsumura \u0026amp; Co. Tsumura \u0026amp; Co. had no role in the study design or data collection and analysis of the clinical research. YO and YT received a consulting fee from Tsumura\u0026amp; Co for conference attendance as ad hoc advisor regarding the basic research. YO received a speaking honoraria from Tsumura \u0026amp; Co. The other authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePARTICIPATING INSTITUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Gastrointestinal and Pediatric Surgery, Mie University Hospital; Department of Gastrointestinal and General Surgery, Mie Prefectural General Medical Center; Department of Surgery, Kuwana City Medical Center; Department of Surgery, Iga Municipal Ueno General Citizen\u0026apos;s Hospital; Oncology Center, Aichi Medical University School of Medicine and Hospital; Department of Surgery, Doshinkai Tohyama Hospital\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT FOR PUBLICATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A: \u003cstrong\u003eGlobal cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide 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\u003cstrong\u003e7\u003c/strong\u003e(1):13.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-colorectal-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcd","sideBox":"Learn more about [International Journal of Colorectal Disease](http://link.springer.com/journal/384)","snPcode":"384","submissionUrl":"https://submission.nature.com/new-submission/384/3","title":"International Journal of Colorectal Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Hochuekkito, TJ-41, systemic inflammation, colorectal cancer","lastPublishedDoi":"10.21203/rs.3.rs-8885578/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8885578/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSystemic inflammation, a hallmark of cancer, is recognized as a key mechanism underlying malnutrition, sarcopenia, and cancer cachexia. Hochuekkito (TJ-41) is a traditional Japanese Kampo formula composed of ten medicinal plants, and several studies have suggested its anti-inflammatory effects in various diseases. Our recent retrospective study, supported by in vitro experiments, was the first to demonstrate an anti-inflammatory effect of TJ-41 in patients with unresectable or metastatic gastrointestinal cancer, including colorectal cancer (CRC). However, no prospective randomized multicenter clinical trial has evaluated TJ-41 in the palliative setting of malignancies, including CRC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePatients with unresectable or metastatic CRC who have received at least two prior systemic regimens or are intolerant to standard therapy, and who show an elevated C-reactive protein (CRP) level\u0026thinsp;\u0026gt;\u0026thinsp;0.5 mg/dL on two consecutive occasions within two months before enrollment, will be eligible. After providing written informed consent, patients will be randomly assigned to Treatment group (standard treatment plus TJ-41) or Control Group (standard treatment alone). Patients in Treatment Group will receive oral TJ-41 (Tsumura \u0026amp; Co., Tokyo, Japan) at 7.5 g/day, divided into three doses (2.5 g per dose), before or between meals for 12 weeks. The primary endpoint is the difference in anti-inflammatory effect between groups, assessed by the change in CRP from baseline to 12 weeks. Secondary endpoints include the effects of TJ-41 on other inflammatory and nutritional parameters; patient-reported symptoms and quality of life (QOL) using QOL-ACD and EORTC QLQ-C30; cytokine-based anti-inflammatory and anti-cachectic effects using serial blood specimens; interactions with other appetite-stimulating agents or nutritional products; and effects on antitumor efficacy and adverse events. Each group will include 44 patients, with recruitment planned from July 1, 2024, to December 31, 2026.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis trial will evaluate whether TJ-41 can attenuate systemic inflammation related to host\u0026ndash;tumor interactions in patients with unresectable or metastatic CRC.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e \u003cp\u003eThis study was registered in the Japan Registry of Clinical Trials on June 26, 2024 (jRCTs041240051).\u003c/p\u003e","manuscriptTitle":"Assessment of Management and Anti-inflammatory Therapy Effectiveness in Colorectal cancer: Randomized Assessment of Supplemental Hochuekkito Therapy: Study protocol for a multicenter randomized controlled trial (AMATERAS study)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-16 06:06:18","doi":"10.21203/rs.3.rs-8885578/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-13T16:43:40+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-09T02:31:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"242028617286580341403845528922342439384","date":"2026-04-08T23:29:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-08T15:58:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-23T09:25:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"68126559230435638454153182621982257330","date":"2026-03-16T23:23:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"225618173618794765187232132127392230429","date":"2026-03-14T01:19:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-11T14:42:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-23T02:32:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-23T02:30:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Colorectal Disease","date":"2026-02-15T11:06:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-colorectal-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcd","sideBox":"Learn more about [International Journal of Colorectal Disease](http://link.springer.com/journal/384)","snPcode":"384","submissionUrl":"https://submission.nature.com/new-submission/384/3","title":"International Journal of Colorectal Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"00006f32-d545-460c-b773-096d32259261","owner":[],"postedDate":"March 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-28T12:23:17+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-16 06:06:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8885578","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8885578","identity":"rs-8885578","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}