XCHT for Irinotecan-Induced Gut Toxicities (Randomized Controlled Trial)

Mechanistic and Pharmacokinetic Studies of Classical Chinese Formula Xiao Chai Hu Tang (XCHT) Against Irinotecan-Induced Gut Toxicities(Clinical Study Part:Randomized Controlled Trial)

Randomized double-blind placebo-controlled trial (RCT) study, to determine the impact of XCHT on irinotecan-induced severe delayed-onset diarrhea (SDOD), and to determine the feasibility of using plasma raloxifene-4'-glucuronide as a probe for intestinal UGT activity.

Study Overview

• Status: Recruiting
• Conditions: Xiao Chai Hu Tang; Irinotecan-induced Diarrhea
• Intervention / Treatment: Drug: Xiao Chai Hu Tang (XCHT); Other: Raloxifene; Drug: Placebo; Drug: Irinotecan regimen

Detailed Description

A total of 98 patients, who are planning to recieve at least 3 cycles of irinotecan chemotherapy, will be randomly assigned, at a 1:1 ratio, to XCHT group or placebo group, using a central randomization system. Patients will be administered with XCHT/placebo (9 g, qd, po) for 5 days each cycle of chemotherapy for 3 cycles. The XCHT/placebo administration begins 3 days before chemotherapy in each cycle, that is the chemotherapy begins on the 4th day of XCHT/placebo administration. Plasma will be collected for pharmacokinetic testing (using raloxifene 60mg po as probe), on the day before chemotherapy, that is on the 3rd day of XCHT/placebo administration in each cycle. The purpose of this study includes 1) to determine the safety and efficacy of XCHT for prevention of irinotecan-induced diarrhea; 2) to determine the PK profile of SN-38, SN-38G, raloxifene, raloxifene-glucuronide, and XCHT components; and 3) to validate the use of raloxifene-4'G as a probe for irinotecan-induced diarrhea.

• Study Type: Interventional
• Enrollment (Estimated): 98
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yanjuan Zhu, Dr.; Phone Number: 34830 86 20 81887233; Email: zyjsophy@gzucm.edu.cn
• Study Contact Backup: Name: Yadong Chen, Dr.; Phone Number: 34830 86 20 81887233; Email: chenyadong@gzucm.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510120
      • Recruiting
      • Guangdong Provincial Hospital of traditional Chinese Medicine
      • Contact: Haibo Zhang, Prof; Phone Number: 34830 86-020-81887233; Email: haibozh@gzucm.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. Malignant tumor confirmed by histology or cytology;
2. Age ≥ 18 years old, ≤ 75 years old;
3. ECOG score of the patient ≤ 2 points;
4. Patients who have diarrhea worse than grade 2 due to irinotecan chemotherapy (the last dose of irinotecan is administered within 1 month);
5. Patients who plan to receive 3 cycles of irinotecan chemotherapy (the dose of irinotecan ≥ 125mg/m2);

6. Normal organ functions which can meet the requirements for systemic chemotherapy:

   • Normal bone marrow function: absolute neutrophil count (ANC) ≥ 1.5×109/L, PLT ≥ 100×109/L, hemoglobin ≥ 90g/L;
   • Normal renal functions: serum creatinine ≤ 1.5mg/dl (133μmol/L) and/or creatinine clearance ≥ 60ml/min;
   • Normal hepatic functions: total serum bilirubin level ≤ 1.5 times of the upper limit of normal value (ULN), serum aspartate aminotransferase (AST) & alanine aminotransferase (ALT) ≤ 2.5× ULN; AST & ALT ≤ 5 × ULN if abnormal hepatic functions are caused by a potentially malignant tumor.
7. Patients who can understand and complete the questionnaires in the case report form;
8. Patients who can understand and sign the informed consent form, is well compliant, and can be followed up.

Exclusion Criteria:

1. Patients with diagnosed depression, obsession or/and schizophrenia;
2. Patients with diagnosed inflammatory bowel diseases (including Crohn's disease, ulcerative colitis)
3. Patient with active tuberculosis and other uncontrolled infections;
4. Patient who has previously received radiotherapy on the abdominal cavity or pelvic cavity;
5. Pregnant or lactating women;
6. Patient who previously had or is now having thromboembolic events.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: XCHT group; Patients will be administered with XCHT (9 g, qd, po) for 5 days each cycle of irinotecan chemotherapy for 3 cycles. The XCHT administration begins 3 days before chemotherapy in each cycle, that is the chemotherapy begins on the 4th day of XCHT administration. Plasma will be collected for pharmacokinetic testing (using raloxifene 60mg po as probe), on the day before chemotherapy, that is on the 3rd day of XCHT administration in each cycle.	Drug: Xiao Chai Hu Tang (XCHT); XCHT 9g, po qd, 3 days before each cycle of chemotherapy for 5 days, for 3 cycles of chemotherapy.; Other Names: Xiao Chai Hu Tang granules from Nin Jiom Medicine Manufactory (Hong Kong) Ltd; Other: Raloxifene; Raloxifene 60mg po, used as probe for pharmacokinetic testing, on Day 3 (the day before chemotherapy), for 3 cycles of chemotherapy.; Drug: Irinotecan regimen; Patients will receive 3 cycles of irinotecan chemotherapy. FOLFIRI regimen:irinotecan (180 mg/m2) intravenous (IV) for over 90 minutes on Day 1. Folinic acid (400 mg/m2) IV over 2 hours on Day 1. 5-fluorouracil (5-FU) IV bolus (400 mg/m2) over 5 minutes on Day 1, followed by 5-FU (2400 mg/m2) IV continuously for 46-48 hours. Every 2 weeks. mXELIRI regimen:irinotecan (200 mg/m2) intravenous (IV) for over 90 minutes on Day 1. Capecitabine (800 mg/m²) PO bid on day 1-14. Every 3 weeks. CapIRI regimen:irinotecan (180 mg/m2) intravenous (IV) for over 90 minutes on Day 1. Capecitabine (1000 mg/m²) PO bid on day 1-14. Every 3 weeks. FOLFOXIRI regimen:irinotecan (165 mg/m2) intravenous (IV) for over 90 minutes on Day 1. Oxaliplatin (85 mg/m2) intravenous (IV) for over 2 hours on Day 1.Folinic acid (400 mg/m2) IV over 2 hours on Day 1, followed by 5-FU (2400 - 3200 mg/m2) IV continuously for 48 hours. Every 2 weeks.
Placebo Comparator: Placebo group; Patients will be administered with placebo (9 g, qd, po) for 5 days each cycle of irinotecan chemotherapy for 3 cycles. The placebo administration begins 3 days before chemotherapy in each cycle, that is the chemotherapy begins on the 4th day of placebo administration. Plasma will be collected for pharmacokinetic testing (using raloxifene 60mg po as probe), on the day before chemotherapy, that is on the 3rd day of placebo administration in each cycle.	Other: Raloxifene; Raloxifene 60mg po, used as probe for pharmacokinetic testing, on Day 3 (the day before chemotherapy), for 3 cycles of chemotherapy.; Drug: Placebo; Placebo 9g, po qd, 3 days before each cycle of chemotherapy for 5 days, for 3 cycles of chemotherapy.; Other Names: Placebo provided by Nin Jiom Medicine Manufactory (Hong Kong) Ltd; Drug: Irinotecan regimen; Patients will receive 3 cycles of irinotecan chemotherapy. FOLFIRI regimen:irinotecan (180 mg/m2) intravenous (IV) for over 90 minutes on Day 1. Folinic acid (400 mg/m2) IV over 2 hours on Day 1. 5-fluorouracil (5-FU) IV bolus (400 mg/m2) over 5 minutes on Day 1, followed by 5-FU (2400 mg/m2) IV continuously for 46-48 hours. Every 2 weeks. mXELIRI regimen:irinotecan (200 mg/m2) intravenous (IV) for over 90 minutes on Day 1. Capecitabine (800 mg/m²) PO bid on day 1-14. Every 3 weeks. CapIRI regimen:irinotecan (180 mg/m2) intravenous (IV) for over 90 minutes on Day 1. Capecitabine (1000 mg/m²) PO bid on day 1-14. Every 3 weeks. FOLFOXIRI regimen:irinotecan (165 mg/m2) intravenous (IV) for over 90 minutes on Day 1. Oxaliplatin (85 mg/m2) intravenous (IV) for over 2 hours on Day 1.Folinic acid (400 mg/m2) IV over 2 hours on Day 1, followed by 5-FU (2400 - 3200 mg/m2) IV continuously for 48 hours. Every 2 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of diarrhea (grade ≥2)	The diarrhea severity will be evaluated following standard criteria in NCI-CTC AE 5.0 Grade 2 is defined as Stool is increased by 4-6 times each day relative to baseline; discharge from stoma moderately increased.	Through study completion, an average of 2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of diarrhea (grade ≥3)	The diarrhea severity will be evaluated following standard criteria in NCI-CTC AE 5.0	Through study completion, an average of 2 months
Incidence of other chemo-related adverse effects	Other adverse reactions will be evaluated following standard criteria in NCI-CTC AE 5.0	Through study completion, an average of 2 months
Occult blood test for stool	Occult blood test for stool, reported as negative, weak positive, and positive.	Through study completion, an average of 2 months
PK parameters(Cmax)	Cmax ,if with complete data, in each cycle of Cmax for XCHT and their metabolites (14 compounds) and intestinal UGT enzyme probe (raloxifene and metabolites)	The blood samples (2.0 ml) will be collected at 4 points for each cycle(hour 0, hour 1, hour 2, hour 4 after raloxifene administration)
PK parameters(AUC)	AUC 0-24hr, if with complete data, in each cycle of AUC0-24hr for XCHT and their metabolites (14 compounds) and intestinal UGT enzyme probe (raloxifene and metabolites)	The blood samples (2.0 ml) will be collected at 4 points for each cycle(hour 0, hour 1, hour 2, hour 4 after raloxifene administration)
PK parameters(T1/2)	T1/2, if with complete data, in each cycle of T1/2 for XCHT and their metabolites (14 compounds) and intestinal UGT enzyme probe (raloxifene and metabolites)	The blood samples (2.0 ml) will be collected at 4 points for each cycle(hour 0, hour 1, hour 2, hour 4 after raloxifene administration)

Collaborators and Investigators

• Sponsor: Guangzhou University of Traditional Chinese Medicine
• Collaborators: University of Houston
• Investigators: Principal Investigator: Haibo Zhang, Prof., Guangdong Provincial Hospital of traditional Chinese Medicine

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: September 9, 2023
• First Submitted That Met QC Criteria: September 24, 2023
• First Posted (Actual): September 26, 2023

Study Record Updates

• Last Update Posted (Estimated): July 1, 2025
• Last Update Submitted That Met QC Criteria: June 29, 2025
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Malignant tumor; Classical Chinese Formula; Irinotecan-induced diarrhea; Xiao Chai Hu Tang; pharmacokinetic mechanism
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Diarrhea; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Bone Density Conservation Agents; Hormone Antagonists; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Irinotecan; Raloxifene Hydrochloride
• Other Study ID Numbers: 2021KT1005-2; 81961128028 (Other Grant/Funding Number: National Nature Science Fundation of China)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No