## Protocol Section
### Identification Module
**NCT ID:** NCT06055179

**Brief Title:** XCHT for Irinotecan-Induced Gut Toxicities (Randomized Controlled Trial)

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

#### Organization Study ID Info
**ID:** 2021KT1005-2
#### Organization
**Class:** OTHER
**Full Name:** Guangzhou University of Traditional Chinese Medicine
#### Secondary ID Infos
**Domain:** National Nature Science Fundation of China
**ID:** 81961128028
**Type:** OTHER_GRANT
### Status Module
#### Completion Date
**Date:** 2025-02-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-03-22

**Type:** ACTUAL

**Last Update Submit Date:** 2024-03-21

**Overall Status:** RECRUITING

#### Primary Completion Date
**Date:** 2024-12-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-03-08

**Type:** ACTUAL

**Status Verified Date:** 2023-09

#### Study First Post Date
**Date:** 2023-09-26
**Type:** ACTUAL
**Study First Submit Date:** 2023-09-09
**Study First Submit QC Date:** 2023-09-24
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** University of Houston

#### Lead Sponsor

**Class:** OTHER

**Name:** Guangzhou University of Traditional Chinese Medicine

#### Responsible Party

**Investigator Affiliation:** Guangzhou University of Traditional Chinese Medicine

**Investigator Full Name:** Haibo Zhang

**Investigator Title:** Professor

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** 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.

**Detailed Description:** A total of 98 patients, who are planning to recieve at least 3 cycles of FOLFIRI/mXELIRI 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.

### Conditions Module

**Conditions:**

- Xiao Chai Hu Tang

- Irinotecan-induced Diarrhea

**Keywords:**

- Malignant tumor

- Irinotecan-induced diarrhea

- Xiao Chai Hu Tang

- Classical Chinese Formula

- pharmacokinetic mechanism

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** QUADRUPLE

**Masking Description:** Patients will be randomly assigned to XCHT/placebo groups, at a 1:1 ratio, using a central randomization system provided by the TCM clinical study methodology group of Guangdong Provincial Hospital of Chinese Medicine. This group is also responsible for blinding, including keeping the blinding codes, supervision, and quality control of blinding, by allocating drug codes for each patient. Investigators will dispense the drug according to the drug codes. The investigators, the study subjects, the care givers, and the outcome assessors will be blinded to the assigned group of subjects.

**Who Masked:**

- PARTICIPANT

- CARE_PROVIDER

- INVESTIGATOR

- OUTCOMES_ASSESSOR

**Primary Purpose:** PREVENTION

#### Enrollment Info

**Count:** 98

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Patients will be administered with XCHT (9 g, qd, po) for 5 days each cycle of FOLFIRI/mXELIRI 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.

**Intervention Names:**

- Drug: Xiao Chai Hu Tang (XCHT)

- Drug: FOLFIRI/mXELIRI regimen

- Other: Raloxifene

**Label:** XCHT group

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Patients will be administered with placebo (9 g, qd, po) for 5 days each cycle of FOLFIRI/mXELIRI 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.

**Intervention Names:**

- Drug: Placebo

- Drug: FOLFIRI/mXELIRI regimen

- Other: Raloxifene

**Label:** Placebo group

**Type:** PLACEBO_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- XCHT group

**Description:** XCHT 9g, po qd, 3 days before each cycle of chemotherapy for 5 days, for 3 cycles of chemotherapy.

**Name:** Xiao Chai Hu Tang (XCHT)

**Other Names:**

- Xiao Chai Hu Tang granules from Nin Jiom Medicine Manufactory (Hong Kong) Ltd

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Placebo group

**Description:** Placebo 9g, po qd, 3 days before each cycle of chemotherapy for 5 days, for 3 cycles of chemotherapy.

**Name:** Placebo

**Other Names:**

- Placebo provided by Nin Jiom Medicine Manufactory (Hong Kong) Ltd

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Placebo group

- XCHT group

**Description:** Patients will receive 3 cycles of FOLFIRI/mXELIRI 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.

**Name:** FOLFIRI/mXELIRI regimen

**Type:** DRUG

#### Intervention 4

**Arm Group Labels:**

- Placebo group

- XCHT group

**Description:** Raloxifene 60mg po, used as probe for pharmacokinetic testing, on Day 3 (the day before chemotherapy), for 3 cycles of chemotherapy.

**Name:** Raloxifene

**Type:** OTHER

### Outcomes Module

#### Primary Outcomes

**Description:** 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.

**Measure:** Incidence of diarrhea (grade ≥2)

**Time Frame:** Through study completion, an average of 2 months

#### Secondary Outcomes

**Description:** The diarrhea severity will be evaluated following standard criteria in NCI-CTC AE 5.0

**Measure:** Incidence of diarrhea (grade ≥3)

**Time Frame:** Through study completion, an average of 2 months

**Description:** Other adverse reactions will be evaluated following standard criteria in NCI-CTC AE 5.0

**Measure:** Incidence of other chemo-related adverse effects

**Time Frame:** Through study completion, an average of 2 months

**Description:** Occult blood test for stool, reported as negative, weak positive, and positive.

**Measure:** Occult blood test for stool

**Time Frame:** Through study completion, an average of 2 months

**Description:** 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)

**Measure:** PK parameters(Cmax)

**Time Frame:** 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)

**Description:** 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)

**Measure:** PK parameters(AUC)

**Time Frame:** 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)

**Description:** 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)

**Measure:** PK parameters(T1/2)

**Time Frame:** 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)

### Eligibility Module

**Eligibility Criteria:** 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 FOLFIRI/mXELIRI chemotherapy;
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.

**Maximum Age:** 75 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** zyjsophy@gzucm.edu.cn

**Name:** Yanjuan Zhu, Dr.

**Phone:** 86 20 81887233

**Phone Ext:** 34830

**Role:** CONTACT

**Contact 2:**

**Email:** chenyadong@gzucm.edu.cn

**Name:** Yadong Chen, Dr.

**Phone:** 86 20 81887233

**Phone Ext:** 34830

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Guangzhou

**Contacts:**

***Contact 1:***

- **Email:** haibozh@gzucm.edu.cn

- **Name:** Haibo Zhang, Prof

- **Phone:** 86-020-81887233

- **Phone Ext:** 34830

- **Role:** CONTACT

**Country:** China

**Facility:** Guangdong Provincial Hospital of Traditional Chinese Medicine

**State:** Guangdong

**Status:** RECRUITING

**Zip:** 510120

#### Overall Officials

**Official 1:**

**Affiliation:** Guangdong Provincial Hospital of Traditional Chinese Medicine

**Name:** Haibo Zhang, Prof.

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000012817

- Term: Signs and Symptoms, Digestive

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

### Condition Browse Module - Browse Leaves

- ID: M7159

- Name: Diarrhea

- Relevance: HIGH

- As Found: Diarrhea

- ID: M15622

- Name: Signs and Symptoms, Digestive

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000003967

- Term: Diarrhea

### Intervention Browse Module - Ancestors

- ID: D000004965

- Term: Estrogen Antagonists

- ID: D000006727

- Term: Hormone Antagonists

- ID: D000006730

- Term: Hormones, Hormone Substitutes, and Hormone Antagonists

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000020845

- Term: Selective Estrogen Receptor Modulators

- ID: D000020847

- Term: Estrogen Receptor Modulators

- ID: D000050071

- Term: Bone Density Conservation Agents

### Intervention Browse Module - Browse Branches

- Abbrev: Micro

- Name: Micronutrients

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: Hemat

- Name: Hematinics

- Abbrev: BDCA

- Name: Bone Density Conservation Agents

- Abbrev: Vi

- Name: Vitamins

### Intervention Browse Module - Browse Leaves

- ID: M6191

- Name: Leucovorin

- Relevance: LOW

- As Found: Unknown

- ID: M8600

- Name: Fluorouracil

- Relevance: LOW

- As Found: Unknown

- ID: M29233

- Name: Levoleucovorin

- Relevance: LOW

- As Found: Unknown

- ID: M377

- Name: Capecitabine

- Relevance: LOW

- As Found: Unknown

- ID: M1671

- Name: Irinotecan

- Relevance: LOW

- As Found: Unknown

- ID: M8618

- Name: Folic Acid

- Relevance: LOW

- As Found: Unknown

- ID: M22601

- Name: Raloxifene Hydrochloride

- Relevance: HIGH

- As Found: 1 mm

- ID: M8116

- Name: Estrogens

- Relevance: LOW

- As Found: Unknown

- ID: M8114

- Name: Estrogen Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M30483

- Name: Estrogen Receptor Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M9789

- Name: Hormones

- Relevance: LOW

- As Found: Unknown

- ID: M9788

- Name: Hormone Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M22599

- Name: Estrogen Receptor Modulators

- Relevance: LOW

- As Found: Unknown

- ID: M22597

- Name: Selective Estrogen Receptor Modulators

- Relevance: LOW

- As Found: Unknown

- ID: T447

- Name: Folinic Acid

- Relevance: LOW

- As Found: Unknown

- ID: T446

- Name: Folic Acid

- Relevance: LOW

- As Found: Unknown

- ID: T448

- Name: Folate

- Relevance: LOW

- As Found: Unknown

- ID: T475

- Name: Vitamin B9

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000020849

- Term: Raloxifene Hydrochloride

### Misc Info Module

- Version Holder: 2024-05-24
