Study of Oral Metronidazole on Postoperative Chemotherapy in Colorectal Cancer

Study Overview
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Brief Summary
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Fusobacterium nucleatum (Fusobacterium nucleatum, Fn) has been identified as an independent risk factor for recurrence of colorectal cancer. In this study, oral metronidazole would be used to reduce the abundance of Fn in patients with high Fn, so as to explore whether oral metronidazole can improve the efficacy of postoperative chemotherapy in patients with colorectal cancer.

Detailed Description
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Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Previously in the investigators' research, the investigators find the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. The investigators found that Fusobacterium nucleatum (Fn) was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, the investigators' bioinformatic and functional studies demonstrated that Fn promoted colorectal cancer resistance to chemotherapy. Metronidazole has been known to treat with anaerobe infection, including Fusobacterium. So oral metronidazole would be used to reduce the abundance of Fn in patients with high Fn, so as to explore whether oral metronidazole can improve the efficacy of postoperative chemotherapy in patients with colorectal cancer.

Official Title
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Fusobacterium Nucleatum Eradication in Postoperative Stage II/III Colorectal Cancer(FINER-PACE)by Oral Metronidazole: A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Conditions
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Colorectal Cancer Stage II, Colorectal Cancer Stage III

Intervention / Treatment
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* Drug: Metronidazole Oral Tablet
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals aged 18-75 years Individuals firstly confirmed by surgery pathology as colorectal cancer (AJCC cancer staging II - III), who need mFOLFOX6 or CapeOX postoperative chemotherapy Individuals with Fn - deltaCT value in colon tissue samples detected by qPCR ≥-12 before receiving chemotherapy Individuals who could tolerate chemotherapy drugs: ECOG (Eastern Cooperative Oncology Group) score ≤2 points, WBC(White Blood Cell) ≥4.0×10^9/L, Hb （Hemoglobin） ≥80g/L, PLT （Platelet） ≥80×10^9/L, ALT （Alanine Aminotransferase）< 2ULN （Upper Limmit of Normal）, Scr （Creatinine）< 1.5ULN Individuals who participate this study and sign the informed consent form willingly. Exclusion Criteria: Individuals with colorectal adenoma or non-colorectal cancer, such as inflammatory bowel disease Individuals with a history of familial adenomatous polyposis (FAP) Individuals with severe heart, lung, brain, kidney, gastrointestinal or systemic diseases Individuals who used antibiotics for more than 5 days in 1 month prior to chemotherapy Individuals with stage I or IV colorectal cancer, or with stage II colorectal cancer who do not need postoperative chemotherapy Individuals with contraindications for metronidazole Individuals who unwilling to participate this study，or unwilling to sign the informed consent form Individuals with any conditions that the researchers considered inappropriate for inclusion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metronidazole<br>supplement of metronidazole 0.4g three times per day for 7 days, which is one treatment every 4 weeks for mFOLFOX6(6 treatments totally),and every 6 weeks for CapeOX (4 treatments totally). | Drug: Metronidazole Oral Tablet<br>* Supplement of metronidazole 0.4g three times per day for 7 days before each two cycles of chemotherapy (mFOLFOX6 once every 4 weeks, CapeOX once every 6 weeks), which is 6 treatments for mFOLFOX6 and 4 treatments for CapeOX totally.<br>|
| Placebo Comparator: Placebo<br>supplement of identical-appearing placebo 0.4g three times per day for 7 days, which is one treatment every 4 weeks for mFOLFOX6 (6 treatments totally),and every 6 weeks for CapeOX 4 treatments totally). | Drug: Placebo oral tablet<br>* Supplement of placebo oral tablet 0.4g three times per day for 7 days before each two cycles of chemotherapy (mFOLFOX6 once every 4 weeks, CapeOX once every 6 weeks), which is 6 treatments for mFOLFOX6 and 4 treatments for CapeOX totally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival, DFS | The time from the initial surgical treatment of colorectal cancer to the earliest evidence of recurrence. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival, OS | The time from the initial surgical treatment of colorectal cancer to death from any cause. | 5 years | 
| Recurrence Rate, RR | Percentage of patients who has recurrence during or after chemotherapy with Metronidazole or Placebo. | 3 years, 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metronidazole, Gut Microbiota, Postoperative Chemotherapy, Colorectal Cancer, Fusobacterium nucleatum