Study of Oral Metronidazole on Postoperative Chemotherapy in Colorectal Cancer

Sponsor

Shanghai Jiao Tong University School of Medicine (Other)

Overall Status

Recruiting

CT.gov ID

NCT04264676

Collaborator

Shanghai Municipal Commission of Health and Family Planning (Other), Ruijin Hospital (Other), Fudan University (Other), Shanghai Zhongshan Hospital (Other), Shanghai Shenkang Hospital Development Center (Other)

294

Enrollment

Locations

Arms

Anticipated Duration (Months)

73.5

Patients Per Site

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Stage II Colorectal Cancer Stage III	Drug: Metronidazole Oral Tablet Drug: Placebo oral tablet	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

294 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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.

Actual Study Start Date :

Mar 31, 2020

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Mar 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Metronidazole 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 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.
Placebo Comparator: Placebo 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 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.

Arm

Intervention/Treatment

Active Comparator: Metronidazole

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

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.

Placebo Comparator: Placebo

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

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.

Outcome Measures

Primary Outcome Measures

Disease Free Survival, DFS [5 years]
The time from the initial surgical treatment of colorectal cancer to the earliest evidence of recurrence.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Division of Gastroenterology and Hepatology, Ren-Ji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai Institute of Digestive Disease; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health	Shanghai	Shanghai	China	200001
2	Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine	Shanghai	Shanghai	China	200025
3	Fudan University Shanghai Cancer Center	Shanghai	Shanghai	China	200032
4	Zhongshan Hospital affiliated to Fudan University	Shanghai	Shanghai	China	200032