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Single center non-randomized study: A trial of a combination therapy of fecal microbial transplantation and antibiotics for inflammatory bowel disease

A trial of a combination therapy of fecal microbial transplantation and antibiotics for inflammatory bowel disease

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Recently, the efficacy and safety of fecal transplantation therapy for ulcerative colitis (UC) have been reported in adults, and it has also begun to be reported in children. Our research group has proposed "antimicrobial fecal transplantation therapy combined with antimicrobial agents (A-FMT)," in which three antimicrobial agents (AFM: amoxicillin, fosfomycin, and metronidazole) are administered as pretreatment before fecal transplantation, aiming for more effective reconstruction of the intestinal microflora and enhanced efficacy of fecal transplant therapy, and began clinical We started clinical studies in July 2014, and conducted "Investigation of the efficacy of stool transplantation therapy combined with antibiotic therapy for ulcerative colitis (UMIN ID: 000014152)", "Investigation of the efficacy of stool transplantation therapy and antibacterial therapy for patients with ulcerative colitis (UMIN ID: 000018642)" and "Analysis of factors related to the efficacy of stool transplantation therapy for patients with ulcerative colitis (UMIN ID: 000018642)". In this study, the age of indication was lowered from these studies to 6 years old, and the scope of participation was expanded to include patients with Crohn's disease, a disease designated as intractable, as a treatment option for patients who are forced to use immunosuppressive drugs from childhood for a long time and are poorly controlled with conventional drug therapy. Patients aged 16 years and older with active UC with a Lichtiger's clinical activity index (CAI) score more than 4 or Mayo endoscopic subscore (MES) more than1 were included in the clinical trial. Relatives or other volunteer donors aged 20 years or older were selected after rigorous screening. After 2 weeks of oral administration of three antibiotics, approximately 200 ml of fresh or frozen donor stools dissolved in saline solution were spread by colonoscopy. The patients were defined as "effective" if their CAI score improved to less than 9 points and more than 3 points after 4 weeks of treatment, and as "remission" if their CAI score improved further to less than 3 points. Seven patients (4 males and 3 females, mean age 37.9 years) and 6 donors (3 males and 3 females) participated in the study. Two patients had total colorectal type, four had left-sided colorectal type, and one had rectal localization, and five patients had severe CAI scores of 10 or more points before treatment, with a mean score of 11.14 points.

Between June 12, 2019 and September 13, 2019, seven patients and six donors were enrolled; starting August 12, 2020, a single-center, randomized, controlled trial evaluating the effect of alginate beverage after FMT, "Alginate Combination Stool Transplant Therapy for Ulcerative Colitis," jRCTs. 051190048 was initiated, so primarily UC patients aged 20 years and older were included in this study. This study was expected to recruit pediatric cases and was continued at the request of the pediatric department; however, no cases were enrolled due to the spread of coronavirus infection.

No serious illnesses or other specific adverse events occurred in this study.

The average CAI score before treatment decreased from 11.14 to 5.5 after 4 weeks. 5 of 7 cases were effective and the efficacy rate (71.0%), 3 cases were induction of remission, and the induction of remission rate was 42.9%. Comparison of efficacy factors between effective and ineffective cases showed no significant difference in blood inflammation markers WBC, CRP, and ESR. On the other hand, there was a significant difference in the reduction or disappearance of goblet cells in the histopathology between the active and inactive cases (p = 0.016). (p = 0.016). The analysis of enterobacterial composition was planned to be performed after the pediatric cases were enrolled, but due to the spread of coronavirus infection, the pediatric cases were not enrolled, and the analysis has not yet been performed. However, due to the spread of coronavirus infection, pediatric cases were not enrolled, and the analysis has not yet been conducted.

Regarding the main evaluation, both efficacy and remission rates were higher than those in previous study data (efficacy rate 56.3%, remission rate 34.5%, Koki Okahara, et al. Clin Med. 2020) in the evaluation of treatment efficacy using CAI, but we believe this was due to the small number of cases. Although no association between blood collection data and efficacy was observed, sap cells and phenomena were associated with therapeutic efficacy in pathological examination, suggesting that there is an associa

April. 30, 2023

Yes

We will submit these data to international medical and scientific journals related to gastroenterology and bacteriology.

https://jrct.mhlw.go.jp/latest-detail/jRCTs031180415

Ishikawa Dai

Juntendo University Hospital

3-1-3 Hongo Bunkyo-ku Tokyo,Japan

dai@juntendo.ac.jp

Ishikawa Dai

Juntendo University Hospital

2-1-1 Hongo, Bunkyo-ku, Tokyo

+81-3-3813-3111

dai@juntendo.ac.jp

Complete

Feb. 01, 2017

Interventional

non-randomized controlled trial

open(masking not used)

uncontrolled control

parallel assignment

treatment purpose

Patients
1. UC patients or CD patients (mild to severe) whose exclusion diagnosis of infectious enterocolitis is done.
2. Hospitalized patients or outpatients.
3. Written and oral informed consent with a sufficient understanding. For minors, in addition to informed assent, informed consent from a custodial person or a guardian.
Stool Donors
1. Healthy persons.
2. The choice of donor will be made according to the needs of the patient.
1) If we use relatives of patients as donor, the patient and their donor candidate will be present in front of the doctor confirming their will and sign the consent forms.
2) If we use non-relative as donor, one of those who have participated in this study or previous clinical studies of our department (Juntendo University Hospital Ethics Committee receipt number: 14-017 or 15-059) or a healthy person whom the investigator judges to have no health problem and who meets other donor selection criteria can be recommended to the patient as a donor.
3. A doctor interviews the donor candidate about the health condition, the past medical history, the life history, and the candidate answers correctly (those who refuse to answer are not allowed to participate).
4. Those who the doctor judged that there is no problem in health condition will take the following examinations.
1) Fecal examination: C.difficile toxin, Microscopy and culture, enterohemorrhagic Escherichia coli, Salmonella, Shigella, Yersinia, and Campylobacter, Ova, cysts, and parasites, fecal occult blood test
2) Blood test: Hepatitis A virus IgM, Hepatitis B virus surface antigen, hepatitis B virus surface antibody, hepatitis B virus core antibody, Hepatitis C virus antibody, HIV type 1 and 2, Human T-cell lymphotropic virus 1, Syphilis (RPR/TP), Cytomegalovirus antigen (C7-HRP), Entamoeba histolytica antibody, Tuberculosis (T-SPOT), Epstein-Barr virus IgM (VCA-IgM), Complete blood count, Electrolytes, urea, and creatinine. Erythrocyte sedimentation rate, C-reactive protein, Liver function tests, Albumin, Hepatitis E virus.

Patients
1. Those from whom the informed consent is not obtained.
2. All cases with liver disease, kidney disease, heart disease and other serious complications, judged inappropriate by the attending doctor.
3. Cases with complications of other autoimmune diseases.
4. Nursing women, pregnant women and all cases with the possibility of pregnancy.
5. Other cases judged inappropriate by the principal investigator.
Stool Donors
1. Those from whom the informed consent is not obtained.
2. Cases suspected of the infectious diseases in inquiries, blood test and fecal examination screening or having a past disease to be excluded.
Excluded disease:
Inflammatory bowel disease, irritable bowel syndrome, chronic diarrhea, severe constipation, colonic polyps, colon cancer, autoimmune diseases, atopic dermatitis, severe obesity, chronic fatigue syndrome.
3. Other cases judged inappropriate by the principal investigator.

Both

Inflammatory Bowel Disease (Ulcerative Colitis, Crohn's Disease)

AFM therapy arm : three antibiotics, amoxicillin (1500 mg/day), fosfomycin (3000 mg/day) and metronidazole (750 mg/day) are administered orally to patients for 2 weeks. For pediatric patients, amoxicillin (50mg/kg), fosfomycin (120mg/kg) and metronidazole (20mg/kg) are administered orally for 2 weeks (the upper limit is the same amount as adults).
FMT arm : Approximately 150 to 250 g of donor stool is diluted with saline (500 mL) and filtered to remove crude components. The diluted and filtered fecal suspension is transferred into the patients colon from cecum to rectum during total colonoscopy. As usual examinations, the patient undergoes biopsy of inflammatory site.
A-FMT arm : Patient undergoes FMT two days after AFM therapy.

Inflammatory Bowel Disease (Ulcerative Colitis, Crohn's Disease)

Antibiotics, FMT

Safety, Efficacy (clinical activity index, endoscopic score), Factors of efficacy (microbiota composition, blood data, pathological tissue analysis)

+81-3-5802-1584

Mar. 05, 2019

none