Fecal Transplantation for Primary Clostridium Difficile Infection

Clostridium Difficile Infection Clinical Trial

— COLONIZE  

Official title:

COmparative Effectiveness of intestinaL microbiOta Versus vaNcomycin for Primary c. Difficile Infection - randomiZEd Trials

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03796650
• Other study ID #: COLONIZE
• Status: Recruiting
• Phase: Phase 3
• Start date: July 17, 2019
• Est. completion date: January 31, 2024

Study information

• Verified date: April 2022
• Source: Oslo University Hospital
• Contact: Kjetil Garborg, MD, PhD
• Phone: +4741578975
• Email: k.k.garborg[@]medisin.uio.no
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In this randomized controlled trial the investigators want to compare the effect of one-time rectal instillation of fecal microbiota transplantation, compared to a ten-day antibiotic course for the treatment of primary Clostridium difficile infection (CDI). The investigators hypothetsize that the instillation of feces from a healthy donor will be non-inferior to vancomycin in inducing a durable cure.

Description:

Up to one third of patients with clostridium difficile infection treated with antibiotics experience recurrent or relapsing symptoms within a few weeks. Even with subsequent antibiotic treatment, multiple recurrences/relapses are frequent. Fecal microbiota transplantation (FMT) has been shown to be significantly more effective in curing recurrent CDI than repeated antibiotic treatment. In current guidelines, FMT is proposed as a treatment option after multiple recurrences/relapses of CDI. The rationale to reserve transplantation of donor feces for recurrent and difficult cases of CDI is a possible risk of pathogen transmittance and the process of finding a donor and screen for communicable disease.

The effect of FMT for recurrent CDI, however, suggests that this therapy may be more effective than antibiotics in inducing a durable cure also for primary CDI. If the therapeutic effect of FMT proves to be equal (non-inferior) or more effective than antibiotics, FMT may be the preferable treatment option due to favourable ecological impact compared to antibiotics. In an era with increasing concerns about overuse of antibiotics and emergence of antibiotic resistant bacteria, it is important to investigate therapeutic alternatives that may reduce the need for antibiotics.

This trial is a phase III multicentre, randomized controlled, open-label non-inferiority parallel group trial with two arms (FMT and antibiotics), and is a continuation of the phase II trial IMT for Primary Clostridium Difficile Infection (NCT02301000). In the current trial, patients with Clostridium difficile infection and no previous CDI within 12 months prior to inclusion will be randomized 1:1 to FMT or 10 days of guideline-recommended antibiotic therapy (vancomycin 125 mg four times a day).

Patients are recruited in Norwegian hospitals.

The investigators plan to use frozen microbiota, because supply is easier to organize, compared to fresh fecal samples. Patients in the FMT treatment group will receive one rectal dose of FMT, originating from screened, healthy donors. Patients who are not cured by the first dose is offered a protocol defined additional FMT treatment. In the case of clinical deterioration, appropriate measures will be undertaken according to current guidelines.

Patient treatment outcomes are evaluated after 14, 60 and 365 days from inclusion and treatment initiation.

An interim analysis is planned after inclusion of the first 94 patients (corresponding to 50% of the planned number of patients).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 188
• Est. completion date: January 31, 2024
• Est. primary completion date: January 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients, =18 years with primary C. difficile infection, defined by the following three criteria:

1. Diarrhea as defined by the WHO (=3 loose stools per day), and

2. Positive stool test for toxin producing C. difficile, and

3. No evidence of previous C. difficile infection during 365 days before enrolment.

• Written informed consent

Exclusion Criteria:

• Known presence of other stool pathogens known to cause diarrhea.

• Ongoing antibiotic treatment for other infections that cannot be stopped before study treatment administration.

• Inflammatory bowel disease or microscopic colitis.

• < 3 months life expectancy.

• Serious immunodeficiency, defined as one of the following:

• Ongoing or recent chemotherapy and current or expected neutropenia with neutrophil count of < 500/µL.

• Active severe immunocompromising disease.

• Inability to comply with protocol requirements.

• Need of intensive care.

• Known irritable bowel syndrome, diarrheal type.

• Pregnancy or nursing.

• Known or suspected toxic megacolon or ileus.

• Total or subtotal colectomy, ileostomy or colonostomy.

• Contraindications for rectal catheter insertion

• Known hypersensitivity or other contraindications to vancomycin

Related Conditions & MeSH terms

• Clostridium Difficile Infection
• Clostridium Infections
• Communicable Diseases
• Enterocolitis, Pseudomembranous
• Infections

Intervention

Other:
• Fecal microbiota transplantation
50 g donor feces suspended in saline with added glycerol, administered by a enema kit.

Drug:
• Vancomycin
Peroral vancomycin 125 mg q.i.d. for ten days.

Locations

Country	Name	City	State
Norway	Ålesund Sjukehus	Ålesund
Norway	Haukeland universitetssykehus	Bergen
Norway	Nordlandssykehuset	Bodø
Norway	Sykehuset Østfold Kalnes	Grålum
Norway	UNN Harstad	Harstad
Norway	Sørlandet Hospital HF	Kristiansand
Norway	Sykehuset Levanger	Levanger
Norway	Sykehuset Innlandet HF	Lillehammer
Norway	Akershus University Hospital	Lørenskog
Norway	Diakonhjemmet Hospital	Oslo
Norway	Lovisenberg sykehus	Oslo
Norway	Oslo University Hospital Rikshospitalet	Oslo
Norway	Oslo University Hospital Ullevål	Oslo
Norway	Vestre Viken HF, Bærum Hospital	Sandvika	Gjettum
Norway	Telemark Hospital HF	Skien
Norway	Stavanger University Hospital	Stavanger
Norway	Sykehuset i Vestfold	Tønsberg
Norway	UNN Tromsø	Tromsø

Sponsors (17)

Lead Sponsor

Collaborator

Oslo University Hospital

Alesund Hospital, Diakonhjemmet Hospital, Haukeland University Hospital, Helse Nord-Trøndelag HF, Helse Stavanger HF, Lovisenberg Diakonale Hospital, Nordlandssykehuset HF, Ostfold Hospital Trust, Sorlandet Hospital HF, South-Eastern Norway Regional Health Authority, Sykehuset Innlandet HF, Sykehuset Telemark, The Hospital of Vestfold, University Hospital of North Norway, University Hospital, Akershus, Vestre Viken Hospital Trust

Country where clinical trial is conducted

Norway, 

References & Publications (5)

Juul FE, Garborg K, Bretthauer M, Skudal H, Øines MN, Wiig H, Rose Ø, Seip B, Lamont JT, Midtvedt T, Valeur J, Kalager M, Holme Ø, Helsingen L, Løberg M, Adami HO. Fecal Microbiota Transplantation for Primary Clostridium difficile Infection. N Engl J Med. 2018 Jun 28;378(26):2535-2536. doi: 10.1056/NEJMc1803103. Epub 2018 Jun 2. — View Citation

Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013 Apr;108(4):500-8. doi: 10.1038/ajg.2013.59. Epub 2013 Mar 19. Review. — View Citation

Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015 Apr 16;372(16):1539-48. doi: 10.1056/NEJMra1403772. Review. — View Citation

McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Shaklee Sammons J, Sandora TJ, Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66(7):987-994. doi: 10.1093/cid/ciy149. — View Citation

van Nood E, Dijkgraaf MG, Keller JJ. Duodenal infusion of feces for recurrent Clostridium difficile. N Engl J Med. 2013 May 30;368(22):2145. doi: 10.1056/NEJMc1303919. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Fecal composition and treatment outcome	Correlation in fecal composition changes before versus after treatment, and treatment outcome (such as bacterial diversity and fecal short chain fatty acids).; Subgroup analyses will be performed for sex, age, co-morbidities, and FMT donor.	60 days
Primary	Patients with durable cure	Proportion of patients with primary clinical cure at day 14 after treatment start and no recurrent C. difficile infection during 60 days after treatment start, with the assigned treatment alone.	60 days
Secondary	Patients with durable cure with additional treatment.	Proportion of patients with primary clinical cure at day 14 after treatment start and no recurrent C. difficile infection during 60 days after treatment start, with or without the need of additional treatment (FMT, metronidazole or vancomycin).	60 days
Secondary	Treatment adverse events	Proportion of patients with adverse events.	60 and 365 days
Secondary	Patients with long-time cure	Proportion of patients with primary clinical cure at day 14 after treatment start and no recurrent C. difficile infection during 60 days after treatment start, and without recurrent C. difficile infection within 365 days after treatment start.	365 days
Secondary	Health-economic evaluation	Health-economic analysis of the two compared treatment modalities	365 days

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