Fecal Transplantation for Primary Clostridium Difficile Infection

NCT ID: NCT03796650

Last Updated: 2024-09-19

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 104 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-07-17
• Study Completion Date: 2024-04-02

Brief 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.

Detailed 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).

Conditions

Clostridium Difficile Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Fecal microbiota transplantation

Fecal microbiota from healthy, screened stool donors at the University Hospital of North Norway. Patients will receive one FMT enema immediately after enrolment.

Group Type: EXPERIMENTAL

Fecal microbiota transplantation

Intervention Type: OTHER

50 g donor feces suspended in saline with added glycerol, administered by a enema kit.

Antibiotic treatment

Patients randomized to the control group will receive a ten-day course of oral vancomycin four times a day. This is according to international guidelines for primary C. difficile treatment.

Group Type: ACTIVE_COMPARATOR

Vancomycin

Intervention Type: DRUG

Peroral vancomycin 125 mg q.i.d. for ten days.

Interventions

Fecal microbiota transplantation

50 g donor feces suspended in saline with added glycerol, administered by a enema kit.

Intervention Type: OTHER

Vancomycin

Peroral vancomycin 125 mg q.i.d. for ten days.

Intervention Type: DRUG

Other Intervention Names

FMT; IMT; Bacteriotherapy

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

South-Eastern Norway Regional Health Authority

OTHER

Sponsor Role: collaborator

University Hospital of North Norway

OTHER

Sponsor Role: collaborator

Haukeland University Hospital

OTHER

Sponsor Role: collaborator

Helse Nord-Trøndelag HF

OTHER

Sponsor Role: collaborator

Vestre Viken Hospital Trust

OTHER

Sponsor Role: collaborator

The Hospital of Vestfold

OTHER

Sponsor Role: collaborator

Sykehuset Telemark

OTHER_GOV

Sponsor Role: collaborator

Alesund Hospital

OTHER

Sponsor Role: collaborator

University Hospital, Akershus

OTHER

Sponsor Role: collaborator

Lovisenberg Diakonale Hospital

OTHER

Sponsor Role: collaborator

Sorlandet Hospital HF

OTHER_GOV

Sponsor Role: collaborator

Ostfold Hospital Trust

OTHER

Sponsor Role: collaborator

Diakonhjemmet Hospital

OTHER

Sponsor Role: collaborator

Nordlandssykehuset HF

OTHER

Sponsor Role: collaborator

Sykehuset Innlandet HF

OTHER

Sponsor Role: collaborator

Helse Stavanger HF

OTHER_GOV

Sponsor Role: collaborator

Oslo University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Kjetil Garborg

Joint Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michael Bretthauer, MD, PhD

Role: STUDY_CHAIR

Oslo Universitetssykehus HF, Rikshospitalet

Locations

Vestre Viken HF, Bærum Hospital

Sandvika, Gjettum, Norway

Diakonhjemmet Hospital

Oslo, Oslo County, 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

Lovisenberg sykehus

Oslo, , Norway

Oslo University Hospital Rikshospitalet

Oslo, , Norway

Oslo University Hospital Ullevål

Oslo, , Norway

Telemark Hospital HF

Skien, , Norway

Stavanger University Hospital

Stavanger, , Norway

UNN Tromsø

Tromsø, , Norway

Sykehuset i Vestfold

Tønsberg, , Norway

Countries

Norway

References

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.

Reference Type: BACKGROUND

PMID: 29562266 (View on PubMed)

Juul FE, Garborg K, Bretthauer M, Skudal H, Oines MN, Wiig H, Rose O, Seip B, Lamont JT, Midtvedt T, Valeur J, Kalager M, Holme O, Helsingen L, Loberg 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. No abstract available.

Reference Type: BACKGROUND

PMID: 29860912 (View on PubMed)

Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015 Apr 16;372(16):1539-48. doi: 10.1056/NEJMra1403772. No abstract available.

Reference Type: BACKGROUND

PMID: 25875259 (View on PubMed)

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. No abstract available.

Reference Type: BACKGROUND

PMID: 23718168 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23511459 (View on PubMed)

Juul FE, Bretthauer M, Johnsen PH, Samy F, Tonby K, Berdal JE, Hoff DAL, Ofstad EH, Abraham A, Seip B, Wiig H, Rognstad OB, Glad IF, Valeur J, Nissen-Lie AE, Ness-Jensen E, Lund KMA, Skjevling LK, Hanevik K, Skudal H, Melsom EJ, Boyar R, Cooper TJ, Ranheim TE, Riise EM, Adami HO, Kalager M, Loberg M, Garborg KK. Fecal Microbiota Transplantation Versus Vancomycin for Primary Clostridioides difficile Infection : A Randomized Controlled Trial. Ann Intern Med. 2025 Jul;178(7):940-947. doi: 10.7326/ANNALS-24-03285. Epub 2025 Jun 17.

Reference Type: DERIVED

PMID: 40523286 (View on PubMed)

Related Links

https://www.med.uio.no/helsam/english/research/groups/clinical-effectiveness/index.html

Investigating research group' home page

Other Identifiers

COLONIZE

Identifier Type: -

Identifier Source: org_study_id