Fecal Transplantation for Primary Clostridium Difficile Infection

Phase 3

• Conditions: Clostridium Difficile Infection
• Interventions: Other: Fecal microbiota transplantation; Drug: Vancomycin

• Registration Number: NCT03796650
• Lead Sponsor: Oslo University Hospital

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).

Study Timeline

• Study First Submitted: 2019-01-04
• Study First Submitted QC: 2019-01-07
• Study First Posted: 2019-01-08
• Study Start: 2019-07-17
• Status Verified: 2022-04
• Last Update Submitted: 2022-04-22
• Last Update Posted: 2022-04-29
• Primary Completion: 2024-01-31
• Study Completion: 2024-01-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 188

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fecal microbiota transplantation	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.
Antibiotic treatment	Vancomycin	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.

Primary Outcome Measures

Name	Time	Method
Patients with durable cure	60 days	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.

Secondary Outcome Measures

Name	Time	Method
Patients with durable cure with additional treatment.	60 days	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).
Treatment adverse events	60 and 365 days	Proportion of patients with adverse events.
Patients with long-time cure	365 days	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.
Health-economic evaluation	365 days	Health-economic analysis of the two compared treatment modalities

Trial Locations

Locations (18)

Sørlandet Hospital HF; 🇳🇴 Kristiansand, Norway

Sykehuset i Vestfold; 🇳🇴 Tønsberg, Norway

Sykehuset Levanger; 🇳🇴 Levanger, Norway

Ålesund Sjukehus; 🇳🇴 Ålesund, Norway

Vestre Viken HF, Bærum Hospital; 🇳🇴 Sandvika, Gjettum, Norway

Haukeland universitetssykehus; 🇳🇴 Bergen, Norway

Nordlandssykehuset; 🇳🇴 Bodø, Norway

Sykehuset Østfold Kalnes; 🇳🇴 Grålum, Norway

UNN Harstad; 🇳🇴 Harstad, 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

Telemark Hospital HF; 🇳🇴 Skien, Norway

Stavanger University Hospital; 🇳🇴 Stavanger, Norway

UNN Tromsø; 🇳🇴 Tromsø, Norway