Fecal Transplantation for Primary Clostridium Difficile Infection (COLONIZE)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Clostridium Difficile Infection
• Intervention / Treatment: Other: Fecal microbiota transplantation; Drug: Vancomycin

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 Type: Interventional
• Enrollment (Anticipated): 188
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Kjetil Garborg, MD, PhD; Phone Number: +4741578975; Email: k.k.garborg@medisin.uio.no
• Study Contact Backup: Name: Frederik Emil Juul, MD; Phone Number: +4797512966; Email: f.e.juul@medisin.uio.no

Study Locations

• Norway
  • Bergen, Norway
    • Recruiting
    • Haukeland Universitetssykehus
    • Contact: Trygve Hausken, MD, PhD
  • Bodø, Norway, 8092
    • Recruiting
    • Nordlandssykehuset
    • Contact: Eirik H Ofstad, MD, PhD
  • Grålum, Norway
    • Recruiting
    • Sykehuset Østfold Kalnes
    • Contact: Jon Birger Haug, MD, PhD
  • Harstad, Norway
    • Recruiting
    • UNN Harstad
    • Contact: Peter H. Johnsen, MD
  • Kristiansand, Norway
    • Recruiting
    • Sørlandet Hospital HF
    • Contact: Håvard Wiig, MD
    • Sub-Investigator: Rita Helleren, MD
  • Levanger, Norway
    • Recruiting
    • Sykehuset Levanger
    • Contact: Eivind Ness-Jensen, MD, PhD
  • Lillehammer, Norway
    • Recruiting
    • Sykehuset Innlandet HF
    • Contact: Ragnhild Eiken, MD
  • Lørenskog, Norway, 1478
    • Recruiting
    • Akershus University Hospital
    • Contact: Jan Erik Berdal, MD, PhD
  • Oslo, Norway, 0319
    • Recruiting
    • Diakonhjemmet Hospital
    • Contact: Raziye B. Cetinkaya, MD, PhD
  • Oslo, Norway
    • Recruiting
    • Lovisenberg sykehus
    • Contact: Jørgen Valeur, MD, PhD
  • Oslo, Norway
    • Recruiting
    • Oslo University Hospital Rikshospitalet
    • Contact: Frederik Emil Juul, MD; Email: f.e.juul@medisin.uio.no
    • Contact: Siv Elisabeth Isaksen
    • Principal Investigator: Kjetil Garborg, MD, PhD
  • Oslo, Norway
    • Recruiting
    • Oslo University Hospital Ullevål
    • Contact: Kristian Tonby, MD, PhD
    • Sub-Investigator: Frederik Emil Juul, MD
  • Skien, Norway
    • Recruiting
    • Telemark Hospital HF
    • Contact: Pavel Gudkov, MD
  • Stavanger, Norway
    • Not yet recruiting
    • Stavanger University Hospital
    • Contact: Trond J Cooper, MD
  • Tromsø, Norway
    • Recruiting
    • UNN Tromsø
    • Contact: Rasmus Goll, MD, PhD
  • Tønsberg, Norway
    • Recruiting
    • Sykehuset i Vestfold
    • Contact: Awet Abraham, MD
  • Ålesund, Norway
    • Recruiting
    • Alesund sjukehus
    • Contact: Dag Arne Lihaug Hoff, MD, PhD
  • Gjettum
    • Sandvika, Gjettum, Norway, 1346
      • Recruiting
      • Vestre Viken HF, Bærum Hospital
      • Contact: Øystein Rose, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Other: Fecal microbiota transplantation; 50 g donor feces suspended in saline with added glycerol, administered by a enema kit.; Other Names: FMT; IMT; Bacteriotherapy
Active Comparator: 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.	Drug: Vancomycin; Peroral vancomycin 125 mg q.i.d. for ten days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Treatment adverse events	Proportion of patients with adverse events.	60 and 365 days
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
Health-economic evaluation	Health-economic analysis of the two compared treatment modalities	365 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: Vestre Viken Hospital Trust; University Hospital of North Norway; Diakonhjemmet Hospital; Ostfold Hospital Trust; Helse Stavanger HF; Haukeland University Hospital; Sorlandet Hospital HF; Sykehuset Innlandet HF; The Hospital of Vestfold; Helse Nord-Trøndelag HF; Alesund Hospital; Sykehuset Telemark; University Hospital, Akershus; Nordlandssykehuset HF; South-Eastern Norway Regional Health Authority; Lovisenberg Diakonale Hospital
• Investigators: Study Chair: Michael Bretthauer, MD, PhD, Oslo Universitetssykehus HF, Rikshospitalet

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• Investigating research group' home page

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2019
• Primary Completion (Anticipated): January 31, 2024
• Study Completion (Anticipated): January 31, 2024

Study Registration Dates

• First Submitted: January 4, 2019
• First Submitted That Met QC Criteria: January 7, 2019
• First Posted (Actual): January 8, 2019

Study Record Updates

• Last Update Posted (Actual): April 29, 2022
• Last Update Submitted That Met QC Criteria: April 22, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Diarrhea; Antibiotics; Clostridium difficile; Fecal microbiota transplantation; Intestinal microbiota therapy; Investigator-initiated
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Infections; Communicable Diseases; Clostridium Infections; Anti-Infective Agents; Anti-Bacterial Agents; Vancomycin
• Other Study ID Numbers: COLONIZE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: The trial adheres to data sharing policies of the ICMJE. Data sharing is considered for each request by the principal investigators. Data sharing is not granted if they overlap with planned analyses. Data sharing requires all approvals by relevant authorities. Costs for data sharing will not be covered by the study group.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No