Clinical trial NCT03796650: Fecal Transplantation for Primary Clostridium Difficile Infection
Official title: COmparative Effectiveness of IntestinaL MicrobiOta Versus VaNcomycin for Primary C. Difficile Infection - RandomiZEd Trials
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Clostridium Difficile Infection
Keywords: Clostridium difficile
Intestinal microbiota therapy
Fecal microbiota transplantation
Investigator-initiated
Antibiotics
Diarrhea
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: South-Eastern Norway Regional Health Authority
name: University Hospital of North Norway
name: Haukeland University Hospital
name: Helse Nord-Trøndelag HF
name: Vestre Viken Hospital Trust
name: The Hospital of Vestfold
name: Sykehuset Telemark
name: Alesund Hospital
name: University Hospital, Akershus
name: Lovisenberg Diakonale Hospital
name: Sorlandet Hospital HF
name: Ostfold Hospital Trust
name: Diakonhjemmet Hospital
name: Nordlandssykehuset HF
name: Sykehuset Innlandet HF
name: Helse Stavanger HF
First posted: 2019-01-08
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized clinical trial with two parallel treatment arms with a 1:1 allocation.
Primary purpose: TREATMENT

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).

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.
* \&lt; 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 \&lt; 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

Primary outcomes:
measure: Patients with durable cure
timeFrame: 60 days
Secondary outcomes:
measure: Patients with durable cure with additional treatment.
timeFrame: 60 days
measure: Treatment adverse events
timeFrame: 60 and 365 days
measure: Patients with long-time cure
timeFrame: 365 days
measure: Health-economic evaluation
timeFrame: 365 days
Other outcomes:
measure: Fecal composition and treatment outcome
timeFrame: 60 days
Locations:
city: Sandvika
country: Norway
facility: Vestre Viken HF, Bærum Hospital
state: Gjettum
city: Bergen
country: Norway
facility: Haukeland universitetssykehus
city: Bodø
country: Norway
facility: Nordlandssykehuset
city: Grålum
country: Norway
facility: Sykehuset Østfold Kalnes
city: Harstad
country: Norway
facility: UNN Harstad
city: Kristiansand
country: Norway
facility: Sørlandet Hospital HF
city: Levanger
country: Norway
facility: Sykehuset Levanger
city: Lillehammer
country: Norway
facility: Sykehuset Innlandet HF
city: Lørenskog
country: Norway
facility: Akershus University Hospital
city: Oslo
country: Norway
facility: Diakonhjemmet Hospital
city: Oslo
country: Norway
facility: Lovisenberg sykehus
city: Oslo
country: Norway
facility: Oslo University Hospital Rikshospitalet
city: Oslo
country: Norway
facility: Oslo University Hospital Ullevål
city: Skien
country: Norway
facility: Telemark Hospital HF
city: Stavanger
country: Norway
facility: Stavanger University Hospital
city: Tromsø
country: Norway
facility: UNN Tromsø
city: Tønsberg
country: Norway
facility: Sykehuset i Vestfold
city: Ålesund
country: Norway
facility: Ålesund Sjukehus
Study officials:
affiliation: Oslo Universitetssykehus HF, Rikshospitalet
name: Michael Bretthauer, MD, PhD
role: STUDY_CHAIR
References:
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.
citation: 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.
citation: 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.
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. No abstract available.
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.