Clinical trial NCT02774382: Rectal Bacteriotherapy, Fecal Microbiota Transplantation or Oral Vancomycin Treatment of Recurrent Clostridium Difficile Infections
Official title: Rectal Bacteriotherapy, Fecal Microbiota Transplantation or Oral Vancomycin Treatment of Recurrent Clostridium Difficile Infections
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Clostridium Difficile
Keywords: Recurrence
Infection
Lead sponsor: Hvidovre University Hospital
Sponsor class: OTHER
First posted: 2016-05-17
Enrollment: 450
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to investigate if treatment with fecal microbiota transplantation or rectal bacteriotherapy is superior to standard vancomycin in patients with recurrent Clostridium Difficile infections.

Detailed description: Clostridium difficile infection (CDI) is the most common nosocomial infection in the western world. CDI is associated with high morbidity and mortality and is a great burden for the health care system leading Center of Disease Control and Prevention (CDC) to identify it as one of three most important/urgent threats to public health.

Despite antimicrobial treatment of CDI, 20% of the patients have recurrence of CDI. Due to a dysbiosis in the gut microbiota the antimicrobial treatment seems to be less effective.

Fecal microbiota transplantation (FMT) is an alternative treatment for recurrent CDI. Studies have shown a cure rate up to 90% in patients with recurrent CDI. One alternative to FMT is rectal bacteriotherapy (RBT) which is a standardized bacterial culture made in the laboratory consisting of 12 different bacteria. RBT has never been investigated in a clinical trial.

The project is a randomized controlled trial including 450 patients with recurrent CDI will be, after accepting participation, allocated to receive vancomycin alone or vancomycin followed by either FMT or RBT. The patients will be followed up for 180 days. Cure is defined as resolution of CDI symptoms 90 days after treatment.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Verified recurrent CDI with symptoms of CDI and microbiological verification (PCR).
* Previously treated for CDI with at least 10 days of vancomycin or metronidazole.
* Be able to read and understand Danish.

Exclusion Criteria:

* Life expectancy \< 3 months.
* Allergy toward vancomycin
* Other infection in the GI tract with clinical symptoms similar to CDI.
* Other illness in the GI tract with clinical symptoms similar to CDI.
* Use of antibiotics for more than 14 days treating other infections
* Planning pregnancy, pregnancy or breast feeding.
* Severe immune suppression which makes FMT/RBT relatively contraindicated

Primary outcomes:
measure: Clinical cure of recurrent Clostridium difficile infection defined as patient-reported abscence of Clostridium difficile infection 90 days after treatment.
timeFrame: 90 days
Secondary outcomes:
measure: Early or late recurrence of CDI after the end of treatment defined as recurrence of symptoms of CDI and a positive stool sample with Clostridium difficile (PCR).
timeFrame: 30 and 180 days after ended treatment
measure: Days with diarrhea
timeFrame: 1, 4, 8 and 12 days after ended treatment
measure: CDI-associated hospital admission and hospital admission of other causes in the follow-up period
timeFrame: 180 days after ended treatment
measure: CDI-associated hospital outpatient contact and hospital outpatient contact of other causes in the follow-up period
timeFrame: 180 days after ended treatment
measure: CDI-associated mortality and all-cause mortality
timeFrame: 30, 90 and 180 days after ended treatment
measure: Compare numbers of patients with clinical cure after study treatment divided into two groups depending on numbers of recurrences of CDI.
timeFrame: 90 days after ended treatment
measure: Effect of the treatment depending on the CD strain - i.e. toxin B CDI cases, toxin B plus binary toxin CDI cases and CD027 CDI cases.
timeFrame: 90 days after ended treatment
measure: Effect of the treatment depending on the patients serum-level of antibodies towards toxin A and B at the time of inclusion.
timeFrame: 90 days after ended treatment
measure: Side effects in the three treatment arms
timeFrame: 14 days after ended treatment
measure: Characterisation of the gut microbiota before and after treatment with FMT/RBT in conjunction with characterisation of the donor's microbiota or the RBT bacterial mix.
timeFrame: 180 days after ended treatment
measure: Other antibiotic treatments associated with new recurrences of CDI
timeFrame: Within 180 days after ended treatment
measure: Evaluation of the composition of bile acids before and after treatment with FMT/RBT.
timeFrame: 90 days after ended treatment
measure: Characterisation of the CD strains by whole genome sequencing
timeFrame: 90 days after ended treatment
measure: Identification of age as a risk factor for treatment success/failure
timeFrame: 90 days after ended treatment
measure: Identifying if Charlson comorbidity index is associated to treatment success/failure.
timeFrame: 90 days after ended treatment
Other outcomes:
Locations:
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital
city: Køge
country: Denmark
facility: Køge sygehus
Study officials:
affiliation: Hvidovre University Hospital
name: Andreas M Petersen, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kelly CP, LaMont JT. Clostridium difficile--more difficult than ever. N Engl J Med. 2008 Oct 30;359(18):1932-40. doi: 10.1056/NEJMra0707500. No abstract available.
citation: Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, Farley MM, Holzbauer SM, Meek JI, Phipps EC, Wilson LE, Winston LG, Cohen JA, Limbago BM, Fridkin SK, Gerding DN, McDonald LC. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015 Feb 26;372(9):825-34. doi: 10.1056/NEJMoa1408913.
citation: Olsen MA, Yan Y, Reske KA, Zilberberg MD, Dubberke ER. Recurrent Clostridium difficile infection is associated with increased mortality. Clin Microbiol Infect. 2015 Feb;21(2):164-70. doi: 10.1016/j.cmi.2014.08.017. Epub 2014 Oct 12.
citation: van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407-15. doi: 10.1056/NEJMoa1205037. Epub 2013 Jan 16.
citation: Cammarota G, Masucci L, Ianiro G, Bibbo S, Dinoi G, Costamagna G, Sanguinetti M, Gasbarrini A. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015 May;41(9):835-43. doi: 10.1111/apt.13144. Epub 2015 Mar 1.
citation: Tvede M, Tinggaard M, Helms M. Rectal bacteriotherapy for recurrent Clostridium difficile-associated diarrhoea: results from a case series of 55 patients in Denmark 2000-2012. Clin Microbiol Infect. 2015 Jan;21(1):48-53. doi: 10.1016/j.cmi.2014.07.003. Epub 2014 Oct 12.