Rectal Bacteriotherapy, Fecal Microbiota Transplantation or Oral Vancomycin Treatment of Recurrent Clostridium Difficile Infections

Clostridium Difficile Clinical Trial

Official title:

Rectal Bacteriotherapy, Fecal Microbiota Transplantation or Oral Vancomycin Treatment of Recurrent Clostridium Difficile Infections

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02774382
• Other study ID #: SJ-478
• Status: Recruiting
• Phase: Phase 3
• First received: April 4, 2016
• Last updated: September 26, 2017
• Start date: May 1, 2017
• Est. completion date: January 2019

Study information

• Verified date: September 2017
• Source: Hvidovre University Hospital
• Contact: Andreas M Petersen, MD, PhD
• Phone: +4538625960
• Email: andreasmunkpetersen[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 450
• Est. completion date: January 2019
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Clostridium Difficile
• Infection

Intervention

Drug:
• Vancomycin
Already incl. in arm description
• Fecal microbiota transplantation
Already incl. in arm description
• Rectal bacteriotherapy
Already incl. in arm description

Locations

Country	Name	City	State
Denmark	Hvidovre Hospital	Hvidovre
Denmark	Køge sygehus	Køge

Sponsors (1)

Lead Sponsor	Collaborator
Hvidovre University Hospital

Country where clinical trial is conducted

Denmark, 

References & Publications (6)

Cammarota G, Masucci L, Ianiro G, Bibbò 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. — View 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. Review. Erratum in: N Engl J Med. 2010 Oct 14;363(16):1585. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical cure of recurrent Clostridium difficile infection defined as patient-reported abscence of Clostridium difficile infection 90 days after treatment.	Clinical cure defined as patient-reported abscence of Clostridium difficile infection 90 days after treatment. The investigator will call the patient by telephone and fill out af digital questionnaire.	90 days
Secondary	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).	Patient with recurrence of CDI in the follow up period will be categorized as an early recurrence if the recurrence is in the first 30 days after treatment and as a late recurrence if the recurrence is after 180 days after treatment. The investigator will call the patient by telephone and fill out af digital questionnaire and thereafter categorize the patient.	30 and 180 days after ended treatment
Secondary	Days with diarrhea		1, 4, 8 and 12 days after ended treatment
Secondary	CDI-associated hospital admission and hospital admission of other causes in the follow-up period		180 days after ended treatment
Secondary	CDI-associated hospital outpatient contact and hospital outpatient contact of other causes in the follow-up period		180 days after ended treatment
Secondary	CDI-associated mortality and all-cause mortality		30, 90 and 180 days after ended treatment
Secondary	Compare numbers of patients with clinical cure after study treatment divided into two groups depending on numbers of recurrences of CDI.	Clinical cure is defined as patient-reported abscence of Clostridium difficile infection 90 days after treatment. The investigator will call the patient by telephone and fill out a digital questionnaire. Number of patients with clinical cure of recurrent Clostridium difficile infection will be divided into two groups according to numbers of recurrences of CDI; Group 1; patients with one recurrence; Group 2; patients with 2 or more recurrences. The division will be done based on patient records and the questionnaire. The information will be aggregated in the digital journal unique to this trial. The numbers of patients with clinical cure in the two groups will be compared to see if one group response better to study treatment than the other.	90 days after ended treatment
Secondary	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.	The investigator will call the patient by telephone and fill out af digital questionnaire. The lab result will give the investigator information about which strain the patient was infected with and this will be aggregated in the digital patient journal.	90 days after ended treatment
Secondary	Effect of the treatment depending on the patients serum-level of antibodies towards toxin A and B at the time of inclusion.	At inclusion the investigator will collect a blood sample to analysis for toxin A and B antibodies. The lab result will be aggregated in the digital patient journal.	90 days after ended treatment
Secondary	Side effects in the three treatment arms		14 days after ended treatment
Secondary	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.	Performed in a subgroup of patients.	180 days after ended treatment
Secondary	Other antibiotic treatments associated with new recurrences of CDI	The investigator will call the patient by telephone and fill out af digital questionnaire. Furthermore the investigator has access to a database with all prescription drugs incl. antibiotics. These informations will be collected and aggregated in the digital patient journal unique for this study.	Within 180 days after ended treatment
Secondary	Evaluation of the composition of bile acids before and after treatment with FMT/RBT.	Analyzed in conjunction with the microbiota composition and the treatment effect. Performed in a subgroup of patients.	90 days after ended treatment
Secondary	Characterisation of the CD strains by whole genome sequencing	Characterisation of the CD strains involved to determine if a potential recurrence is a true recurrence or a reinfection with another strain. Whole genome sequencing will be performed by the department of Clinical Microbiology in Hvidovre Hospital. This information will be collected by the investigator and aggregated in the digital patient journal unique for this trial.	90 days after ended treatment
Secondary	Identification of age as a risk factor for treatment success/failure	The investigator will call the patient by telephone for information about abscence of CDI and fill out af digital questionnaire. This information and the patient's age will be aggregated in the digital patient journal.	90 days after ended treatment
Secondary	Identifying if Charlson comorbidity index is associated to treatment success/failure.	At inclusion the patient's Charlson Comorbidity index will be calculated and put in the patient's record unique to this trial.	90 days after ended treatment

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