A Novel Faecal Microbiota Transplantation System for Treatment of Primary and Recurrent Clostridium Difficile Infection

Study Overview
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Brief Summary
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This study is a two-arm, interventional, prospective, open-label, multi-center clinical trial with randomized and non-randomized study groups to evaluate the safety and effectiveness of faecal microbiota transplantation (FMT) for the treatment of adult patients suffering from primary or recurrent Clostridium difficile infection (CDI), using a novel, standardized microbiota transplantation system.

Detailed Description
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Clostridium difficile is an anaerobe, spore-forming bacillus. Infections with its toxin-producing strains are capable of causing CD associated enteral disease ranging in severity from mild diarrhea to fatal fulminant colitis. CD infection(CDI) occurs among patients who have taken antibiotics previously, suggesting that the normal gut flora is capable of preventing CDI. The disease is mainly treated with antibiotics, however, these antibiotics show high therapeutic failure and recurrence rates. There is significant interest in the development of alternative therapeutic strategies. Among the alternative methods only faecal microbiota transplantation (FMT) is gaining acceptance due to its excellent cure rate and low recurrence rate. FMT is a new approach to treating CDI, since no further antibiotics are administered, instead the normal gut flora being restored by administering faecal homogenisate from a healthy donor. Immediate risks of FMT are minimal, its efficacy is excellent,but further data is required about its short and long term safety, its most appropriate timing during the course of CDI and the optimal technical protocol for preparing the fecal homogenisate. In addition, the procedure is also challenging and the intervention itself is unappealing in nature. To address the challenges described above a novel faecal transplantation system has been designed (Burgin-Matic System, BMS), which is suitable for the production of faecal bacterial suspension in a standardized and controlled environment. Using this new approach, a multi-center,prospective,interventional clinical study involving two groups of patients has been designed: 1. In a non-randomized group(R) the safety and efficacy of FMT with the new, automated transplantation system will be assessed on 50 patients suffering from Recurrent CDI. 2. In a randomized group (F) FMT will be compared with the gold standard vancomycin treatment for 2x50 patients, with their First episode of CDI, suffering from severe infection or at risk of developing recurrent or severe disease and not responding to at least 72 hours of antibiotic treatment. In the non-randomized group(R), the safety and efficacy of FMT will be assessed,with the hypothesis that FMT with the BMS is equally safe and effective(non-inferior)as reported in the international studies. In the randomized group (F) primary endpoints will be the clinical cure rate at various time points, global cure rate at 10 weeks, time to clinical cure and time to global cure, while as secondary endpoints the cost effectiveness, quality of life, mortality will be assessed also. Our hypothesis is, that FMT with the BMS is superior to vancomycin treatment in terms of primary and secondary endpoints for these patients.

Official Title
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Two-arm, Interventional, Prospective, Open-label, Multi-center Trial to Evaluate the Safety & Effectiveness of FMT for Treatment of Adult Patients With Primary or Recurrent CDI, Using a Novel, Standardized Microbiota Transplantation System

Conditions
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Clostridium Difficile Infection

Intervention / Treatment
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* Biological: faecal human microbiota transplant (FMT)
* Drug: Vancomycin or Fidaxomicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Group R:- recurrent CDI;- positive stool toxin test within 72 hours before enrolment Group F:- first (initial) episode of CDI;- enrolled patient falls in at least one of the following categories:high risk of recurrence or high risk of developing severe CDI or severe or life-threatening CDI;- patient requires hospitalization or CDI occurs during a hospital stay;- persisting symptoms despite least 72 hours of adequate antibiotic treatment;-positive stool CD toxin test obtained within 72 hours before screening;- in all cases, primary consideration must be given to the severity and pace of the patient's CDI when deciding whether early use of FMT is appropriate to prevent further clinical deterioration. Exclusion Criteria: absence of either patient's or its legally authorized representative's informed consent inability or unwillingness to comply with protocol requirements severe co-morbidities, terminal underlying disease with a life expectancy of less than 90 days pregnancy or breastfeeding active gastroenteritis caused by microorganisms other than CD underlying chronic gastrointestinal disease that causes diarrhoea such as autonomic diabetic neuropathy, short bowel syndrome, faecal incontinence, active inflammatory bowel disease alimentary or over-the-counter drog allergy with previous anaphylactic reaction absolute contraindication to FMT

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recurrent CDI FMT<br>Non-randomized group (R) for treatment of recurrent CDI with FMT | Biological: faecal human microbiota transplant (FMT)<br>* Non-randomized group R: Patients with recurrent CD infection are treated with FMT in this group. Randomized group FFMT: patients with initial CD infection who have severe disease or who are at high risk of recurrence or high risk of developing severe disease are treated with FMT.<br>* Other names: FMT;|
| Active Comparator: Primary CDI antibiotic<br>Randomized group (F AB) for the treatment of primary CDI with antibiotics (vancomycin or fidaxomicin) | Drug: Vancomycin or Fidaxomicin<br>* Randomized group FAB: patients with initial CD infection who have severe disease or who are at high risk of recurrence or high risk of developing severe disease are treated with antibiotics (vancomycin per os 125mg four times a day for 10 days) in this group. In case of treatment failure changes in antibiotic regime (e.g. fidaxomicin per os 200mg per two times a day for 10 days) will be allowed in the line with the recommendations of current CDI treatment guidelines(13).<br>|
| Experimental: Primary CDI FMT<br>Randomized group (F FMT) for the treatment of primary CDI with FMT | Biological: faecal human microbiota transplant (FMT)<br>* Non-randomized group R: Patients with recurrent CD infection are treated with FMT in this group. Randomized group FFMT: patients with initial CD infection who have severe disease or who are at high risk of recurrence or high risk of developing severe disease are treated with FMT.<br>* Other names: FMT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global cure rate at 10 weeks |  | 10 weeks after enrolment | 
| Time to clinical cure | The number of days between enrolment and the resolution of diarrhoea | Through study completion, an average of 18 months | 
| Time to global cure | The number of days between enrolment and the resolution of diarrhoea without relapse | Through study completion, an average of 18 months | 
| Cure rate at 2 weeks |  | 2 weeks after enrolment | 
| Cure rate at 4 weeks |  | 4 weeks after enrolment | 
| Treatment failure rate |  | Through study completion, an average of 18 months | 
| Recurrence rate 8 weeks after clinical cure |  | 8 weeks after clinical cure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events (AE) | Number of participants with treatment related adverse events | Through study completion, an average of 18 months | 
| Number of serious adverse events (SAE) | Number of participants with treatment related serious adverse events | Through study completion, an average of 18 months | 
| Time of hospitalization |  | Through study completion, an average of 18 months | 
| Days without diarrhoea during study period |  | Through study completion, an average of 18 months | 
| Patient related quality of life | Measured with EuroQoL 5Q-TL questionnaire | 0, 7, 14 days after enrolment | 
| Professional acceptance | A modified TSQM-14 questionnaire for assessing professional acceptance will be used during the study | Through study completion, an average of 18 months | 
| General health survey for patients | Measured with SF-36v2 questionnaire | 0, 7, 14 days after enrolment | 
| Patient anxiety and depression | Measured with HAD Scale (HADS) | 0, 14, 70 days after enrolment | 
| Patient acceptance of treatment | Measure with TSQM-14 questionnaire | 14,70 days after enrolment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fecal microbiota transplantation (FMT), Clostridium difficile infection, gut flora, human microbiome, colitis