Primary or Recurrent Clostridioides Difficile Infection Treatment With Capsules of Lyophilised Faecal Microbiota vs Fidaxomicin

Study Overview
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Brief Summary
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Patients with microbiota alterations developed after being exposed to antibiotics are especially susceptible to Clostridioides difficile infections (CDI). The incidence and severity of CDI has increased in recent years and CDI recurrences (r-CDI) due to the appearance of new episodes in patients with a previous cured CDI, represent a serious and complex clinical issue. Although antibiotics are the recommended therapy for the first episode of CDI, treatment with oral vancomycin and/or metronidazole often results in significant treatment failure. In addition, the treatment of r-CDI is not adequately standardized, and although the most widely used treatment is the administration of fidaxomicin and bezlotoxumab, its efficacy in patients who already have r-CDI is not proven. In the late years, Fecal Microbiota Transfer (FMT) has emerged as the preferred non-pharmacological treatment to manage CDI with multiple recurrences and recent clinical trials have evaluated its potential efficacy and safety in the treatment of patients with primary CD infection. The objective of this study is to assess the efficacy and safety of the MBK-01 medication, consisting of heterologous lyophilized fecal microbiota capsules coming from healthy donors in comparison to the treatment with Fidaxomicin, in 66 patients with primary or r-CDI.

Detailed Description
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This is a Phase III, multicenter, controlled and open label clinical trial in which patients who suffered an episode of Clostridioides difficile infection (either the first episode or subsequent recurrences) will be randomly assigned (1:1) to one of the following arms: Dificlir (Fidaxomicina) MBK-01 (heterologous lyophilized fecal microbiota) Objective: To assess the efficacy of FMT with capsules of lyophilized fecal microbiota (MBK-01), compared to the control (fidaxomicin) at 8 weeks after the start of the treatment. To assess the safety of MBK-01 and the quality of life of patients participating in the study. Follow up: participants will return for clinic visits at 72 hours, week 3 and week 8 after the start of the treatment, and will receive follow-up phone calls at month 3 and month 6 after the start of the treatment. Stool samples will be collected from participants for further studies at time 0 and week 8 after the start of the treatment. Study Outcomes are detailed in the specific section of this website. Rationale: The transferred microbiota restores the recipient's intestinal microbiota by reintroducing bacterial taxa that were absent or in low proportion in the recipient before the FMT, supporting the expansion of the recipient's own commensal microbiota and re-establishing a microbiota community with a high biodiversity. Donors: All donors are screened to ensure they meet the strict requirements necessary to maintain the safety of the MBK-01. Justification: The treatment of Clostridioides difficile infections (CDI) with antibiotics is usually effective for acute symptoms, but after the initial treatment, the probability of recurrence at 8 weeks ranges from 10-20 % of cases, and once a patient has a recurrence, the probability of further recurrences increases up to 40-65 %. In recent years, Fecal Microbiota Transfer (FMT) has emerged as the preferred non-pharmacological treatment to manage CDI with multiple recurrences and recent clinical trials have evaluated its potential efficacy and safety in the treatment of patients with primary CD infection. Although antibiotics are the recommended therapy for the first episode of CDI, treatment with oral vancomycin and/or metronidazole often results in significant treatment failure, with recurrences occurring in up to 30-40% of patients. Furthermore, antibiotic treatment does not correct deficiencies in the intestinal microbiota that facilitate CD infection and is associated with the risk of the emergence of antibiotic-resistant bacteria. Moreover, the treatment of recurrences is not adequately standardized. In recent years, although the most widely used alternatives have been fidaxomicin and bezlotoxumab, their efficacy in patients who already suffer from r-CDI is not proven. The administration of the FMT through oral capsules, although it is not standardized, has proven to be effective in the restoration of intestinal microbiota of patients with r-CDI. In addition, the use of lyophilized formulas facilitates the concentration of bacteria and further optimizes the donors' sample and reduces the amount of capsules that the patient has to ingest.

Official Title
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A Randomised, Controlled, Open-label Phase III Clinical Trial in Patients With Primary or Recurrent Clostridioides Difficile (CD) Infection, to Evaluate the Efficacy and Safety of Capsules of Lyophilised Faecal Microbiota vs Fidaxomicin.

Conditions
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Recurrent Clostridium Difficile Infection, Primary Clostridium Difficile Infection

Intervention / Treatment
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* Biological: MBK-01
* Drug: Dificlir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of both genders, over 18 years. Patients that undergo an episode of CD infection (either the first episode or subsequent recurrences). Presence of an episode of diarrhea defined as ≥3 stools/24 hours, at the beginning of the episode. Confirmation of the presence of CD toxin A and/or B in faeces, by a direct toxin detection test or by the PCR technique for the detection of toxin/s producing genes, at the start of the episode that is going to be treated in the clinical trial (the toxin test must be positive within 7 days prior to the enrolment of the patient in the trial). Exclusion Criteria: Previous faecal microbiota transfer. Transplanted patients, except those with a solid organ transplant of more than 2 years, with good organ function. Absolute neutrophil count <500 cells /μL at the time of the enrollment in the study. Pregnancy, breastfeeding, or pregnancy intentions over the course of the study. Active treatment with bile acid sequestrants (for instance: cholestyramine). Positive patients for the human immunodeficiency virus (HIV) except those with lymphocytes T CD4 count > 200 cells/μL and viral load less than 20 copies. Swallowing dysfunction or no oral motor coordination. Patient admitted in an intensive care unit or expected to be admitted in an intensive care unit due to serious illness. History of significant medical conditions that, in the opinion of the investigator, would not allow an adequate evaluation or follow-up of the patient.

Ages Eligible for Study
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Minimum Age: 18 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: MBK-01<br>Participants will receive MBK-01 capsules of fecal microbiota coming from healthy donors (33 patients). | Biological: MBK-01<br>* A single dose of 4 capsules of MBK-01 (heterologous lyophilized fecal microbiota coming from healthy donors) orally.<br>* Other names: Fecal microbiota transfer;|
| Active Comparator: Fidaxomicin<br>Participants will receive Fidaxomicin (33 patients). | Drug: Dificlir<br>* Oral administration of 200mg/12 hours of fidaxomicin for 10 days.<br>* Other names: Fidaxomicin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global Absence of diarrhea: Number of episodes of diarrhea (3 or more stools/24 hours) 8 weeks after the start of the treatment | Diarrhea resolution: <3 stools/24 hours for at least 2 consecutive days after the end of the treatment. | 8 weeks after the start of the treatment | 
| Absence of diarrhea: Number of episodes of diarrhea (3 or more stools/24 hours) 72 hours after the start of the treatment | Diarrhea resolution: <3 stools/24 hours for at least 2 consecutive days after the end of the treatment. | 72 hours after the start of the treatment | 
| Absence of diarrhea: Number of episodes of diarrhea (3 or more stools/24 hours) 3 weeks after the start of the treatment | Diarrhea resolution: <3 stools/24 hours for at least 2 consecutive days after the end of the treatment. | 3 weeks after the start of the treatment | 
| Absence of diarrhea: Number of episodes of diarrhea (3 or more stools/24 hours) 3 months after the start of the treatment | Diarrhea resolution: <3 stools/24 hours for at least 2 consecutive days after the end of the treatment. | 3 months after the start of the treatment | 
| Absence of diarrhea: Number of episodes of diarrhea (3 or more stools/24 hours) 6 months after the start of the treatment | Diarrhea resolution: <3 stools/24 hours for at least 2 consecutive days after the end of the treatment. | 6 months after the start of the treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of hospitalisation | Time, in days, that the patient remains in the hospital as a result of CDI. | Up to 8 weeks after the start of the treatment | 
| Good/bad progress of the patient | A bad progress of the patient is defined as the detection 48-72 hours after the start of the treatment (MBK-01 or Fidaxomicin) of: A worsening of the diarrhea episode (at least one stool more than at baseline, baseline being understood as the time of the start of the study treatment (fidaxomicin or MBK01)). And, at least, one of the following factors: Increase in C-reactive protein (CRP) value (> 5 % of the baseline value). Increase in white blood cell count (> 5 % of the baseline value). Progression to sepsis: hypotension or organ failure with no other apparent cause. | Up to 72 hours after the start of the treatment | 
| Time to recurrence depending on randomisation groups | Recurrence: Reappearance of clinical manifestations of a new CDI episode in a patient with an CDI episode treated and cured in the previous 8 weeks. | Up to 6 months after the start of the treatment | 
| Duration of treatment | Duration in days of the treatment. | Up to 10 days | 
| Overall survival | Percentage of patients that are still alive after a defined period of time from the beginning of the treatment. | Up to 6 months after the start of the treatment | 
| Number of Adverse Events per randomisation group | Number of Adverse Events per randomisation group since baseline. | Up to 6 months after the start of the treatment | 
| Type of Adverse Events per ramdomisation group | Type of Adverse Events per ramdomisation group since baseline. | Up to 6 months after the start of the treatment | 
| Number of Serious Adverse Events per ramdomisation group | Number of Serious Adverse Events per ramdomisation group since baseline. | Up to 6 months after the start of the treatment | 
| Type of Serious Adverse Events per ramdomisation group | Type of Serious Adverse Events per ramdomisation group since baseline. | Up to 6 months after the start of the treatment | 
| Adverse Events related to the treatment | Adverse Events related to the treatment since baseline. | Up to 6 months after the start of the treatment | 
| Adverse Event Seriousness | Adverse Event Seriousness since baseline. | Up to 6 months after the start of the treatment | 
| Adverse Events related to the CDI | Adverse Events related to the CDI since baseline. | Up to 6 months after the start of the treatment | 
| Mortality associated with CDI | Percentage of patients that die due to CDI after a defined period of time from the beginning of the treatment. | Up to 6 months after the start of the treatment | 
| Intensive Care Unit admissions (ICU) | Percentage of patients admitted in the ICU after a defined period of time from the beginning of the treatment. | Up to 6 months after the start of the treatment | 
| Adverse Events of special interest | Adverse Events of special interest since baseline. | Up to 6 months after the start of the treatment | 
| SF36 questionnaire (The Short Form-36 Health Survey) to evaluate the quality of life | For each dimension (physical functioning, role limits-physical, bodily pain, general health, vitality, social functioning, role limits-emotional, mental health), the scale ranges from 0 (the worst health status for that dimension) to 100 (the best health status). | Day 0, 8 weeks and 6 months after the start of the treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clostridium difficile, FMT, Fecal Microbiota Transfer