Bezlotoxumab Versus FMT for Multiple Recurrent CDI

Study Overview
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Brief Summary
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The objective of this trial is to investigate whether a treatment strategy offering bezlotoxumab before FMT in patients suffering from multiple recurrent CDI results in equal efficacy compared with a treatment strategy with initial FMT. Strategy A includes bezlotoxumab as ancillary treatment as first option, and FMT in case of failure. Option B includes FMT as ancillary treatment as first option, and antibiotic treatment with fidaxomicin in case of failure. A secondary objective is to provide a point estimate of recurrence after bezlotoxumab for the treatment of multiple recurrent CDI.

Official Title
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New Treatment Strategy for Patients With Multiple Recurrent Clostridioides Difficile Infection With Bezlotoxumab as First Option

Conditions
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Clostridium Infections, Clostridioides Difficile, Enterocolitis, Pseudomembranous

Intervention / Treatment
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* Drug: Bezlotoxumab
* Procedure: Fecal Microbiota Transplantation (FMT)
* Drug: Vancomycin oral


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-90 years old diarrhea (3 or more unformed stools per 24h for two consecutive days; or >= 8 unformed stools per 48h) XML File Identifier: KqQEbBLRYEZjGgsIl5GcI+NXCyM= Page 10/22 positive PCR test for toxin A/B genes and/or positive toxin EIA for current and previous episodes (low PCR cycle threshold value when only PCR performed) a minimum of two prior CDI episodes previous episode is maximum of 3 months prior to the current episode the current episode responds well to Standard of Care treatment (vancomycin or fidaxomicin orally). Assessment of the severity of the disease will be performed according to the ESCMID recommendations. Both mild and severe CDI will be included Exclusion Criteria: Severe complicated CDI, i.e presence of: hypotension, septic shock, elevated serum lactate, ileus, toxic megacolon, bowel perforation, or any fulminant course of disease. ICU admission for underlying disease pregnancy or current desire for pregnancy breastfeeding (prolonged) use of antibiotics (other than for treatment of CDI) during the study period or directly after the intervention previous use of bezlotoxumab or fecal microbiota transplantation a history of underlying congestive heart failure (potential safety signal phase-III trail bezlotoxumab). Diagnosis of inflammatory bowel disease in medical history.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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
Interventional Model Description: Multicenter open label randomized controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Strategy A: initial SoC + bezlotoxumab. SoC + FMT rescue therapy.<br>initial bezlotoxumab in addition to 14 days SoC oral antibiotic treatment with vancomycin 125 mg QID. 14 days of vancomycin 125mg QID plus fecal microbiota in case of treatment failure. | Drug: Bezlotoxumab<br>* single intravenous infusion of bezlotoxumab 10 mg/kg<br>Drug: Vancomycin oral<br>* 14 days vancomycin oral 125mg QID (250mg QID when 125mg not available)<br>|
| Active Comparator: Strategy B: initial SoC + FMT. Fidaxomicin rescue therapy.<br>fecal microbiota transplantation in addition to 14 days SoC oral antibiotic treatment with vancomycin 125 mg QID. 10 days of fidaxomicin 200 mg BID in case of treatment failure. | Procedure: Fecal Microbiota Transplantation (FMT)<br>* single infusion of 198 cc fecal suspension (derived from 60g donor feces) via duodenal tube or coloscopy<br>Drug: Vancomycin oral<br>* 14 days vancomycin oral 125mg QID (250mg QID when 125mg not available)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global cure of the treatment strategy | Defined as cure without relapse of CDI within 12 weeks after completion of the treatment strategy in the study arm, i.e. after completion of secondary treatment in case of failure on initial treatment. | 12 weeks (after rescue therapy if applicable) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Initial cure after treatment with bezlotoxumab or FMT | Defined as cure after completion of the primary CDI treatment in the study arm. Initial cure is assessed at day 2 after end of treatment (EOT). | 2 days after end of treatment | 
| Recurrence after initial treatment with bezlotoxumab or FMT | Defined as CDI relapse within 12 weeks after initial cure | 12 weeks | 
| Sustained cure after initial treatment with bezlotoxumab or FMT | Sustained cure is defined as cure without relapse of CDI within 12 weeks after completion of the initial treatment. | 12 weeks | 
| Adverse events | Throughout the entire study all adverse events will be noted. After the final study procedure of the last patient, all adverse events will be categorized: Most likely related to ancillary CDI treatment (bezlotoxumab or FMT) May be related to ancillary CDI treatment Not related to ancillary CDI treatment | 12 weeks | 
| Post-treatment IBS-like symptoms | Development of post-treatment irritable bowel syndrome like symptoms associated with bezlotoxumab treatment or FMT treatment | 12 weeks | 
| Duration of hospitalization |  | 12 weeks | 
| Rate of antibiotic use |  | 12 weeks | 
| Eradication of toxigenic C. difficile | As assessed by PCR | 3 and 12 weeks | 
| Fecal microbiota (16S) alfa- and beta-diversity | As assessed by 16S rRNA amplicon sequencing | Pre-treatment and 3 and 12 weeks | 
| Cost-effectiveness | Costs per cured patient (global and sustained cure) and costs per QALY gained, using the EQ-5D-5L health questionaire that assesses five domains by 5 point scale, e.g. no/slight/moderate/severe/extreme impairment and a visual analogue 0-100 scale of health rating, higher is better) | 12 weeks |