Bezlotoxumab Versus FMT for Multiple Recurrent CDI (BSTEP)

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Clostridium Infections; Enterocolitis, Pseudomembranous; Clostridioides Difficile
• Intervention / Treatment: Drug: Bezlotoxumab; Drug: Vancomycin oral; Procedure: Fecal Microbiota Transplantation (FMT)

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam University Medical Centers, AMC
  • Den Haag, Netherlands
    • Haaglanden Medical Center
  • Leiden, Netherlands
    • Leiden University Medical Center
  • Rotterdam, Netherlands
    • Erasmus Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Strategy A: initial SoC + bezlotoxumab. SoC + FMT rescue therapy.; 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; single intravenous infusion of bezlotoxumab 10 mg/kg; Drug: Vancomycin oral; 14 days vancomycin oral 125mg QID (250mg QID when 125mg not available)
Active Comparator: Strategy B: initial SoC + FMT. Fidaxomicin rescue therapy.; 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.	Drug: Vancomycin oral; 14 days vancomycin oral 125mg QID (250mg QID when 125mg not available); Procedure: Fecal Microbiota Transplantation (FMT); single infusion of 198 cc fecal suspension (derived from 60g donor feces) via duodenal tube or coloscopy

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient wellbeing	As assessed by questionnaire, that includes: self rated health - 5 point scale, higher is worse outcome; happiness - 7 points scale, higher is worse outcome; optimism - 6 items; patient health questionnaire PHQ-9 - 9 items with 4 point scale, higher is worse outcome; hospital anxiety and depression scale HADS - 14 items	Pre-treatment and 12 weeks
Rate of patients with improved defecation pattern	As assessed by personal diary	12 weeks

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Erasmus Medical Center; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Medical Center Haaglanden; OLVG
• Investigators: Principal Investigator: J van Prehn, Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2022
• Primary Completion (Anticipated): July 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: September 21, 2021
• First Submitted That Met QC Criteria: September 30, 2021
• First Posted (Actual): October 13, 2021

Study Record Updates

• Last Update Posted (Actual): March 28, 2023
• Last Update Submitted That Met QC Criteria: March 24, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Infections; Enterocolitis; Clostridium Infections; Enterocolitis, Pseudomembranous; Anti-Infective Agents; Anti-Bacterial Agents; Vancomycin
• Other Study ID Numbers: BSTEP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No