Clostridium Infections, Clostridioides Difficile, Enterocolitis, Pseudomembranous
Conditions
Brief summary
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.
Interventions
DRUGBezlotoxumab
single intravenous infusion of bezlotoxumab 10 mg/kg
PROCEDUREFecal Microbiota Transplantation (FMT)
single infusion of 198 cc fecal suspension (derived from 60g donor feces) via duodenal tube or coloscopy
DRUGVancomycin oral
14 days vancomycin oral 125mg QID (250mg QID when 125mg not available)
Sponsors
OLVG
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Erasmus Medical Center
Medical Center Haaglanden
Leiden University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Multicenter open label randomized controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Global cure of the treatment strategy | 12 weeks (after rescue therapy if applicable) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-treatment IBS-like symptoms | 12 weeks | Development of post-treatment irritable bowel syndrome like symptoms associated with bezlotoxumab treatment or FMT treatment |
| Fecal microbiota (16S) alfa- and beta-diversity | Pre-treatment and 3 and 12 weeks | As assessed by 16S rRNA amplicon sequencing |
| Cost-effectiveness | 12 weeks | 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) |
| Initial cure after treatment with bezlotoxumab or FMT | 2 days after end of treatment | 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). |
| Sustained cure after initial treatment with bezlotoxumab or FMT | 12 weeks | Sustained cure is defined as cure without relapse of CDI within 12 weeks after completion of the initial treatment. |
| Adverse events | 12 weeks | 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: 1. Most likely related to ancillary CDI treatment (bezlotoxumab or FMT) 2. May be related to ancillary CDI treatment 3. Not related to ancillary CDI treatment |
| Recurrence after initial treatment with bezlotoxumab or FMT | 12 weeks | Defined as CDI relapse within 12 weeks after initial cure |
| Duration of hospitalization | 12 weeks | — |
| Rate of antibiotic use | 12 weeks | — |
| Eradication of toxigenic C. difficile | 3 and 12 weeks | As assessed by PCR |
Other
| Measure | Time frame | Description |
|---|---|---|
| Rate of patients with improved defecation pattern | 12 weeks | As assessed by personal diary |
| Patient wellbeing | Pre-treatment and 12 weeks | As assessed by questionnaire, that includes: 1. self rated health - 5 point scale, higher is worse outcome 2. happiness - 7 points scale, higher is worse outcome 3. optimism - 6 items 4. patient health questionnaire PHQ-9 - 9 items with 4 point scale, higher is worse outcome 5. hospital anxiety and depression scale HADS - 14 items |
Countries
Netherlands
Outcome results
None listed