An interventional study of encapsulated 10^4 CFU toxigenic. C. difficile spores and Vancomycin in C. Difficile, C. Difficile Infection and Controlled Human Infection, sponsored by Leiden University Medical Center. Not yet recruiting at 1 site in Netherlands. Open to participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-11-22.
Sponsored by Leiden University Medical Center · Not applicable, Interventional, and Prevention
This study will investigate in healthy study subjects, the safety and tolerability of a controlled infection with Clostridioides difficile, a gut bacterium that can cause diarrhoea. It is also examined which dosing regimen (with or without antibiotic pretreatment) is required to induce mild symptoms (like diarrhoea) in the majority of study subjects and which microbiota and immunological factors influence this.
To investigate this, healthy adult study subjects will be asked to ingest capsules (pills) containing the Clostridioides bacterium.
This will be a first in human, open-label, adaptive clinical trial investigating the oral exposure of toxigenic C. difficile in healthy volunteers. The trial will consist of at least one cohort (cohort A), with an option to escalate to a second (cohort B) and third cohort (cohort C) if needed. In every cohort volunteers will be exposed for 12 consecutive days (D0-D11) to once a day a capsule with 10\^4 CFU toxigenic C. difficile spores. Escalation will be done by adding antibiotic pretreatment (vancomycin in cohort B and clindamycin in cohort C) the five days before C. difficile exposure (D-6 - D-1). Escalation will be based upon safety first and secondly upon microbiological and clinical endpoints (ideally aiming for a 70% attack rate in both). In every cohort there will be first a pilot group of 5 volunteers, after which there is an option to include a confirmatory group of 15 more participants in the same cohort if the exposure is safe and the threshold for the microbiological and clinical endpoint is met.
Immediately following the first ingestion of the C. difficile spores (day 0), volunteers will be closely and strictly monitored for adverse events (AEs) and vital signs in an outpatient setting. Until day 35, AEs, vital signs and stool samples for C. difficile toxin PCR/EIA, culture, and microbiota analysis will be collected every other day, safety laboratory measurements will be performed once in four days (starting from day 0). Immunology samples will be collected on day 0, 2, 20, 35 and 84. If a volunteer develops symptoms of CDI the volunteer needs to visit the research clinic the same day for a physical check-up, and collection of a blood and stool sample, and, if needed (antibiotic) treatment will be started according to standard of care. Any recurrent episode of a C. difficile infection will be treated with fecal microbiota transplantation (FMT). A final visit will take place after three months (day 84), with collection of feces and blood. If a volunteer is still C. difficile positive at this timepoint, they will be followed every three months until decolonisation is reached, up to a maximum of one year after the start of the trial. Decolonisation will be de-fined as having a negative molecular C. difficile test on at least two different timepoints.
Leiden University Medical Center is the lead sponsor of 333 studies on the registry; 109 are open to participants now.
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Exclusion Criteria:
Volunteers in cohort A will be exposed to a once a day capsule with 10\^4 CFU TCD spores for 12 days. First, a pilot group of 5 volunteers will be exposed to flag safety signals. If in this pilot group TCD exposure is well tolerated and less than 70% of the volunteers (\< 4 out of 5 volunteers) reaches a microbiological AND clinical endpoint, the trial will escalate to the second cohort, cohort B. If, however, in the pilot group TCD exposure is well tolerated and at least 70% of the volunteers (≥4 out of 5 volunteers) reaches a microbiological AND clinical endpoint, a confirmatory group of another 15 volunteers will be included in cohort A (total 20 volunteers). If in this total of 20 volunteers sat least 70% (≥ 14 out of 20 volunteers) reaches a clinical AND microbiological endpoint, no further escalation to cohort B or C will be done. If, however, less than 70% of the 20 volunteers in cohort A reaches a clinical AND microbiological endpoint, escalation will continue to cohort B.
Other: encapsulated 10^4 CFU toxigenic. C. difficile spores
Volunteers in cohort B will be exposed first to 5 days of oral vancomycin pretreatment, 4 times a day 250mg, followed immediately by once a day capsule with 10\^4 CFU TCD spores for 12 days. First, a pilot group of 5 volunteers will be exposed to flag safety signals. If in this pilot group TCD exposure is well tolerated and less than 70% of the volunteers (\< 4 out of 5 volunteers) reaches a microbiological AND clinical endpoint, the trial will escalate to the third cohort, cohort C. If, however, in the pilot group TCD exposure is well tolerated and at least 70% of the volunteers (≥4 out of 5 volunteers) reaches a microbiological AND clinical endpoint, a confirmatory group of another 15 volunteers will be included in cohort B (total 20 volunteers). If in this total of 20 volunteers at least 70% (≥ 14 out of 20 volunteers) reaches a clinical AND microbiological endpoint, no further escalation to cohort C will be done. If, however, this is less then 70%, escalation continues to cohort C.
Other: encapsulated 10^4 CFU toxigenic. C. difficile spores · Drug: Vancomycin
Volunteers in cohort C will be exposed first to five days of oral clindamycin pretreatment, three times a day 600mg, followed immediately by once-a-day dosing of 104 CFU TCD spores (capsules) for 12 consecutive days. First, a small pilot group of five volunteers will be exposed to flag safety signals. If in this pilot group TCD exposure is well tolerated and less than 70% of the volunteers (\< 4 out of 5 volunteers) reaches a microbiological AND clinical endpoint, the trial will stop. If, however, in the pilot group TCD exposure is well tolerated and at least 70% of the volunteers (≥4 out of 5 volunteers) reaches a microbiological AND clinical endpoint, a confirmatory group of another 15 volunteers will be included in cohort C (total 20 volunteers), after which the trial will stop.
Other: encapsulated 10^4 CFU toxigenic. C. difficile spores · Drug: Clindamycin
12 consecutive days of once a day a capsule with 10\^4 CFU toxigenic C. difficile spores.
oral vancomycin pretreatment, 4 times a day 250mg, given the five days before toxigenic C. difficile exposure.
oral clindamycin pretreatment, 3 times a day 600mg, given the five days before toxigenic C. difficile exposure
Safety of exposure to toxigenic C. difficile spores with optional antibiotic pretreatment
number and grade of (related) adverse events
Time frame: from day 0 until day 35 for cohort A and from day -5 until day 35 for cohort B and C.
Colonisation with the challenge C. difficile strain
1. Proven: a positive culture of toxigenic C. difficile with the same molecular identity as the challenge strain, without symptoms of CDI. 2. Probable: a positive toxin EIA on stool samples OR a positive feces tcdB-PCR, without symptoms of CDI.
Time frame: on at least two timepoints from day 14 until day 35
Infection with the challenge C. difficile strain
1. Proven: clinical findings compatible with CDI (clinical findings should include at least diarrhoea: Bristol stool chart type 6-7 plus ≥ 3 stools in 24 hours) and a positive culture of toxigenic C. difficile with the same molecular identity as the challenge strain 2. Probable: clinical findings compatible with CDI (clinical findings should include at least diarrhoea: Bristol stool chart type 6-7 plus ≥ 3 stools in 24 hours) and a positive toxin EIA on stool samples OR a positive feces tcdB-PCR
Time frame: from day 0 until day 35
Colonisation with a non-challenge C. difficile strain
Proven microbiological endpoint/colonisation with non-challenge strain: a positive culture of C. difficile with another molecular identity than the challenge strain, without symptoms of CDI.
Time frame: on at least two timepoints from day 14 until day 35
Infection with non-challenge C. difficile strain
Clinical findings compatible with CDI (clinical findings should include at least diarrhoea: Bristol stool chart type 6-7 plus ≥ 3 stools in 24 hours) and a positive culture of C. difficile with another molecular identity than the challenge strain
Time frame: from day 0 until day 35
Kinetics of C. difficile colonisation/infection over time
Quantitative measurement of C. difficile by qPCR at samples taken every other day
Time frame: from day 0 until day 35
Systemic immune response following C. difficile colonisation and/or infection
Anti-Toxin A and anti-Toxin B neutralizing antibody titers by toxin neutralization assay (TNA) on serum samples
Time frame: at day 0, 20, 35 and 84.
Antibody response following C. difficile colonisation and/or infection
ELISA for antibody responses against various antigens in serum and faecal samples
Time frame: at day 0, 20, 35, 84 and first day of C. difficile infection symptoms.
Cytokine response related to C. difficile colonisation and/or infection
Cytokine measurement in serum and faecal samples
Time frame: at day 0, 2, 20 and first day of C. difficile infection symptoms.
Calprotectin and potential other biomarkers related to C. difficile colonisation and/or infection
Calprotectin and potential other biomarkers for inflammation (like lactoferrin) in faecal samples
Time frame: on day 0, 20 and 35
Plan to share: No
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Studies of the drugs tested here: Vancomycin · Clindamycin
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