Clostridioides Difficile Controlled Human Infection Model

NCT06702345 | Not Yet Recruiting DMC

• 2 other identifiers: CloDiCHIGrant number: 101007799
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

C. Difficile; C. Difficile Infection; Controlled Human Infection

Outcome Measures

Primary Outcomes (3)

• Safety of exposure to toxigenic C. difficile spores with optional antibiotic pretreatment

  number and grade of (related) adverse events

  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.

  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

  from day 0 until day 35

Secondary Outcomes (7)

• Colonisation with a non-challenge C. difficile strain

  on at least two timepoints from day 14 until day 35

• Infection with non-challenge C. difficile strain

  from day 0 until day 35

• Kinetics of C. difficile colonisation/infection over time

  from day 0 until day 35

• Systemic immune response following C. difficile colonisation and/or infection

  at day 0, 20, 35 and 84.

• Antibody response following C. difficile colonisation and/or infection

  at day 0, 20, 35, 84 and first day of C. difficile infection symptoms.

Study Arms (3)

Cohort A (TCD spores only)

EXPERIMENTAL

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

Cohort B (vancomycin pretreatment + TCD spores)

EXPERIMENTAL

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

Cohort C (clindamycin pretreatment + TCD spores)

EXPERIMENTAL

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

Interventions

encapsulated 10^4 CFU toxigenic. C. difficile spores OTHER

12 consecutive days of once a day a capsule with 10\^4 CFU toxigenic C. difficile spores.

Cohort A (TCD spores only); Cohort B (vancomycin pretreatment + TCD spores); Cohort C (clindamycin pretreatment + TCD spores)

Vancomycin DRUG

oral vancomycin pretreatment, 4 times a day 250mg, given the five days before toxigenic C. difficile exposure.

Cohort B (vancomycin pretreatment + TCD spores)

Clindamycin DRUG

oral clindamycin pretreatment, 3 times a day 600mg, given the five days before toxigenic C. difficile exposure

Cohort C (clindamycin pretreatment + TCD spores)

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject is aged ≥18 and ≤45 years and in good health;
• Body mass index (BMI) ≥18.0 and \<30.0 kg/m2;
• Subject has adequate understanding of the procedures of the study and is able and willing to abide strictly thereby;
• Subject is able to communicate well with the investigator, is willing to follow hygienic measures and instructions;
• For women of childbearing potential: subject agrees to use adequate contra-ception (see Appendix D for the different adequate contraception methods for this study) and not to breastfeed for the duration of the study;
• Subject has signed informed consent.

You may not qualify if:

• Any physical or psychiatric illness or conditions that could threaten or com-promise the health of the subject during the study, influence their ability to par-ticipate in the trial or interfere with the interpretation of the study results, as de-termined by the trial physician;
• Use of systemic (IV or oral) antibiotics within three months prior to screening; other microbiota influencing medication (that could influence the trial, based on the Investigator's opinion) within 1 month prior to screening visit. Prior use of topical antibiotics is permitted if there is no clinically relevant systemic ex-pected following assessment of the trial physician and are expected to be dis-continued during the start of the first study activity.
• Has had a recent hospitalization (e.g. 3 months prior to screening) and/or has someone in immediate social circle who is frequently hospitalized (≥3 times in a 12-month period) or frequently exposed to hospital settings (≥ one time a month, e.g. dialysis units);
• Regular use (defined by more than once weekly) of proton-pump inhibitors or H2-blockers during one month prior to screening;
• Chronic use of immunosuppressive drugs, e.g. systemic corticosteroids or other immune modifying drugs (with exception of oral anti-histamines and top-ical/inhaled corticosteroids);
• Positive HIV, Hepatitis B or C screening tests;
• Known immunodeficiency disorders;
• The use of strong P-glycoprotein-inhibitors (like ciclosporin, ketoconazole, erythromycin, clarithromycin, verapamil and amiodaron) during the trial;
• Known allergy to vancomycin, clindamycin, fidaxomicin (and macrolides), or metronidazole;
• Any known significant allergy against the excipients of C. difficile inoculum or inability to swallow capsules;
• Known gastro-intestinal disease including but not limited to inflammatory bow-el diseases (Crohn's disease, Colitis ulcerosa), a history of bowel resection or any other gastro-intestinal surgery which has significantly changed the ana-tomical structure or physiological function of the gastro-intestinal tract, bile ac-id secretion abnormalities, constipation defined by bowel movements less than every second day or chronic use of laxatives;
• Positive fecal culture or PCR with toxigenic or non-toxigenic Clostridioides spp. or SSYC (Salmonella spp., Shigella spp., Yersinia spp. or Campylobac-ter spp.) at screening, or recent (\<14 days) history of diarrhoea (i.e. as ≥3 loose stools (Bristol stool scale 6-7) in 24 hours);
• Any condition that would put household members or close contacts at a great-er risk for transmission e.g. no access or use of flush toilet;
• Individuals living, working or having close contact with people who belong to vulnerable populations such as hospitalized patients, pregnant women, im-mune compromised individuals, children younger than 2 years, residents of nursing homes, elderly older than 70 years of age, or any person with a medi-cal condition at risk of developing severe CDI.
• Individuals working in food preparation;

Sponsors & Collaborators

• Leiden University Medical Center: lead
• Helmholtz Centre for Infection Research: collaborator
• GlaxoSmithKline: collaborator
• University of Oxford: collaborator
• University of Cologne: collaborator

Study Sites (1)

Leiden University Medical Center

Leiden, South Holland, 2333ZA, Netherlands

Location

MeSH Terms

Interventions

Vancomycin; Clindamycin

Intervention Hierarchy (Ancestors)

Glycopeptides; Glycoconjugates; Carbohydrates; Peptides; Amino Acids, Peptides, and Proteins; Lincomycin; Lincosamides; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Glycosides

Central Study Contacts

Prof. dr. Meta Roestenberg

CONTACT

0031715262102; m.roestenberg@lumc.nl

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. dr. M. Roestenberg

Model Details: This will be a first in human, open-label, adaptive design, escalating clinical trial, investigating the oral exposure of toxigenic C. difficile in healthy volunteers. The adaptive design is aimed at a stepwise escalation to ensure safety of trial participants and gear towards the optimal balance between endpoints and tolerability. The study will start with one cohort of volunteers, cohort A, with an option to escalate to a second cohort, cohort B, and a third cohort, cohort C, if needed. Escalation to the subsequent cohort will be performed by adding antibiotic pretreatment. Escalation will be based upon safety first and secondly upon microbiological and clinical endpoints (ideally aiming for an attack rate of 70% in both). In every cohort small pilot groups (of five volunteers each) will be used to flag safety signals and determine the escalation schedule, having the option to include 15 more participants to the same cohort or escalate to the pilot group of the subsequent cohort.

Study Record Dates

• First Submitted: November 18, 2024
• First Posted: November 22, 2024
• Study Start: March 1, 2025
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: November 22, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)