Clinical trial NCT06702345: Clostridioides Difficile Controlled Human Infection Model
Official title: Establishing a Clostridioides Difficile Controlled Human Infection Model
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: C. Difficile
C. Difficile Infection
Controlled Human Infection
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Helmholtz Centre for Infection Research
name: GlaxoSmithKline
name: University of Oxford
name: University of Cologne
First posted: 2024-11-22
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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.
Primary purpose: PREVENTION

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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Subject is aged ≥18 and ≤45 years and in good health;
2. Body mass index (BMI) ≥18.0 and \<30.0 kg/m2;
3. Subject has adequate understanding of the procedures of the study and is able and willing to abide strictly thereby;
4. Subject is able to communicate well with the investigator, is willing to follow hygienic measures and instructions;
5. 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;
6. Subject has signed informed consent.

Exclusion Criteria:

1. 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;
2. 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.
3. 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);
4. Regular use (defined by more than once weekly) of proton-pump inhibitors or H2-blockers during one month prior to screening;
5. 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);
6. Positive HIV, Hepatitis B or C screening tests;
7. Known immunodeficiency disorders;
8. The use of strong P-glycoprotein-inhibitors (like ciclosporin, ketoconazole, erythromycin, clarithromycin, verapamil and amiodaron) during the trial;
9. Known allergy to vancomycin, clindamycin, fidaxomicin (and macrolides), or metronidazole;
10. Any known significant allergy against the excipients of C. difficile inoculum or inability to swallow capsules;
11. 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;
12. 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);
13. 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;
14. 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.
15. Individuals working in food preparation;
16. Individuals having close contact with healthcare personal/individuals working in food preparation;
17. For women of childbearing potential; a positive serological pregnancy test at screening or lactating at screening/ during the trial;
18. History of drug or alcohol abuse interfering with normal social functioning in the period of one year prior to study onset, positive urine toxicology test for il-licit drug use at screening;
19. Receipt of another investigational agent within 90 days prior or 60 days after C. difficile ingestion;
20. Any condition or situation that could influence the independent consent of par-ticipant (e.g. being a direct colleague or family member of study personnel).

Primary outcomes:
measure: Safety of exposure to toxigenic C. difficile spores with optional antibiotic pretreatment
timeFrame: from day 0 until day 35 for cohort A and from day -5 until day 35 for cohort B and C.
measure: Colonisation with the challenge C. difficile strain
timeFrame: on at least two timepoints from day 14 until day 35
measure: Infection with the challenge C. difficile strain
timeFrame: from day 0 until day 35
Secondary outcomes:
measure: Colonisation with a non-challenge C. difficile strain
timeFrame: on at least two timepoints from day 14 until day 35
measure: Infection with non-challenge C. difficile strain
timeFrame: from day 0 until day 35
measure: Kinetics of C. difficile colonisation/infection over time
timeFrame: from day 0 until day 35
measure: Systemic immune response following C. difficile colonisation and/or infection
timeFrame: at day 0, 20, 35 and 84.
measure: Antibody response following C. difficile colonisation and/or infection
timeFrame: at day 0, 20, 35, 84 and first day of C. difficile infection symptoms.
measure: Cytokine response related to C. difficile colonisation and/or infection
timeFrame: at day 0, 2, 20 and first day of C. difficile infection symptoms.
measure: Calprotectin and potential other biomarkers related to C. difficile colonisation and/or infection
timeFrame: on day 0, 20 and 35
Other outcomes:
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
state: Zuid Holland
Study officials:
References: