CloDiCo: Clostridioides Difficile Colonisation
Study Details
Study Description
Brief Summary
This study will investigate experimental colonisation with non-toxigenic C.difficile (NTCD) in healthy volunteers. Main outcomes will be safety, tolerability, dose needed to obtain colonisation with NTCD and host microbiota factors associated with colonisation.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This will be an adaptive design, randomised double-blind controlled clinical trial investigating oral exposure to NTCD spores in healthy volunteers, who are not colonised with C.difficile prior to the study and have not used antibiotics within one month prior to inclusion. A total of 50 volunteers will be included, divided over two consecutive intervention phases. The first phase will consist of 25 volunteers, randomised in three groups: group A (N=10) will receive 5 doses of 10E4 NTCD spores, group B (N=10) will receive 5 doses of 10E7 NTCD spores and group C (N=5) will receive 5 doses of placebo. Depending on the outcome of phase 1, the dose given in phase 2 will either be reduced (if colonisation frequency in phase 1 is high), or the doses will be preceded by vancomycin pre-treatment (if the colonisation frequency in phase 1 is low) according to predefined criteria. The second phase will also consist of 25 volunteers, randomized in 3 groups: group D (N=10), group E (N=10) and the control group F (N=5).
All volunteers in both phases will visit the trial center on the days of spores or placebo ingestion, with collection of feces for C.difficile and microbiota analysis before ingestion. During the four follow-up weeks volunteers will visit the trial center three times a week for fecal sample collection (for Cdiff and microbiota analysis), with weekly follow-up visit for AE collection and 2 times a safety blood tests. After three months there will be a final follow-up visit for AEs and fecal sample collection. Should a volunteer still be positive for C.difficile at the three month timepoint, the volunteer is asked to return for follow-up every one to two months for fecal sample collection until the sample is negative for C.difficile, up till a maximum of one year after the start of the trial. Because colonisation with NTCD is very common in the general population, NTCD colonisation will not be terminated with antibiotics. Rescue treatment for NTCD is available in case of unexpected adverse events.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Group A (phase 1) (N=10) 5 doses of 10E4 NTCD spores on day 0-4. |
Biological: 10E4 NTCD spores
in enteric capsule for oral ingestion.
|
| Experimental: Group B (phase 1) (N=10) 5 doses of 10E7 NTCD spores on day 0-4. |
Biological: 10E7 NTCD spores
in enteric capsule for oral ingestion.
|
| Placebo Comparator: Group C (phase 1) (N=5) 5 doses of placebo on day 0-4. |
Other: placebo
in enteric capsule for oral ingestion.
|
| Experimental: Group D (phase 2) (N=10) Based upon the colonisation results of phase 1, there are three dosing options for this group, one of the three options will be chosen, the chosen option number will be congruent for all of the groups: Option 1: 3 doses of 10E4 NTCD spores on day 0-2. Option 2: 3 doses of 10E7 NTCD spores on day 0-2. Option 3: 1 dose of vancomycin on day -7, followed by 5 doses of 10E4 NTCD spores on day 0-4. |
Biological: 10E4 NTCD spores
in enteric capsule for oral ingestion.
Biological: 10E7 NTCD spores
in enteric capsule for oral ingestion.
Drug: Vancomycin
One dose of Vancomycin (250mg)
|
| Experimental: Group E (phase 2) (N=10) Based upon the colonisation results of phase 1, there are three dosing options for this group, one of the three options will be chosen, the chosen option number will be congruent for all of the groups: Option 1: 1 dose of 10E4 NTCD spores on day 0, and 2 doses of placebo on day 1-2. Option 2: 1 dose of 10E7 NTCD spores on day 0, and 2 doses of placebo on day 1-2. Option 3: 1 dose vancomycin on day -7 folllowed by 5 doses of 10E7 NTCD spores on day 0-4. |
Biological: 10E4 NTCD spores
in enteric capsule for oral ingestion.
Biological: 10E7 NTCD spores
in enteric capsule for oral ingestion.
Drug: Vancomycin
One dose of Vancomycin (250mg)
|
| Placebo Comparator: Group F (phase 2) (N=5) Based upon the colonisation results of phase 1, there are three dosing options for this group, one of the three options will be chosen, the chosen option number will be congruent for all of the groups: Option 1: 3 doses of placebo on day 0-2. Option 2: 3 doses of placebo on day 0-2. Option 3: 1 dose of vancomycin on day -7, followed by 5 doses of placebo on day 0-4. |
Other: placebo
in enteric capsule for oral ingestion.
Drug: Vancomycin
One dose of Vancomycin (250mg)
|
Outcome Measures
Primary Outcome Measures
- Safety and tolerability of colonisation with non-toxigenic C.difficile [During the first month after ingestion of NTCD spores.]
Number and grade of related adverse events from day 1 to 28 after ingestion of (two different doses of) NTCD spores or placebo
Secondary Outcome Measures
- Dose needed to obtain colonisation with non-toxigenic C. difficile. [During the first month after ingestion of NTCD spores.]
The number of volunteers successfully colonised with non-toxigenic C.difficile. Colonisation is defined as a positive PCR for C.difficile on stool or a positive culture for C.difficile on at least two timepoints between three days and four weeks post-exposure
- Determine markers in the host microbiota prior to exposure associated with colonisation. [3 months after ingestion of NTCD spores.]
Microbiota markers prior to exposure which are associated with C.difficile colonisation through microbiota analysis with 16S amplicon sequencing.
Other Outcome Measures
- Determine changes in the host microbiota following colonisation. [3 months after ingestion of NTCD spores.]
Identification of changes in microbiota components following C.difficile colonisation through microbiota analysis with 16S amplicon sequencing.
- Investigate C. difficile in-vivo evolution. [3 months after ingestion of NTCD spores.]
Identification of genetic changes of C.difficile after passage through the human host through C.difficile PCR and culturing.
Eligibility Criteria
Criteria
Inclusion Criteria:
In order to be eligible to participate in this study, a subject must meet all of the following criteria:
-
Subject is aged ≥ 18 and ≤ 45 years and in good health.
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Subject has adequate understanding of the procedures of the study and is able and willing to abide strictly thereby.
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For female subjects: subject agrees to use adequate contraception and not to breastfeed for the duration of study.
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Subject has signed informed consent.
Exclusion Criteria:
A potential subject who meets any of the following criteria will be excluded from participation in this study:
-
Any physical or psychiatric illness or conditions that could threaten or compromise the health of the subject during the study, influence their ability to participate in the trial or interfere with the interpretation of the study results, as determined by the trial physician.
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Use of antibiotics within one month prior to inclusion.
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Known immunosuppressive condition, including infection with Human Immunodeficiency Virus (HIV), use of systemic corticosteroids or other immune modifying drugs (with exception of antihistamines and topical steroids).
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Regular use (defined by more than once weekly) of proton-pump inhibitors or H2- blockers during one month prior to inclusion.
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The use of strong P-glycoprotein-inhibitors (like Ciclosporin, Ketoconazole, Erythromycin, Clarithromycin, Verapamil and Amiodaron).
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Known allergy to vancomycin, metronidazole or fidaxomicin.
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Known allergy to glycerol.
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Known immunodeficiency disorders.
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Known gastro-intestinal disease including but not limited to inflammatory bowel diseases (Crohn's disease, Colitis Ulcerosa), recent gastro-intestinal surgery, constipation defined by bowel movements less than every second day.
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Positive fecal culture or PCR with Clostridiodes or SSYC (Salmonella, Shigella, Yersinia or Campylobacter spp.) at screening.
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Any condition that would put household members at a greater risk for transmission e.g. no access or use of flush toilet, household members belonging to vulnerable populations such as persons who are immunocompromised, children younger than 2 years of age and elderly older than 70 years of age.
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For women of child bearing potential: a positive serological pregnancy test at screening or lactating at screening / during the trial.
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Being an employee or student of the Experimental bacteriology group or the controlled human infection center at LUMC.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Leiden University Medical Center | Leiden | Netherlands | 2333 ZA |
Sponsors and Collaborators
- Leiden University Medical Center
Investigators
- Principal Investigator: Meta Roestenberg, MD, PhD, Leiden University Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CloDiCo