search
Back to results

Clostridioides Difficile Colonisation (CloDiCo)

Primary Purpose

Clostridioides Difficile Infection

Status
Recruiting
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
10E4 NTCD spores
10E7 NTCD spores
placebo
Vancomycin Oral Capsule
Sponsored by
Leiden University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Clostridioides Difficile Infection focused on measuring Colonization

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesAccepts Healthy Volunteers

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. Subject has adequate understanding of the procedures of the study and is able and willing to abide strictly thereby. For female subjects: subject agrees to use adequate contraception and not to breastfeed for the duration of study. 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. Use of antibiotics (or other microbiota influencing products) within one month prior to inclusion. 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). Regular use (defined by more than once weekly) of proton-pump inhibitors or H2- blockers during one month prior to inclusion. The use of strong P-glycoprotein-inhibitors (like Ciclosporin, Ketoconazole, Erythromycin, Clarithromycin, Verapamil and Amiodaron). Known allergy to vancomycin, metronidazole or fidaxomicin. Known allergy to glycerol. Known immunodeficiency disorders. 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. Positive fecal PCR with Clostridiodes or SSYC (Salmonella, Shigella, Yersinia or Campylobacter spp.) at screening. 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. For women of child bearing potential: a positive urine pregnancy test before inclusion or lactating at screening / during the trial. Being an employee or student of the Experimental bacteriology group or the controlled human infection center at LUMC.

Sites / Locations

  • Leiden University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm Type

Experimental

Experimental

Placebo Comparator

Experimental

Experimental

Placebo Comparator

Experimental

Experimental

Placebo Comparator

Arm Label

Group A (phase 1) (N=10)

Group B (phase 1) (N=10)

Group C (phase 1) (N=4)

Group D (phase 2) (N=10)

Group E (phase 2) (N=10)

Group F (phase 2) (N=3 or 6)

Group G (phase 3) (N=10)

Group H (phase 3) (N=10)

Group I (phase 3) (N=3)

Arm Description

5 doses of 10E4 NTCD spores on day 0-4.

5 doses of 10E7 NTCD spores on day 0-4.

5 doses of placebo on day 0-4.

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 three groups in phase 2: 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 day of vancomycin on day -7, followed by 5 doses of 10E4 NTCD spores on day 0-4.

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 three groups in phase 2: 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 day vancomycin on day -7 followed by 5 doses of 10E7 NTCD spores on day 0-4.

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 (N=6): 3 doses of placebo on day 0-2. Option 2 (N=6): 3 doses of placebo on day 0-2. Option 3 (N=3): 1 day vancomycin on day -7, followed by 5 doses of placebo on day 0-4.

Escalation to the third phase will only be done if option 3 is selected in phase 2. Based upon the colonisation results of phase 2, 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 in phase 3: Option 1: 1 day vancomycin on day -7, followed by 3 doses of 10E4 NTCD spores on day 0-2. Option 2: 1 day vancomycin on day -7, followed by 3 doses of 10E7 NTCD spores on day 0-2. Option 3: 5 days of vancomycin on day -11 until day -7, followed by 5 doses of 10E4 NTCD spores on day 0-4.

Escalation to the third phase will only be done if option 3 is selected in phase 2. Based upon the colonisation results of phase 2, 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 in phase 3: Option 1: 1 day of vancomycin on day -7, followed by 1 dose of 10E4 NTCD spores on day 0, and 2 doses of placebo on day 1-2. Option 2: 1 day of vancomycin on day -7, followed by 1 dose of 10E7 NTCD spores on day 0 and 2 doses of placebo on day 1-2. Option 3: 5 days of vancomycin on day -11 until day -7, followed by 5 doses of 10E7 NTCD spores on day 0-4.

Escalation to the third phase will only be done if option 3 is selected in phase 2. Based upon the colonisation results of phase 2, 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 in phase 3: Option 1: 1 day of vancomycin on day -7, followed by 3 doses of placebo on day 0-2. Option 2: 1 day of vancomycin on day -7, followed by 3 doses of placebo on day 0-2. Option 3: 5 days of vancomycin on day -11 until day -7, followed by 5 doses of placebo on day 0-4.

Outcomes

Primary Outcome Measures

Safety and tolerability of colonisation with non-toxigenic C.difficile
Number and grade of related adverse events from day 1 to 28 after ingestion of NTCD spores.
To establish the effective protocol to obtain colonisation with non-toxigenic C. difficile in the majority of subjects.
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 two weeks after the last exposure day.

Secondary Outcome Measures

To determine factors in the host microbiota associated with successful colonisation.
Microbiota markers which are associated with successful C.difficile colonisation through microbiota analysis with 16S amplicon sequencing.

Full Information

First Posted
December 21, 2022
Last Updated
October 16, 2023
Sponsor
Leiden University Medical Center
search

1. Study Identification

Unique Protocol Identification Number
NCT05693077
Brief Title
Clostridioides Difficile Colonisation
Acronym
CloDiCo
Official Title
Establishing Colonisation With Non-toxigenic Clostridioides Difficile in Healthy Volunteers
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 22, 2023 (Actual)
Primary Completion Date
June 2024 (Anticipated)
Study Completion Date
June 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Leiden University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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 to ultimately determine host microbiota factors associated with susceptibility to colonisation.
Detailed Description
This will be an adaptive dose design, randomized double-blind controlled clinical trial investigating oral exposure to NTCD spores in healthy volunteers. The trial will consist of two or, if necessary, three different consecutive intervention phases. The second and third phase are dependent on results of the preliminary phases. In every phase one cohort volunteers will be randomized to different dose levels of NTCD spores or placebo. 50 to 70 healthy volunteers will be included, of which in total 10 volunteers will be exposed to placebo. The first phase will consist of 24 volunteers, randomized 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=4) 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 >60%), or the doses will be preceded by vancomycin pre-treatment (if the colonisation frequency in phase 1 is <60%) according to predefined criteria. There are three dosing options for phase 2: for the first two options (reduced doses of NTCD) 26 volunteers will be divided over 3 groups group D (N=10), group E (N=10) and the control group F (N=6), for the third option (vancomycin pre-treatment) 23 volunteers will be divided over 3 groups; group D (N=10), group E (N=10) and the control group F (N=3). For the dosing schedules of the three options op the second phase please refer to the section below 'Arms and Interventions'. Escalation to the third phase will only be done if option 3 is selected in phase 2.Depending on the outcome of phase 2, the dose given in phase 3 will either be reduced (if colonisation frequency in phase 2 is >60%) or the vancomycin pre-treatment will be extended to five days (if the colonisation frequency in phase 2 is <60%) according to predefined criteria. 23 volunteers will be divided over 3 groups: group G (N=10), group H (N=10) and the control group I (N=3). For dosing schedules of the three options of the third phase please refer to the section below 'Arms and Interventions'. All volunteers in all phases will visit the trial center on the days of spores or placebo ingestion (and if needed also on the first day of vancomycin 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. Antibiotic rescue treatment (or in case of persistent disturbances to the host microbiota, a fecal microbiota transplantation) for NTCD is available in case of unexpected adverse events.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Clostridioides Difficile Infection
Keywords
Colonization

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
The trial consists of two or, if necessary, three consecutive intervention phases with each three parallel intervention arms. The first phase consists 24 volunteers, the second phase of 23 or 26 volunteers, and the optional third phase of another 23 volunteers. The volunteers will be divided over three intervention arms.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
The trial is double-blind, placebo-controlled.
Allocation
Randomized
Enrollment
70 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group A (phase 1) (N=10)
Arm Type
Experimental
Arm Description
5 doses of 10E4 NTCD spores on day 0-4.
Arm Title
Group B (phase 1) (N=10)
Arm Type
Experimental
Arm Description
5 doses of 10E7 NTCD spores on day 0-4.
Arm Title
Group C (phase 1) (N=4)
Arm Type
Placebo Comparator
Arm Description
5 doses of placebo on day 0-4.
Arm Title
Group D (phase 2) (N=10)
Arm Type
Experimental
Arm Description
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 three groups in phase 2: 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 day of vancomycin on day -7, followed by 5 doses of 10E4 NTCD spores on day 0-4.
Arm Title
Group E (phase 2) (N=10)
Arm Type
Experimental
Arm Description
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 three groups in phase 2: 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 day vancomycin on day -7 followed by 5 doses of 10E7 NTCD spores on day 0-4.
Arm Title
Group F (phase 2) (N=3 or 6)
Arm Type
Placebo Comparator
Arm Description
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 (N=6): 3 doses of placebo on day 0-2. Option 2 (N=6): 3 doses of placebo on day 0-2. Option 3 (N=3): 1 day vancomycin on day -7, followed by 5 doses of placebo on day 0-4.
Arm Title
Group G (phase 3) (N=10)
Arm Type
Experimental
Arm Description
Escalation to the third phase will only be done if option 3 is selected in phase 2. Based upon the colonisation results of phase 2, 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 in phase 3: Option 1: 1 day vancomycin on day -7, followed by 3 doses of 10E4 NTCD spores on day 0-2. Option 2: 1 day vancomycin on day -7, followed by 3 doses of 10E7 NTCD spores on day 0-2. Option 3: 5 days of vancomycin on day -11 until day -7, followed by 5 doses of 10E4 NTCD spores on day 0-4.
Arm Title
Group H (phase 3) (N=10)
Arm Type
Experimental
Arm Description
Escalation to the third phase will only be done if option 3 is selected in phase 2. Based upon the colonisation results of phase 2, 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 in phase 3: Option 1: 1 day of vancomycin on day -7, followed by 1 dose of 10E4 NTCD spores on day 0, and 2 doses of placebo on day 1-2. Option 2: 1 day of vancomycin on day -7, followed by 1 dose of 10E7 NTCD spores on day 0 and 2 doses of placebo on day 1-2. Option 3: 5 days of vancomycin on day -11 until day -7, followed by 5 doses of 10E7 NTCD spores on day 0-4.
Arm Title
Group I (phase 3) (N=3)
Arm Type
Placebo Comparator
Arm Description
Escalation to the third phase will only be done if option 3 is selected in phase 2. Based upon the colonisation results of phase 2, 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 in phase 3: Option 1: 1 day of vancomycin on day -7, followed by 3 doses of placebo on day 0-2. Option 2: 1 day of vancomycin on day -7, followed by 3 doses of placebo on day 0-2. Option 3: 5 days of vancomycin on day -11 until day -7, followed by 5 doses of placebo on day 0-4.
Intervention Type
Biological
Intervention Name(s)
10E4 NTCD spores
Intervention Description
in capsule for oral ingestion.
Intervention Type
Biological
Intervention Name(s)
10E7 NTCD spores
Intervention Description
in capsule for oral ingestion.
Intervention Type
Other
Intervention Name(s)
placebo
Intervention Description
in capsule for oral ingestion.
Intervention Type
Drug
Intervention Name(s)
Vancomycin Oral Capsule
Intervention Description
4 times a day 250mg
Primary Outcome Measure Information:
Title
Safety and tolerability of colonisation with non-toxigenic C.difficile
Description
Number and grade of related adverse events from day 1 to 28 after ingestion of NTCD spores.
Time Frame
During the first month after ingestion of NTCD spores.
Title
To establish the effective protocol to obtain colonisation with non-toxigenic C. difficile in the majority of subjects.
Description
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 two weeks after the last exposure day.
Time Frame
During the first month after ingestion of NTCD spores.
Secondary Outcome Measure Information:
Title
To determine factors in the host microbiota associated with successful colonisation.
Description
Microbiota markers which are associated with successful C.difficile colonisation through microbiota analysis with 16S amplicon sequencing.
Time Frame
3 months after ingestion of NTCD spores.
Other Pre-specified Outcome Measures:
Title
Determine changes in the host microbiota following colonisation.
Description
Identification of changes in microbiota components following C.difficile colonisation through microbiota analysis with 16S amplicon sequencing.
Time Frame
3 months after ingestion of NTCD spores.
Title
Investigate C. difficile in-vivo evolution.
Description
Identification of genetic changes of C.difficile after passage through the human host through C.difficile PCR and culturing.
Time Frame
3 months after ingestion of NTCD spores.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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. Subject has adequate understanding of the procedures of the study and is able and willing to abide strictly thereby. For female subjects: subject agrees to use adequate contraception and not to breastfeed for the duration of study. 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. Use of antibiotics (or other microbiota influencing products) within one month prior to inclusion. 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). Regular use (defined by more than once weekly) of proton-pump inhibitors or H2- blockers during one month prior to inclusion. The use of strong P-glycoprotein-inhibitors (like Ciclosporin, Ketoconazole, Erythromycin, Clarithromycin, Verapamil and Amiodaron). Known allergy to vancomycin, metronidazole or fidaxomicin. Known allergy to glycerol. Known immunodeficiency disorders. 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. Positive fecal PCR with Clostridiodes or SSYC (Salmonella, Shigella, Yersinia or Campylobacter spp.) at screening. 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. For women of child bearing potential: a positive urine pregnancy test before inclusion or lactating at screening / during the trial. Being an employee or student of the Experimental bacteriology group or the controlled human infection center at LUMC.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Meta Roestenberg, MD, PhD
Phone
+31715262102
Email
M.Roestenberg@lumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Meta Roestenberg, MD, PhD
Organizational Affiliation
Leiden University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Leiden University Medical Center
City
Leiden
ZIP/Postal Code
2333 ZA
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
M. Roestenberg, MD. PhD.
First Name & Middle Initial & Last Name & Degree
M. Roestenberg, MD. PhD.
First Name & Middle Initial & Last Name & Degree
A.D.O. Hensen, MD.

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Clostridioides Difficile Colonisation

We'll reach out to this number within 24 hrs