Establishing Colonisation With Non-toxigenic Clostridioides Difficile in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- Safety and tolerability of colonisation with non-toxigenic C.difficile
研究概览
简要总结
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.
详细描述
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'.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The trial is double-blind, placebo-controlled.
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Group A (phase 1) (N=10)
5 doses of 10E4 NTCD spores on day 0-4.
干预措施: 10E4 NTCD spores (Biological)
Group B (phase 1) (N=10)
5 doses of 10E7 NTCD spores on day 0-4.
干预措施: 10E7 NTCD spores (Biological)
Group C (phase 1) (N=4)
5 doses of placebo on day 0-4.
干预措施: placebo (Other)
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 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.
干预措施: 10E4 NTCD spores (Biological)
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 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.
干预措施: 10E7 NTCD spores (Biological)
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 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.
干预措施: Vancomycin Oral Capsule (Drug)
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 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.
干预措施: 10E4 NTCD spores (Biological)
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 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.
干预措施: 10E7 NTCD spores (Biological)
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 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.
干预措施: placebo (Other)
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 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.
干预措施: Vancomycin Oral Capsule (Drug)
Group F (phase 2) (N=3 or 6)
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.
干预措施: placebo (Other)
Group F (phase 2) (N=3 or 6)
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.
干预措施: Vancomycin Oral Capsule (Drug)
Group G (phase 3) (N=10)
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.
干预措施: 10E4 NTCD spores (Biological)
Group G (phase 3) (N=10)
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.
干预措施: 10E7 NTCD spores (Biological)
Group G (phase 3) (N=10)
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.
干预措施: Vancomycin Oral Capsule (Drug)
Group H (phase 3) (N=10)
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.
干预措施: 10E4 NTCD spores (Biological)
Group H (phase 3) (N=10)
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.
干预措施: 10E7 NTCD spores (Biological)
Group H (phase 3) (N=10)
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.
干预措施: placebo (Other)
Group H (phase 3) (N=10)
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.
干预措施: Vancomycin Oral Capsule (Drug)
Group I (phase 3) (N=3)
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.
干预措施: placebo (Other)
Group I (phase 3) (N=3)
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.
干预措施: Vancomycin Oral Capsule (Drug)
结局指标
主要结局
Safety and tolerability of colonisation with non-toxigenic C.difficile
时间窗: During the first month after ingestion of NTCD spores.
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.
时间窗: 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 two weeks after the last exposure day.
次要结局
- To determine factors in the host microbiota associated with successful colonisation.(3 months after ingestion of NTCD spores.)
研究者
Meta Roestenberg
Prof. dr.
Leiden University Medical Center