Evaluation of the Immune Response to Clostridium Difficile in Adults With Clostridium Difficile Infection (CDI)

Study Overview
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Brief Summary
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This study aims to 1) evaluate the C. difficile-specific immune response in CDI patients and 2) explore the difference in immune response between the patients with CDI recurrence and those with a sustained clinical response.

Detailed Description
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Patients with an initial episode of CDI will be followed up for CDI recurrence or sustained clinical response. The subjects will be allocated into 2 groups at the study end: Recurrence Group: Subjects who experience recurrence of CDI after clinical response to antibiotic treatment to treat the initial CDI episode. Sustained response Group: Subjects who do not experience recurrence of CDI after clinical response to the antibiotic treatment to treat the initial CDI episode. This protocol has been amended twice to improve recruitment of subjects in the study.

Official Title
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A Serological Study in Adult Subjects With Clostridium Difficile Infection

Conditions
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Infections, Clostridium Difficile

Intervention / Treatment
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* Procedure: Blood sampling
* Other: Stool sample collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that they can and will comply with the requirements of the protocol or/ and subjects who can receive assistance from his/ her legally acceptable representative (LAR) or a designate who can and will comply with the requirements of the protocol. A male or female aged 18 years or older at the time of enrolment. Written informed consent obtained from the subject/ LAR of the subject. A reasonable prognosis of survival during the study period as judged by the investigator. Outpatients, emergency room and/ or hospitalized subjects diagnosed with CDI for which the symptoms started maximum 14 days prior to study enrolment. Subjects who receive or plan to receive antibiotic treatment to treat the CDI episode. Exclusion Criteria: Concurrently participating or planning to participate in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product. Previous CDI episode within the previous 6 months before study enrolment (except for up to  25% of the subjects). Chronic diarrheal illness such as, but not limited to, ulcerative colitis or Crohn's disease. Planned surgery for CDI within 24 hours after study entry. Previous vaccination against Clostridium difficile. Having received a Clostridium difficile monoclonal antibody product(s) within the previous 3 months or planned administration during the study period. Administration of immunoglobulins within the previous 3 months or planned administration during the study period. Subject having any other condition that, in the opinion of the investigator, would jeopardize the safety or rights of the subject participating in the study, would make it unlikely for the subject to complete the study, or would confound the results of the study. Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs within the previous 6 months. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history. Family history of congenital or hereditary immunodeficiency. Major congenital defects.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Recurrence group<br>Male or female subjects aged 18 years or older at the time of enrollment, who experienced recurrence of Clostridium difficile infection (CDI) after clinical response to antibiotic treatment to treat the initial CDI episode. | Procedure: Blood sampling<br>* Blood sampling will be done at Day 0, at Day 14, at recurrence (if applicable) and at end of follow-up.<br>Other: Stool sample collection<br>* Stool samples will be collected around Day 0, around Day 14 and at recurrence (if applicable).<br>|
| Other: Sustained response group<br>Male or female subjects aged 18 years or older at the time of enrollment, who did not experience recurrence of CDI after clinical response to the antibiotic treatment to treat the initial CDI episode. | Procedure: Blood sampling<br>* Blood sampling will be done at Day 0, at Day 14, at recurrence (if applicable) and at end of follow-up.<br>Other: Stool sample collection<br>* Stool samples will be collected around Day 0, around Day 14 and at recurrence (if applicable).<br>|
| Other: Failure to antibiotic Group<br>Male or female subjects aged 18 years or older at the time of enrollment, withdrawn due to failure of antibiotic treatment to treat the initial CDI episode. | Procedure: Blood sampling<br>* Blood sampling will be done at Day 0, at Day 14, at recurrence (if applicable) and at end of follow-up.<br>Other: Stool sample collection<br>* Stool samples will be collected around Day 0, around Day 14 and at recurrence (if applicable).<br>|
| Other: Unclassified Group<br>Male or female subjects aged 18 years or older at the time of enrollment, who couldn't be classified as sustained response, recurrence, or failure to antibiotic due to missing data. | Procedure: Blood sampling<br>* Blood sampling will be done at Day 0, at Day 14, at recurrence (if applicable) and at end of follow-up.<br>Other: Stool sample collection<br>* Stool samples will be collected around Day 0, around Day 14 and at recurrence (if applicable).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Anti-toxin A and Anti-toxin B Antibody Concentrations at Day 14 | Serum anti-toxin B antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), as measured by the Enzyme Linked Immunosorbent Assay (ELISA) for the cut-off of equal to or above (≥) 100 EU/mL. | At Day 14 | 
| Serum F2 C-terminal Anti-toxin B Antibody Concentrations | Serum F2 C-terminal anti-toxin B antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), as measured by ELISA for the cut-off of 13.16 EU/mL. | At Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Anti-toxin A and Anti-toxin B Antibody Concentrations at Day 0 and Day 72 | Serum anti-toxin B antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), as measured by ELISA for the cut-off equal to or above (≥) 100 EU/mL. | At Day 0 and at Day 72 | 
| Serum Neutralizing Anti-toxin A and Anti-toxin B Antibody Titers at Day 14 | Neutralizing antibody concentrations were expressed as Geometric Mean Titers (GMTs), as measured in an inhibition of cytotoxicity assay (toxin neutralization assays) for the cut-off of 2, expressed in 1/DIL unit, in which DIL is the sample dilution corresponding to 50% neutralization. | At Day 14 | 
| Serum Neutralizing Anti-toxin A and Anti-toxin B Antibody Titers at Day 0, Within 10 Days After Recurrence and at Day 72 | Neutralizing antibody concentrations were expressed as Geometric Mean Titers (GMTs), as measured in an inhibition of cytotoxicity assay (toxin neutralization assays) for the cut-off of 2, expressed in 1/DIL unit, in which DIL is the sample dilution corresponding to 50% neutralization. This measure concerned only diarrhea recurrence. No CDI recurrence was considered as part of the Group Sustained Response. | At Day 0, within 10 days after start of recurrent episode if any, and at end of follow-up (Day 72) | 
| Number of Subjects With Clostridium Difficile Infection (CDI) Recurrence | A CDI recurrence is defined as the development of a new episode of CDI following clinical response at the end of standard of care (SoC) for the initial CDI episode. | From Day 0 to Day 72 | 
| CDI Initial Episodes Severity Characteristics, in All Subjects | Severity characteristics were expressed in duration of days for hospitalization, intensive care unit, Standard of Care (SoC) and CDI episodes. | At Day 0 | 
| Number of Subjects With Initial CDI Episode by Severity, in All Subjects | Initial CDI episodes were recorded by severity criteria: medical attention given, admission to intensive care unit, colectomy, death, high white blood cells (WBC) count, high creatinine count, hypotension/shock, clinical response to Standard of Care (SoC). | At Day 0 | 
| Number of Subjects With CDI Recurrence by Severity, in Those Subjects Who Recur | A CDI recurrence is defined as the development of a new episode of CDI following clinical response at the end of standard of care (SoC) for the initial CDI episode. An episode of diarrhea was not considered as a recurrence of CDI if the stool was negative for C. difficile or if the diarrhea was attributed to another cause than C. difficile. The severity criteria for CDI recurrent episodes were categorized into non-severe and severe. | At recurrence (within 10 days of start diarrhea) during a follow up period of up to 72 days per participant | 
| Number of Subjects With Failure of Antibiotic Treatment | Failure of antibiotic treatment against C. difficile is defined as the persistence or the incomplete resolution of symptoms (more than one unformed stool per day) after a full course of antibiotic(s) therapy (minimum 7 days). Aminopen+BetaLactam Inhib,1st Gen.Cephalosporin = Aminopenicillin+Beta-Lactamase Inhibitor and 1st Generation Cephalosporin. Aminopen+BetaLactam Inhib, 3rd Gen.Cephalosporin = Aminopenicillin+Beta-Lactamase Inhibitor and 3rd Generation Cephalosporin excluding Ceftazidime and Fluoroquinolone. Aminopen+BetaLactam Inhib and Fluoroquinolone = Aminopenicillin+Beta-Lactamase Inhibitor and Fluoroquinolone. Antipseudom Pen+BetaLactam Inhib and Cephalosporin = Antipseudomonal Penicillin+Beta-Lactamase Inhibitor and 1st Generation Cephalosporin and 3rd Generation Cephalosporin excluding Ceftazidime and Fluoroquinolone and Glycopeptides (Iv). Antipseudom Pen+BetaLactam Inhib and Glycopeptides = Antipseudomonal Penicillin+Beta-Lactamase Inhibitor and Glycopeptides (Iv). | Within 3 months before the initial CDI episodes | 
| Number of Subjects With Risk Factors Associated With the Initial CDI Episode | Risk factors for CDI included factors in three main domains involving host factors (advanced age, impaired immune status, co-morbidities); increased exposure to C. difficile spores (longer length of stays, healthcare environment, infected roommates or hand carriage by personnel); and factors that disrupt the normally protective colonic microflora layer (antimicrobials, other medications or procedures). CDI episodes within 6 months: Protocol exclusion criteria for enrolment allowed up to maximum 25% of the planned subjects having a previous CDI episode within the previous 6 months. Antibiotic taken within 3 months: Antibiotic not prescribed to treat C. difficile taken within 3 months before the current CDI episode. | At Day 0 | 
| Number of Subjects With Risk Factors Associated With the CDI Recurrence | Risk factors for CDI included factors in three main domains involving host factors (advanced age, impaired immune status, co-morbidities); increased exposure to C. difficile spores (longer length of stays, healthcare environment, infected roommates or hand carriage by personnel); and factors that disrupt the normally protective colonic microflora layer (antimicrobials, other medications or procedures). | At recurrence (within 10 days of start diarrhea) during a follow up period of up to 72 days per participant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Serological, Adults, Clostridium difficile, Adult CDI patients