Study of a Candidate Clostridium Difficile Toxoid Vaccine in Subjects at Risk for C. Difficile Infection

Study Overview
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Brief Summary
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The aim of this study was to evaluate the efficacy of the Clostridium difficile vaccine to prevent primary symptomatic C. difficile infection (CDI) in participants at risk for CDI where there is a substantial unmet medical need. Primary objective: To assess the efficacy of the C. difficile vaccine in preventing the onset of symptomatic primary CDI confirmed by polymerase chain reaction (PCR) in adult participants aged >= 50 years who are at risk for CDI and have received at least 1 injection. Secondary Objectives: Efficacy: To assess prevention of symptomatic PCR-confirmed primary CDI cases after 3 injections administered at 0, 7, and 30 days. To assess prevention of symptomatic PCR-confirmed primary CDI cases after completion of at least 2 injections. Immunogenicity: To describe the immunogenicity to toxin A and toxin B at specific time points in a subset of participant and in participants with CDI at Day 0 and Day 60. Safety: To describe the safety profile of all participants who received at least 1 injection.

Detailed Description
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The study was designed as an event-driven group sequential protocol with 4 interim analyses at defined information milestones and a final analysis when a specific number of clinical endpoints are reached. Analyses of trial futility (non-efficacy) were to be performed at the first 2 interim analyses, and the study was to be stopped if either of those analyses provided robust and compelling evidence that meaningful levels of vaccine efficacy (VE) would not be demonstrated. Following completion of the first interim analysis (50 cases of confirmed CDI observed), the futility criterion was met and in accordance with IDMC recommendation, enrollment and further vaccination ceased in November 2017. Due to the early termination of the study, some of the planned secondary efficacy endpoints could not be analyzed as all planned data were not collected. Participants were randomized to receive either the candidate vaccine or a placebo that was to be administered in a 3-dose schedule. At the time of group assignment, 928 participants (10% of total enrollment) were randomized to an immunogenicity subset; and 1859 participants (20% of total enrollment) were randomized to a reactogenicity subset. Safety was assessed in all participants in terms of unsolicited adverse events from Day 0 to Day 60, as well as serious adverse events (SAEs) throughout the study. Solicited adverse reactions were collected for 6 days following each injection in the reactogenicity subset.

Official Title
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Efficacy, Immunogenicity, and Safety Study of Clostridium Difficile Toxoid Vaccine in Subjects at Risk for C. Difficile Infection (Cdiffense™)

Conditions
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Clostridium Difficile Infection

Intervention / Treatment
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* Biological: C. difficile Toxoid Vaccine
* Biological: Placebo: 0.9% normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged >= 50 years on the day of inclusion Informed consent form had been signed and dated. Attended all scheduled visits and complied with all trial procedures. Covered by health insurance (if required). Must fulfill at least 1 of the following criteria Risk Stratum 1: Had at least 2 hospital stays, each lasting at least >= 24 hours, in the 12 months before enrollment, and Had received systemic (not topical) antibiotics in the 12 months before enrollment, or Risk Stratum 2: Was anticipated to have an in-patient hospitalization for a planned surgical procedure within 60 days of enrollment. The impending hospital stay was planned to be >= 72 hours for a surgery involving 1 of the following: Kidney/bladder/urinary system Musculoskeletal system Respiratory system Circulatory system Central nervous system. Exclusion Criteria: Participant was pregnant, or lactating, or of childbearing potential (to be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination and until at least 4 weeks after the last vaccination). Participation in the 4 weeks preceding the first trial vaccination or participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure. Receipt of any vaccine in the 4 weeks preceding the first trial vaccination except for influenza (seasonal or pandemic) and pneumococcal vaccines. This exception includes monovalent pandemic influenza vaccines and multivalent influenza vaccines. Previous vaccination against C. difficile with either the trial vaccine, another vaccine, or monoclonal antibodies. Diarrhea on day of enrollment. Self-reported current or prior CDI episode. Anticipated or current receipt of kidney dialysis treatment. History of gastrointestinal surgery for gastrointestinal malignancy (Note: Colonoscopy, polypectomy, and appendectomy are not exclusion criteria). History of inflammatory bowel disease, irritable bowel syndrome (must include diarrhea as a symptom), colostomy, or small or large intestine bowel surgery where resection was performed. Receiving enteral feeding (e.g., nasogastric, gastrostomy, and jejunostomy tube feeding). Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months). Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccine used in the trial or to a vaccine containing any of the same substances. Self-reported thrombocytopenia, contraindicating intramuscular vaccination. Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily. Current alcohol abuse or drug addiction that might interfere with the ability to comply with trial procedures in the opinion of the Investigator. Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion. Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature >= 38.0 degree Celsius [>= 100.4°Fahrenheit]). A prospective participant should not be included in the study until the condition has resolved or the febrile event has subsided. Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study, or identified as an immediate family member (i.e., parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study was observer-blind. The vaccine preparer and administrator may have been unblinded to treatment assignment due to the steps necessary for vaccine preparation. However, the participant, the Investigator, and study staff members who collected the safety data and laboratory personnel who analyzed the blood and stool samples were all blinded to the group assignment.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: C. difficile Vaccine Group<br>Participants received 1 injection of 0.5 mL C. difficile toxoid vaccine at Days 0 (Injection 1), 7 (Injection 2), and 30 (Injection 3). | Biological: C. difficile Toxoid Vaccine<br>* 0.5 mL, Intramuscular<br>|
| Placebo Comparator: Placebo Group<br>Participants received 1 injection of 0.5 mL placebo matched to vaccine at Days 0 (Injection 1), 7 (Injection 2), and 30 (Injection 3). | Biological: Placebo: 0.9% normal saline<br>* 0.5 mL, Intramuscular<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Symptomatic Polymerase Chain Reaction (PCR)-Confirmed Primary C. Difficile Infection (CDI) Cases | Symptomatic PCR-confirmed CDI cases were defined as the number of participants with combination of clinical and laboratory findings. Clinical components were: >= 3 loose stools in <= 24 hours, loose stools (defined as type 6 [fluffy pieces with ragged edges, mushy] or type 7 [watery, no solid pieces] according to the Bristol Stool Chart) lasting >= 24 hours. Laboratory findings were: stool sample positive for C. difficile Toxin B by PCR at central laboratory or diagnosis of pseudomembranous colitis visualized at colonoscopy. | Up to 3 years post injection 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Severe PCR-Confirmed Primary CDI Cases | Severe CDI cases were defined as number of participants with at least one of the following symptoms: fever >= 38.5 degree Celsius (°C), white blood cell count >= 15,000 cells/mm^3, ileus, pseudomembranous colitis, serum albumin <3 gram per deciliter, abdominal distension, abdominal tenderness, or admission to the intensive care unit within 7 days of CDI diagnosis. | Up to 3 years post injection 1 | 
| Number of Participants With Loose Stool Episodes | Loose stools were defined as type 6 (fluffy pieces with ragged edges, mushy) or type 7 (watery, no solid pieces) according to the Bristol Stool Chart. In this outcome measure, participants with number of loose stool episodes (categorized as: loose stool episodes less than 3, 3 to 6, 7 to 10, 11 to 15 and greater than 15) were reported. | Up to 3 years post injection 1 | 
| Number of Participants With Symptomatic PCR Confirmed CDI Cases: Per-Protocol Population | Symptomatic PCR confirmed CDI cases were defined as the number of participants with combination of clinical and laboratory findings. Clinical components were: >= 3 loose stools in <= 24 hours, loose stools (defined as type 6 [fluffy pieces with ragged edges, mushy] or type 7 [watery, no solid pieces] according to the Bristol Stool Chart) lasting >= 24 hours. Laboratory findings were: stool sample positive for C. difficile Toxin B by PCR at central laboratory or diagnosis of pseudomembranous colitis visualized at colonoscopy. Analysis was performed on per-protocol efficacy analysis set (PPEAS). | Up to 3 years post injection 1 | 
| Serum Antibody Concentrations Against Toxins A and B Measured by Enzyme-Linked Immunosorbent Assay (ELISA) | Serum antibody concentrations against toxins A and B were measured by ELISA and expressed as geometric mean concentration (GMC). The 2-sided 95% Confidence Interval (CI) of GMC was based on the Student t-distribution. Analysis was performed on Per Protocol Immunogenicity Analysis Set, which included participants who had at least 1 injection, no relevant protocol deviations (not met inclusion criteria/ met exclusion criteria, not received vaccine/ not received in proper time window, received different vaccine than randomized, preparation and/ or administration of vaccine not per protocol, protocol-restricted therapy, not provided post-dose serology sample/serology sample did not produced a valid test result). | Day 0, Day 14, Day 30, Day 60, Day 210, Day 390, Day 570, Day 750, Day 930, and Day 1110 | 
| Percentage of Participants With >= 2 and 4-Fold Rise in Serum Antibody Concentrations From Baseline Against Toxins A and B Measured by ELISA | Percentage of Participants with >= 2 and 4-fold rise in serum antibody concentrations against toxins A and B were measured by ELISA. The 2-sided 95% Cl of the percentage was based on Exact method calculations. | Day 60 | 
| Serum Antibody Concentrations Against Toxins A and B Measured by ELISA in Participants With CDI | Serum antibody concentrations against toxins A and B were measured by ELISA and expressed as GMC. The 2-sided 95% CI GMC was based on the Student t-distribution. Symptomatic PCR-confirmed CDI cases were defined as the number of participants with combination of clinical and laboratory findings. Clinical components were: >= 3 loose stools in <= 24 hours, loose stools (defined as type 6 [fluffy pieces with ragged edges, mushy] or type 7 [watery, no solid pieces] according to the Bristol Stool Chart) lasting >= 24 hours. Laboratory findings were: stool sample positive for C. difficile Toxin B by PCR at central laboratory or diagnosis of pseudomembranous colitis visualized at colonoscopy. | Day 0 and Day 60 | 
| Serum Antibody Concentrations Against Toxins A and B Measured by Toxin Neutralization Assay (TNA) | Serum antibody concentrations against toxins A and B were measured by TNA and expressed as geometric mean titer (GMT). The 2-sided 95% Cl of GMT was based on the Student t-distribution. | Day 0, Day 14, Day 30, Day 60, Day 210, Day 390, Day 570, Day 750, Day 930, and Day 1110 | 
| Percentage of Participants With >= 2 and 4-Fold Rise in Serum Antibody Concentrations From Baseline Against Toxins A and B Measured by TNA | Percentage of Participants with >= 2 and 4-fold rise in serum antibody concentrations against toxins A and B were measured by TNA. The 2-sided 95% CI of the percentage was based on Exact method calculations. | Day 60 | 
| Serum Antibody Concentrations Against Toxins A and B Measured by TNA in Participants With CDI | Serum antibody concentrations against toxins A and B were measured by TNA and were expressed as GMT. The 2-sided 95% CI GMC was based on the Student t-distribution. Symptomatic PCR confirmed CDI cases were defined as the number of participants with combination of clinical and laboratory findings. Clinical components were: >= 3 loose stools in <= 24 hours, loose stools (defined as type 6 [fluffy pieces with ragged edges, mushy] or type 7 [watery, no solid pieces] according to the Bristol Stool Chart) lasting >= 24 hours. Laboratory findings were: stool sample positive for C. difficile Toxin B by PCR at central laboratory or diagnosis of pseudomembranous colitis visualized at colonoscopy. | Day 0 and Day 60 | 
| Percentage of Participants Reporting Solicited Injection Site and Systemic Reactions | Solicited injection site reactions: pain, erythema, and swelling. Pain: Grade 1: no interference with activity, Grade 2: some interference with activity, Grade 3: significant; prevents daily activity; Erythema and swelling: Grade 1: >= 25 to <=50 mm, Grade 2: >51 to <=100 mm, Grade 3: >100 mm. Solicited systemic reactions: fever, headache, malaise, myalgia, and arthralgia. Fever: Grade 1: >= 38.0°C to <=38.4°C or >= 100.4° Fahrenheit (F) to <=101.1°F, Grade 2: >=38.5°C to <= 38.9°C or >=101.2°F to <=102.0°F, Grade 3: >=39.0°C or >=102.1°F. Headache, malaise, and myalgia: Grade 1: no interference with activity, Grade 2: some interference with activity, Grade 3: significant; prevents daily activity; Arthralgia: Grade 1: free range of motion but complains of pain or discomfort, Grade 2: decreased range of motion due to pain or discomfort, Grade 3: unwilling to move due to pain. | Day 0 to Day 6 after any vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clostridium difficile Toxoid Vaccine, Clostridium difficile infection, Cdiffense