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