Efficacy, Immunogenicity, and Safety Study of Clostridium Difficile Toxoid Vaccine in Subjects at Risk for C. Difficile Infection (Cdiffense™)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 9,302
- 试验地点
- 485
- 主要终点
- Number of Participants With Symptomatic Polymerase Chain Reaction (PCR)-Confirmed Primary C. Difficile Infection (CDI) Cases
研究概览
简要总结
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.
详细描述
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.
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
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
结局指标
主要结局
Number of Participants With Symptomatic Polymerase Chain Reaction (PCR)-Confirmed Primary C. Difficile Infection (CDI) Cases
时间窗: Up to 3 years post injection 1
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.
次要结局
- Number of Participants With Severe PCR-Confirmed Primary CDI Cases(Up to 3 years post injection 1)
- Number of Participants With Loose Stool Episodes(Up to 3 years post injection 1)
- Number of Participants With Symptomatic PCR Confirmed CDI Cases: Per-Protocol Population(Up to 3 years post injection 1)
- Serum Antibody Concentrations Against Toxins A and B Measured by Toxin Neutralization Assay (TNA)(Day 0, Day 14, Day 30, Day 60, Day 210, Day 390, Day 570, Day 750, Day 930, and Day 1110)
- Serum Antibody Concentrations Against Toxins A and B Measured by TNA in Participants With CDI(Day 0 and Day 60)
- Percentage of Participants With >= 2 and 4-Fold Rise in Serum Antibody Concentrations From Baseline Against Toxins A and B Measured by ELISA(Day 60)
- Serum Antibody Concentrations Against Toxins A and B Measured by Enzyme-Linked Immunosorbent Assay (ELISA)(Day 0, Day 14, Day 30, Day 60, Day 210, Day 390, Day 570, Day 750, Day 930, and Day 1110)
- Serum Antibody Concentrations Against Toxins A and B Measured by ELISA in Participants With CDI(Day 0 and Day 60)
- Percentage of Participants With >= 2 and 4-Fold Rise in Serum Antibody Concentrations From Baseline Against Toxins A and B Measured by TNA(Day 60)
- Percentage of Participants Reporting Solicited Injection Site and Systemic Reactions(Day 0 to Day 6 after any vaccination)