Anthrax Vaccine Adsorbed: Human Reactogenicity and Immunogenicity Trial to Address Change in Route of Administration and Dose Reduction
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 1,564
- 试验地点
- 10
- 主要终点
- Systemic AEs
研究概览
简要总结
Anthrax Clinical Trial Objectives:
To assess whether:
- Anthrax vaccine (AVA or BioThrax, BioPort Corp. Lansing MI) administered by the intramuscular (IM) route elicits antibody responses that are not inferior (i.e., "non-inferior") to that achieved by the currently licensed schedule.
- BioThrax administered by the IM route and containing fewer numbers of doses elicits antibody responses that are not inferior (i.e., "non-inferior") to that achieved by the currently licensed schedule.
- Differences in reactogenicity exist between the IM and subcutaneous (SQ) administration of BioThrax.
Additionally for the final report we will assess whether:
- Occurrence of adverse events following AVA administration is influenced by selected risk factors.
详细描述
This study is a 43-month prospective, randomized, double-blind, placebo-controlled comparison of immunogenicity and reactogenicity elicited by BioThrax given by different routes of administration (SQ versus IM) and dosing regimens (as many as 8 doses versus as few as 4 doses). Sterile saline is used as the placebo where doses are dropped in regimens using AVA, and in the all-placebo study group.
This study is conducted among a total of 1564 healthy adult men and women (18 to 61 years of age) at five sites in the United States. Participants were randomized into one of 6 study groups with 260 participants per group. One group receives BioThrax given as currently licensed (SQ with 6 doses followed by annual boosters); another group is given placebo IM (130 participants) or SQ (130 participants) in the currently licensed dosing regimen. The four other groups receive BioThrax IM in modified dosing regimens; placebo is given when a dose of BioThrax is omitted from the licensed dosing regimen. There are a total of 25 required visits for this study, during which all participants receive an injection of vaccine or placebo (8 injections total), have a blood sample drawn (16 or 17 total), and have an in-clinic examination for adverse events (22 total).
Immunogenicity is assessed by assaying 16 serial blood samples obtained from all participants and a 17th sample from a subset of participants before vaccination and at other specified times. Total anti-protective antigen IgG antibody (anti-PA IgG) is quantified using a standardized and validated enzyme-linked immunosorbent assay (ELISA); the primary study endpoints are 4-fold rise in antibody titer and antibody concentration relative to the pre-vaccination titers or assay reactivity threshold. A subset of serum samples is also assayed in an in vitro toxin neutralization assay (TNA) to measure the functional activity of anti-BioThrax antibodies. The kinetics of the immune response to BioThrax are examined at 3 time points in the study and blood samples from a subset of participants will be further tested in correlates of protection and immunogenetics substudies. All adverse events (AEs), including vaccine reactogenicity, are actively monitored. While all AEs will be ascertained among study participants, several endpoints will be defined based on the likelihood of their occurrence and/or their clinical importance. Of primary interest is the occurrence of local AEs such as warmth, tenderness, itching, pain, arm motion limitation, erythema, induration, nodule, and bruise. Systemic AEs such as fever, fatigue, muscle ache, headache, temperature, and painful axillary adenopathy are also evaluated.
This study is expected to provide the basis for consideration of change in route of BioThrax administration from SQ to IM and reduction in number of vaccine doses required for primary and booster immunization.
There is an interim analysis of data collected through each participant's first 7 months of this study for consideration in changing the route of BioThrax administration from SQ to IM, and elimination of the 2 week vaccine priming dose.
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)
入排标准
- 年龄范围
- 18 Years 至 61 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Read/sign Informed Consent Document; Female or male, 18 to 61 years old (up to 62nd birthday); Females must agree to exercise adequate birth control from the time of the screening procedures to one month after the last vaccination; willingness/ability to return for all follow-up visits and blood collections for the duration of the study; ability to understand/comply with planned study procedures; agree to complete the Participant Diary (Appendix G) and to report concomitant medications and AEs during the study period; thave two intact upper arms with sufficient subcutaneous and intramuscular tissue in the deltoid regions for vaccine administration.Potential participants with a history of the following conditions remain eligible for study enrollment: gestational diabetes; treated, controlled, uncomplicated hypertension; treated hypo- or hyperthyroidism; cured nonmetastatic cancer; disease-free for 5 years (excluding hematologic malignancies); localized skin cancer, resected (including squamous cell and basal cell carcinomas, participants with a history of melanoma must be disease-free for 5 years); exercise-induced bronchospasm; mild asthma: use of inhalers only for control of symptoms is acceptable (Persons who have required hospitalization for asthma within the previous 2 years or those who require chronic or frequent oral/parenteral steroids will not be eligible; use of low to medium doses of inhaled steroids; history of coronary artery disease, asymptomatic (NYHA Function Class I), on a stable medical regimen. Persons meeting these criteria must be at least 2 years post-myocardial infarction, cardiac bypass surgery, and/or percutaneous coronary intervention (e.g., angioplasty, stent placement, etc) in order to qualify. Persons with a history of cardiac disease must be under the care of a physician.
排除标准
- •Prior history of anthrax or immunization against anthrax; Known allergy to aluminum hydroxide, formaldehyde, benzethonium chloride, or latex; Pregnant/plans to become pregnant for duration of study/does not agree to use adequate birth control from the time of screening procedures to one month after last vaccination; Used cytotoxic therapy in previous 5 years; Cardiovascular disease with significant likelihood of progression over 5 years; Moderate to severe asthma, chronic obstructive pulmonary disease, other significant pulmonary disease; using high doses of inhaled steroids; Clinically recognized hepatic or renal insufficiency; Inflammatory, vasculitic, or rheumatic disease including systemic lupus erythematosis, polymyalgia rheumatica and rheumatoid arthritis, scleroderma; Known HIV, hepatitis B or hepatitis C infection; Other conditions known to produce or be associated with immune suppression; Neuropathy or other evolving neurologic condition; Unstable/moderate to severe mental illness; Ongoing drug abuse/dependence (including alcohol); Seizure disorder; Active malignancy or history of metastatic or hematologic malignancy; current diabetes; Anyone who plans to receive within 60 days of study entry: cytotoxic therapy, experimental products, a live vaccine outside this trial, immunosuppressive therapy, parenteral immunoglobulin or blood products; Anyone who plans to receive an inactivated vaccine outside this trial within 42 days after study entry;: experimental products, a live vaccine outside this trial, immunosuppressive therapy; Anyone who received an inactivated vaccine outside this trial within 14 days prior to study entry, parenteral immunoglobulin or blood products within three months of study. In addition to conditions listed above, temporary exclusion would result from moderate or severe illness and/or oral temperature >100.4˚F within 3 days of injection or chronic condition that, in opinion of investigator, would render injection unsafe or would interfere with evaluations.
结局指标
主要结局
Systemic AEs
时间窗: 4 weeks after each injection
Fatigue, Muscle Ache, Headache, Fever, Tender Axillary Lymphnode The number of injections analyzable varies for each event based on the presence or absence of reported data.
Anti-protective Antigen IgG Geometric Mean Titer
时间窗: 4 weeks after the m1, m6 and m42 injections
Geometric mean of the Dilutional Titer. The Dilutional Titer is the reciprocal of the dilution at which the anti-PA IgG response reaches a threshold. The lower limit of quantification (LLOQ) is 58, results below the LLOQ have been replaced by 1/2 LLOQ (29) before taking the geometric mean.
4-fold Rise in Anti-protective Antigen IgG Titer Response
时间窗: 4 weeks after the m1, m6 and m42 injections
Percent of participants who achieved a 4-fold or greater rise in anti-PA IgG Titer relative to the pre-vaccination level at month 0. The Dilutional Titer is the reciprocal of the dilution at which the anti-PA IgG response reaches a threshold. The lower limit of quantification (LLOQ) is 58, results below the LLOQ have been replaced by LLOQ (58) before calculating the fold response. Thus the lowest titer that can achieve 4-fold rise is 4\*58 = 232.
Local AEs
时间窗: 4 weeks after each injection
warmth, tenderness, itching, pain, arm motion limitation, erythema, induration, nodule, and bruise. The number of injections analyzable varies for each event based on the presence or absence of reported data.
Anti-protective Antigen IgG Geometric Mean Concentration
时间窗: 4 weeks after the m1, m6 and m42 injections
Geometric mean of the Anti-PA IgG Concentration measured in μg/mL. The lower limit of quantification (LLOQ) is 3.7, results below the LLOQ have been replaced by 1/2 LLOQ (1.85) before taking the geometric mean.
次要结局
- TNA ED50 Titer(4 weeks after the m1, m6 and m42 injections)