A Randomized, Double-Blinded, Placebo-controlled, Dose-Escalation, Age-Descending Study to Assess the Safety and Tolerability of Live Attenuated, Oral Shigella WRSS1 (Walter Reed S. Sonnei) Vaccine in Bangladeshi Adults and Children
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 103
- 试验地点
- 1
- 主要终点
- Number and Percentage of Participants With Serious Adverse Events (SAEs)
研究概览
简要总结
This is a research study about an experimental (investigational) oral Shigella sonnei - Walter Reed S. sonnei (WRSS1). WRSS1 is a live vaccine that is being made to prevent disease from Shigella, which causes bloody, watery diarrhea. Infants and children living in developing countries experience the greatest consequences of this disease. The purpose of this study is to find a dose of the vaccine that is safe, tolerable, and develops an immune response. About 39 healthy adults, ages 18-39, and 48 healthy children, ages 5-9, will participate in this study. Once the vaccine is proven safe and tolerable in adults, then it will be tested in the children. This study will require volunteers to stay in the research facility for several nights for the first dose; they will not be required to stay overnight for the second and third doses. Participants will be assigned to receive 1 of 3 vaccine dose levels by mouth. Study procedures include: stool samples, blood samples and documenting side effects. Participants will be involved in study related procedures for about 8 months.
详细描述
This is a single site, double-blind, randomized, placebo-controlled, dose-escalation, age-descending study that will start testing the vaccine in healthy adults and move subsequently into school-age children. The study is designed as 2 parts, each part comprising 3 cohorts. The cohort receiving the lowest dose in Parts A and B will receive only one administration of vaccine or placebo; the subsequent two higher dose cohorts in Parts A and B will receive three administrations of vaccine or placebo. In each cohort, the first dose and immediate safety evaluation will be conducted at the International Centre for Diarrhoeal Disease Research (icddr,b) Inpatient Unit, where the participants will be admitted for observation for 72 hours. Follow-up visits for participants in A1 and B1 will take place on an outpatient basis at the Mirpur, Bangladesh (Mirpur) Field Office. Second and third vaccinations within A2, A3, B2, and B3 cohorts and all follow-up visits will take place on an outpatient basis at the Mirpur Field Office. Before enrolling participants in subsequent cohorts to receive a higher vaccine dose, or to move to the lower age group, the safety data from the previous cohort(s) (through Study Day 7) will be evaluated and reviewed by the Internal Protocol Safety Team (IPST) comprised of the study physician, the Medical Monitor from GVK Biosciences (GVK), the principal investigator, and the Medical Monitor from PATH Vaccine Solutions (PVS). Upon completion of the last adult cohort, the Data Safety Monitoring Board (DSMB -an advisory body to the Ethical Review Committee) will convene to review the cumulative safety data and IPST recommendation, and determine whether to proceed to Part B (children). Adverse events (AE)s will be graded according to standardized criteria. The immunogenicity outcome measures of interest include serum immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies by Antibodies in Lymphocyte Supernatant (ALS) assay against S. sonnei2a lipopolysaccharide (LPS), shedding profile of WRSS1, and vaccine-specific mucosal IgA responses.
The proposed study builds upon successful preliminary observations with this vaccine in the US, Israel and Thailand. While secondary objectives include studying the immunogenicity of the WRSS1 vaccine, the primary goal of the current trial is to establish a clear safety profile for the WRSS1 vaccine in adults and children 5-9 years old.The primary objective of the study is to evaluate the safety and tolerability of the vaccine; the secondary objective is to evaluate vaccine immunogenicity.
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
- 5 Years 至 39 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy male or female adults from 18-39 years old, inclusive
- •General good health as determined by the screening evaluation no greater than 30 days before admission
- •Properly informed about the study, able to understand it and sign the informed consent form
- •Normal bowel habits (< 3 grade 1 or 2 stools each day; ≥ 1 grade 1 or 2 stools every 2 days)
- •Free of obvious health problems as established by medical history and clinical examination before entering into the study.
- •Available for the entire period of the study and reachable by study staff throughout the entire follow-up period
- •Females of childbearing potential who are willing to take a serum pregnancy test at screening and urine pregnancy tests before each vaccination. Pregnancy tests must be negative before each vaccination. Females of childbearing potential must agree to use an efficacious hormonal or barrier method of birth control during the study. Abstinence is also acceptable.
- •Signed Informed Consent
排除标准
- •Presence of a significant medical or psychiatric condition that in the opinion of the Investigator precludes participation in the study
- •Known infection with Hepatitis C or Human Immunodeficiency Virus (HIV)
- •History of congenital abdominal disorders, intussusception, abdominal surgery or any other congenital disorder.
- •Participation in research involving another investigational product (defined as receipt of investigational product) 30 days before planned date of first vaccination or concurrently participating in another clinical study, at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational product
- •Clinically significant abnormalities on physical examination
- •Clinically significant abnormalities in screening hematology, serum chemistry, or urinalysis as determined by the PI or the PI in consultation with the Study Physician
- •History of febrile illness within 48 hours prior to vaccination
- •Known or suspected impairment of immunological function based on medical history and physical examination
- •Prior receipt of any Shigella vaccine
- •Fever at the time of immunization. Fever is defined as a temperature ≥ 37.5 degrees Celsius (99.5 degrees Fahrenheit) on axillary, oral, or tympanic measurement
- •Clinical evidence of active gastrointestinal illness
- •Prior receipt of a blood transfusion or blood products, including immunoglobulins
- •Presence of any significant systemic disorder (cardiovascular, pulmonary, hepatic, renal, gastrointestinal, endocrine, immunological, dermatological, neurological, cancer or autoimmune disease) as determined by medical history and/or physical examination which would endanger the participant's health or is likely to result in non-conformance to the protocol.
- •History of any neurologic disorders or seizures.
- •Acute disease at the time of enrolment
- •Evidence of current excessive alcohol consumption
- •Evidence of current illicit drug use or drug dependence
- •Current use of iron or zinc supplements within the past 7 days; current use of antacids (Histamine H2-receptor antagonists (H2 blockers), Omeprazole, over the counter (OTC) agents) or immunosuppressive drug
- •Allergy to quinolone, sulfa, and penicillin classes of antibiotics
- •History of any of the following conditions within the past 10 years:
- •Arthritis (two or more episodes of joint pain and swelling)
- •Gastrointestinal disease (diagnosed by a doctor as having irritable bowel disease, Crohn's disease, ulcerative colitis (biopsy confirmed), celiac disease, stomach or intestinal ulcers
- •Dyspepsia (indigestion or heartburn requiring medication more than once per week)
- •History of gallbladder disease
- •History of chronic heart disease
- •Any conditions which, in the opinion of the investigator, might jeopardize the safety of study participants or interfere with the evaluation of the study objectives
- •Receipt of antimicrobial drugs for any reason or a fever ≥ 38 degrees Celsius within 7 days before vaccination
- •History of diarrhea during the 7 days before vaccination.
- •Has any household member(s) who is immunocompromised or under the age of 2 years old.
研究组 & 干预措施
Part A (Adults): Cohort A3
Three oral doses of ~3x10^6 cfu WRSS1(10 participants) or placebo (3 participants)
干预措施: WRSS1 (Biological)
Part A (Adults): Cohort A2
Three oral doses of ~3x10^5 cfu WRSS1(10 participants) or placebo (3 participants)
干预措施: WRSS1 (Biological)
Part B (Children): Cohort B1
One oral dose of ~3x10^3 cfu WRSS1(12 participants) or placebo (4 participants)
干预措施: WRSS1 (Biological)
Part B (Children): Cohort B2
Three oral doses of ~3x10^4 cfu WRSS1(12 participants) or placebo (4 participants)
干预措施: WRSS1 (Biological)
Part B (Children): Cohort B3
Three oral doses of ~3x10^5 cfu WRSS1(12 participants) or placebo (4 participants)
干预措施: WRSS1 (Biological)
Part B (Children): Cohort B4
Three oral doses of ~3x10^6 cfu WRSS1(12 participants) or placebo (4 participants)
干预措施: WRSS1 (Biological)
Part A (Adults): Cohort A1
One oral dose of ~3x10^4 cfu WRSS1(10 participants) or placebo (3 participants)
干预措施: WRSS1 (Biological)
结局指标
主要结局
Number and Percentage of Participants With Serious Adverse Events (SAEs)
时间窗: Day -1(admission day) through 6 months (Day 224 +/- 14 days) after the third vaccination for Cohorts A2,A3, B2, B3, B4, and after the first vaccination (Day 168 +/- 14 days) for Cohorts A1 and B1.
Based on maximum severity per participant over all serious adverse events (SAEs) within 6 months of any vaccination. A Serious Adverse Event, including serious suspected adverse reaction or serious adverse reaction as determined by the Investigator or the sponsor, was any event that results in any of the following outcomes: Inpatient hospitalization or prolongation of existing hospitalization , life-threatening AE that in the opinion of the investigator or sponsor put the participant at immediate risk of death, persistent or significant incapacity or substantial disruption, congenital abnormality or birth defect, a medically important event that may have jeopardized the participant or may have required intervention to prevent one of the other outcomes listed or death.
Number and Percentage of Participants With Any Non-serious Unsolicited Adverse Events
时间窗: Day -1(admission day) through 6 months (Day 224 +/- 14 days) after the third vaccination for Cohorts A2,A3, B2, B3, B4, and after the first vaccination (Day 168 +/- 14 days) for Cohorts A1 and B1.
Based on subject count over all non-serious adverse events. An Adverse event was defined as any untoward medical occurrence in humans, whether or not considered drug related, that occurred during the conduct of a clinical trial. Any change in clinical status, ECGs, routine labs, x-rays, physical examinations, etc., that was considered clinically significant by the study investigator, was considered an AE. This definition also included an exacerbation or worsening of pre-existing conditions or events, inter-current illnesses, injuries, or vaccine or drug interaction, or worsening of abnormal clinical laboratory values. All AEs were assessed by the clinician using a protocol defined grading system.
Number and Percentage of Participants With Solicited Systemic and Intestinal Reactions
时间窗: Day 0 through Day 7 after any vaccination
Maximum severity per participant of any systemic or any gastrointestinal reactogenicity recorded within 7 days of any vaccination is reported. Solicited Systemic reactogenicity events assessed included fever, headache, malaise, generalized myalgia, arthralgia, chills, reactive arthritis and decreased appetite. Intestinal solicited reactogenicity events assessed included abdominal cramps, abdominal pain, nausea, vomiting, loose stool, diarrhea, dysentery, bloating, excess flatulence and constipation. Diarrhea and dysentery were assessed both during inpatient (first three day period post-vaccination) and outpatient ( post-vaccination days 4-7) periods post-vaccination 1. Vaccinations 2 and 3 did not have an inpatient admission period for any participants. Diarrhea severity was determined on the basis of stool number, grading and stool weight during the inpatient period and by stool number and grading only during the outpatient period.
Number and Percentage of Participants With Any Unsolicited AEs and SAEs Judged as Having a Reasonable Possibility That the Study Product Caused the Event
时间窗: SAEs at any time and AEs after any vaccination until Day 168 (Cohort A1, B1) and Day 224 (all other Cohorts).
Adverse event (AE) was defined as any untoward medical occurrence in humans, whether or not considered drug related, that occurs during the conduct of a clinical trial. A Serious Adverse Event (SAE) , including serious suspected adverse reaction or serious adverse reaction as determined by the Investigator or the sponsor, was any event that results in any of the following outcomes: Inpatient hospitalization or prolongation of existing hospitalization , life-threatening AE that in the opinion of the investigator or sponsor put the participant at immediate risk of death, persistent or significant incapacity or substantial disruption, congenital abnormality or birth defect, a medically important event that may have jeopardized the participant or may have required intervention to prevent one of the other outcomes listed or death. Causality of the AE/SAE to the study drug was assessed by the Investigator as reasonable possibility that the study product caused the reported event.
次要结局
- Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in ALS: Invaplex(Day 63)
- Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in Serum(At any time (Day 7 to Day 84))
- Number and Percentage of Participants With a 4-fold Rise From Baseline in Immunoglobulin A (IgA) Antibodies in Antibody Titers in Lymphocyte Supernatant (ALS)(Day 7)
- Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in ALS(At any time (Day 7 to Day 63))
- Number and Percentage of Participants With a 4-fold Rise From Baseline in Immunoglobulin G (IgG ) IgG Antibodies in ALS(Day 7)
- Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in ALS(At any time (Day 7 to Day 63))
- Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in ALS: Lipopolysaccharide (LPS)(Day 63)
- Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in ALS : LPS(Day 63)
- Number and Percentage of Participants With a 4-fold Rise From Baseline in IgG Antibodies in Serum(At any time (Day 7 to Day 84))
- Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in ALS(At any time (Day 7 to Day 63))
- Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in ALS: Invaplex(Day 63)
- Number and Percentage of Child Participants With a 4-fold Rise From Baseline in IgM Antibodies in ALS: LPS(Day 35)
- Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Serum(At any time (Day 7 to Day 84))
- Number and Percentage of Child Participants With a 4-fold Rise From Baseline in (Immunoglobulin M) IgM Antibodies in Serum(Day 7)
- Number and Percentage of Adult Participants With a 2-fold Rise From Baseline in IgA and IgG Antibodies in ASC(At any time (Day 7 to Day 63))
- Number and Percentage of Participants With a 4-fold Rise From Baseline in IgA Antibodies in Stool(At any time (Day 7 to Day 84))
- Number and Percentage of Participants With a 4-fold Rise From Baseline in Ratio of Specific IgA to Total IgA Antibodies in Stool(At any time (Day 7 to Day 84))
- Number and Percentage of Adult Participants With WRSS1 Shedding at Any Time After Vaccination(At any time (Day 0 to Day 84))