A Phase 1a, Dose-finding, Open-label Trial Followed by a Phase 1b, Double-blind, Randomised, Placebo-controlled Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of the Tuberculosis Subunit Vaccine H107e/CAF®10b in Adults
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 140
- 试验地点
- 1
- 主要终点
- Percentage of participants with solicited injection site reactions recorded up to seven days after each vaccination (i.m. or i.d.) (phase 1b)
研究概览
简要总结
Tuberculosis (TB) is an infection caused by bacteria passed from one person to another through the air when an infected person for instance coughs, speaks, or sneezes. This study tests the safety and vaccine-induced immune response of a new preventive TB vaccine called H107e/CAF®10b. H107e is a copy of protein parts from the bacterium causing tuberculosis, Mycobacterium tuberculosis, which are also called antigens. CAF®10b is an adjuvant which helps the body discover the antigen. The adjuvant and antigen are mixed together to formulate the final vaccine. The final formulated vaccine enhances the immune system's response against the antigen.
This is a first-in-human study, meaning this vaccine is being given to people for the first time. The primary objective is to evaluate the safety of the vaccine and its components; however, the study will also evaluate the specific immune responses generated by the new vaccine. The study is divided into two parts, phase 1a and phase 1b. Phase 1a investigates unadjuvanted H107e, CAF®10b adjuvant, H107e/CAF®10b vaccine (low adjuvant dose), and H107e/CAF®10b vaccine (full adjuvant dose). The trial products are administered twice intramuscularly. H107e is also administered intranasally in one of the groups on Day 85. Phase 1b investigates H107e/CAF®10b, H107e/CAF®10b+Bacillus Calmette-Guérin (BCG), BCG, and placebo. A placebo is a look-alike substance that contains no active drug. All groups in phase 1b receive H107e intranasally on Day 211.
A preventive TB vaccine such as H107e/CAF®10b should be able to introduce the body's immune system to antigens from Mycobacterium tuberculosis. This will result in memory in the immune system, meaning that when a person gets infected with Mycobacterium tuberculosis, the immune system will recognise and target the bacteria to prevent disease, thereby avoiding the need for antibiotic treatment and/or other treatments and their side effects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- None
盲法说明
Phase 1a is open label
Phase 1b is double-blind, randomised, and placebo controlled
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy adults aged ≥18 years and ≤ 45 years of age on the day of the screening visit
- •Completed the written informed consent process
- •Confirmed HIV-negative at screening
- •Confirmed Xpert MTB/RIF Ultra-negative at screening
- •Laboratory values within the indicated ranges obtained at screening:
- •Absolute neutrophil count (ANC) ≥800 cells/mm3
- •Haemoglobin ≥ 11 g/dL for females and >10.5 g/dL for males
- •Platelet count ≥ 100,000/mm3
- •Serum creatinine ≤ 1.5 X upper limit of normal (ULN)
- •AST (SGOT), ALT (SGPT), and alkaline phosphatase, ≤ 2.5 X ULN
- •Total bilirubin ≤ 2 X ULN)
- •Agrees to refrain from blood donation during the course of the trial
- •Women of child-bearing potential must use a highly effective form of birth control (confirmed by the investigator) throughout the trial
- •A highly effective method of birth control is defined as hormonal contraceptives (oral, injection, transdermal patch, or implant), bilateral tubal occlusion or intrauterine device. The participants must have used the contraceptive method continuously for at least 21 days prior to the pregnancy test at baseline (Day 1)
- •A female is defined as not being of child-bearing potential if she is postmenopausal (aged 50 and above with at least 12 months with no menses without an alternative medical cause prior to screening. If less than 50 years old, then confirmatory Follicular stimulating hormone testing is required)
- •A female is defined as not being of child-bearing potential if she is surgically sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). Written evidence of surgical sterility would be optimal
- •Agrees to give access to medical records for trial related purposes
- •Agrees to stay in contact with the trial site for the duration of the trial, provide updated contact information as necessary and has no current plans to move from the area for the duration of the trial
排除标准
- •Previous diagnosis or current diagnosis of TB, including suspected subclinical TB
- •Reported current household contact with TB. Note: Daily caregivers to TB infected persons will be considered as household contacts
- •History of or ongoing severe disease that in the opinion of the investigator might affect the safety of the participant or the immunogenicity of the trial product
- •Insulin-dependent diabetes
- •History of allergic disease or reactions likely to be exacerbated by any component of the trial product
- •History of chronic allergic rhinitis likely to interfere with the assessment of the mucosal recall
- •History of frequent or severe epistaxis
- •History or laboratory evidence of primary and/or acquired immunodeficiency, autoimmune disease, or immunosuppression
- •History of a malignant condition (e.g. lymphoma, leukaemia, Hodgkin's disease or other tumours of the reticuloendothelial system)
- •History of chronic hepatitis
- •Has a body mass index ≤18 or ≥35 at screening (weight [kg] / (height [m] * height [m]))
- •Abnormal chest X-ray at screening
- •Receipt or planned receipt of any other investigational TB vaccine
- •Receipt or planned receipt of any other investigational drug
- •Receipt of emergency use authorised/emergency use listed [EUA/EUL] vaccines or licensed live attenuated vaccines (e.g., measles, mumps, and rubella [MMR], oral polio vaccine [OPV], varicella, yellow fever, live attenuated influenza vaccine, live attenuated COVID-19 vaccine) within 30 days prior to screening
- •Receipt of any EUA/EUL or licensed vaccines that are not live attenuated vaccines (e.g., tetanus, pneumococcal, Hepatitis A or B, not live attenuated COVID-19 vaccine) within 14 days prior to screening
- •Receipt of anticoagulant therapy, including daily acetylsalicylic acid product. NOTE: Intermittent symptomatic use is permitted
- •Receipt of treatment likely to modify the immune response (e.g. blood products, immunoglobulins) within 42 days before screening
- •Receipt of immunosuppressive medications, including radiotherapy, nasal corticosteroids and inhaled corticosteroids. NOTE: Use of the following is permitted:
- •Topical corticosteroids for mild, uncomplicated dermatologic conditions except if administered on the site of injection of trial products
- •A single course of oral/parenteral prednisone or equivalent at doses <60 mg/day and for <11 days with completion at least 30 days prior to screening
- •Female participants: if lactating/nursing, or pregnant as per positive pregnancy test
- •Not suitable for inclusion in the opinion of the investigator
研究组 & 干预措施
Arm 1 (phase 1b)
H107e/CAF®10b
干预措施: i.d. placebo (Biological)
Arm 3 (phase 1b)
BCG
干预措施: BCG (Biological)
Arm 1 (phase 1b)
H107e/CAF®10b
干预措施: H107e/CAF®10b (Biological)
Arm 1 (phase 1a)
H107e
干预措施: H107e (Biological)
Arm 2 (phase 1a)
CAF®10b
干预措施: CAF®10b (Biological)
Arm 3 (phase 1a)
H107e/CAF®10b - low adjuvant dose
干预措施: H107e/CAF®10b - low adjuvant dose (Biological)
Arm 4a (phase 1a)
H107e/CAF®10b - full adjuvant dose - low dose intranasal H107e
干预措施: H107e/CAF®10b - full adjuvant dose (Biological)
Arm 4a (phase 1a)
H107e/CAF®10b - full adjuvant dose - low dose intranasal H107e
干预措施: Low dose intranasal H107e (Biological)
Arm 4b (phase 1a)
H107e/CAF®10b - full adjuvant dose - full dose intranasal H107e
干预措施: H107e/CAF®10b - full adjuvant dose (Biological)
Arm 4b (phase 1a)
H107e/CAF®10b - full adjuvant dose - full dose intranasal H107e
干预措施: Full dose intranasal H107e (Biological)
Arm 1 (phase 1b)
H107e/CAF®10b
干预措施: Intranasal H107e (Biological)
Arm 2 (phase 1b)
H107e/CAF®10b + BCG
干预措施: H107e/CAF®10b (Biological)
Arm 2 (phase 1b)
H107e/CAF®10b + BCG
干预措施: BCG (Biological)
Arm 2 (phase 1b)
H107e/CAF®10b + BCG
干预措施: Intranasal H107e (Biological)
Arm 3 (phase 1b)
BCG
干预措施: i.m. placebo (Biological)
Arm 3 (phase 1b)
BCG
干预措施: Intranasal H107e (Biological)
Arm 4 (phase 1b)
Placebo
干预措施: i.m. placebo (Biological)
Arm 4 (phase 1b)
Placebo
干预措施: i.d. placebo (Biological)
Arm 4 (phase 1b)
Placebo
干预措施: Intranasal H107e (Biological)
结局指标
主要结局
Percentage of participants with solicited injection site reactions recorded up to seven days after each vaccination (i.m. or i.d.) (phase 1b)
时间窗: Up to Day 8 (7 days after first dose) and Day 29 up to Day 36 (7 days after second dose)
Percentage of participants with adverse events of special interest occurring up to last visit (phase 1b)
时间窗: Up to Day 281 (280 days after first dose)
Adverse events of special interest represent a subset of AEs that include autoimmune diseases and other systemic disorders of interest which could potentially have an autoimmune etiology
Percentage of participants with solicited injection site reactions recorded up to seven days after each i.m. vaccination (phase 1a)
时间窗: Up to Day 8 (7 days after first dose) and Day 29 up to Day 36 (7 days after second dose)
Percentage of participants with solicited adverse events occurring up to seven days after i.n. mucosal recall (phase 1a)
时间窗: Day 85 up to Day 92 (7 days after mucosal recall)
This outcome is only measured for phase 1a Arm 4a and Arm 4b. Solicited adverse events related to mucosal recall consist of local and systemic reactions
Percentage of participants with SAEs occurring up to last visit (phase 1b)
时间窗: Up to Day 281 (280 days after first dose)
Percentage of participants with unsolicited adverse events occurring up to 28 days after i.n. mucosal recall (phase 1b)
时间窗: Day 211 up to Day 239 (28 days after mucosal recall)
Percentage of participants with solicited systemic reactions recorded up to seven days after each i.m. vaccination (phase 1a)
时间窗: Up to Day 8 (7 days after first dose) and Day 29 up to Day 36 (7 days after second dose)
Percentage of participants with unsolicited adverse events occurring up to 28 days after last i.m. vaccination (phase 1a)
时间窗: Up to Day 57 (28 days after second dose)
Percentage of participants with unsolicited adverse events occurring up to 28 days after last vaccination (phase 1b)
时间窗: Up to Day 57 (28 days after second dose)
Percentage of participants with unsolicited adverse events occurring up to 28 days after i.n. mucosal recall (phase 1a)
时间窗: Day 85 up to Day 113 (28 days after mucosal recall)
This outcome is only measured for phase 1a Arm 4a and Arm 4b
Percentage of participants with adverse events of special interest occurring up to last visit (phase 1a)
时间窗: Up to Day 197 (196 days after first dose)
Adverse events of special interest represent a subset of AEs that include autoimmune diseases and other systemic disorders of interest which could potentially have an autoimmune etiology
Percentage of participants with serious adverse events (SAEs) occurring up to last visit (phase 1a)
时间窗: Up to Day 197 (196 days after first dose)
Percentage of participants with solicited systemic reactions recorded up to seven days after each vaccination (i.m. or i.d.) (phase 1b)
时间窗: Up to Day 8 (7 days after first dose) and Day 29 up to Day 36 (7 days after second dose)
Percentage of participants with solicited adverse events occurring up to seven days after i.n. mucosal recall (phase 1b)
时间窗: Day 211 up to Day 218 (7 days after mucosal recall)
Solicited adverse events related to mucosal recall consist of local and systemic reactions
Frequencies of H107e-specific CD4+ T-cells producing any combination of Th1 cytokines (IFN-γ, TNF, and/or IL-2) induced by H107e/CAF®10b vs. placebo and vs. H107e/CAF®10b + BCG before vaccination (Day 1) and 2 weeks after 2nd vaccination (phase 1b)
时间窗: Day 1 and Day 43
Whole blood ICS is used to evaluate this outcome
次要结局
- Frequencies of H107e-specific IFN-γ producing T-cells before first i.m. vaccination and two weeks after the second i.m. vaccination (phase 1a)(Day 1 and Day 43)
- Frequencies of BCG-specific CD4+ T-cells producing any combination of Th1 cytokines (i.e., IFN-γ, TNF and/or IL-2) induced by H107e/CAF®10b + BCG vs. BCG alone (Day 1 and 43) (phase 1b)(Day 1 and Day 43)