An Open Label, Randomized Non-Inferiority Trial Comparing Safety and Immunogenicity of Intradermal Versus Intramuscular Administration of Registered Rabies Vaccine (by Popular Pharmaceuticals PLC.) in Healthy Bangladeshi Population
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 90
- 试验地点
- 1
- 主要终点
- Seroconversion Rate
研究概览
简要总结
Background:
Burden: Rabies is a viral zoonotic disease that is 100% fatal if left untreated. Globally, Bangladesh is ranked third in terms of rabies infections. In 2009, the estimated human fatality from rabies in Bangladesh surpassed 2,000. However, the death toll has steadily declined to 26 in 2020, owing to the implementation of the 'National Rabies Elimination Program' beginning in 2010, which included the introduction of the cell culture vaccine. Though this infection is entirely preventable by vaccination, the available intramuscular regimen is costly and requires multiple high doses.
Knowledge gap: The safety and immunogenicity of an intradermal rabies vaccine regimen in the Bangladeshi population needs to be assessed to comply with the recommendation of DGDA to obtain approval to be administered through an alternate route.
Relevance: Intradermal rabies vaccine administration is a safe method that reduces the amount of vaccine needed and the number of doses required by producing immunogenicity similar to that of the intramuscular regimen. This translates to 60-80% cost reductions while preserving the safety and immunogenicity of the vaccine. The intramuscular rabies vaccine by Popular Pharmaceuticals PLC has already been granted marketing authorization by DGDA. However, the vaccine's administration via the intradermal route is yet to receive approval from DGDA for marketing as per the regulatory requirements.
Hypothesis: The immunogenicity and safety of the Intradermal rabies vaccine (Popular Pharmaceutical PLC) will be non-inferior to the intramuscular regimen of the same vaccine.
Objectives:
- To compare the seroconversion level of the intradermal rabies vaccine to the intramuscular regimen by Popular Pharmaceuticals PLC. in healthy Bangladeshi individuals
- To compare the safety of the intradermal rabies vaccine to the intramuscular regimen by Popular Pharmaceuticals PLC. in healthy Bangladeshi individuals
Methods: This will be an open-label, non-inferiority, single-blinded, randomized controlled trial where the safety and immunogenicity of the intradermal rabies vaccine will be assessed compared with the standard intramuscular regimen, both by Popular Pharmaceuticals PLC., amongst healthy individuals. The study will be conducted at the Infectious Disease and Tropical Medicine Department (Surya Kanta Hospital), Mymensingh Medical College Hospital, Mymensingh. We will enroll 90 participants and randomly assign them to two equal groups: a test group and a reference group. The test groups will receive 0.2 ml Inj. Rabivax intradermally (0.1 ml in each arm), whereas the reference group will receive 1 ml Injectable Rabivax (2.5 IU/ml) intramuscularly. The participants will be followed up on days 21, 35, and 187 for clinical and biochemical evaluation. A comparative analysis of safety and immunogenicity will be conducted on intradermal and intramuscular administration based on the collected data.
Outcome measures/variables:
- A seroconversion level of 0.5 IU/ml or more when tested for Rabies Virus Neutralizing Antibody (RVNA) following intradermal vaccination by Popular Pharmaceuticals PLC. during the study period
- Non-inferior safety parameters of the intradermal rabies vaccine regimen in comparison with the available intramuscular regimen by Popular Pharmaceuticals PLC.
详细描述
Epidemiology of Rabies:
Rabies is a vaccine-preventable zoonotic viral disease that primarily targets the central nervous system, leading to severe neurological symptoms and, if untreated, is 100% fatal. It is transmitted through the bite or saliva of an infected animal, with dogs being the most common source of human infections worldwide. The virus travels from the site of infection through the peripheral nerves to the brain, where it causes encephalitis, characterized by confusion, agitation, paralysis, and ultimately, coma and death.
Globally, rabies is responsible for around 59,000 deaths each year, with the majority occurring in Asia and Africa. An alarming 40% of those affected are children under the age of 15. This infection comes with an economic burden of $8.6 billion annually. A similar scenario prevails in Bangladesh. Bangladesh is ranked third globally in terms of rabies infections, right after China and India. In 2009, rabies-related human deaths in Bangladesh were estimated to exceed 2,000. However, the death toll has steadily declined to 26 in 2020, owing to the implementation of the 'National Rabies Elimination Program' beginning in 2010, which included the introduction of the cell culture vaccine.
Treatment of Rabies from a Bangladeshi Perspective:
Despite being ultimately fatal when symptoms show, rabies is 100% preventable by vaccination. Louis Pasteur was the first to administer the rabies vaccine to a patient in 1885. Currently, two types of vaccines are available for protection against rabies: nerve tissue vaccines and cell culture vaccines. The World Health Organization (WHO) recommends replacing nerve tissue vaccines with more effective and safer cell culture-based vaccines as soon as possible. Recent advancements in cell culture vaccines have made them more affordable and require smaller doses. Cell-culture-based rabies vaccines can be administered through two different routes: intramuscular (IM) and intradermal (ID). As per the National Guideline for Animal Bite Management in Bangladesh, (i) a 1-site IM regimen or 2-site ID regimen for Pre-exposure Prophylaxis (PrEP), and (ii) a 1-site IM regimen or 2-site ID regimen for Post-exposure Prophylaxis (PEP) is available for Rabies prevention. The IM regimen is more commonly used in clinical settings, as observed in various studies. However, the IM regimen has been found to elicit a serious adverse event (SAE) in a previous study. Seven days after receiving an intramuscular rabies vaccine regimen, Bell's Palsy was reported as a suspected unexpected SAE. Moreover, multiple studies conducted worldwide have demonstrated the superiority of the ID regimen over IM in terms of seroprotection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 5 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy volunteers aged >4 years
- •Able to comply with the research process and provide informed consent
- •Able to attend all the scheduled visits and comply with the trial procedures
- •Medical history and clinical examination demonstrating that the subject is healthy
- •Women willing to follow any method of contraception throughout the duration of the study.
排除标准
- •Subjects participating in other clinical trials in the 4 weeks preceding the first trial vaccination dose
- •Subjects with a history of previous rabies vaccination (either pre- or post-exposure prophylaxis)
- •Subjects with a history of receiving Rabies immunoglobulin (Ig (human/equine) prior to the study
- •Subjects with a fever (≥37.2°C) or any moderate or severe acute illnesses or active infections on the day of vaccination
- •History of systemic hypersensitivity to any component included in the vaccine or a history of adverse events as a reaction to previous experimental vaccine studies
- •History of receiving any immunoglobulin, blood, or blood-based product in the last 3 months or planning to donate blood in the following 3 months, which may interfere with the immune response
- •Screened as positive for HBsAg, Anti-HCV, and anti-HIV
- •Subjects receiving any vaccine at least 4 weeks prior to enrolment or expected to receive any vaccine 4 weeks after the administration of the trial vaccine.
- •Lactating women or pregnant women as detected by the urine hCG strip test.
- •History of alcohol or any substance abuse (benzodiazepines, methamphetamines, opioids, cannabinoids, cocaine, barbiturates) within 1 year
- •Subjects with congenital or acquired immunodeficiency or subjected to short- or long-term corticosteroid or immunosuppressive therapy
- •Thrombocytopenia, bleeding disorders, or anticoagulants used during the 3 weeks prior to trial vaccination to avoid intramuscular haemorrhage
- •Any major psychiatric disorder such as schizophrenia, major depressive disorder, severe anxiety disorder, etc.
- •History of cardiac arrhythmias, such as bradycardia, tachycardia, supraventricular tachycardia (SVT), ventricular tachycardia (VT), ventricular fibrillation (VF), atrial fibrillation (AF), etc., as assessed by the electrocardiogram report
- •History of renal insufficiency or dialysis
- •Any immunosuppressive disorder, such as cancers, multiple myeloma (MM), various autoimmune diseases, etc.
- •Participants with clinically significant or abnormal laboratory parameters (serum creatinine, SGPT, AST, serum electrolytes) in the opinion of the investigator.
- •Any condition that presents an unacceptable risk of injury, as assessed by the site investigator
- •Subjects planning to have surgery in the 3 months preceding the completion of the project
- •Subjects concurrently using anti-malarial drugs
- •Any condition that, in the researcher's opinion, would jeopardize the safety or rights of the subject or prevent the subject from completing the procedures of the study protocol
- •Subjects exposed to any rabid animal bite in the 4 weeks preceding the commencement of the study.
- •Subjects with Type I or Type II Diabetes, as assessed by Random Blood Sugar level.
- •All research facility staff directly participating in this study, including their immediate family and relatives.
结局指标
主要结局
Seroconversion Rate
时间窗: 14 days, 28 days, and 180 days following the completion of vaccination doses
Rabies Virus Neutralizing Antibody: ≥ 0.5 IU/mL
次要结局
- Number of participants with treatment-related serious adverse events as assessed by CTCAE v5.0(Participants will be followed up 14 days, 28 days, and 180 days following the completion of vaccination doses. They will also contact the research team for self-reporting of adverse events.)
- Number of participants with post-vaccination laboratory abnormalities(The number of participants with post-vaccination laboratory values will be assessed on day 21 and day 187 of the study.)
- Number of participants with post-vaccination abnormalities in vital signs(Vital signs will be evaluated on the day of check-in (day 0), day 7, and during post-vaccination follow-up (day 21, 35, and 187); 30 minutes before dosing on vaccination days)
- Number of participants with post-vaccination abnormalities found in physical examination(General and systematic examination will be conducted on check-in (Day 0), day 7, and during post-vaccination follow-up (Days 21, 35, and 187) and)