NCT05870150进行中（未招募）不适用
The Development of a Non-typhoidal Salmonella Human Challenge Model: A Safety and Dose Escalation Study
适应症
干预措施
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- The dose in CFU of Salmonella enterica subspecies enterica serovar Typhimurium (S. Typhimurium) 4/74 and D23580 strains required for 60-75% of volunteers to develop systemic Salmonellosis following oral challenge
研究概览
简要总结
This protocol describes the challenge non-typhoidal Salmonella (CHANTS) study. This is a first-in-human phase 1, double-blinded, randomised, dose-escalation human infection study, conducted in healthy volunteers aged 18 to 50 years. The primary objective of the study is to perform a dose escalation with two strains (ST19 or ST313) to determine the infectious dose required for 60-75% of volunteers to develop Salmonellosis using a composite diagnostic criterion. The secondary objectives of the study are to describe and compare the clinical and laboratory features following controlled human infection. It is hoped that the successful establishment of an NTS human challenge model can be used in the future to test candidate vaccines for NTS disease.
详细描述
The overall aim of this study is to establish a controlled human infection model of invasive non-typhoidal Salmonella (iNTS) infection. The investigators will challenge healthy volunteers with two strains of Salmonella Typhimurium. Participants will be admitted to an inpatient quarantine facility after the challenge and treated with antibiotics when they meet defined criteria. The primary objective of the study is to perform a dose escalation to determine the infectious dose required for 60-75% of volunteers to develop Salmonellosis using a composite diagnostic criterion. The secondary objectives of the study are to describe and compare the clinical and laboratory features following controlled human infection with Salmonella Typhimurium. It is hoped that the successful establishment of an NTS human challenge model can be used in the future to test candidate vaccines for NTS disease.
Study design: Double-blinded randomised human infection study
Number of visits: 21 to 26 (depending on the outcome of the challenge)
Sample size: Up to 80 (depending on the outcome of the dose escalation study)
Study participants: Healthy adults aged 18 to 50 years inclusive
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blinded
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants must satisfy all the following criteria to be considered eligible for the study:
- •Agree to give informed consent for participation in the study.
- •Aged between 18 and 50 years inclusive at time of challenge.
- •In good health as determined by medical history, physical examination, and clinical judgment of the study team.
- •Agree (in the study team's opinion) to comply with all study requirements, including capacity to adhere to good personal hygiene and infection control precautions.
- •Agree to allow his or her General Practitioner (and/or Consultant if appropriate), to be notified of participation in the study.
- •Agree to allow study staff to contact his or her GP to access the participant's medical history and vaccination records.
- •Agree to allow UKHSA and the local health protection unit to be informed of their participation in the study.
- •Agree to give his or her close contacts written information informing them of the participant's involvement in the study and offer them voluntary screening for Salmonella carriage.
- •Agree to a period of inpatient quarantine whilst symptomatic (In exceptional circumstances, the duration of inpatient quarantine may be extended.)
- •Agree to have 24-hour contact with study staff during the four weeks post challenge and can ensure that they are contactable by mobile phone for the duration of the study period until antibiotic completion.
- •Agree to allow the study team to hold the name and 24-hour contact number of a close friend, relative or housemate who will be kept informed of the study participant's whereabouts for the duration of the challenge period after quarantine (from the time of challenge until completion of antibiotic course). This person will be contacted if study staff are unable to contact the participant after discharge from inpatient quarantine.
- •Have internet access to allow completion of the e-diary and real-time safety monitoring.
- •Agree to avoid antipyretic/anti-inflammatory treatment from the time of challenge (Day 0) until advised by a study doctor or until 14 days after challenge.
- •Agree to refrain from donating blood for the duration of the study.
- •Agree to provide their National Insurance/Passport number for the purposes of Trial over-volunteering prevention system (TOPS) registration and for payment of reimbursement expenses.
- •Participants must have received at least two doses of a SARS-CoV-2 vaccines that has been approved for use by the MHRA (or other national regulatory authority) four weeks prior to enrolment.
- •Proficient in English at a level sufficient to understand, retain, weigh up and communicate the study details as outlined in the participant information sheet, in the opinion of the study investigator.
排除标准
- •The participant will not be enrolled if any of the following apply:
- •History of microbiologically confirmed Salmonella infection.
- •History of significant organ-specific and/or systemic disease that could interfere with trial conduct or completion. Including, for example, but not restricted to:
- •Cardiovascular disease, including specifically Atherosclerotic disease Stable or unstable angina Previous myocardial infarction Valvular heart disease Vascular disease, including specifically
- •Documented aneurysmal arterial disease
- •Peripheral arterial disease
- •Endovascular prosthesis oRespiratory disease
- •Haematological disease including sickle cell disease and sickle cell trait.
- •Endocrine disorders, including specifically diabetes mellitus
- •Renal or bladder disease, including history of renal calculi
- •Biliary tract disease, including specifically biliary colic, asymptomatic gallstones, or previous cholecystectomy
- •Gastro-intestinal disease including specifically, a current requirement for antacids, H2-receptor antagonists, proton pump inhibitors or laxatives OR Inflammatory bowel disease OR Confirmed diagnosis of irritable bowel syndrome as defined by the Rome IV criteria.
- •Neurological disease
- •Metabolic disease
- •Autoimmune disease
- •Psychiatric illness requiring hospitalisation
- •Known or suspected drug and/or alcohol misuse disorder
- •Chronic/Active Infectious disease including active tuberculosis
- •Severe infection requiring hospitalisation for intravenous antibiotics within the last 10 years. Exceptions to this would include a short course of intravenous antibiotics for appendicitis, biliary sepsis, diverticulitis, and cellulitis.
- •History of malaria infection within the past 12 months
- •History of joint replacement
- •History of any orthopaedic/osseous implanted prosthesis
- •Presence of other internal implanted device e.g. permanent pacemaker
- •Have any known or suspected impairment of immune function, alteration of immune function, or prior immune exposure that may alter immune function to Salmonella infection resulting from, for example:
- •Congenital or acquired immunodeficiency, including IgA deficiency
- •Human Immunodeficiency Virus infection or symptoms/signs suggestive of an HIV-associated condition
- •Evidence of severe primary immunodeficiency, for example, severe combined immunodeficiency, Wiskott-Aldrich syndrome, and other combined immunodeficiency syndromes.
- •Currently being treated for malignant disease with immunosuppressive chemotherapy or radiotherapy, or who have received such treatment within at least the last six months
- •Individuals who have received a solid organ transplant and are currently on immunosuppressive treatment
- •Individuals who have received a bone marrow transplant, until within 12 months of finishing all immunosuppressive treatment,
- •Individuals receiving systemic high-dose steroids until at least three months after treatment has stopped.
- •Individuals receiving other types of immunosuppressive drugs (alone or in combination with lower doses of steroids) until at least six months after terminating such treatment.
- •Receipt of immunoglobulin or any blood product transfusion within 3 months of study start.
- •History of cancer (except squamous cell or basal cell carcinoma of the skin and cervical carcinoma in situ).
- •Moderate or severe depression or anxiety as classified by the Hospital Anxiety and Depression Score at screening or challenge that is deemed clinically significant by the study doctors .
- •Weight less than 50kg .
- •Anyone taking long-term medication (e.g. analgesia, anti-inflammatories or antibiotics) that may affect symptom reporting or interpretation of the study results.
- •Contraindication to cephalosporin, fluroquinolone, or macrolide antibiotics.
- •Female participants who are pregnant, lactating or who are unwilling to ensure that they or their partner use effective contraception 30 days prior to challenge and continue to do so until two negative stool samples, a minimum of 3 weeks after completion of antibiotic treatment, have been obtained.
- •Full-time, part-time, or voluntary occupations involving:
- •Clinical healthcare work
- •Social work with direct contact with young children (defined as those attending pre-school groups or nursery or aged under 2 years), or other clinically vulnerable children, adolescents
- •Clinical or social work with direct contact with highly susceptible patients or persons in whom Salmonella infection would have particularly serious consequences (unless willing to avoid work until demonstrated not to be infected with Salmonella in accordance with guidance from Public Health England and willing to allow study staff to inform their employer).
- •Full time, part time or voluntary occupations involving:
- •o Commercial food handling (involving preparing or serving unwrapped foods not subjected to further heating)
- •Close household contact with:
- •Young children (defined as those attending pre-school groups, nursery or those aged less than 2 years)
- •Any individual who is immunocompromised.
- •Pregnant women
- •Household contacts aged over 70 years
- 另有 22 项未显示
研究组 & 干预措施
ST19
Experimental
Healthy volunteers will be challenged with Salmonella Typhimurium ST19
干预措施: Salmonella Typhimurium (Biological)
ST313
Experimental
Healthy volunteers will be challenged with Salmonella Typhimurium ST313
干预措施: Salmonella Typhimurium (Biological)
结局指标
主要结局
The dose in CFU of Salmonella enterica subspecies enterica serovar Typhimurium (S. Typhimurium) 4/74 and D23580 strains required for 60-75% of volunteers to develop systemic Salmonellosis following oral challenge
时间窗: Up to Day 14 post challenge (Inclusive)
The proportion of participants who develop either: Fever ≥38°C on ≥2 occasions ≥12 hours apart AND/OR Salmonella Typhimurium bacteraemia
次要结局
- The persistent fever rate following oral challenge with Salmonella Typhimurium 4/74 and D23580 at different doses.(Up to Day 14 post challenge (Inclusive))
- The Salmonella colonisation rate following oral challenge with Salmonella Typhimurium 4/74 and D23580 strains at different doses(Up to Day 14 post challenge (Inclusive))
- The safety of oral challenge with S. Typhimurium 4/74 and D23580 strains(Up to Day 14 post challenge (Inclusive))
- Microbiological features of bloodstream infection following oral challenge with S. Typhimurium 4/74 or S. Typhimurium D23580 strains(Up to Day 14 post challenge (Inclusive))
- The Salmonella gastroenteritis rate following oral challenge of Salmonella Typhimurium 4/74 and D23580 strains at different doses.(Up to Day 14 post challenge (Inclusive))
- Biochemical and haematological laboratory parameters following oral challenge with S. Typhimurium 4/74 or S. Typhimurium D23580 strains(Up to Day 365 post challenge (Inclusive))
- Cell-mediated immune response following oral challenge with S. Typhimurium 4/74 or S. Typhimurium D23580 strains(Up to Day 365 post challenge (Inclusive))
- The rate of systemic Salmonellosis according to an alternative composite diagnostic criterion following oral challenge of Salmonella Typhimurium 4/74 and D23580 at different doses.(Up to Day 14 post challenge (Inclusive))
- Mucosal antibody response following oral challenge with S. Typhimurium 4/74 or S. Typhimurium D23580 strains.(Up to Day 365 post challenge (Inclusive))
- Microbiological features of gastrointestinal infection following oral challenge with S. Typhimurium 4/74 or S. Typhimurium D23580 strains(Up to Day 14 post challenge (Inclusive))
- Clinical features following oral challenge with S. Typhimurium 4/74 or S. Typhimurium D23580 strains(Up to Day 14 post challenge (Inclusive))
- Serum antibody response following oral challenge with S. Typhimurium 4/74 or S. Typhimurium D23580 strains(Up to Day 365 post challenge (Inclusive))
研究者
研究点 (1)
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