| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Salmonella enterica serovar Typhi infection |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039446 |
| E.1.2 | Term | Salmonella typhi infection |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Using an established model of human typhoid infection, whereby healthy adults are deliberately exposed to typhoid-causing bacteria, we will determine how effective a new typhoid vaccine (Vi-TCV) is in preventing infection. The new typhoid vaccine will be compared with a control vaccine (meningococcal ACYW which does not provide protection against typhoid infection). Additionally, the protective effect of the currently used typhoid vaccine (Vi-PS) will also be studied and compared with the control vaccine using this model of typhoid infection. |
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| E.2.2 | Secondary objectives of the trial |
1. To compare clinical responses and laboratory features of the response to typhoid infection in participants who have been vaccinated with Vi-TCV, control or Vi-PS vaccines.
2. To compare the response of the immune system following vaccination with Vi-TCV, control or Vi-PS vaccine by assessing immunological laboratory assays before and after vaccination including antibody, cellular and mucosal responses.
3. To assess how the immune system is affected after typhoid challenge and to relate these changes to the protective effect of vaccination by comparing immune responses after vaccination with changes after typhoid infection
4. To assess the persistence of immunological markers following vaccination and typhoid infection
5. To explore how the genetic response (which protein encoding-genes within the participants DNA are switched on and off) to vaccination in the three vaccine groups varies, and how the genetic response changes after exposure to typhoid challenge.
6. T |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants must satisfy all of the following criteria to be considered eligible for the study:
1. Agree to give informed consent for participation in the study.
2. Aged between 18 and 60 years inclusive at time of enrolment.
3. In good health as determined by medical history, physical examination and clinical judgment of the study team.
4. 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.
5. Agree to allow his or her General Practitioner (and/or Consultant if appropriate), to be notified of participation in the study.
6. Agree to allow study staff to contact his or her General Practitioner to access the participant's vaccination records.
7. Agree to allow Public Health England to be informed of their participation in the study.
8. 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 Typhi carriage.
9. Agree to have 24-hour contact with study staff during the four weeks post challenge and are able to ensure that they are contactable by mobile phone for the duration of the challenge period until antibiotic completion.
10. 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 (from the time of challenge until completion of antibiotic course). This person will be contacted if study staff are unable to contact the participant.
11. Have internet access to allow completion of the e-diary and real-time safety monitoring.
12. 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.
13. Agree to refrain from donating blood for the duration of the study
14. Agree to provide their National Insurance/Passport number for the purposes of TOPS registration and for payment of reimbursement expenses.
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| E.4 | Principal exclusion criteria |
The participant will not be enrolled if any of the following apply:
1. History of significant organ/system disease that could interfere with trial conduct or completion. Including, for example, but not restricted to cardiovascular, respiratory, haematological, endocrine, neurological, metabolic, autoimmune, renal, bladder or infectious disease. Biliary tract disease, including biliary colic, asymptomatic gallstones or previous cholecystectomy. Gastro-intestinal disease including requirement for antacids, H2-receptor antagonists, proton pump inhibitors or laxatives. Psychiatric illness requiring hospitalisation or known or suspected drug and/or alcohol misuse (alcohol misuse defined as an intake exceeding 42 units per week).
2. Have any known or suspected impairment of immune function, alteration of immune function, or prior immune exposure that may alter immune function to typhoid resulting from, for example:
a. Congenital or acquired immunodeficiency, including IgA deficiency
b. Human Immunodeficiency Virus infection or symptoms/signs suggestive of an HIV-associated condition
c. Receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 12 months or long-term systemic corticosteroid therapy
d. Receipt of immunoglobulin or any blood product transfusion within 3 months of study start.
e. History of cancer (except squamous cell or basal cell carcinoma of the skin and cervical carcinoma in situ).
3. 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 .
4. Weight less than 50kg .
5. Presence of implants or prosthesis.
6. Anyone taking long-term medication (e.g. analgesia, anti-inflammatories or antibiotics) that may affect symptom reporting or interpretation of the study results.
7. Contraindication to ciprofloxacin or macrolide antibiotics.
8. Female participants who are pregnant, lactating or who are unwilling to ensure that they or their partner use effective contraception one month prior to challenge and continue to do so until two negative stool samples, a minimum of 2 weeks after completion of antibiotic treatment, have been obtained.
9. Full-time, part-time or voluntary occupations involving clinical or social work with direct contact with young children (defined as those attending pre-school groups or nursery or aged under 2 years), or clinical or social work with direct contact with highly susceptible patients or persons in whom typhoid infection would have particularly serious consequences (unless willing to avoid work until demonstrated not to be infected with S. Typhi in accordance with guidance from Public Health England and willing to allow study staff to inform their employer).
10. Full time, part time or voluntary occupations involving commercial food handling (involving preparing or serving unwrapped foods not subjected to further heating)
11. Close household contact with young children (defined as those attending pre-school groups, nursery or those aged less than 2 years )or individual(s) who is (are) immunocompromised.
12. Scheduled elective surgery or other procedures requiring general anaesthesia during the study period.
13. Participants who have participated in another research study involving an investigational product that might affect risk of typhoid infection or compromise the integrity of the study within the 30 days prior to enrolment (e.g. significant volumes of blood already taken in previous study) .
14. Detection of any abnormal results from screening investigations (at the clinical discretion of the study doctors).
15. Inability to comply with any of the study requirements (at the discretion of the study staff and the participant’s General Practitioner).
16. Any other social, psychological or health issues which, in the opinion of the study staff, may put the participant or their contacts at risk because of participation in the study, adversely affect the interpretation of the primary endpoint data, impair the participant’s ability to participate in the study.
17. Having previously received any typhoid vaccine
18. Having been resident in an enteric fever endemic country for 6 months or more.
19. Have previously been diagnosed with laboratory-confirmed typhoid or paratyphoid infection or been given a diagnosis compatible with enteric fever.
20. Have participated in previous typhoid or paratyphoid challenge studies (with ingestion of challenge agent).
21. Have received vaccination with a vaccine containing tetanus toxoid within the past 12 months.
22. Have any history of allergy to vaccine components (including tetanus toxoid or Diphtheria CRM protein)
23. Have a prolonged corrected QT interval (>450 milliseconds) on ECG screening
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of participants developing clinical or microbiologically proven typhoid infection following oral challenge with Salmonella Typhi (Quailes strain) delivered with sodium bicarbonate solution given 28 days after vaccination with Vi conjugated (Vi-TCV) vaccine or Vi unconjugated (Vi-PS) vaccine in comparison to control vaccine (meningococcal ACYW) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Participants will be closely monitored for 14 days after challenge with Salmonella Typhi for a diagnosis of typhoid fever.
Typhoid fever will be diagnosed if any of the following occur:
1. A positive blood culture for Salmonella Typhi from 72 hours post-challenge
2. A positive blood culture for Salmonella Typhi within 72 hours post-challenge, with one or more signs/symptoms of typhoid infection (such as recorded temperature ≥38oC)
3. Persistent positive blood cultures (two or more blood cultures taken at least 4 hours apart) for Salmonella Typhi within 72 hours post-challenge.
4. Oral temperature ≥38oC persisting for 12 hours |
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| E.5.2 | Secondary end point(s) |
1. Comparison of the clinical course of typhoid infection after challenge between control and Vi-TCV and Vi-PS vaccination groups, in particular:
a. time to onset of symptoms
b. duration of illness
c. symptom severity
d. time to onset of bacteraemia
e. time to onset of stool shedding
f. inflammatory response
Using clinical reporting, physical examination findings, microbiological assays to detect Salmonella Typhi in blood and stool, and laboratory assays to monitor inflammatory responses
2. Immunological laboratory assays to assess innate, humoral, cell-mediated and mucosal responses to vaccination at baseline (Day -28) and post-vaccination time points, including:
a. Salmonella Typhi antigen specific antibodies and serum bactericidal antibody titres
b. Cell-mediated responses (including antigen specific cell frequencies, description of lymphocyte populations, B cell repertoire)
c. Cytokine profile
3. Immunological laboratory assays to assess innate, humoral, cell-mediated and mucosal responses to challenge will be taken at various time points following challenge, these may include:
a. Cell-mediated responses (including antigen specific cell frequencies, description of lymphocyte populations, B cell repertoire)
b. Mucosal responses including Salmonella Typhi specific salivary antibodies and faecal coproantibodies
c. Cytokine profile and kinetics
d. Salmonella Typhi antigen specific IgA, IgM and IgG antibodies
4. Immunological laboratory assays to measure anti-Vi GMT and other antibodies targeting Salmonella Typhi specific antigens at baseline, post-vaccination, post-challenge and follow up time points (Day 90, 180, 365)
5. Laboratory and high-throughput assays to measure gene expression and protein translation at baseline, post-vaccination and post-challenge time points
6. Exploratory analysis of blood, faeces, saliva and urine samples including use of assays such as PCR and mass-spectrometry-based techniques
7. Comparison of the typhoid infection recovery between participants randomised to receive either ciprofloxacin or azithromycin antibiotic therapy, in particular:
a. time to symptom resolution
b. time to clearance of bacteraemia
c. time to cessation of stool shedding
d. antibiotic tolerability
Using clinical reporting, microbiological assays to detect Salmonella Typhi in blood and stool, and assays to detect antibiotic drug concentrations
8. Immunological response data post-vaccination (including Salmonella Typhi specific antibody titres, cell-mediated responses) will be combined with vaccine efficacy data following Salmonella Typhi challenge to investigate if particular immunological markers could be used to predict protection from typhoid infection
9. Clinical observation and participant responses to assess Vi-TCV vaccine tolerability and safety using Vi-PS and control vaccines as comparators.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Participants will be randomised and vaccinated on day -28
Post-vaccination timepoints for follow up regarding vaccine tolerability and safety, and to obtain samples will occur on day -27,-25,-21 and day -14.
Salmonella Typhi challenge will occur on day 0 (approximately 28 days post-vaccination).
Post-challenge, participants will be reviewed daily for symptoms of typhoid fever and sample collection until diagnosed with typhoid or until day 14 post-challenge (if no diagnosis of typhoid fever is made).
In participants who develop typhoid fever, further visits and samples will be obtained (12, 24, 48, 72 and 96 hours post-diagnosis).
After the 14 day intensive challenge period, participants will be reviewed for further sample collection at 28, 90, 180 and 365 days post-challenge. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The clinical phase of the study has ended when the last participant completes their last visit. The definition of the end of the study is when the last assay is performed. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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