Challenge Non-Typhoidal Salmonella (CHANTS) Study — CHANTS  

Gastroenteritis Clinical Trial

Official title: The Development of a Non-typhoidal Salmonella Human Challenge Model: A Safety and Dose Escalation Study

Status Recruiting

Clinical Trial Summary

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.

Clinical Trial Description

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

Challenge strain(s) Salmonella enterica subspecies enterica serovar Typhimurium strain 4/74 - Dose range from 1-5 x 10e1 to 1-5 x10e6 CFU suspended in sodium bicarbonate prior to oral ingestion. Produced to GMP.

Salmonella enterica subspecies enterica serovar Typhimurium strain D23580 - Dose range from 10e1-10e6 CFU suspended in sodium bicarbonate prior to oral ingestion. Produced to GMP.

Research procedures:

Screening Participants will complete an online questionnaire to assess their eligibility and provide information about their medical history. They may then be contacted by telephone to discuss any information they have provided or invited directly for a face-to-face appointment. The purpose of screening is to assess eligibility and provide an opportunity for the participant to be fully informed about the study and to ask any questions they may have.

At the screening visit, the study team will go through the study in detail and consent the participant to enrollment in the study.

If following the consent process the participant was willing to do so the study investigators would ask participants to complete a short quiz to ensure that the study had been understood and sign an informed consent form.

The study investigators will then ask questions about the participant's health, travel, medication and vaccination history, occupational and household contacts, undertake a physical examination including an ECG ('heart tracing') and take a urine and blood sample to assess eligibility.

Blood is screened for general health (to check a full blood cell count, kidney and liver function), HIV, hepatitis B and C, and coeliac disease as well as for a congenital immune deficiency that some people have without knowing (called IgA deficiency). Blood is also tested for the presence of the HLA-B27 gene which encodes for a protein called human leukocyte antigen B27 on the surface of white blood cells.

All participants are asked to complete a questionnaire to assess anxiety and depression. A separate questionnaire will be used to screen for symptoms of irritable bowel syndrome. In addition, participants are asked to attend a separate appointment for an abdominal ultrasound to check for gallstones and for aortic aneurysms,

For all females, the study investigators will perform a pregnancy test on their urine samples.

The study investigators will ask permission to contact the participant's GP to confirm eligibility and provide medical and vaccination records.

Once the results from these tests are received the study team will make an assessment of eligibility and this will be communicated to the participant. Once eligibility is confirmed then arrangements will be made for the challenge.

Enrollment The pre-challenge visit marks the start of formal enrolment in the study. This will take place one week before the challenge visit. At this visit, participants are asked to sign a second consent form to confirm that they are still willing to take part. The study investigators will check that there have been no changes to their health since the screening visit. The study investigators will also perform a brief medical examination and collect some extra tests, including blood, and urine. Will will give participants a kit to collect faecal samples to bring in at their next visit.

Challenge The day of the challenge is designated as Day 0. It marks the start of the busy study period. The challenge starts by admitting participants to our dedicated inpatient facility. Participants have a blood test taken and women would take a urine pregnancy test. Will also perform a lateral flow test for COVID-19. Participants are administered a sodium bicarbonate solution to neutralise stomach acid. This will be followed by a solution containing one of the two Salmonella Typhimurium strains. Participants will fast for a further 90 minutes after challenge.

After the challenge, participants are to remain as inpatients in quarantine for at least 7 days. Participants will be discharged when defined discharge criteria are met.

Discharge criteria

Participants will be discharged from the inpatient quarantine unit if the following criteria are met:

• Medically fit for discharge in the opinion of the study physician AND

• Complete resolution of diarrhoea (Bristol stool type 6-7) for 48 hours1 AND

• Seven days (168 hours) have elapsed since challenge

For patients diagnosed with Salmonellosis from day 0 to day 7, the following criteria apply:

• Antibiotic treatment has been initiated and patient has completed SD+96hrs follow up OR

• Resolution of Salmonella Typhimurium bacteraemia (if applicable)

After 7 days, participants will be allowed to leave the quarantine facility. They will continue to be seen in an outpatient setting for a further 7 days. At follow-up visits, diary entries will be reviewed, observations will be taken plus blood and stool samples.

Diagnosis and treatment After the challenge participants may develop symptoms of Salmonella infection or remain well. Participants may develop symptoms of Salmonella at any point after the challenge. The study investigaors might expect symptoms to start as soon as 12-48 hours after the challenge, but this can range from as short as 4 hours to as long as 3 days. Symptoms are expected to last between 3 to 7 days on average. If a participant develops pre-specified treatment criteria or invasive Salmonella infection the study investigators will start antibiotic treatment,

Treatment criteria

Antibiotics are commenced if ANY of the following apply:

• Any participant with Salmonella Typhimurium bacteraemia

• Fever ≥38oC for ≥12hrs

• Any participant with severe gastroenteritis

• Moderate gastroenteritis plus:

• fever ≥38°C on one occasion and/or

• ≥1 Grade 2 systemic symptoms

• Any participant with 3 or more of the following symptoms on the same day at Grade 2 or higher;

• Headache

• Fatigue/Malaise

• Anorexia

• Abdominal pain

• Nausea

• Vomiting

• Myalgia

• Arthralgia

• Cough

• Any participant from whom Salmonella has been detected from at least two stool culture/PCR and 24hrs apart who has not received antibiotics by day 14 post-challenge

• Any participant in whom antibiotic use is felt to be clinically necessary (as decided by a medically qualified study doctor)

Follow up All participants will have to attend follow-up visits on day 28, 90, day 180, and day 365 where blood, saliva and stool samples will be taken. For safety reasons, pregnancy tests will be performed on female participants prior to the challenge and prior to starting antibiotics.

Vital signs, physical examination, blood and urine sampling, ECG, and mood assessment can be performed at any stage in the study if felt to be clinically indicated.

From these procedures, the study investigators will collect data including:

• the proportion of participants diagnosed with infection following challenge at different doses of the two challenge strains.

• safety and tolerability of challenge with the two strains of Salmonella Typhimurium (4/74 and D23580)

• the immune response following challenge which may correlate with protection from disease. ;

Related Conditions & MeSH terms

• Bacterial Infections
• Communicable Disease
• Communicable Diseases
• Gastroenteritis
• Infections
• Infections, Bacterial
• Salmonella Infections
• Typhoid Fever

• NCT number: NCT05870150
• Study type: Interventional
• Source: Imperial College Healthcare NHS Trust
• Contact: Malick M Gibani
• Phone: 07866914157
• Email: m.gibani@imperial.ac.uk
• Status: Recruiting
• Phase: N/A
• Start date: August 31, 2023
• Completion date: June 13, 2025