Clinical Trial: Investigating Typhoid Fever Pathogenesis

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Investigating the Role of Typhoid Toxin in the Pathogenesis of Enteric Fever: A Double-blinded, Randomised, Outpatient Human Challenge Study.

Brief Summary:

Typhoid fever results from infection with a bacterium called Salmonella Typhi and is a major cause of illness worldwide. It is estimated to infect 20-25 million people every year and can affect people of all ages, but is particularly common in young children. The disease is spread through contaminated food and water, and efforts to improve water quality, sanitation and hygiene will likely go a long way to reducing the global burden of disease. Unfortunately, improving access to clean water and sanitation improvements is very costly and difficult to implement on a large scale. Vaccination against typhoid fever is likely to be a cost-effective way of reducing the global disease burden. There are two vaccines currently available against typhoid fever. Whilst these vaccines provide some protection against disease (in the region of 50-70%) these vaccines are less effective in young children, who are the population group at highest risk of disease. In order to develop a new generation of typhoid vaccines it is important to have a more complete understanding of how the bacterium causes disease. In this study, the investigators are aiming to understand more about the Salmonella Typhi bacteria and how it causes disease. In particular, the investigators aim to study the importance of a toxin produced by the typhoid bacteria, called the typhoid toxin. The typhoid toxin has only recently been discovered. It is made only by the typhoid bacteria and closely related bacteria, such as paratyphoid. From studies done in the laboratory, there is evidence that the typhoid toxin is important in causing typhoid disease. It is thought that the typhoid toxin might be important in causing symptoms of typhoid disease, however the exact role of the typhoid toxin during infection in humans hasn't been studied before. Studying this might impact on the design new vaccines against typhoid.

In this stud

Detailed Summary:
Sponsor: University of Oxford

Current Primary Outcome: Clinical or microbiologically proven typhoid infection [ Time Frame: Up to 14 days after challenge dose administered ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Clinical features following challenge with either wild-type S. Typhi Quailes strain (WT) or typhoid toxin-deficient isogenic mutant S. Typhi Quailes strain SB6000 (TN). [ Time Frame: Up to one year after challenge ]
  Time to onset of symptoms - Time (Days) to first recorded solicited symptoms in the diary card OR first temperature ≥38oC, excluding the first 48 hours following challenge.
• Clinical features following challenge with either wild-type (WT) or typhoid toxin-deficient (TN) S. Typhi Quailes strain [ Time Frame: Up to one year after challenge ]
  Duration of illness:Time (Days) from first recorded individual solicited symptoms to complete resolution of individual recorded symptoms in the diary card, excluding the first 48 hours following challenge.
• Clinical features following challenge with either wild-type (WT) or typhoid toxin-deficient (TN) S. Typhi Quailes strain [ Time Frame: Up to one year after challenge ]
  Fever clearance time:Time (Hours/Days) from first dose of treatment until temperature ≤37.5°C for a 48 hour period.
• Clinical features following challenge with either wild-type (WT) or typhoid toxin-deficient (TN) S. Typhi Quailes strain [ Time Frame: Up to one year after challenge ]

  Symptom severity as measured by: a.The proportion of participants with maximum symptom severity score graded as mild, moderate or severe following challenge; The proportion of participants meeting the criteria for severe enteric fever (Defined as Oral temperature > 40.0oC; Systolic blood pressure < 85 mmHg; Significant lethargy or confusion; Gastrointestinal bleeding; Gastrointestinal perforation; Any grade 4 or above laboratory abnormality, as defined in the study protocol); The proportion of participants reporting the typhoid symptom triad (fever, headache and abdominal pain); The proportion of participants recording one or more severe solicited symptoms following challenge.

  e. Total symptom scores calculated by summing numerical values assigned to the severity of all solicited symptoms between Day 0 to Day 14 (0=not present; 1=mild; 2=moderate; 3=severe);Individual symptom severity scores calculated by summing numerical values assigned to the severity of individual symptoms

• Clinical features following challenge with either wild-type (WT) or typhoid toxin-deficient (TN) S. Typhi Quailes strain [ Time Frame: Up to one year after challenge ]
  Time to diagnosis:Time (Hours/Days) from challenge until fulfilment of diagnostic criteria (taken as date/time Gram negative rods are detected in blood culture AND/OR recorded temperature ≥38oC for 12hours)
• Microbiological features following challenge with either wild-type (WT) or typhoid toxin-deficient (TN) S. Typhi Quailes strain [ Time Frame: Up to one year after challenge ]
  Time to onset of bacteraemia:(Hours/Days) from challenge until the date/time first positive blood culture collected; Duration of bacteraemia: Time (Hours/Days) from collection of first positive blood culture until date/time of the first negative blood culture and blood cultures are persistently negative;Quantification of bacteraemia at time of diagnosis ( Concentration of bacteria (CFU/ml) in 10ml blood taken at the time of diagnosis using the Wampole™ Isostat® Isolator system (Oxoid Ltd, Basingstoke);Time to onset of stool shedding - Time from challenge (Hours/Days) to the first positive stool culture; Duration of stool shedding - Cumulative number of days where positive stool culture for Salmonella Typhi collected; Pattern of stool shedding - Descriptive
• Comparison of haematological and biochemical parameters features following challenge with either wild-type S. Typhi Quailes strain (WT) or typhoid toxin-deficient isogenic mutant S. Typhi Quailes strain SB6000 (TN). [ Time Frame: Up to one year after challenge ]
  •Temporal change and deviation from reference values for the haematological and biochemical parameters below: Total Haemoglobin (g/L) Haemoglobin change from baseline (Hb g/l D0 - Hb g/l D14);Total White Cell Count (x109/l);Platelet counts (x109/l);Neutrophil count (x109/l); Lymphocyte count (x109/l); Monocyte count (x109/l); Eosinophil count (x109/l); Monocyte/Lymphocyte ratio; Urea & Electrolytes (Na, K+, Urea, Creatinine -mmol/l);C-reactive protein (mg/l);Liver function tests (Bilirubin [umol/l], aspartate transaminase (AST IU/l), alkaline phosphatase (ALP IU/l), alanine transaminase (ALT IU/l), Albumin (g/L)
• Measures of host immune responses following challenge with either wild-type S. Typhi Quailes strain (WT) or typhoid toxin-deficient isogenic mutant S. Typhi Quailes strain SB6000 (TN). [ Time Frame: Up to one year after challenge ]
  Comparison of the host innate, humoral and cell-mediated responses to challenge with WT and TN strains at baseline (Day 0) and post-challenge time points, with particular reference to, but not limited to: S. Typhi specific antibody concentrations measured by ELISA;Frequency and magnitude of S. Typhi specific antibody-secreting cells as measure
  
  

  Original Secondary Outcome: Same as current
  
  Information By: University of Oxford
  

  Dates:
  Date Received: December 9, 2016
  Date Started: December 2016
  Date Completion: August 2018
  Last Updated: February 23, 2017
  Last Verified: February 2017
  

  

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