Clinical Trial: Understanding Paratyphoid Infection

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: Development of a Human Model of Salmonella Enterica Serovar Paratyphi A Challenge in Healthy Adult Volunteers

Brief Summary:

Enteric fever is responsible for over 20 million illnesses and 200,000 deaths each year. S. Paratyphi A accounts for a substantial and increasing proportion of these cases, as high as 90% in some regions of Asia. There are currently no vaccines directed against S. Paratyphi A, although there some candidates in preclinical and phase 1 trials. This study is funded by the European Vaccine Initiative and the Bill and Melinda Gates Foundation. Paratyphoid is a human-restricted infection, for which there are currently no small animal models available. In order to further our understanding of the host-pathogen interactions, this study will develop a novel human challenge model in which to investigate this infection, using a recent successful typhoid challenge model as its template.

Healthy subjects to ingest a dose of Salmonella enterica serovar Paratyphi A, strain NVGH308, after drinking a bicarbonate buffer. Intensive follow up over 14 days will establish whether each participant meets clearly defined criteria for diagnosis of paratyphoid infection. Statistical analysis will be performed on this outcome will determine if it consistently gives an attack rate of 60 to 75%. If this is not reached with the first cohort of 20 participants, the dose will be escalated and the process repeated. A maximum of 80 participants will be enrolled. Total follow up will be over the course of one year. Descriptive clinical and laboratory data collected from participant observations, samples of blood, faeces, urine and saliva will allow insights into the disease and the host response. These insights will forward our knowledge of paratyphoid disease and may help discover or develop diagnostic methods.

This study is funded by the European Vaccine Initiative and the Bill and Melinda Gates Foundation. Paratyphoid is a human-restricted infection, for

Detailed Summary:
Sponsor: University of Oxford

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

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Human physiological response [ Time Frame: Clinical signs and solicited symptoms measured in the 21 day period after challenge; laboratory and unsolicited symptoms followed up over the course of one year ]
  Description of the clinical course after challenge using, for example, participant symptom profiles, temperature measurements and other recorded clinical and laboratory observations. The outcomes will be measured in terms of number of participants and/or proportion of participants developing a certain clinical observation. For certain observations mean time from dosing to the development of that observation (e.g. development of a temperature >38C).
• Evaluation of the sensitivity of paratyphoid diagnostic criteria [ Time Frame: Up to one year after challenge ]

  Determination of challenge dose/kg (dose/surface area) actually ingested by those developing and those not developing paratyphoid infection at each dose level.

  Analysis of the attack rate using alternative criteria including, for example, passive field surveillance definitions, alternative temperature thresholds and adjunctive microbiological and laboratory diagnostic assays.

• Describe the characteristics of bacterial dynamics post challenge [ Time Frame: Up to one year after challenge ]
  Microbiological assays to detect and characterise Salmonella Paratyphi after challenge in blood, stool and urine.
• Describe the human immune response to S. Paratyphi [ Time Frame: Up to one year after challenge ]
  Immunological laboratory assays to measure innate, humoral, cell-mediated and mucosal responses to challenge.
• Genetic features [ Time Frame: Up to one year after challenge ]
  Laboratory and high-throughput assays to measure genetic factors affecting susceptibility, gene expression and protein translation.
• Discovery/ development of diagnostic methods [ Time Frame: Up to one year after challenge ]
  Exploratory analysis of blood, faeces, saliva and urine samples using experimental assays and diagnostics. For example, identification of molecules in urine associated with disease using mass spectrometry.
• Exploration of participants' motivation for involvement in challenge studies [ Time Frame: Up to one year after challenge ]
  Participant responses using questionnaires during the course of the study.

Original Secondary Outcome: Same as current

Information By: University of Oxford

Dates:
Date Received: November 12, 2013
Date Started: March 2014
Date Completion: August 2017
Last Updated: May 4, 2017
Last Verified: May 2017