Dose-Finding Study of WS6788A and LSN03-016011/A Enterotoxigenic E. Coli ETEC Challenge Strains That Express CS17
Condition: Travelers' Diarrhea
MeSH terms: Diarrhea
Study type: Interventional
Phase: Phase 1

Summary: 
      This will be a strain and dose-finding study in which LSN03-016011/A ETEC will be
      administered at a starting inoculum of 5x108 cfu to 5 subjects to establish a human disease
      model. If 80% attack rate (AR) is achieved without high output diarrhea, the same inoculum
      will be given to 10 more subjects for confirmation of AR. If 80% AR is not achieved, attack
      rate and severity of disease will be evaluated to determine if the dose should be increased.
      The same sequence may be conducted with WS6788A if applicable. If the LSN strain causes high
      output diarrhea the dose will be adjusted down and further dose characterization continued.
      An iterative process will be used to select the optimal strain and dose with each step
      reviewed and approved by the medical monitor.
    

Detailed description: 
      This is a phase 1, open-label, strain and dose-finding study designed to establish a human
      challenge model for CS17+ ETEC that causes > 80% attack rate without causing high output
      diarrhea. Based on the strain histories, testing will commence using LSN03-016011/A. This
      strain was isolated from a naïve adult U.S. citizen living in Turkey with a typical clinical
      presentation for ETEC diarrheal disease and no bacterial co-pathogens isolated from the
      stool. The host is representative of the study population for this study and for future
      efficacy studies with anti-CS17+ ETEC vaccines. As shown in the figure below, 5x108 cfu of
      ETEC strain (LSN03-016011/A) will initially be administered to 5 subjects. If an attack rate
      of >80% (at least 4/5 subjects) occurs with no high output diarrhea, results will be
      confirmed in an additional 10 subjects. Additionally, an inoculum at least ½ log lower
      (1x108) (depending on the severity of illness documented) may be administered to 10 subjects
      to characterize the dose-response relationship. If the 5x108 cfu inoculum does cause high
      output diarrhea, then the inoculum will be reduced appropriatelyIf the 5x108 cfu of
      LSN03-016011/A does not cause a > 80% attack rate, the next step will depend on the observed
      attack rate and severity of illness. A low attack rate with mild disease would prompt a
      change to the alternate strain (WS7688A) for testing, using the same pathway used with the
      LSN strain . An attack rate < 80% with most diarrhea classified as at least moderate diarrhea
      would prompt an upward adjustment of the LSN inoculum appropriate to the findings. The
      decision to move up or down in inoculum or to change CS17 + strains will only occur with the
      concurrence of the medical monitor. Following each step in the strain and dose finding
      iterations, a report summarizing the results of that step, and detailing the planned next
      step will be signed by the principal investigator and the medical monitor. The maximum dose
      of either strain is 1 X 109. The anticipated maximum number of subjects planned for this
      study is 25.

      Subjects will be admitted to the inpatient facility on study day -1. On study day 0, subjects
      will have their morning meal, fast for 90 minutes, and then be given 120mL of sodium
      bicarbonate buffer to neutralize stomach acidity. Approximately one minute later they will
      ingest the appropriate dose and strain (either LSN03-016011/A or WS6788A ) of CS17+ ETEC
      diluted in 30mL sodium bicarbonate buffer. Doses of the challenge inoculum will be prepared
      by one of the study staff microbiologists. Treatment with antibiotics will start on study day
      5, or earlier if criteria for early antibiotic treatment are fulfilled. Subjects will be
      discharged when they feel well and have 2 consecutive stool cultures negative for CS17+ ETEC.

      For each group of 5 study subjects, the study period will include the screening period, one
      month for the inpatient and outpatient phases, and six-months for the final phone check. The
      study period, accounting for the serial scheduling of multiple groups of 5, processing
      immunology specimens, study analysis and report writing, is 1 ½ years.
    

Intervention name(s): CFA/I and CS17 challenge strain
Intervention type(s): Biological
Intervention description(s): Wild type ETEC strain expressing the colonization factor CS17, and heat labile (LT) enterotoxin
Other intervention name(s): Experimental
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Screening
Keywords: Diarrhea ETEC