This is a randomized, double-blind, placebo-controlled study to investigate if Travelan® protects healthy adult volunteers from moderate-to-severe diarrhea upon challenge with Enterotoxigenic Escherichia coli (ETEC) strain H10407.
Up to 60 subjects will be randomized to receive either the Travelan® product or a placebo followed by challenge with ETEC strain H10407. Subjects will receive Travelan® or placebo caplets beginning 2 days prior to experimental challenge with ETEC strain H10407. Travelan®/placebo will be administered for a total of 7 days, or until antibiotic treatment has been initiated. Antibiotic treatment will be initiated after early antibiotic treatment criteria are met or 5 days after challenge. Early antibiotic treatment will commence when any of the following criteria are met and a physician determines it to be warranted: 1. Severe diarrhea based on volume (800 g in 24 hours) 2. Diarrhea of any severity AND 2 or more of the following symptoms: severe abdominal pain, severe abdominal cramps, severe nausea, severe headache, severe myalgias, severe arthralgia), any fever (≥ 38.0°C), or any vomiting 3. Any fever ≥ 39.0°C 4. Subjects who experience unexpectedly severe events such as symptomatic hypotension (disproportionate to volume loss), renal dysfunction, or altered mental state at the discretion of the investigators. 5. A study physician determines that early treatment is warranted for other reasons. The placebo is a commercially-sourced high-protein milk product repackaged and masked to mirror the Travelan® product. Upon admission to the inpatient unit, clinical monitoring will consist of daily medical assessments with adverse event (AE) determination, vital signs at least three times daily, examination and weighing of all stools, stool culture work-up for the challenge strain up to three times daily, and safety laboratory tests. Any subject passing a grade 3-5 stool will be encouraged to start drinking oral fluids at a rate equal to 1.5 times their stool output (or at the same rate as their emesis output as applicable). Intravenous (IV) rehydration will be provided if pre-specified criteria are met. All subjects will be treated with ciprofloxacin (500 mg by mouth twice daily for three days) or other antibiotic where applicable starting five days after ingesting the H10407 challenge inoculum unless early treatment criteria are met. Subjects will be discharged from the inpatient facility when clinical symptoms are resolved or resolving and two consecutive stool cultures (taken at least 12 hours apart) are negative for the ETEC challenge strain. Subjects may be discharged earlier than Day 8 if they meet criteria.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
60
Pharmaron Clinical Pharmacology Center
Baltimore, Maryland, United States
To measure the protective efficacy of oral administration of Travelan compared to placebo against moderate-to-severe diarrhea following with E.coli (ETEC) challenge.
The number of subjects who encounter moderate to severe diarrhea (defined as ≥4 Grade 3-5 stools in any 24-hour period post-challenge or ≥401 grams of Grade 3-5 stools in any 24-hour period post-challenge) will be recorded for the Travelan group and the placebo group. All stool samples will be collected, weighed and graded. Stool grading scale: Grade 1 = Fully formed (normal) Grade 2 = Soft (normal) Grade 3 = Thick liquid (diarrheal) Grade 4 = Opaque watery (diarrheal) Grade 5 = Rice-water (diarrheal). Diarrhea (Grade 3-5 stools) severity in a 24 hour period (1g = 1ml): 1-mild (2-3 loose/liquid stool totaling \<400 g), 2-moderate (4 to 5 loose/liquid stools or \>401 to 800 g), 3-severe (6 or more loose/liquid stools totaling \>800 g).
Time frame: Monitoring for the Inpatient Study Phase, Study Days -3 to Day 8 or day of dismissal from the clinical trial facility
Subjects requiring oral rehydration solution and/or intravenous fluids post ETEC challenge for the Travelan group and the placebo group
Measurement of the number of subjects who require oral rehydration solution and/or intravenous fluids on one or more days post challenge. Numbers will be monitored daily and expressed as a percentage of the Travelan or placebo group.
Time frame: Monitoring post challenge on Study Days 1-8 or Day of dismissal from the clinical trial facility.
Density of ETEC organisms in post-challenge stool samples at 48 hours post ETEC challenge for the Travelan group and the placebo group
The number of colony forming units (CFUs) of ETEC challenge strain measured by quantitative bacterial stool culture 48 hours post challenge per gram of stool (1g = 1ml).
Time frame: Monitoring on Study Day 3 or 48 hours post challenge
Safety and tolerability of oral doses of Travelan compared to placebo. Measurement ofthe number of AEs graded as moderate-to-severe (Grade 2-4) for Diarrhea, fever, vomiting and other listed AEs as assessed using the CTCAE v5.0 criteria for AEs.
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All AEs will be recorded for the Travelan group and the placebo group using the following criteria (1-4): 1. Diarrhea severity (Grade 3-5 stools) in a 24 hour period (1g = 1ml):1-mild (2-3 loose/liquid stool totaling \<400 g), 2-moderate (4 to 5 loose/liquid stools or \>401 to 800 g), 3-severe (6 or more loose/liquid stools totaling \>800 g). 2. Temperature maximum measured in a 24 hr period: no fever (\<38.0°C), 1-mild (38.0-38.4°C), 2-moderate (38.5-38.9°C), 3-severe (\>39.0°C); 4-Potentially life threatening (\>40oC). 3. Vomiting in a 24 hr period: 0-no episodes, 1-mild (1-2 episodes), 2-moderate (2-3 episodes), or 3-severe (\>5 episodes). 4. Nausea, abdominal discomfort and pain, abdominal cramps, headache, malaise or anorexia graded as follows: 0-Non-existent, 1 -mild (not interfering with routine activities), 2 -moderate (interfering but not precluding routine activities), 3 -severe (precluding routine activities), 4 - potentially life threatening (requires hospitalization)
Time frame: Monitoring for the inpatient study phase: Study Days -3 to Day 8 or day of dismissal from the clinical trial facility.]
Percent of subjects with severe diarrhea post ETEC challenge for the Travelan group and the placebo group
Severe diarrhea defined as 6 or more loose liquid stools in a 24 hour period totaling \>800g. (1g = 1ml). All stools will be collected, weighed (1g = 1ml) and graded. Stool Grading Scale: Grade 1 = Fully formed (normal) Grade 2 = Soft (normal) Grade 3 = Thick liquid (diarrheal) Grade 4 = Opaque watery (diarrheal) Grade 5 = Rice-water (diarrheal). Diarrhea severity (Grade 3-5 stools) in a 24 hour period post-challenge (1g = 1ml): 1-mild (2-3 loose/liquid stool totaling \<400 g), 2-moderate (4 to 5 loose/liquid stools or \>401 to 800 g), 3-severe (6 or more loose/liquid stools totaling \>800 g).
Time frame: Monitoring post challenge on Study Days 1-8 or Day of dismissal from the clinical trial facility.