This is a randomized, double-blind, placebo-controlled study to investigate a single daily dose of Travelan® protects healthy adult volunteers from moderate-to-severe diarrhea upon challenge with Enterotoxigenic Escherichia coli (ETEC) strain H10407.
Sixty 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 tablets as a single daily dose 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 if 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 and safety laboratory tests. Any subject passing a loose diarrheal (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 5 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
63
Pharmaron Clinical Pharmacology Center
Baltimore, Maryland, United States
Protective Efficacy of a Single Daily Dose of Travelan Against Moderate-to-severe Diarrhea Following Challenge With Enterotoxigenic E. Coli (ETEC) Strain H10407.
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 the 5-day 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 period - Days 1 to Day 5 post challenge
Number of Subjects With Severe Diarrhea Post ETEC Challenge
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 period - Days 1 to Day 5 post challenge
Subjects With Diarrhea of Any Severity
The number of subjects who encounter diarrhea of any severity 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).
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Time frame: Monitoring period - Days 1 to Day 5 post challenge
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.
Time frame: Monitoring period - Days 1 to Day 5 post challenge
Subjects Requiring Early Antibiotic Treatment
Early antibiotic treatment commenced when any of the follow criteria were met and a physician determined it was warranted: 1. Severe diarrhea (Grade 3-5 stools) based on volume (\>800g in 24 hrs) 2. Diarrhea of any severity AND 2 or more of the following symptoms classified as severe (CTCAE v5.0, Grade 3) abdominal pain, abdominal cramps, nausea, arthralgia, fever \>38oC. 3. Any fever \>39oC 4. Subjects who experienced unexpected 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
Time frame: Monitoring period - Days 1 to Day 5 post challenge
Number of Participants With 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.
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 period - Days 1 to Day 5 post challenge