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Human Challenge Model Refinement With Enterotoxigenic Escherichia Coli Strain B7A

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ClinicalTrials.gov Identifier: NCT02773446
Recruitment Status : Completed
First Posted : May 16, 2016
Results First Posted : July 6, 2018
Last Update Posted : July 6, 2018
Sponsor:
Collaborators:
United States Department of Defense
PATH
Naval Medical Research Center
Information provided by (Responsible Party):
Johns Hopkins Bloomberg School of Public Health

Tracking Information
First Submitted Date  ICMJE May 10, 2016
First Posted Date  ICMJE May 16, 2016
Results First Submitted Date  ICMJE November 29, 2017
Results First Posted Date  ICMJE July 6, 2018
Last Update Posted Date July 6, 2018
Actual Study Start Date  ICMJE April 2016
Actual Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2018)
  • Number of Participants With Safety- Solicited Symptoms Related to Challenge Administration [ Time Frame: 6 days post-challenge ]
    Solicited symptoms (vomiting, abdominal pain, bloating, lightheadedness, anorexia, generalized myalgia, arthralgias, abdominal cramping, constipation, nausea, malaise, headache, flatulence)
  • Moderate-severe Diarrhea [ Time Frame: 5 days post challenge (Cohort 1 and Cohort 2 group B) 7 days post challenge (Cohort 2 Group A) ]
    Moderate-severe diarrhea post challenge defined as
    • moderate diarrhea: 4 to 5 loose/liquid stools or 401-800 of loose/liquid stool in any 24-hour period
    • Severe diarrhea greater than or equal to 6 loose/liquid stools or greater than 800 g of loose/liquid stools in any 24-hour period
  • Moderate-severe Diarrhea in Subjects Receiving Homologous Rechallenge [ Time Frame: 7 days post-challenge ]
    Moderate-severe diarrhea post-challenge defined as
    • Moderate diarrhea: 4 to 5 loose/liquid stools or 401-800g of loose/liquid stool in any 24- hour period
    • Severe diarrhea: greater than or equal to 6 loose/liquid stools or greater than 800 g of loose/liquid stool in any 24-hour period
  • Number of Participants With Safety -Solicited Symptoms Unrelated to Challenge Administration [ Time Frame: 6 days post-challenge ]
    Safety solicited symptoms unrelated to challenge administration (vomiting, abdominal pain, bloating, lightheadedness, anorexia, generalized myalgia, arthralgias, abdominal cramping, constipation, nausea, malaise, headache, flatulence)
Original Primary Outcome Measures  ICMJE
 (submitted: May 11, 2016)
  • Evaluate safety of challenge strain [ Time Frame: 6 months ]
    Symptoms induced by the challenge strain will be graded using protocol defined toxicity tables. We expect that some volunteers will become ill, but that no unanticipated serious adverse events will be due to the challenge.
  • Identify a dose and fasting regimen that induces moderate-severe diarrhea in at least 70% of naïve subjects without causing high output diarrhea (determined by stool output volumes or signs and symptoms associated with hypovolemia) [ Time Frame: 5 days ]
    We will assess the number of volunteers who meet the criteria for moderate to severe diarrhea by volume or number of stools.
  • Assess protection upon repeat exposure to homologous ETEC strain (applying previously determined orally administered challenge inoculum) [ Time Frame: 3 months ]
    Volunteers who became ill during the first challenge will be invited back to receive a second challenge to see if they are protected from developing moderate or severe diarrhea
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2018)
  • Immune Response to Challenge (Serology) [ Time Frame: 28 days post challenge ]
  • Immune Response to Challenge [ Time Frame: 6 days post challenge ]
    Antibody in Lymphocyte Supernatant (ALS) Immunoglobin G (IgG) (CS6) coli surface antigen 6 Immunoglobin G (IgG) heat labile Toxin (LT) Immunoglobin G (IgG) (LPS) Lipopolysaccharide Immunoglobin A (IgA) (CS6) coli surface antigen 6 Immunoglobin A (IgA) heat labile Toxin (LT) Immunoglobin A (IgG) (LPS) Lipopolysaccharide
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Human Challenge Model Refinement With Enterotoxigenic Escherichia Coli Strain B7A
Official Title  ICMJE Human Challenge Model Refinement for B7A, An Enterotoxigenic Escherichia Coli (ETEC) Challenge Strain That Expresses CS6
Brief Summary

The purpose of this study is to determine the safe and optimal dose and regimen (fasting duration) for administering the challenge ETEC strain B7A, a CS6 expressing ETEC strain.

Additionally, an assessment of homologous protection following rechallenge with B7A will be assessed.

Detailed Description

Enterotoxigenic Escherichia coli (ETEC) is the most common causes of infectious diarrhea in children in resource limited countries, and is also a frequent cause of traveler's diarrhea in civilian and military travelers to endemic countries. ETEC strains express one or both of two enterotoxins (heat labile toxin (LT) and heat stable toxin (ST)) that cause help the bacteria cause the main symptom of watery diarrhea. They also express a variety of colonization factors (CF) that help them attach to the intestinal wall. Each colonization factor has one or more surface antigens (CS).

Vaccines and treatments to prevent ETEC disease are under development. Some of these target specific enterotoxins or colonization factors. For over 40 years, we have used ETEC human challenge studies to understand the ETEC disease process, immune response, and more recently, to determine whether treatments or vaccines are protective or effective in mitigating disease. One concern about these challenge study is the use of high doses of bacteria given may overwhelm the protective efficacy of the vaccine or treatment. Several strains of ETEC have been used in these challenge studies; a frequently used strain is B7A (CS6+, LT+, ST+. O148:H28).

This study will explore the optimal dosing strategy for B7A, in order to minimize the dose of ETEC necessary to produce disease in healthy adult volunteers. There will be two inpatient admissions. The first will examine 4 dosing and fasting regimens in healthy volunteers. The second admission will include volunteers who became ill during the first admission, as well as a new group of volunteers. This second admission will validate the optimal dose from the first admission, as well as to determine if previous infection with B7A ETEC will protect against a new infection. Trying to understand the immune response to this challenge organism may help us optimize vaccine design and delivery to protect people from this infection.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Healthy Volunteer
Intervention  ICMJE Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer
ETEC Bacteria
Study Arms  ICMJE
  • Experimental: Cohort 1 group A
    Volunteers will receive 8 logs of E. coli strain B7A after overnight fast
    Intervention: Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer
  • Experimental: Cohort 1 group B
    Volunteers will receive 9 logs of E. coli strain B7A after 90 minute fast
    Intervention: Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer
  • Experimental: Cohort 1 group C
    Volunteers will receive 9 logs of E. coli strain B7A after overnight fast
    Intervention: Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer
  • Experimental: Cohort 1 group D
    Volunteers will receive 10 logs of E. coli strain B7A after 90 minute fast
    Intervention: Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer
  • Experimental: Cohort 2 group A
    subjects from Cohort 1 who met primary endpoint will receive optimal regimen as determined by analysis after Cohort 1.
    Intervention: Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer
  • Experimental: Cohort 2 group B
    Naive subjects who will receive optimal regimen as determined by analysis after Cohort 1
    Intervention: Biological: ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 8, 2017)
47
Original Estimated Enrollment  ICMJE
 (submitted: May 11, 2016)
43
Actual Study Completion Date  ICMJE December 2016
Actual Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male or female between 18 and 50 years of age, inclusive.
  2. General good health, without clinically significant medical history, physical examination findings or clinical laboratory abnormalities per clinical judgment of the PI.
  3. Completion of a training session and demonstration of comprehension of the protocol procedures and knowledge of ETEC-associated illness by passing a written examination.
  4. Willingness to participate after informed consent obtained.
  5. Availability for the study duration, including all planned follow-up visits.
  6. Negative pregnancy test with understanding to not become pregnant during the study or within three months following last scheduled study visit.

Exclusion Criteria:

  1. Presence of a significant medical condition which in the opinion of the investigator precludes participation in the study.
  2. Significant abnormalities in screening hematology or serum chemistry as determined by PI or PI in consultation with the research monitor and sponsor.
  3. Evidence of confirmed infection with HIV, Hepatitis B, or Hepatitis C.
  4. Evidence of Immunoglobulin A (IgA) deficiency (serum IgA < 7 mg/dL or below the limit of detection of assay).
  5. Evidence of current excessive alcohol consumption or drug dependence (a targeted drug screen may be used to evaluate at the clinician's discretion).
  6. Evidence of impaired immune function.
  7. Recent vaccination or receipt of an investigational product (within 30 days before receipt of challenge).
  8. Any other criteria which, in the investigator's opinion, would compromise the ability of the subject to participate in the study, the safety of the study, or the results of the study.
  9. History of microbiologically confirmed ETEC or cholera infection in last 3 years.
  10. Occupation involving handling of ETEC or Vibrio cholerae currently, or in the past 3 years.
  11. Symptoms consistent with Travelers' Diarrhea concurrent with travel or planned travel to countries where ETEC infection is endemic.
  12. Vaccination for or ingestion of ETEC, cholera, or E coli heat labile toxin within 3 years prior to dosing.
  13. Any prior experimental infection with ETEC strain B7A.
  14. Abnormal stool pattern.
  15. Regular use of laxatives, antacids, or other agents to lower stomach acidity.
  16. Use of any medication known to affect the immune function.
  17. Known allergy to two of the following antibiotics: ciprofloxacin, trimethoprim-sulfamethoxazole, and amoxicillin.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02773446
Other Study ID Numbers  ICMJE CIR303 B7A
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data will be published in Peer reviewed journal
Responsible Party Johns Hopkins Bloomberg School of Public Health
Study Sponsor  ICMJE Johns Hopkins Bloomberg School of Public Health
Collaborators  ICMJE
  • United States Department of Defense
  • PATH
  • Naval Medical Research Center
Investigators  ICMJE
Principal Investigator: Kawsar R. Talaat, MD Johns Hopkins Bloomberg School of Public Health
PRS Account Johns Hopkins Bloomberg School of Public Health
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP