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Human Challenge Model Refinement With Enterotoxigenic Escherichia Coli Strain B7A

Primary Purpose

Healthy Volunteer

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer

About this trial

This is an interventional prevention trial for Healthy Volunteer focused on measuring ETEC, Escherichia coli, enteritis, Challenge, CS6, Enterotoxigenic

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

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

Exclusion Criteria:

Presence of a significant medical condition which in the opinion of the investigator precludes participation in the study.
Significant abnormalities in screening hematology or serum chemistry as determined by PI or PI in consultation with the research monitor and sponsor.
Evidence of confirmed infection with HIV, Hepatitis B, or Hepatitis C.
Evidence of Immunoglobulin A (IgA) deficiency (serum IgA < 7 mg/dL or below the limit of detection of assay).
Evidence of current excessive alcohol consumption or drug dependence (a targeted drug screen may be used to evaluate at the clinician's discretion).
Evidence of impaired immune function.
Recent vaccination or receipt of an investigational product (within 30 days before receipt of challenge).
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.
History of microbiologically confirmed ETEC or cholera infection in last 3 years.
Occupation involving handling of ETEC or Vibrio cholerae currently, or in the past 3 years.
Symptoms consistent with Travelers' Diarrhea concurrent with travel or planned travel to countries where ETEC infection is endemic.
Vaccination for or ingestion of ETEC, cholera, or E coli heat labile toxin within 3 years prior to dosing.
Any prior experimental infection with ETEC strain B7A.
Abnormal stool pattern.
Regular use of laxatives, antacids, or other agents to lower stomach acidity.
Use of any medication known to affect the immune function.
Known allergy to two of the following antibiotics: ciprofloxacin, trimethoprim-sulfamethoxazole, and amoxicillin.

Sites / Locations

Johns Hopkins Center for Immunization Research

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Arm Label

Cohort 1 group A

Cohort 1 group B

Cohort 1 group C

Cohort 1 group D

Cohort 2 group A

Cohort 2 group B

Arm Description

Volunteers will receive 8 logs of E. coli strain B7A after overnight fast

Volunteers will receive 9 logs of E. coli strain B7A after 90 minute fast

Volunteers will receive 9 logs of E. coli strain B7A after overnight fast

Volunteers will receive 10 logs of E. coli strain B7A after 90 minute fast

subjects from Cohort 1 who met primary endpoint will receive optimal regimen as determined by analysis after Cohort 1.

Naive subjects who will receive optimal regimen as determined by analysis after Cohort 1

Outcomes

Primary Outcome Measures

Number of Participants With Safety- Solicited Symptoms Related to Challenge Administration

Solicited symptoms (vomiting, abdominal pain, bloating, lightheadedness, anorexia, generalized myalgia, arthralgias, abdominal cramping, constipation, nausea, malaise, headache, flatulence)

Moderate-severe Diarrhea

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

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

Safety solicited symptoms unrelated to challenge administration (vomiting, abdominal pain, bloating, lightheadedness, anorexia, generalized myalgia, arthralgias, abdominal cramping, constipation, nausea, malaise, headache, flatulence)

Secondary Outcome Measures

Immune Response to Challenge (Serology)

Immune Response to 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

Full Information

NCT ID

NCT02773446

First Posted

May 10, 2016

Last Updated

June 6, 2018

Sponsor

Johns Hopkins Bloomberg School of Public Health

Collaborators

United States Department of Defense, PATH, Naval Medical Research Center

1. Study Identification

Unique Protocol Identification Number

NCT02773446

Brief Title

Human Challenge Model Refinement With Enterotoxigenic Escherichia Coli Strain B7A

Official Title

Human Challenge Model Refinement for B7A, An Enterotoxigenic Escherichia Coli (ETEC) Challenge Strain That Expresses CS6

Study Type

Interventional

2. Study Status

Record Verification Date

April 2018

Overall Recruitment Status

Completed

Study Start Date

April 2016 (Actual)

Primary Completion Date

December 2016 (Actual)

Study Completion Date

December 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Johns Hopkins Bloomberg School of Public Health

Collaborators

United States Department of Defense, PATH, Naval Medical Research Center

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Healthy Volunteer

Keywords

ETEC, Escherichia coli, enteritis, Challenge, CS6, Enterotoxigenic

7. Study Design

Primary Purpose

Prevention

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

47 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1 group A

Arm Type

Experimental

Arm Description

Volunteers will receive 8 logs of E. coli strain B7A after overnight fast

Arm Title

Cohort 1 group B

Arm Type

Experimental

Arm Description

Volunteers will receive 9 logs of E. coli strain B7A after 90 minute fast

Arm Title

Cohort 1 group C

Arm Type

Experimental

Arm Description

Volunteers will receive 9 logs of E. coli strain B7A after overnight fast

Arm Title

Cohort 1 group D

Arm Type

Experimental

Arm Description

Volunteers will receive 10 logs of E. coli strain B7A after 90 minute fast

Arm Title

Cohort 2 group A

Arm Type

Experimental

Arm Description

subjects from Cohort 1 who met primary endpoint will receive optimal regimen as determined by analysis after Cohort 1.

Arm Title

Cohort 2 group B

Arm Type

Experimental

Arm Description

Naive subjects who will receive optimal regimen as determined by analysis after Cohort 1

Intervention Type

Biological

Intervention Name(s)

ETEC strain B7A (O148:H28 CS6+ LT+ST+) (Lot 0481) in Buffer

Intervention Description

ETEC Bacteria

Primary Outcome Measure Information:

Title

Number of Participants With Safety- Solicited Symptoms Related to Challenge Administration

Description

Solicited symptoms (vomiting, abdominal pain, bloating, lightheadedness, anorexia, generalized myalgia, arthralgias, abdominal cramping, constipation, nausea, malaise, headache, flatulence)

Time Frame

6 days post-challenge

Title

Moderate-severe Diarrhea

Description

Time Frame

5 days post challenge (Cohort 1 and Cohort 2 group B) 7 days post challenge (Cohort 2 Group A)

Title

Moderate-severe Diarrhea in Subjects Receiving Homologous Rechallenge

Description

Time Frame

7 days post-challenge

Title

Number of Participants With Safety -Solicited Symptoms Unrelated to Challenge Administration

Description

Time Frame

6 days post-challenge

Secondary Outcome Measure Information:

Title

Immune Response to Challenge (Serology)

Time Frame

28 days post challenge

Title

Immune Response to Challenge

Description

Time Frame

6 days post challenge

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female between 18 and 50 years of age, inclusive. General good health, without clinically significant medical history, physical examination findings or clinical laboratory abnormalities per clinical judgment of the PI. Completion of a training session and demonstration of comprehension of the protocol procedures and knowledge of ETEC-associated illness by passing a written examination. Willingness to participate after informed consent obtained. Availability for the study duration, including all planned follow-up visits. Negative pregnancy test with understanding to not become pregnant during the study or within three months following last scheduled study visit. Exclusion Criteria: Presence of a significant medical condition which in the opinion of the investigator precludes participation in the study. Significant abnormalities in screening hematology or serum chemistry as determined by PI or PI in consultation with the research monitor and sponsor. Evidence of confirmed infection with HIV, Hepatitis B, or Hepatitis C. Evidence of Immunoglobulin A (IgA) deficiency (serum IgA < 7 mg/dL or below the limit of detection of assay). Evidence of current excessive alcohol consumption or drug dependence (a targeted drug screen may be used to evaluate at the clinician's discretion). Evidence of impaired immune function. Recent vaccination or receipt of an investigational product (within 30 days before receipt of challenge). 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. History of microbiologically confirmed ETEC or cholera infection in last 3 years. Occupation involving handling of ETEC or Vibrio cholerae currently, or in the past 3 years. Symptoms consistent with Travelers' Diarrhea concurrent with travel or planned travel to countries where ETEC infection is endemic. Vaccination for or ingestion of ETEC, cholera, or E coli heat labile toxin within 3 years prior to dosing. Any prior experimental infection with ETEC strain B7A. Abnormal stool pattern. Regular use of laxatives, antacids, or other agents to lower stomach acidity. Use of any medication known to affect the immune function. Known allergy to two of the following antibiotics: ciprofloxacin, trimethoprim-sulfamethoxazole, and amoxicillin.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kawsar R. Talaat, MD

Organizational Affiliation

Johns Hopkins Bloomberg School of Public Health

Official's Role

Principal Investigator

Facility Information:

Facility Name

Johns Hopkins Center for Immunization Research

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21205

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Data will be published in Peer reviewed journal

Citations:

PubMed Identifier

26938983

Citation

Porter CK, Riddle MS, Alcala AN, Sack DA, Harro C, Chakraborty S, Gutierrez RL, Savarino SJ, Darsley M, McKenzie R, DeNearing B, Steinsland H, Tribble DR, Bourgeois AL. An Evidenced-Based Scale of Disease Severity following Human Challenge with Enteroxigenic Escherichia coli. PLoS One. 2016 Mar 3;11(3):e0149358. doi: 10.1371/journal.pone.0149358. eCollection 2016.

Results Reference

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PubMed Identifier

21852546

Citation

Harro C, Chakraborty S, Feller A, DeNearing B, Cage A, Ram M, Lundgren A, Svennerholm AM, Bourgeois AL, Walker RI, Sack DA. Refinement of a human challenge model for evaluation of enterotoxigenic Escherichia coli vaccines. Clin Vaccine Immunol. 2011 Oct;18(10):1719-27. doi: 10.1128/CVI.05194-11. Epub 2011 Aug 18.

Results Reference

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PubMed Identifier

26581889

Citation

Chakraborty S, Harro C, DeNearing B, Ram M, Feller A, Cage A, Bauers N, Bourgeois AL, Walker R, Sack DA. Characterization of Mucosal Immune Responses to Enterotoxigenic Escherichia coli Vaccine Antigens in a Human Challenge Model: Response Profiles after Primary Infection and Homologous Rechallenge with Strain H10407. Clin Vaccine Immunol. 2015 Nov 18;23(1):55-64. doi: 10.1128/CVI.00617-15. Print 2016 Jan.

Results Reference

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PubMed Identifier

21723899

Citation

Isidean SD, Riddle MS, Savarino SJ, Porter CK. A systematic review of ETEC epidemiology focusing on colonization factor and toxin expression. Vaccine. 2011 Aug 26;29(37):6167-78. doi: 10.1016/j.vaccine.2011.06.084. Epub 2011 Jul 1.

Results Reference

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PubMed Identifier

23828581

Citation

Ahmed T, Bhuiyan TR, Zaman K, Sinclair D, Qadri F. Vaccines for preventing enterotoxigenic Escherichia coli (ETEC) diarrhoea. Cochrane Database Syst Rev. 2013 Jul 5;2013(7):CD009029. doi: 10.1002/14651858.CD009029.pub2.

Results Reference

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PubMed Identifier

21628659

Citation

McKenzie R, Porter CK, Cantrell JA, Denearing B, O'Dowd A, Grahek SL, Sincock SA, Woods C, Sebeny P, Sack DA, Tribble DR, Bourgeois AL, Savarino SJ. Volunteer challenge with enterotoxigenic Escherichia coli that express intestinal colonization factor fimbriae CS17 and CS19. J Infect Dis. 2011 Jul 1;204(1):60-4. doi: 10.1093/infdis/jir220.

Results Reference

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PubMed Identifier

21616116

Citation

Porter CK, Riddle MS, Tribble DR, Louis Bougeois A, McKenzie R, Isidean SD, Sebeny P, Savarino SJ. A systematic review of experimental infections with enterotoxigenic Escherichia coli (ETEC). Vaccine. 2011 Aug 11;29(35):5869-85. doi: 10.1016/j.vaccine.2011.05.021. Epub 2011 May 25.

Results Reference

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PubMed Identifier

24551265

Citation

Lamberti LM, Bourgeois AL, Fischer Walker CL, Black RE, Sack D. Estimating diarrheal illness and deaths attributable to Shigellae and enterotoxigenic Escherichia coli among older children, adolescents, and adults in South Asia and Africa. PLoS Negl Trop Dis. 2014 Feb 13;8(2):e2705. doi: 10.1371/journal.pntd.0002705. eCollection 2014 Feb.

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Citation

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Results Reference

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Human Challenge Model Refinement With Enterotoxigenic Escherichia Coli Strain B7A

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