Clinical trial NCT00198796: Dose-finding Study of WS6788A, DS37-4 and H10407 Enterotoxigenic Escherichia Coli (ETEC) Challenge Strains
Official title: Dose-finding Study of WS6788A, DS37-4 and H10407 Enterotoxigenic E. Coli (ETEC) Challenge Strains That Express Colonization Factors CS17 and CFA/I
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diarrhea
Lead sponsor: Johns Hopkins Bloomberg School of Public Health
Sponsor class: OTHER
Collaborators: name: Henry M. Jackson Foundation for the Advancement of Military Medicine
name: Naval Medical Research Center
name: Walter Reed Army Institute of Research (WRAIR)
name: U.S. Army Medical Research and Development Command
First posted: 2005-09-20
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: We will initially study the effects of a 1x109 dose of H10407 (in 5 subjects) and then proceed to the dose-finding portion of the trial to study the effects of low (5x108) or higher doses (5x109) of the CS17 expressing strains (total of 20 subjects)
Primary purpose: SCREENING

Brief summary: Five subjects will be admitted to the General Clinical Research Center (GCRC). The next day they will eat a light breakfast, fast for 90 minutes, ingest ETEC strain H10407, and fast for 90 more minutes. After this challenge they will be monitored closely , and all stools will be collected, graded and weighed. On Day 5, or sooner if indicated, they will begin antibiotics to eradicate the challenge strain. They will be scheduled for discharge on Day 7 but may leave a few days earlier if early antibiotic treatment is given.

Hypothesis:

A challenge dose of 10(9) colony forming unit (CFU) of ETEC strain H10407, will cause diarrhea in at least 60% of subjects.

Detailed description: The rationale for validation H10407 in the challenge study proposed at Johns Hopkins University is that this initial challenge study will support additional challenge studies planned for the future. In these future studies, a bovine milk immunoglobulin containing high levels of antibodies specific for colonization factor antigen (CFA/I) or CFA/I-derived colonization factor will be investigated as a potential oral prophylaxis to neutralize subsequent challenge against CFA/I-expressing H10407 in the clinical setting. The goal here is therefore to validate a challenge dose of 1x109 h10407 organisms in the hands of the Johns Hopkins investigative team and to then use this dose in the future prophylaxis/challenge studies. Challenge doses equal to or comparable to the 1x109 dose proposed for the Johns Hopkins University (JHU) study have been used in 6 of the 9 challenge studies that have been done with the H10407 strain. The subsequent challenge studies using H10407 will be registered as part of other protocols.

Eligibility criteria: Inclusion Criteria:

* Healthy adults age 18 to 45 years old who are willing to participate, complete training on ETEC and diarrhea and procedures of the protocol, pass the test documenting knowledge of the study, and give informed consent.

Exclusion Criteria:

1. age\<18 or \>45 years
2. Chronic illness, chemical dependency, or significant medical illness as determined by the investigator.
3. immunosuppressive condition or IgA (Immunoglobulin A) deficiency
4. HIV antibody positive
5. hepatitis B surface antigen positive
6. hepatitis C antibody positive
7. travel to ETEC endemic area within 2 years
8. vaccination or other exposure to ETEC, cholera, or heat labile toxin (LT) toxin within 3 years
9. pregnancy as defined by + serum or urine - human chorionic gonadotropin (HCG) on the day before immunization
10. inability to pass the written examination
11. use of antibiotic, H2 blocking agent or proton pump inhibitor within 7 days of challenge
12. regular use of laxatives antacids or other agents to lower stomach acidity
13. significant abnormality in screening lav hematology and chemistry tests as determined by the investigator.
14. significant abnormality on EKG for those 40 to 50 years old as determined by the investigator.
15. allergy to quinolones, penicillin's and Bactrim.
16. abnormal stool pattern (fewer than 3 stools per week or more than 3 stools per day).

Primary outcomes:
measure: To validate a dose for ETEC H10407 that will cause diarrhea in 50% or more of subjects without causing high output diarrhea, as determined by stool output volumes or signs and symptoms associated with hypovolemia.
timeFrame: 6 months
Secondary outcomes:
measure: To measure mucosal and systemic immune response to the somatic and toxin antigens of the H10407 strain.
timeFrame: 6 months
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: General Clinical Research Center
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Robin McKenzie, M.D.
role: PRINCIPAL_INVESTIGATOR
References: