Efficacy of B7A BSIgG Against E. Coli Strain B7A Challenge

Study Overview
=================
Brief Summary
-----------------
Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea worldwide. Vaccines and therapeutics are under development to prevent ETEC disease in children and travelers. One approach is to use passive protection (antibodies) to prevent infection. The purpose of this study are to assess the safety of serum-derived bovine immunoglobulins in healthy adult subjects when orally administered and to estimate protective efficacy of those preparations against moderate-severe diarrhea upon challenge with the ETEC strain B7A.

Detailed Description
-----------------
Enterotoxigenic Escherichia coli (ETEC) is one of 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 a variety of colonization factors (CF) that help them attach to the intestinal wall. Each colonization factor has one or more surface antigens (CS). One of the major surface antigens of ETEC is CS6 (Coli surface antigen 6). 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. B7A is the only CS6 expressing ETEC challenge strain currently used. A modality that has shown some success in the prevention of diarrhea is passive, oral administration of bovine milk IgG with specific activity against viral, bacterial and parasitic enteropathogens. Passive oral administration of Bovine Serum Immunoglobulins (BSIgG) may protect against ETEC-mediated infectious diarrhea. The hypothesized mechanism of protection stems from the passive administration of bovine anti-tip adhesion or fimbriae antibodies preventing their adherence in the human small intestine (the initial step in pathogenesis), thereby preventing downstream pathogenic processes and symptomatic illness. This study will establish the foundation for evaluating BSIgG products against numerous ETEC CFs. This study will explore if anti-B7A and anti- CS6 BSIgG provides protection against oral challenge with B7A in healthy adult volunteers. There will be two inpatient admissions of approximately 30 subjects (up to 60 total). They will receive one of three investigational products (IP) three times daily following meals beginning 2 days prior to challenge. Each volunteer will be challenged with CS6 expressing ETEC B7A on Day 0. The investigational product/placebo will be administered for a total of 7 days, or until antibiotic treatment has been administered. The investigators hypothesize that anti-CS6 BSIgG will provide protection against B7A mediated moderate to severe diarrhea upon challenge.

Official Title
-----------------
Protective Efficacy of Orally Delivered Bovine Serum Immunoglobulin (BSIgG) Specific for the Colonization Factor CS6 Following Challenge With the CS6-expressing Enterotoxigenic E. Coli (ETEC) Strain B7A

Conditions
-----------------
Healthy Volunteer

Intervention / Treatment
-----------------
* Biological: Anti CS6 BSIgG product (Lot PD1601105CS)
* Biological: Anti B7A BSIgG product (Lot PD1601132ET)
* Biological: Bovine Immunoglobin Negative Control (Lot PD161071NC)
* Biological: B7A- CS6-expressing ETEC challenge strain


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female between 18 and 50 years of age, inclusive. General good health, without significant medical illness, abnormal physical examination findings or clinical laboratory abnormalities as determined by principal investigator (PI) or PI in consultation with the research monitor and sponsor. Demonstrate comprehension of the protocol procedures and knowledge of ETEC illness by passing a written examination (pass grade ≥ 70%) Willing to participate after informed consent obtained. Available for all planned follow-up visits. Negative serum pregnancy test at screening and negative serum and/or urine pregnancy test on the day of admittance to the inpatient phase for female subjects of childbearing potential. Females of childbearing potential must agree to use an efficacious hormonal or barrier method of birth control during the study. Abstinence is acceptable. Female subjects unable to bear children must have this documented (e.g., tubal ligation or hysterectomy). Exclusion Criteria: General health criteria Presence of a significant medical condition, (e.g. psychiatric conditions or gastrointestinal disease, such as peptic ulcer, symptoms or evidence of active gastritis or gastroesophageal reflux disease, inflammatory bowel disease, alcohol or illicit drug abuse/dependency, or other laboratory abnormalities which in the opinion of the investigator precludes participation in the study. Immunosuppressive illness or Immunoglobulin A (IgA) deficiency (serum IgA < 7 mg/dL or below the limit of detection of assay) Evidence of confirmed infection with HIV, HBsAg, or Hepatitis C Virus (HCV), with confirmatory assays. Use of any investigational product within 30 days preceding the receipt of the investigational products, or planned use during the active study period Significant abnormalities in screening lab hematology or serum chemistries, as determined by PI or PI in consultation with the research monitor and sponsor. Lactation or breastfeeding. Research-related exclusions applicable to challenge 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. Travel to countries where ETEC or cholera infection is endemic (most of the developing world) within 3 years prior to dosing. Symptoms consistent with Travelers' Diarrhea concurrent with travel to countries where ETEC infection is endemic (most of the developing world) within 3 years prior to dosing, OR planned travel to endemic countries during the length of the study. 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. Study-specific Exclusion Criteria (potential increased risk or complicating outcome ascertainment) Abnormal stool pattern (fewer than 3 per week or more than 3 per day). History of diarrhea in the 2 weeks prior to planned inpatient phase. Regular use of laxatives, antacids, or other agents to lower stomach acidity (regular defined as at least weekly). Use of antibiotics during the 7 days before receipt of any investigational

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-CS6 group<br>Anti-CS6 BSIgG and challenge strain CS6-expressing ETEC (B7A) | Biological: Anti CS6 BSIgG product (Lot PD1601105CS)<br> <br> Biological: B7A- CS6-expressing ETEC challenge strain<br> <br> |
| Experimental: Anti-whole cell B7A<br>Anti- whole cell B7A (killed) BSIgG and challenge strain CS6-expressing ETEC (B7A) | Biological: Anti B7A BSIgG product (Lot PD1601132ET)<br> <br> Biological: B7A- CS6-expressing ETEC challenge strain<br> <br> |
| Experimental: control Immunoglobulin group<br>Negative Control (Nonhyperimmune BSIgG placebo) and challenge strain CS6-expressing ETEC (B7A) | Biological: Bovine Immunoglobin Negative Control (Lot PD161071NC)<br> <br> Biological: B7A- CS6-expressing ETEC challenge strain<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Serum Derived Bovine Immunoglobulins (BSIgG) | Number of Participants with adverse events in groups receiving B7A- and CS6- hyperimmune (BSIgG) compared with the group receiving the nonhyperimmune product. | 28 days | 
| Efficacy of B7A and CS6- Hyperimmune Bovine Serum Immunoglobin to Protect Against Moderate to Severe Diarrhea After Challenge With the CS6 Expressing ETEC Strain B7A | Comparison of the number and percentage of volunteers in the arms receiving the B7A- and CS6 BSIgG vs the arm receiving the nonhyperimmune BSIgG who develop moderate to severe diarrhea. | 28 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CS6, ETEC, Escherichia coli, enteritis, challenge, B7A