CampETEC Hyperimmune Bovine Colostrum (HBC)

Study Overview
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Brief Summary
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Gastrointestinal infections cause significant morbidity in the form of acute diarrheal illness in the United States (US) and among travelers to low- and middle-income countries (LMICs). One approach is to use passive protection (antibodies) to prevent infection. The purpose of this study are to assess the safety and tolerability 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 Campylobacter C. jejuni strain CG8421.

Detailed Description
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Controlled Human Infection ModelCampylobacter is a leading cause of foodborne disease in the US, is associated with 7.5 million disability adjusted life years globally and is a pathogen of concern in pediatric populations in LMICs and adult travelers to those same regions. Campylobacteriosis disproportionately affects poor and marginalized populations of the developing world and is particularly hazardous to the health and viability of infants in this region. The global diarrhea burden caused by Campylobacter spp. is estimated to include 88 million episodes in children aged ≤5 years, resulting in roughly 41,000 deaths. Among all age groups, the estimates of episodes and deaths are roughly 172 million and 75,000, respectively. In the US, Campylobacter causes more than 1.5 million illnesses each year mostly due to the handling and consumption of raw or undercooked poultry. For travelers, Campylobacter causes a severe form of Traveler's Diarrhea (TD), often associated with longer illness duration, increased number of unformed stools, and a high frequency of other symptoms (abdominal pain, nausea, vomiting, and fever) in comparison with other TD etiologies. In addition, Campylobacter infection is associated with several important sequelae, including Guillain-Barré syndrome (GBS), reactive arthritis, irritable bowel syndrome, and, to a lesser extent, inflammatory bowel disease. Until recently, campylobacteriosis has been viewed as a self-limiting illness that is ameliorated by antibiotic treatment; however, resistance of Campylobacter to antibiotics, particularly fluoroquinolones, has become a concern. Thus, alternative measures to control infection are needed. C. jejuni lacks virulence factors analogous to those of better-characterized pathogens. However, the C. jejuni Capsular polysaccharide (CPS) was recently identified and is now recognized as a major virulence factor and the focus of vaccine development efforts. A total of 47 C. jejuni capsule types have been described and through structure homology can be collapsed into 35 groups. Based on scant epidemiological data from developing countries, it appears that a limited number of C. jejuni capsule types are responsible for the majority of the disease. One modality that has shown considerable promise in diarrhea prevention is passive, oral administration of HBC, hyperimmune bovine colostrum. In a number of clinical trials, HBC as well as bovine serum IgG (BSIgG), with specific activity against enteropathogens like Enterotoxigenic E. coli (ETEC), Shigella, and rotavirus, have shown to prevent diarrheal disease in Controlled Human Infection Models (CHIM). This study will establish the foundation for evaluating HBC products against Campylobacter. This randomized, double-blinded, placebo- controlled study will explore if Hyperimmune bovine colostrum provides protection against oral challenges with Campylobacter in healthy adult participants. There will be an inpatient admission of approximately 30 subjects. Participants will be randomized to receive the investigational product (IP) or placebo three times daily following meals beginning 2 days prior to challenge. Each volunteer will be challenged with C.jeuni strain CG8421 on Day 1. The investigational product/placebo will be administered for a total of 7 days, or until antibiotic treatment has been administered. The investigators hypothesize that HBC will provide protection against C. jejuni strain CG8421 mediated moderate to severe diarrhea upon challenge.

Official Title
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Double-blind, Placebo-Controlled Trial Assessing the Efficacy and Safety of CampETEC Hyperimmune Bovine Colostrum (HBC) for the Prevention of Campylobacter-Mediated Diarrheal Diseases

Conditions
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Healthy Volunteer

Intervention / Treatment
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* Biological: CampETEC HBC product
* Biological: ProMilk 85
* Biological: C. jejuni CG8421 Challenge strain


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult 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, requirements, and CHIM by passing a written examination (passing grade ≥ 70%). Willing to participate, as evidenced by signing the informed consent document. 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 participants of childbearing potential. Participants of childbearing potential must agree to use an efficacious hormonal or barrier method of birth control during the study. Abstinence from intercourse with a male partner is acceptable. Participants who no longer have childbearing potential must have this documented (e.g., tubal ligation or hysterectomy). Exclusion Criteria: General health issues Presence of a significant medical condition (e.g., psychiatric conditions such as significant anxiety, depression, or somatization disorder; gastrointestinal disease, such as peptic ulcer, symptoms or evidence of active gastritis/dyspepsia, gastroesophageal reflux disease, inflammatory bowel disease, irritable bowel syndrome (as suggested by the functional bowel disorder survey or medical diagnosis); alcohol or illicit drug abuse/dependency; or laboratory abnormalities that in the opinion of the investigator preclude participation in the study. Significant medical conditions include HIV, active Hepatitis B or C infection, ongoing immunosuppression for any reason, autoimmune disease, evidence of cardiac, pulmonary, endocrine, or renal disease that is uncontrolled or poorly controlled, any gastrointestinal illness (chronic reflux, inflammatory bowel disease, ulcer), any diabetes mellitus, and other such illnesses that can put a volunteer at increased risk. Exclusionary laboratory abnormalities include any abnormality that is grade 2 or above. Immunosuppressive illness or evidence of immunoglobulin A( IgA) deficiency (serum IgA < 7 mg/dL or below the limit of detection of assay). This includes any disease that requires immunosuppressive medication such corticosteroids, monoclonal antibodies that target key aspects of the immune system (e.g. rituximab or tumor necrosis factor (TNF) blockers, or any autoimmune disease). Positive serology results for HIV, HBsAg, or hepatitis C virus (HCV) antibodies, and confirmatory tests if appropriate. Positive urine toxicology screen for Amphetamines, Barbiturates, Benzodiazepines, cocaine metabolite, Methadone metabolite, Opiates, Oxycodone, and/or Phencyclidine. Significant abnormalities in screening laboratory hematology or serum chemistry, as determined by PI or PI in consultation with the research monitor and sponsor. Use of any medication known to affect immune function (e.g., regular systemic corticosteroids, monoclonal antibodies that target key aspects of the immune system (such as rituximab or tumor necrosis factor blockers); others [topical, intranasal and inhaled steroids will be permitted]) within 30 days preceding receipt of the investigational product or planned to be used during the active study period. Nursing or lactating on the day of admittance to the inpatient unit. Inability to tolerate 150 mL sodium bicarbonate buffer (based on requirement for frequent dosing). Recent vaccination (including licensed vaccines) or receipt of an investigational product (within 30 days before challenge through 30 days following the challenge dose). Prior history of C. difficile infection History of diarrhea in the 2 weeks prior to planned inpatient phase. Fewer than 3 stools per week or more than 3 stools per day as the usual frequency, or loose or liquid stools other than on an occasional basis. Regular use of laxatives or any agent that increases gastric pH (regular defined as at least weekly). Use of proton pump inhibitors, H2 blockers, or antacids within 48 hours of dosing. A fever (≥ 38.0°C) in the 2 weeks prior to time of challenge. Use of antibiotics during the 7 days before bacterial dosing or receipt of more than 2 courses of antibiotics over the two months prior to dosing. Blood donation within 30 days prior to the planned receipt of this investigational product. Lactose intolerance or allergy to milk or milk products. Personal or documented family history of Guillain-Barré syndrome or neuromuscular disease; or an inflammatory arthritis such as reactive arthritis, ankylosing spondylitis, or rheumatoid arthritis. Evidence of inflammatory arthritis on exam human leukocyte antigen B27(HLA B27) positive Allergy or prior intolerance to two or more of the following: fluoroquinolone, azithromycin, augmentin or cephalosporins. Have household contacts who are <2 years old or > 80 years old or infirm or immunocompromised. Employment as a healthcare worker with direct patient care, in a daycare center (for children or the elderly), or direct food handler; includes individuals who work directly with food in commercial establishments. History of microbiologically confirmed Campylobacter infection in the last 3 years. Serological immunological evidence of prior Campylobacter exposure as Campylobacter antigen-specific (GE) specific anti glycine extract serum IgA endpoint tier > 1:4,000. Occupation involving handling of Campylobacter currently, or in the past 3 years. Symptoms consistent with travelers' diarrhea concurrent with travel to countries where Campylobacter, Salmonella, Shigella, Typhoid or ETEC infection are 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 Campylobacter, Cholera, Salmonella, Shigella, Typhoid or ETEC, within 5 years prior to dosing. Other dietary or environmental exposures that may place the participant at high risk for prior Campylobacter exposure (to be determined on a case by case basis by the PI).

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CampETEC HBC group<br>CampETEC HBC (hyper immune bovine colostrum) and challenge strain C. jejuni CG8421 | Biological: CampETEC HBC product<br>* Immunoglobulin from bovine milk/colostrum and challenge strain<br>Biological: C. jejuni CG8421 Challenge strain<br>* Challenge strain C. jejuni CG8421<br>|
| Placebo Comparator: Placebo ProMilk 85 group<br>ProMilk 85 (placebo) and challenge strain C.jejuni CG8421 | Biological: ProMilk 85<br>* Placebo ProMilk 85<br>Biological: C. jejuni CG8421 Challenge strain<br>* Challenge strain C. jejuni CG8421<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | The primary safety and tolerability outcome is the presence of CampETEC HBC associated adverse events during the study period. Safety of CampETEC HBC. | 28 days | 
| Number of participants with campylobacteriosis patterns | The primary efficacy outcome is campylobacteriosis, defined as a clinical illness meeting at least one of the following patterns starting within 144 hours of challenge Moderate diarrhea (4 to 5 loose/liquid stools or 401-800 grams in any 24 hour period) OR Severe diarrhea (≥ 6 loose/liquid stools or > 800 grams in any 24 hour period) OR Fever (present on at least 2 occasions, at least 20 minutes apart) without diarrhea, plus an associated symptom (nausea, vomiting, abdominal cramps, tenesmus, or dysentery (gross blood in ≥ 2 grade 3 - 5 stools with in any 24 hour period); with consideration of potential alternative diagnosis per clinical investigator based on illness time course and associated symptoms. | Within 144 hours of challenge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Campylobacter, CG8421, Challenge, Hyperimmune Bovine