The primary study objectives are: 1) Assess safety of the anti-CsbD and anti-CS17 bovine milk IgG among healthy adult volunteers when orally administered three times a day over 7 days. 2) Determine efficacy of the anti-CsbD bovine milk IgG preparation against ETEC diarrhea upon challenge with CS17-ETEC, and 3)Determine efficacy of the anti-CS17 bovine milk IgG preparation against ETEC diarrhea upon challenge with CS17-ETEC. A secondary objective is to determine efficacy of the anti-CsbD and anti-CS17 bovine milk IgG preparations against moderate to severe ETEC diarrhea upon challenge with CS17-ETEC.
STUDY DESIGN This is a Phase II, randomized, double-blind, placebo-controlled study designed to investigate whether hyperimmune bovine milk IgG products specific for CsbD and CS17, protect subjects against diarrhea upon challenge with a CS-17-ETEC strain LSN03-016011/A. The study will also evaluate safety and tolerability of these bovine milk IgG products and describe the immune responses following challenge.
Subjects (N=39) will be randomized into three groups receiving anti-CS17 bovine milk IgG, anti-CsbD bovine milk IgG, or a placebo control (a commercially available lactose-free infant formula called LactoFree® Lipil®) on study day -2. Subjects will receive three doses a day of the test article 15 minutes (range 10 - 25 minutes) after each of their three daily meals (breakfast, lunch and dinner) for a period of 7 days (i.e., from study day -2 to study day 4). The study will be divided into two cohorts, An initial cohort of 9 subjects (3 per treatment group), will be admitted to the General Clinical Research Center (GCRC) of the Johns Hopkins Hospital for the initial testing of the bovine milk IgG products. A second cohort of 30 subjects will then be admitted to the Bayview inpatient facility to complete the prophylaxis study. Logistical considerations and/or withdrawals or disqualifications prior to admission or after randomization, but prior to receiving the ETEC challenge, may require a third cohort to be admitted to either of these facilities. Allowing for these contingencies, the minimum number of subjects to be challenged with ETEC is 33 total and the maximum number of subjects will be 42. The GCRC Project Review Committee will review the protocol prior to subject admission at the GCRC. A brief description of the two inpatient facilities to be used in this study is provided in Section 6.1.2. Unit doses of the test article powders (as detailed in Table 5) will be suspended in 150 mL of water containing 2 grams of sodium bicarbonate buffer. Doses of the test articles/placebo will be prepared by study staff under the supervision of the research pharmacist. The study staff involved in dose preparation will not be collecting clinical data on subjects. On the fourth day of the inpatient phase (study day 0), after their morning meal and receipt of test article/placebo, subjects will be given 120mL of sodium bicarbonate buffer to neutralize their stomach acidity. About 1 minute later they will ingest a dose of CS17-ETEC strain LSN03-016011/A (5 X 109 cfu) diluted in 30 ml sodium bicarbonate buffer. Subjects will continue to receive three doses a day of the test articles/placebo until study day 4. Subjects meeting preset criteria will be treated with antibiotics within 24 hours of determination by the investigator and test article/placebo administration will be discontinued with initiation of treatment. Subjects who do not receive early antibiotic treatment will start antibiotic treatment on study day 5. Routine discharge is scheduled for day 7, when most subjects are expected to meet the discharge criteria of: they feel well(clinical symptoms resolved or resolving and have taken at least one dose of antibiotic and have 1 stool culture negative for the challenge strain. Subjects may be discharged earlier than day 7 on a case-by-case basis if they meet discharge criteria. The duration of the active study period is approximately seven months, encompassing up to 6 and 1/2 weeks of screening/enrollment, 4 weeks of the inpatient/outpatient phase when data and samples will be collected, 12 weeks for immunology assays, and 2 months for analysis and report.
