A Blinded Randomized Comparative Study of Hepatitis A Vaccine and Immune Globulin for Postexposure Prophylaxis for Hepatitis A Disease

Title: An Epidemiologic Study of Hepatitis A Vaccine for Postexposure Prophylaxis Clinical Phase: Investigation of an application unrelated to original approved use.

Primary Objective: To compare the clinical efficacy of vaccine and IG in the prevention of confirmed hepatitis A disease when given within 14 days of exposure to a confirmed case of hepatitis A disease.

Primary Hypothesis: The proportion of initially seronegative subjects who receive vaccine within 14 days of exposure to an index case of hepatitis A disease and who have onset of a confirmed case of hepatitis A disease within 56 days of exposure will be similar to the proportion of initially seronegative subjects who receive IG within 14 days of exposure to an index case and who have onset of a confirmed case of hepatitis A disease within 56 days of exposure. The date of exposure is defined as the date of onset of clinical symptoms in the index case.

(The statistical methods to examine this hypothesis require computing the relative risk, and corresponding 90% confidence interval, of confirmed hepatitis A disease among those receiving vaccine compared to those receiving IG, within 14 days of exposure. Inference of similarity involves examining the upper bound of this confidence interval and translating this RR bound into a lower bound of the 90% confidence interval for vaccine efficacy. Translation from relative risk to efficacy depends on an assumption of the point estimate of the efficacy of IG, based on historical data, the particular design of this study and assumptions regarding how transmission of hepatitis A virus occurred in the study population.) Study Design and Duration: Randomized, double-blinded, comparative, experimental epidemiologic study. Study will be conducted among exposed contacts 2-40 years of age in the household exposure group and is expected to last 18 months.

Sample Size: Enrollment will continue until 44 hepatitis A cases in randomized subjects are observed. Assuming a 30% secondary attack rate in evaluable, confirmed contacts of index cases and a 90% efficacy rate of IG, to observe 44 laboratory-confirmed cases of hepatitis A, 1468 randomized subjects will need to be evaluable (734/group). Evaluable is defined as seronegative at baseline and with clinical follow-up data at Day 56. Assuming 90% of subjects have follow-up data and 45% of subjects are seronegative at baseline, 4067 subjects ages 2 to 40 years must be randomized (2038/group). The actual enrollment may be different based on validity of these assumptions.