A Study to Compare the Efficacy of Hepatitis A Vaccine and Immune Globulin When Given After Exposure to Hepatitis A
Condition: Hepatitis A
MeSH terms: Hepatitis A; Hepatitis
Study type: Interventional

Summary: 
      Immune globulin is effective about 85% of the time in preventing hepatitis A in people who
      have been exposed, if it is given within 14 days of exposure. Several lines of evidence
      suggest that hepatitis A vaccine might also be effective in this setting, and vaccine has the
      advantage of providing long term protection. In this study, we compare how well immune
      globulin and hepatitis A vaccine work in preventing clinical hepatitis A in household
      contacts of persons with the disease. The study's hypothesis is that the the proportion of
      exposed household contacts who receive hepatitis A vaccine within 14 days of exposure and
      develop hepatitis A disease will be similar to the proportion of exposure household contacts
      who receive immune globulin within 14 days of exposure and develop hepatitis A disease.
    

Detailed description: 
      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.

      Dosage and Route: Within an exposed group, subjects will be randomized to receive either
      hepatitis A vaccine, VAQTA™, or immune globulin (IG) intramuscular (IM). Clinical material
      will be administered by unblinded study personnel but subjects will not be told which
      clinical material is being administered. The unblinded personnel will not be involved with
      any other study procedures for that exposed group. Syringes will be masked to avoid any
      possible chance at subject unblinding. The dose of VAQTA™ to be used will depend on the
      subject's age. Persons 2 to 18 years of age will receive a 25-U dose of VAQTA™ administered
      intramuscularly in the arm in a 0.5 mL volume. Persons 19 to 40 years of age and less than or
      equal to 75 kg in weight will receive a 50-U dose of VAQTA™ administered intramuscularly in
      the arm in a 1.0 mL volume. Persons 19 to 40 years of age and greater than 75 kg in weight
      will receive a 50-U dose of VAQTA™ (administered as two 25-U doses) administered
      intramuscularly with 0.5 mL in each arm. Persons 2 to 18 years of age will receive IG in one
      arm; persons 19 to 40 years of age and less than or equal to 75 kg in weight will receive IG
      in one arm; and persons 19 to 40 years of age and greater than 75 kg in weight will receive
      IG with the total dose equally divided between each arm. All persons randomized to receive IG
      will receive a dose of 0.02 mL/kg of body weight, up to a maximum of 1.5 mL for those less
      than or equal to 75 kg in weight and 3.0 mL for those greater than 75 kg in weight. All
      subjects less than or equal to 75 kg will receive 1 injection and only subjects 19 to 40
      years of age and greater than 75 kg will receive 2 injections.

      Efficacy Measurements: The primary measurement variable for efficacy is the proportion of
      subjects with confirmed hepatitis A disease (hepatitis A IgM positive or serum or stool PCR
      positive for HAV RNA and ALT twice the upper limit of normal with 1 or more of the clinical
      signs/symptoms of hepatitis A disease).

      Safety Measurements: Subjects will be evaluated for serious or unusual reactions throughout
      the study period. The rate of serious adverse experiences in each group will be compared.

      Data Analysis: In this study, efficacy comparisons will be made by estimation of the relative
      risk of laboratory-confirmed clinical hepatitis A in the vaccine group compared to the IG
      group. The relative risk is calculated as follows:

        -  where PV and PIG are the incidence rates of secondary cases of confirmed hepatitis A
           disease in the vaccine and immune globulin treatment groups, respectively.

      The primary analysis will be performed at the one-sided ɑ=0.05 level and examine the upper
      bound of the 90% confidence for the relative risk of vaccine versus IG. A secondary efficacy
      analysis will adjust for the exposure group in the estimation of the relative risk.

      The sample size and power are based upon a fixed number of events design assuming equal
      incidence rates in both the IG and vaccine populations and a one-sided significance level of
      ɑ=0.05, and were calculated under the following testing hypotheses: Ho: PV / PIG ≥3.0 versus
      Ha: PV / PIG <3.0. This is equivalent to testing that the upper bound of the 90% confidence
      interval on the observed relative risk is <3.0. For a fixed accrual of 44 evaluable secondary
      cases of confirmed hepatitis A, the study has 95% power to rule out a relative risk of 3.0 or
      greater. If the total number of cases observed in this study is 44 and if no more than 27
      (i.e., 61.4%) of the cases are in the vaccine group, there will be significant evidence to
      reject the above null hypothesis. If the total number of cases is larger than 44, the maximum
      number of cases in the vaccine group that can be observed and still declare success will
      increase accordingly.

      An internal pilot will be performed in a blinded fashion when ~25% of the 28 cases have
      occurred. This assessment will be done to check the assumptions pertaining to the incidence
      rate that was used to calculate the projected enrollment. A new sample size projection based
      upon the incidence rate (total across treatment groups) that had been observed thus far will
      be calculated for planning/budgetary concerns.

      In addition, an interim analysis is proposed for the primary endpoint for potential early
      study termination if there is overwhelming evidence that vaccine is less efficacious than IG.
      The Independent Data Monitoring Committee (IDMC) will be responsible for making the
      recommendation on whether or not to continue the study based on the results of the interim
      analysis and relevant safety data. The interim analysis will be performed when 14 (~50%) of
      the 28 expected cases of laboratory-confirmed clinical hepatitis A have been observed. Using
      the same assumptions that were used for the original power calculation, the probability of
      meeting the success criteria at the end of the study conditioned on the number of cases that
      were observed in the vaccine group for the interim analysis will be calculated. If the
      probability is 20% or greater that vaccine will meet the assumed statistical criteria by the
      end of the study, then the study will definitely continue. In addition, if after 12 months
      from study start, very few cases have been observed, the IDMC will assess the need for study
      termination.
    

Intervention name(s): Hepatitis A vaccine
Intervention type(s): Biological
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double
Primary purpose: Prevention
Keywords: hepatitis A; hepatitis A vaccine; immune globulin