A Study to Compare the Efficacy of Hepatitis A Vaccine and Immune Globulin When Given After Exposure to Hepatitis A
Information source: Centers for Disease Control and Prevention
ClinicalTrials.gov processed this data on August 20, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hepatitis A
Intervention: Hepatitis A vaccine (Biological)
Phase: N/A
Status: Completed
Sponsored by: Centers for Disease Control and Prevention Official(s) and/or principal investigator(s): Beth P Bell, MD, MPH, Principal Investigator, Affiliation: Centers for Disease Control and Prevention
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.
Clinical Details
Official title: A Blinded Randomized Comparative Study of Hepatitis A Vaccine and Immune Globulin for Postexposure Prophylaxis for Hepatitis A Disease
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double-Blind, Primary Purpose: Prevention
Primary outcome: clincal hepatitis A disease
Secondary outcome: 1) subclinical hepatitis A2) asymptomatic hepatitis A virus infection, with hepatitis A virus viremia
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 =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
=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.
Eligibility
Minimum age: 2 Years.
Maximum age: 40 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria: Exposure to an index case of hepatitis A within 14 days of onset of
illness; at least 2 years and no more than 40 years of age at time of study entry;
susceptible to hepatitis A; give informed consent or have informed consent given by a
responsible parent/guardian -
Exclusion Criteria: history of hepatitis A; prior receipt of hepatitis A vaccine; receipt
of immune globulin within 180 days before study entry; evidence of liver disease; receipt
of any live virus vaccine within 21 days prior to study entry; moderate or severe
intercurrent illness or axillary temperature of 37. 5 degrees or higher at time of study
entry; various other medical conditions;
-
Locations and Contacts
Sanitary EpidemiologyAuthority, Almaty, Kazakhstan
Additional Information
Starting date: September 2003
Last updated: August 29, 2005
|