Ignite Creation Date:
2024-05-05 @ 11:48 AM
Last Modification Date:
2024-10-26 @ 9:14 AM
Study NCT ID:
NCT00139139
Status:
COMPLETED
Last Update Posted:
2022-01-13
First Post:
2005-08-29
Brief Title:
A Study to Compare the Efficacy of Hepatitis A Vaccine and Immune Globulin When Given After Exposure to Hepatitis A
Sponsor:
Centers for Disease Control and Prevention
Organization:
Centers for Disease Control and Prevention
Study Overview
Official Title:
A Blinded Randomized Comparative Study of Hepatitis A Vaccine and Immune Globulin for Postexposure Prophylaxis for Hepatitis A Disease
Status:
COMPLETED
Status Verified Date:
2021-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 studys 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 734group 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 2038group 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 subjects age Persons 2 to 18 years of age will receive a 25-U dose of VAQTA administered intramuscularly in the arm in a 05 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 10 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 05 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 002 mLkg of body weight up to a maximum of 15 mL for those less than or equal to 75 kg in weight and 30 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 signssymptoms 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 ɑ005 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 ɑ005 and were calculated under the following testing hypotheses Ho PV PIG 30 versus Ha PV PIG 30 This is equivalent to testing that the upper bound of the 90 confidence interval on the observed relative risk is 30 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 30 or greater If the total number of cases observed in this study is 44 and if no more than 27 ie 614 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 planningbudgetary 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
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 734group 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 2038group 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 subjects age Persons 2 to 18 years of age will receive a 25-U dose of VAQTA administered intramuscularly in the arm in a 05 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 10 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 05 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 002 mLkg of body weight up to a maximum of 15 mL for those less than or equal to 75 kg in weight and 30 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 signssymptoms 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 ɑ005 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 ɑ005 and were calculated under the following testing hypotheses Ho PV PIG 30 versus Ha PV PIG 30 This is equivalent to testing that the upper bound of the 90 confidence interval on the observed relative risk is 30 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 30 or greater If the total number of cases observed in this study is 44 and if no more than 27 ie 614 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 planningbudgetary 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| ASPHS19642121 | None | None | None |