Immunogenicity & Safety of Hepatitis A Vaccine Co-admin With a Measles/Mumps/Rubella & a Varicella Vaccine in Children

Study Overview
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Brief Summary
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This is a study to evaluate the immune response and safety of GSK Biologicals 2-dose inactivated hepatitis A vaccine when administered with a measles/mumps/rubella vaccine and a varicella (chickenpox) vaccine in children as young as 15 months of age. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Detailed Description
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An open, controlled comparison of Havrix™ administered alone or with MMR II and Varivax™. The three groups evaluated are: 1) Havrix™ alone, 2) Havrix™ + MMR II and Varivax™ and 3) MMR II and Varivax™ followed by Havrix™ one month later.

Official Title
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Immunogenicity & Safety of GSK Biologicals' Inactivated Hepatitis A Vaccine (Havrix™) Co-administered With Merck & Company, Inc. Measles-Mumps-Rubella Vaccine (M-M-RII) & Merck & Co Varicella Vaccine (VARIVAX™) to Children 15 Months of Age

Conditions
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Hepatitis A

Intervention / Treatment
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* Biological: Havrix®
* Biological: M-M-R®II
* Biological: VARIVAX®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects whose parents/guardians are believed by the investigator to be willing to comply with the requirements of the protocol A male or female child 12 and 13 months of age at the time of entry into the Enrollment Phase Written informed consent obtained from the parents or guardian of the subject, Free of obvious health problems as established by medical history and history-directed physical examination before entering into the study, and Parents/guardian of the subject must have a telephone or be able to be contacted by telephone Exclusion Criteria: Use of any investigational or non-registered drug or vaccine other than the study vaccine(s) within 42 days preceding the first dose of study vaccine, or planned use during the study period, Chronic administration (defined as more than 14 days) of immuno-suppressant or other immune-modifying drugs within six months prior to vaccination or planned administration at any time during the study period. (For corticosteroids, this will mean prednisone, or equivalent, ≥0.5 mg/kg/day. Inhaled, nasal and topical steroids are allowed.) Planned administration or administration of any vaccine not foreseen by the study protocol during the period 31 days before and 31 days after each dose of study vaccine(s). Previous vaccination against hepatitis A, History of hepatitis A, Known exposure to hepatitis A, Previous vaccination against measles, mumps, rubella and/or varicella, History of measles, mumps, rubella and/or varicella, Known exposure to measles, mumps, rubella and/or varicella within 30 days prior to the start of the study, Planned chronic use of salicylates during the 6-week period following administration of the doses of study vaccine(s), Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection, A family history of congenital, hereditary or infectious immunodeficiency or parental risk factors for HIV infection, History of allergic disease/reactions or hypersensitivity likely to be exacerbated by any component of HavrixTM, M-M-RII or VARIVAXTM, including 2-phenoxyethanol, neomycin and gelatin, History of anaphylactic or anaphylactoid reactions to egg proteins, History of hypersensitivity/allergic reaction to latex. Note: The tip cap and the rubber plunger of the HavrixTM needleless pre-filled syringes contain dry natural latex rubber. Major congenital defects or serious chronic illness, Active untreated tuberculosis, History of significant blood dyscrasias History of any neurologic disorder (a history of febrile seizures not associated with an underlying neurological disorder does not exclude the subject) Acute disease at the time of vaccination Administration of immunoglobulins and/or any blood products within three months prior to the first dose of study vaccine or planned administration at any time during the entire study period

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 13 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: HAV Group<br>Subjects received 2 doses of Havrix® (1 dose at Day 0 and 1 dose between Month 6 and Month 9) | Biological: Havrix®<br>* 2 doses administered intramuscularly<br>|
| Experimental: HAV+MMR+V Group<br>Subjects received 1 dose of Havrix®, coadministered with M-M-R®II and VARIVAX®, at Day 0 and 1 dose of Havrix® between Month 6 and Month 9 | Biological: Havrix®<br>* 2 doses administered intramuscularly<br>Biological: M-M-R®II<br>* 1 dose administered subcutaneously<br>Biological: VARIVAX®<br>* 1 dose administered subcutaneously<br>|
| Active Comparator: MMR+V→HAV Group<br>Subjects received 1 dose of M-M-R®II and VARIVAX® at Day 0 and then 2 doses of Havrix® (1 dose at Day 42 and 1 dose between Month 7.5 and Month 10.5) | Biological: Havrix®<br>* 2 doses administered intramuscularly<br>Biological: M-M-R®II<br>* 1 dose administered subcutaneously<br>Biological: VARIVAX®<br>* 1 dose administered subcutaneously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-hepatitis A Virus (HAV) Antibody Concentrations in HAV and HAV+MMR+V Groups. | Concentrations are given as geometric mean concentrations (GMCs) expressed as milli-international units per milliliter (mIU/mL). | 31 days following the second dose of Havrix® | 
| Number of Subjects With Anti-hepatitis A Virus (HAV) Antibody Concentration Equal or Above the Cut-off Value in HAV and HAV+MMR+V Groups | Anti-HAV antibody cut-off value assessed include 15 milli-international units per milliliter (mIU/mL). | 31 days following the second dose of Havrix® | 
| Number of Subjects Seroconverted for Anti-measle, Anti-mumps and Anti-varicella Antibodies in HAV+MMR+V and MMR+V→HAV Groups | Seroconversion is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off values assessed include 150 milli-international units per milliliter (mIU/mL) for anti-measles antibodies, 28 Effective Dose 50 (ED50) for anti-mumps antibodies and 1:5 for anti-varicella antibodies. | 42 days following the administration of M-M-R®II and VARIVAX® | 
| Number of Subjects With Vaccine Response for Anti-rubella Antibodies in HAV+MMR+V and MMR+V→HAV Groups | Vaccine response is defined as the appearance of antibodies with titers greater than or equal to the predefined cut-off value in the serum of subject seronegative before vaccination. Cut-off value assessed include 10 milli-international units per milliliter (mIU/mL). | 42 days following administration of M-M-R®II and VARIVAX® | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-measles, Anti-mumps, Anti-rubella and Anti-varicella Antibody Titers in HAV+MMR+V and MMR+V→HAV Groups | Titers are given as geometric mean titers (GMTs). | 42 days following the administration of M-M-R®II and VARIVAX® | 
| Anti-hepatitis A Virus (HAV) Antibody Concentrations in HAV and HAV+MMR+V Groups | Concentrations are given as geometric mean concentrations (GMCs). | 42 days following the first dose of Havrix® | 
| Number of Subjects With Anti-hepatitis A Virus (HAV) Antibody Concentration Equal or Above the Cut-off Value in HAV and HAV+MMR+V Groups | Anti-HAV antibody cut-off value assessed include 15 milli-international units per millilitre (mIU/mL). | 42 days following the first dose of Havrix® | 
| Anti-hepatitis A Virus (HAV) Antibody Concentrations in MMR+V→HAV Group | Concentrations are given as geometric mean concentrations (GMCs). | 31 days following the second dose of Havrix® | 
| Number of Subjects With Anti-hepatitis A Virus (HAV) Antibody Concentrations Above the Cut-off Value in MMR+V→HAV Group | Anti-HAV antibody cut-off value assessed include 15 milli-international units per millilitre (mIU/mL). | 31 days following the second dose of Havrix® | 
| Number of Subjects With Vaccine Response to Havrix® | Vaccine response was defined as: 1) a detectable anti-hepatitis A virus (HAV) antibody concentration 31 days following the second dose in subjects who were initially seronegative; and 2) a 2-fold increase in anti-HAV antibody concentrations above the pre-study concentration 31 days following the second dose in subjects who were initially seropositive. | 31 days following the second dose of Havrix® | 
| Number of Subjects Reporting Solicited Local Symptoms | Solicited local symptoms assessed include pain, rash (local), redness and swelling. | During the 4-day period following each dose of vaccine | 
| Number of Subjects Reporting Solicited General Symptoms | Solicited general symptoms assessed include drowsiness, fever, irritability, loss of appetite and rash (general). | During the 4-day period following each dose of vaccine | 
| Number of Subjects Reporting Measles, Mumps, Rubella and Varicella Specific Solicited General Adverse Events | Specific adverse events assessed include papules, vesicles, crusts, parotid/salivary gland swelling and suspected signs of meningitis/febrile seizures. | During the 43-day period following each dose of vaccine | 
| Number of Subjects Reporting Unsolicited Adverse Events (AEs) | Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms | During the 31-day period following each dose of vaccine | 
| Number of Subjects Reporting Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. | During the Active Phase (from Day 0 up to Day 31 after the second dose) and the Extended Safety Follow-up Phase of the study (from Day 31 after the second dose up to study end) | 
| Number of Subjects Reporting New Chronic Illnesses | New Chronic illnesses include autoimmune disorders, asthma, type I diabetes, allergies. | During the Active Phase (from Day 0 up to Day 31 after the second dose) and the Extended Safety Follow-up Phase of the study (from Day 31 after the second dose up to study end) | 
| Number of Subjects Reporting Medically Significant Events | Medically significant events include, but are not limited to, diabetes, autoimmune disease, asthma, allergies and/or conditions prompting emergency room or physician office visits that are not related to well-child care, vaccination or common acute illnesses (e.g., upper respiratory infection, otitis media, pharyngitis, gastroenteritis, injury and visits for routine physical examination). | During the Active Phase (from Day 0 up to Day 31 after the second dose) and the Extended Safety Follow-up Phase of the study (from Day 31 after the second dose up to study end) |