Evaluate Vaccine Against Chickenpox and a Combined Vaccine Against 4 Viral Childhood Diseases: Measles, Mumps, Rubella and Chickenpox

Study Overview
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Brief Summary
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An observer-blind study to evaluate GlaxoSmithKline Biologicals' live attenuated varicella vaccine and GlaxoSmithKline Biologicals' combined measles-mumps-rubella-varicella vaccine in the prevention of varicella disease in children. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Detailed Description
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According to treatment group allocation, participants will receive study vaccines and be followed for antibody titres and occurrence of varicella disease. This study is conducted in 2 phases. Phase A includes the vaccination period and an observation period for efficacy. The efficacy endpoints will be evaluated over at least two years after vaccination. During this period, the immunogenicity endpoints will be evaluated with respect to the immune response 43 days after vaccination and the persistence of antibodies over two years to varicella (for all subjects) and to measles, mumps and rubella (for a subset of subjects). Regarding the safety endpoints, SAEs (including any complicated varicella cases if observed) will be assessed for all subjects during the whole Phase A duration, whereas, solicited (local and general) and unsolicited adverse events will be assessed in a subset of subjects within a 43-day period after vaccination. Phase B is an extension of Phase A. It is a long-term follow-up until Year 10 to examine the long-term efficacy of the study vaccines against clinical varicella disease as well as the long-term persistence of antibodies to varicella (for all subjects) and to measles, mumps and rubella (in a subset of subjects) after vaccination.

Official Title
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Study in Healthy Children (<2 Years) to Evaluate the Safety and Efficacy of GSK Biologicals' Live Attenuated Varicella Vaccine (VarilrixTM) and of GSK Biologicals' Combined Measles-Mumps-Rubella-Varicella Vaccine

Conditions
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Varicella, Chickenpox Vaccines

Intervention / Treatment
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* Biological: Priorix-tetra™
* Biological: Priorix™
* Biological: Varilrix™


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Subjects for whom the investigator believes that their parents/guardians can and will comply with the requirements of the protocol for the whole duration of the study. Male or female subject between 12 and 22 months of age at the time of the first vaccination. Subjects free of obvious health problems, as established by medical history and physical examination before entering the study. Written informed consent obtained from the parents/guardians of the subject after they have been informed on the risks and benefits of the study, in a language they clearly understand and before performance of any study procedure. Subjects whose parents/guardians have direct access to telephone/mobile phone. Subjects: with at least one sibling (with negative history of varicella disease/vaccination) at home, or attending day care center, or attending childminders, i.e. someone taking care of several children, or who are in contact for at least once a week with other children without a known positive history of varicella disease/vaccination, while playing in close physical contact for more than 5 minutes. Exclusion criteria: Previous vaccination against measles, mumps, rubella and/or varicella. History of previous measles, mumps, rubella and/or varicella/ herpes zoster diseases. Known exposure to measles, mumps, rubella and/or varicella/herpes zoster within 30 days prior to the start of the study. Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose. Administration of immunoglobulins and/or any blood products within three months prior to the first vaccine dose or planned administration during the study period. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical. Family history of congenital or hereditary immunodeficiency. History of allergic diseases or reactions likely to be exacerbated by any component of the vaccines, including systemic allergy to egg proteins or neomycin. Major congenital defects or serious chronic illness. Residence in the same household as newborns (0-4 weeks of age), pregnant women who are varicella-susceptible, persons with a known immunodeficiency or any other persons at high risk for varicella. History of any neurologic disorders or seizures. Use of any investigational or non-registered product (drug/vaccine other than the study vaccines) within 14 days prior to vaccination and planned use during the study period. Additional exclusion criteria for subjects included in the subset: - Administration of a licensed vaccine within 14 days prior to vaccination and planned use until approximately 42 days after the last study vaccine dose (Day 84) with the exception of oral polio vaccine (OPV).

Ages Eligible for Study
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Minimum Age: 11 Months
Maximum Age: 22 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MMRV Group<br>Subjects in this group received 2 doses of Priorix-Tetra vaccine, administered subcutaneously in the deltoid region of the left arm, one at Day 0 (Visit 1) and the other at Day 42 (Visit 2). | Biological: Priorix-tetra™<br>* 2 doses administered subcutaneously, one at Day 0 and the other at Day 42 to subjects in MMRV Group<br>|
| Experimental: OKAH Group<br>Subjects in this group received 1 dose of Priorix at Day 0 (Visit 1) and 1 dose of Varilrix at Day 42 (Visit 2). Both vaccines were administered subcutaneously in the deltoid region of the left arm. | Biological: Priorix™<br>* 2 doses administered subcutaneously, one at Day 0 and the other at Day 42 to subjects in MMR Group and one dose administered subcutaneously at Day 0 to subjects in OKAH Group<br>Biological: Varilrix™<br>* 1 dose administered subcutaneously at Day 42 to subjects in OKAH Group<br>|
| Active Comparator: MMR Group<br>Subjects in this group received 2 doses of Priorix, administered subcutaneously in the deltoid region of the left arm, one at Day 0 (Visit 1) and the other at Day 42 (Visit 2). | Biological: Priorix™<br>* 2 doses administered subcutaneously, one at Day 0 and the other at Day 42 to subjects in MMR Group and one dose administered subcutaneously at Day 0 to subjects in OKAH Group<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase A: Number of Subjects With Confirmed Varicella Case | Confirmed varicella case = A case that met the clinical case definition [an illness with acute onset of diffuse, generalized maculopapulovesicular rash (i.e. spots, papules and/or vesicles) without other apparent cause] at least in the opinion of the investigator and was confirmed by laboratory test [Polymerase Chain Reaction (PCR) (+)] OR a case that met the clinical definition confirmed by the Independent Data Monitoring Committee (IDMC) and was epidemiologically linked [Epi (+)] to a valid index case. | From 42 days post dose 2 until the end of Phase A | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase A: Number of Subjects With Moderate or Severe Confirmed Varicella Case | Confirmed varicella case: A case that met the clinical case definition at least in the opinion of the investigator and was confirmed by laboratory test [PCR (+)] OR a case that met the clinical definition confirmed by the IDMC and was epidemiologically linked [Epi (+)] to a valid index case. Moderately severe disease: 8-15 points; severe disease: ≥ 16 points (scored by IDMC using the modified Vázquez scale). | From 42 days post dose 2 until the end of Phase A | 
| Phase A: Number of Subjects With Probable or Confirmed Varicella Case | Probable or confirmed varicella case = A case that met the clinical case definition (as determined by the IDMC) but was not laboratory confirmed [PCR (-)] AND was not epidemiologically linked [Epi (-)] to another probable or confirmed case. | From 42 days post dose 2 until the end of Phase A | 
| Phase A: Immune Response to Varicella Vaccine With Respect to Anti-Varicella Zoster Virus (Anti-VZV) Antibody Concentrations | Anti-VZV antibody concentrations are presented as Geometric Mean Concentrations (GMCs), expressed in milliinternational units per milliliter (mIU/mL). | At Day 0, Day 42, Day 84, Year 1 and Year 2 time points | 
| Phase A: Number of Subjects With Seroconversion/Seroresponse to VZV | Seronegative (S-) = Subjects with antibody concentration less than (<) 25 mIU/mL prior to vaccination. Seropositive (S+) = Subjects with antibody concentration greater than or equal to (≥) 25 mIU/mL prior to vaccination. Seroconversion was defined as the appearance of antibodies (i.e. titer greater than or equal to the cut-off value) in the serum of subjects seronegative before vaccination. | At Day 0, Day 42, Day 84, Year 1 and Year 2 time points | 
| Phase A: Immune Response to Measles With Respect to Anti-measles Antibody Concentrations in a Subset of Subjects | Anti-measles antibody concentrations are presented as Geometric Mean Concentrations (GMCs), expressed in milliinternational units per milliliter (mIU/mL). | At Day 0, Day 42, Day 84, Year 1 and Year 2 time points | 
| Phase A: Number of Subjects With Seroconversion/Seroresponse to Measles in a Subset of Subjects | Seronegative (S-) = Subjects with antibody concentration < 150 mIU/mL prior to vaccination. Seropositive (S+) = Subjects with antibody concentration ≥ 150 mIU/mL prior to vaccination. Seroconversion was defined as the appearance of antibodies (i.e. titer greater than or equal to the cut-off value) in the serum of subjects seronegative before vaccination. | At Day 0, Day 42, Day 84, Year 1 and Year 2 time points | 
| Phase A: Immune Response to Mumps With Respect to Anti-mumps Antibody Concentrations in a Subset of Subjects | Anti-mumps antibody concentrations are presented as Geometric Mean Concentrations (GMCs), expressed in units per milliliter (U/mL). | At Day 0, Day 42, Day 84, Year 1 and Year 2 time points | 
| Phase A: Number of Subjects With Seroconversion/Seroresponse to Mumps in a Subset of Subjects | Seronegative (S-) = Subjects with antibody concentration < 231 U/mL prior to vaccination. Seropositive (S+) = Subjects with antibody concentration ≥ 231 U/mL prior to vaccination. Seroconversion was defined as the appearance of antibodies (i.e. titer greater than or equal to the cut-off value) in the serum of subjects seronegative before vaccination. | At Day 0, Day 42, Day 84, Year 1 and Year 2 time points | 
| Phase A: Immune Response to Rubella With Respect to Anti-rubella Antibody Concentrations in a Subset of Subjects | Anti-rubella antibody concentrations are presented as Geometric Mean Concentrations (GMCs), expressed in International Units per milliliter (IU/mL). | At Day 0, Day 42, Day 84, Year 1 and Year 2 time points | 
| Phase A: Number of Subjects With a Seroconversion/Seroresponse to Rubella in a Subset of Subjects | Seronegative (S-) = Subjects with antibody concentration < 4 IU/mL prior to vaccination. Seropositive (S+) = Subjects with antibody concentration ≥ 4 IU/mL prior to vaccination. Seroconversion was defined as the appearance of antibodies (i.e. titer greater than or equal to the cut-off value) in the serum of subjects seronegative before vaccination. | At Day 0, Day 42, Day 84, Year 1 and Year 2 time points | 
| Phase A: Number of Subjects With Confirmed Cases of Herpes Zoster | The number of subjects with confirmed cases of herpes zoster is reported. | From Day 0 until the end of Phase A (Year 2) | 
| Phase A: Number of Subjects Reporting Fever | All fever = Occurrence of any fever (measured rectally) regardless of its intensity grade or relationship to vaccination. Related = fever (measured rectally) assessed by the investigator to be causally related to the study vaccination. Medical Advice = seek for medical advice. | Within 43 days (Day 0-42) post-vaccination period following each dose | 
| Phase A: Number of Subjects Reporting Fever | All fever = Occurrence of any fever (measured rectally) regardless of its intensity grade or relationship to vaccination. Related fever = fever (measured rectally) assessed by the investigator to be causally related to the study vaccination. Medical Advice = seek for medical advice. | Within 15 days (Day 0-14) post-vaccination period following each dose | 
| Phase A: Number of Subjects Reporting Solicited Local Symptoms | Solicited local symptoms assessed were pain, redness and swelling. Any solicited local symptom = Occurrence of any local symptom regardless of their intensity grade. Grade 3 pain = Cried when limb was moved/spontaneously painful. Grade 3 redness and swelling = greater than (>) 20 mm. | 4 days post-vaccination period following each dose | 
| Phase A: Number of Subjects Reporting Meningism | Any = Occurrence of meningism regardless of its intensity grade. Grade 3 meningism = Prevented normal, everyday activities. Related = Assessed by the investigator to be causally related to the study vaccination. | Within 43 days (Day 0-42) post-vaccination period following each dose | 
| Phase A: Number of Subjects Reporting Parotitis | Any = Occurrence of parotitis regardless of its intensity grade. Grade 3 parotitis = Swelling with accompanying general symptoms. Related = Assessed by the investigator to be causally related to the study. | Within 43 days (Day 0-42) post-vaccination period following each dose | 
| Phase A: Number of Subjects Reporting Rash | Any = Occurrence of rash regardless of its intensity grade. Grade 3 rash = 101-500 lesions. Grade 4 rash = > 500 lesions. Related rash = Assessed by the investigator to be causally related to the study vaccination. | Within 43 days (Day 0-42) post-vaccination period following each dose | 
| Phase A: Number of Subjects With Suspected Sign of Meningism Including Febrile Convulsions | Any = Occurrence of meningism including febrile convulsions regardless of intensity grade. | Within 43 days (Day 0-42) post-vaccination period following each dose | 
| Phase A: Number of Subjects Reporting Unsolicited Adverse Events (AEs) | Unsolicited AE assessed included 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. Any = Occurrence of any unsolicited symptom regardless of intensity grade or relation to vaccination. | Within 43 days (Day 0-42) post-vaccination period following each dose | 
| Phase A: Number of Subjects Reporting Serious Adverse Events (SAEs) | SAEs assessed included medical occurrences that resulted in death, were life-threatening, required hospitalisation or prolongation of hospitalisation or resulted in disability/incapacity. Any SAE = occurrence of SAE regardless of intensity grade or relation to vaccination. | From Day 0 until the end of Phase A (Year 2) | 
| Phase A: Health Economics Analysis of Factors Leading to Indirect Costs Due to Varicella Illness | Parameters assessed: 1. Number of hours lost from work by parents/guardians as a result of taking care of their child due to varicella. 2. Number of hours the child lost attendance in: day care/childminder, school, or in any extra-curricular activities (e.g. sports or recreation or any type of organised leisure activities) due to varicella. 3. Number of hours spent by a nurse, a babysitter or any type of existing paid caregiver to look after the child (if applicable). | During Phase A (from Day 0 up to Year 2) | 
| Phase B: Number of Subjects With Confirmed Varicella Case | Confirmed varicella case = A case that met the clinical case definition at least in the opinion of the investigator and was confirmed by laboratory test [PCR (+)] OR a case that met the clinical definition confirmed by the IDMC and was epidemiologically linked [Epi (+)] to a valid index case. | From the beginning of Phase B (Year 2) up to study end (Year 10) | 
| Phase B: Number of Subjects With Moderate or Severe Confirmed Varicella Case | Confirmed varicella case = A case that met the clinical case definition at least in the opinion of the investigator and was confirmed by laboratory test [PCR (+)] OR a case that met the clinical definition confirmed by the IDMC and was epidemiologically linked [Epi (+)] to a valid index case. Moderately severe disease = 8-15 points; severe disease: ≥ 16 points (scored by IDMC using the modified Vázquez scale). | From the beginning of Phase B (Year 2) up to study end (Year 10) | 
| Phase B: Number of Subjects With Probable or Confirmed Varicella Case | Probable or confirmed varicella = A case that met the clinical case definition (as determined by the IDMC) but was not laboratory confirmed [PCR (-)] AND was not epidemiologically linked [Epi (-)] to another probable or confirmed case. | From the beginning of Phase B (Year 2) up to study end (Year 10) | 
| Phase B: Characteristics of Varicella Cases | Varicella cases were characterized by type, number and character of lesions, duration of rash, incidence of fever, systemic signs, the assessment by investigator, complications, treatment, outcome and intensity of severity. | From the beginning of Phase B (Year 2) up to study end (Year 10) | 
| Phase B: Immune Response to Varicella Vaccine With Respect to Anti-Varicella Zoster Virus (Anti-VZV) Antibody Concentrations | Anti-VZV antibody concentrations are presented as Geometric Mean Concentrations (GMCs), expressed in milliinternational units per milliliter (mIU/mL). | At Year 4, Year 6, Year 8 and Year 10 time points | 
| Phase B: Number of Subjects With Anti-VZV Antibody Concentrations Above the Cut-off Value | The anti-VZV antibody concentration cut-off value assessed was greater than or equal to (≥) 25 mIU/mL, in the sera of subjects seronegative before vaccination. | At Year 4, Year 6, Year 8 and Year 10 time points | 
| Phase B: Immune Response to Measles With Respect to Anti-measles Antibody Concentrations | Anti-measles antibody concentrations are presented as Geometric Mean Concentrations (GMCs), expressed in milliinternational units per milliliter (mIU/mL). | At Year 4, Year 6, Year 8 and Year 10 time points | 
| Phase B: Number of Subjects With Anti-measles Antibody Concentrations Above the Cut-off Value | The anti-measles antibody concentration cut-off value assessed was ≥ 150 mIU/mL, in the sera of subjects seronegative before vaccination. | At Year 4, Year 6, Year 8 and Year 10 time points | 
| Phase B: Immune Response to Mumps With Respect to Anti-mumps Antibody Concentrations | Anti-mumps antibody concentrations are presented as Geometric Mean Concentrations (GMCs), expressed in units per milliliter (U/mL). | At Year 4, Year 6, Year 8 and Year 10 time points | 
| Phase B: Number of Subjects With Anti-mumps Antibody Concentrations Above the Cut-off Value | The anti-mumps antibody concentration cut-off value assessed was ≥ 231 U/mL, in the sera of subjects seronegative before vaccination. | At Year 4, Year 6, Year 8 and Year 10 time points | 
| Phase B: Immune Response to Rubella With Respect to Anti-rubella Antibody Concentrations | Anti-rubella antibody concentrations are presented as Geometric Mean Concentrations (GMCs), expressed in international units per milliliter (IU/mL). | At Year 4, Year 6, Year 8 and Year 10 time points | 
| Phase B: Number of Subjects With Anti-rubella Antibody Concentrations Above the Cut-off Value | The anti-rubella antibody concentration cut-off value assessed was ≥ 4 IU/mL, in the sera of subjects seronegative before vaccination. | At Year 4, Year 6, Year 8 and Year 10 time points | 
| Phase B: Characteristics of Zoster Cases | Zoster cases were characterized by number and character of lesions, duration of rash, incidence of fever, systemic signs, the assessment by investigator, complications, treatment, outcome and intensity of severity. | From 6 weeks after Dose 2 until study end (Year 10) | 
| Phase B: Number of Subjects Reporting Serious Adverse Events (SAEs) | SAEs assessed included medical occurrences that resulted in death, were life-threatening, required hospitalisation or prolongation of hospitalisation or resulted in disability/incapacity. Any SAE = occurrence of SAE regardless of intensity grade or relation to vaccination. | From the beginning of Phase B (Year 2) up to study end (Year 10) | 
| Phase B: Health Economics Analysis of Factors Leading to Indirect Costs Due to Varicella Illness | Parameters assessed: 1. Number of hours lost from work by parents/guardians as a result of taking care of their child due to varicella. 2. Number of hours the child lost attendance in: day care/childminder, school, or in any extra-curricular activities (e.g. sports or recreation or any type of organised leisure activities) due to varicella. 3. Number of hours spent by a nurse, a babysitter or any type of existing paid caregiver to look after the child (if applicable). | During Phase B |