Immunogenicity and Safety of Kinrix + (Measles Mumps Rubella) MMR Vaccine With and Without Varicella Vaccine in Healthy Children 4-6 Years

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the immunogenicity and safety of Kinrix when co-administered with varicella (Varivax® [varicella virus vaccine live], Merck and Company) and (measles mumps rubella) MMR vaccines, compared to Kinrix co-administered with MMR vaccine alone. Both Kinrix and the second dose of Varivax are indicated in children 4-6 years of age, and there is great potential for the vaccines to be given concurrently. The aim of this trial is to demonstrate that co-administered Varivax does not negatively affect the immunogenicity or reactogenicity of Kinrix.

Detailed Description
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Subjects 4-6 years of age will be randomized into two groups to receive either Kinrix, Varivax and M-M-RII on day 0 (Group 1) or Kinrix and M-M-RII on day 0 and Varivax at month 1(Group 2). All subjects in both groups to provide blood samples prior to vaccination on day 0 and at month 1 (for Group 2, blood sampling is prior to vaccination with Varivax). Duration of the study will be approximately 6 months for each subject with a safety telephone contact 6 months after vaccinations.

Official Title
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Immunogenicity and Safety Study of Kinrix® Co-administered With Varivax®

Conditions
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Tetanus, Acellular Pertussis, Diphtheria

Intervention / Treatment
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* Biological: GSK Biologicals'Kinrix®
* Biological: Merck and Company's MMRII
* Biological: Merck and Company's Varivax


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. A male or female child between 4 and 6 years of age, inclusive. Written informed consent obtained from the parent or guardian of the subject. Healthy subjects as established by medical history and clinical examination before entering into the study. Having received 4 doses of (Diphtheria, Tetanus Acellular Pertussis) DTaP vaccine using Pediarix and/or Infanrix, and 3 doses of poliovirus vaccine using Pediarix and/or (inactivated poliovirus vaccine, Aventis Pasteur) IPOL in the first 2 years of life. Previously received 1 dose of M-M-RII and Varivax (separate or combined) in the second year of life. Exclusion Criteria: Use of any investigational or non-registered drug or vaccine other than the study vaccines within 30 days preceding the administration of study vaccines, or planned use during the study period. Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or non-investigational product or device. History of previous or intercurrent diphtheria, tetanus, pertussis, polio, measles, mumps, rubella or varicella disease, or of vaccination against these diseases given after the second year of life. Known exposure to diphtheria, tetanus, pertussis, or polio, prior to vaccination. Poliovirus vaccination with one or more doses of (oral polio virus) OPV vaccine. Administration or planned administration of a vaccine not foreseen by the study protocol within 30 days of study vaccination and ending at Day 30. Chronic administration or planned administration of immunosuppressants or other immune modifying drugs within six months prior to study vaccination or planned administration during the study period ending at Day 30. Administration of immunoglobulins and/or any blood products at any time prior to study vaccination or planned administration during the study period ending at Day 30. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection. History of seizures or progressive neurological disorder, including infantile spasms, uncontrolled epilepsy or progressive encephalopathy. Major congenital defects or serious chronic illness. Acute disease at the time of enrolment. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine(s). History of anaphylactic reaction to egg proteins or previous doses of the vaccine(s). Encephalopathy within 7 days of administration of previous dose of Infanrix or Pediarix. Fever >=40.5°C or 104.9°F (rectal temperature) (39.5°C or 103.1°F, oral/axillary) within 48 hours of previous dose of Infanrix or Pediarix not due to another identifiable cause. Collapse or shock-like state within 48 hours of previous dose of DTaP or DTaP-containing vaccine. Persistent, severe, inconsolable screaming or crying lasting ³3 hours occurring within 48 hours of administration of previous dose of DTaP or DTaP-containing vaccine. Thrombocytopenia following a previous dose of M-M-RII or its component vaccines Inability to contact a parent/guardian of the subject by telephone. Blood dyscrasias, leukemia, lymphomas or other malignant neoplasms affecting the bone marrow or lymphatic systems. Family history of congenital or hereditary immunodeficiency, unless the immune competence of the subject has been demonstrated. Residence in the same household as the following persons: New-born infants (0-4 weeks of age). Pregnant mother/women without documented positive history of chickenpox disease or laboratory evidence of prior varicella vaccination. Pregnant women at or beyond 28 weeks gestation regardless of varicella vaccination status or varicella disease history. Persons with known immunodeficiency. Active untreated tuberculosis.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 6 Years

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 |
| --- | --- |
| Experimental: Kinrix + M-M-R II + Varivax<br>Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively. | Biological: GSK Biologicals'Kinrix®<br>* One dose as intramuscular injection at visit 1<br>Biological: Merck and Company's MMRII<br>* One dose as subcutaneous injection at visit 1<br>Biological: Merck and Company's Varivax<br>* One dose as subcutaneous injection at visit 1 or at visit 2<br>|
| Active Comparator: Kinrix + M-M-R II -> Varivax<br>Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm. | Biological: GSK Biologicals'Kinrix®<br>* One dose as intramuscular injection at visit 1<br>Biological: Merck and Company's MMRII<br>* One dose as subcutaneous injection at visit 1<br>Biological: Merck and Company's Varivax<br>* One dose as subcutaneous injection at visit 1 or at visit 2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Booster Responses to Diphteria and Tetanus | Anti-diphteria (anti-D) and anti-tetanus (anti-T) booster response was defined as: initially seronegative subjects (sero-) (pre-booster antibody concentration below cut-off of < 0.1 international units per milliliter (IU/mL)) with an increase of at least four times the cut-off one month after vaccination (post-booster antibody concentration ≥0.4 IU/mL) initially seropositive subjects (sero+) (pre-booster antibody concentration ≥0.1 IU/mL) with an increase of at least four times the pre-booster antibody concentration one month after vaccination | One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group. | 
| Number of Subjects With Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Hemagglutinin (FHA) and Anti-pertactin (Anti-PRN) Booster Responses, Measured in Enzyme-Linked Immunosorbent Assay Units Per Milliliter (EL.U/mL) | anti-PT, anti-FHA and anti-PRN booster response : initially sero- (pre-booster antibody concentration below cut-off < 5.0 EL.U/mL) with increase of at least four times cut-off one month after vaccination (concentration post-booster ≥20.0 EL.U/mL) initially sero+ with pre-booster antibody concentration ≥5.0 EL.U/mL and < 20.0 EL.U/mL with increase of at least four times pre-booster concentration one month post-booster initially sero+ with pre-booster antibody concentration ≥20.0 EL.U/mL with an increase of at least two times the pre-booster antibody concentration one month post-booster | One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group. | 
| Geometric Mean Titers (GMTs) for Antibodies to Poliovirus Types 1, 2 and 3 | Titers are expressed as GMTs. | One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anti-D and Anti-T Antibody Concentrations Above Cut-off Value | Cut-off value was defined as greater than or equal to 1.0 international units per milliliter (IU/mL). | One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group. | 
| Geometric Mean Concentrations (GMCs) for Anti-D and Anti-T Antibodies | Concentrations were expressed as GMCs in IU/mL. | One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group. | 
| GMCs for Anti-PT, Anti-FHA, Anti-PRN Antibodies | Concentrations are expressed as GMCs in Enzyme-Linked Immunosorbent Assay (ELISA) Units per milliliter (EL.U/mL). | One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group. | 
| Number of Subjects With an Anti-polio 1, 2, 3 Booster Response | Anti-poliovirus 1, anti-poliovirus 2 and anti-poliovirus 3 booster response: initially seronegative subjects (pre-booster antibody titer below cut-off of 8 ED50) with an antibody titer ≥ 32 ED50 one month after vaccination initially seropositive subjects (pre-booster antibody titers ≥ 8 ED50) with an increase at least four times the pre-booster antibody titer one month after vaccination. ED50 is defined here as the reverse of the dilution resulting in 50% inhibition. The lowest dilution at which serum samples were tested is 1:8 from which a test was considered positive. | One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group. | 
| Number of Subjects Seroprotected Against Diphteria and Tetanus | Seroprotection status was defined as: anti-D antibody concentration greater than or equal to 0.1 IU/mL anti-T antibody concentration greater than or equal to 0.1 IU/mL | One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group. | 
| Number of Subjects Protected Against Poliovirus 1, 2 and 3 | Seroprotection was defined: * anti-poliovirus type 1, 2 or 3 antibody titer greater than or equal to 8 ED50. ED50 is defined here as the reverse of the dilution resulting in 50% inhibition. | One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group. | 
| Number of Subjects Seropositive for Anti-PT, Anti-FHA and Anti-PRN Antibodies | Seropositivity was defined as a concentration greater than or equal to 5.0 EL.U/mL | One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group. | 
| Number of Subjects With Any Solicited Local Symptoms | Solicited local symptoms included pain, redness and swelling at the injection site. Any was defined as incidence of a particular symptom regardless of intensity grade. | Within 4 days (Day 0 to 3) after booster immunization * for Kinrix + M-M-R II -> Varivax Group before vaccination with Varivax | 
| Number of Subjects With Any Solicited General Symptoms | Solicited general symptoms included fever [temperature equal to or greater than 37.5 degrees Celsius (°C)], drowsiness and loss of appetite. Any was defined as incidence of a particular symptom regardless of intensity grade. | Within 4 days (Day 0 to 3) after booster immunization * for Kinrix + M-M-R II -> Varivax Group before vaccination with Varivax | 
| Number of Subjects With Unsolicited Adverse Events | An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study. Also any solicited symptom with onset outside the specified period of follow-up for solicited symptoms will be reported as an unsolicited adverse event. | Up to 31 days (Day 0 through Day 30) after booster vaccination * for Kinrix + M-M-R II -> Varivax Group before vaccination with Varivax | 
| Number of Subjects With Serious Adverse Events (SAEs) | Serious adverse events are 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 entire study period (from Day 0 to 6 months post-vaccination) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Booster, Co-administration, Immunization, Preschool