Immunogenicity and Safety Study of GlaxoSmithKline (GSK) Biologicals' Combined Measles-mumps-rubella (MMR) Vaccine in Subjects Four to Six Years of Age

Study Overview
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Brief Summary
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The purpose of this study is to support licensure of GSK Biologicals' MMR vaccine (Priorix®) in the US by generating immunogenicity and safety data in contrast to the US standard of care, Merck's MMR vaccine (M-M-R®II), when given as a second dose to children four to six years of age.

Detailed Description
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The GSK Biologicals' MMR vaccine (Priorix®) and Merck's MMR vaccine (M-M-R®II) are referred to as Inv_MMR vaccine and Com_MMR vaccine respectively. 2 lots of the comparator vaccine (Com_MMR_L1 and Com_MMR_L2) will be used, but the 2 lots will be analysed as a pool. The Inv_MMR vaccine will be administered as a second dose to children who already received a first dose Com_MMR vaccine. Since the second dose of a MMR vaccine in the US is routinely co-administered with DTaP-IPV vaccine (Kinrix®) and varicella vaccine (VV) (ProQuad® or Varivax®), some children will receive one dose of these vaccines along with either of the MMR vaccines.

Official Title
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Immunogenicity and Safety Study of GSK Biologicals' Combined Measles-mumps-rubella Vaccine in Subjects Four to Six Years of Age (209762)

Conditions
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Measles-Mumps-Rubella

Intervention / Treatment
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* Biological: Priorix
* Biological: M-M-R II
* Biological: Kinrix
* Biological: ProQuad


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that they and/or their parent(s) or LAR/s can and will comply with the requirements of the protocol. Male or female subjects 4 to 6 years of age at the time of vaccination. Written informed consent is obtained from the parent(s)/LAR(s) of the subject (assent will be obtained from subjects in line with local rules and regulations). Subjects in stable health as determined by investigator's physical examination and assessment of subjects' medical history. Subjects received either a single dose of M-M-R II, M-M-R VaxPro or ProQuad in the second year of life. For subjects enrolled in the sub-cohort receiving co-administered DTaP-IPV and VV: subjects received previous DTaP vaccine doses with INFANRIX® and/or PEDIARIX® for the first three doses and INFANRIX® for the fourth dose of the DTaP-containing vaccine. subjects received a first dose of VV in the second year of life. Exclusion Criteria: Child in care. Use of any investigational or non-registered product other than the study vaccine during the period starting 30 days before the day of study vaccination/s or planned during the entire study period. Previous vaccination with a second dose of measles, mumps, rubella containing vaccine/s. Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting 180 days prior to Day 0 or any planned administration of immunosuppressive and immune-modifying drugs during the entire study. Inhaled and topical steroids are allowed. Administration of immunoglobulins and/or any blood products during the period starting 180 days before entering the study or planned administration from the date of vaccination through the immunogenicity evaluation at Visit 2. Planned administration/ administration of a vaccine not foreseen by the study protocol during the period starting 30 days prior to the study vaccination/s and ending 42 days after the vaccination/s (at Visit 2), with the exception of live intranasal or inactivated influenza (flu) vaccine, which may be given at any time during the study, including the day of study vaccination/s. Inactivated influenza vaccine must be administered at a different location from the study vaccine. Any age appropriate vaccine may be given starting at Visit 2, and anytime thereafter. 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 a non-investigational product. History of measles, mumps, and/or rubella disease. Known exposure to measles, mumps and/or rubella during the period starting 30 days prior to enrollment. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine(s), including systemic hypersensitivity to neomycin or gelatin. Blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems. Acute disease at the time of enrollment. Acute disease is defined as the presence of a moderate or severe illness with or without fever. Fever is defined as temperature ≥38°C (100.4°F) measured by any age appropriate route. All vaccines can be administered to persons with a minor illness such as diarrhea, mild upper respiratory infection without fever. Active untreated tuberculosis according to the subject's medical history. Any other condition which, in the opinion of the investigator, prevents the subject from participating in the study. In addition, for subjects enrolled in the sub-cohort receiving co-administered DTaP-IPV+VV: Previous vaccination with a second dose of varicella-containing vaccine. Receipt of any varicella-containing vaccine during the period starting 90 days before the day of study vaccination. History of varicella/zoster disease. Known exposure to varicella/zoster during the period starting 30 days prior to enrollment. History of diphtheria, tetanus, pertussis, and/or poliomyelitis disease. Vaccination against diphtheria, tetanus, pertussis or polio given after the second year of life. Occurrence of transient thrombocytopenia or neurological complications following an earlier immunization against diphtheria and/or tetanus toxoids. Following a previous administration of DTP vaccine: temperature ≥40.6°C (>105°F) during the period starting 48 hours not due to another identifiable cause, collapse or shock-like state during the period starting 48 hours, persistent, inconsolable crying lasting three hours or more within 48 hours, seizures with or without fever occurring during the period starting three days, or encephalopathy of unknown aetiology occurring during the period starting 7 days of a previous administration of DTP vaccine. Hypersensitivity reaction to any component of the DTaP-IPV and/or varicella vaccines.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inv _MMR_CO Group<br>Subjects received one dose of the study vaccine Priorix along with Kinrix and ProQuad vaccines at Visit 1 (Day 0). | Biological: Priorix<br>* One dose administered subcutaneously in the triceps region of the right arm.<br>Biological: Kinrix<br>* One dose administered by deep intramuscular injection in the upper left deltoid.<br>Biological: ProQuad<br>* One dose administered subcutaneously in the triceps region of the left arm.<br>|
| Active Comparator: Com_MMR_CO Group<br>Subjects received one dose of the licensed vaccine M-M-R II (also known as M-M-R Vax Pro) Lot 1 or Lot 2 along with Kinrix and ProQuad vaccines at Visit 1 (Day 0). | Biological: M-M-R II<br>* One dose administered subcutaneously in the triceps region of the right arm.<br>Biological: Kinrix<br>* One dose administered by deep intramuscular injection in the upper left deltoid.<br>Biological: ProQuad<br>* One dose administered subcutaneously in the triceps region of the left arm.<br>|
| Experimental: Inv_MMR_I Group<br>Subjects received one dose of Priorix at Visit 1 (Day 0). | Biological: Priorix<br>* One dose administered subcutaneously in the triceps region of the right arm.<br>|
| Active Comparator: Com_MMR_I Group<br>Subjects received one dose of M-M-R II (also known as M-M-R Vax Pro) vaccine from Lot 1 or Lot 2 at Visit 1 (Day 0). | Biological: M-M-R II<br>* One dose administered subcutaneously in the triceps region of the right arm.<br>|
| Experimental: Inv _MMR_S Group<br>Subjects in this safety cohort received one dose of Priorix at Visit 1 (Day 0). | Biological: Priorix<br>* One dose administered subcutaneously in the triceps region of the right arm.<br>|
| Active Comparator: Com_MMR_S Group<br>Subjects in this safety cohort received one dose of M-M-R II (also known as M-M-R Vax Pro) vaccine from Lot 1 or Lot 2 at Visit 1 (Day 0). | Biological: M-M-R II<br>* One dose administered subcutaneously in the triceps region of the right arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anti-measles Virus Antibody Concentration Equal to or Above the Cut-off-value | Seroresponse was defined as post-vaccination anti-measles virus antibody concentration equal to or above (≥) 200 milli-international Units per milliliter (mIU/mL). Analysis was done in sub-cohorts 1 and 2 only. | 42 days post vaccination (At Day 42) | 
| Number of Subjects With Anti-mumps Virus Antibody Concentration Equal to or Above the Cut-off-value | Seroresponse was defined as post-vaccination anti-mumps virus antibody concentration ≥ 10 ELISA Units per milliliter (EU/mL). Analysis was done in sub-cohorts 1 and 2 only. | 42 days post vaccination (At Day 42) | 
| Number of Subjects With Anti-rubella Virus Antibody Concentration Equal to or Above the Cut-off-value | Seroresponse was defined as post-vaccination anti-rubella virus antibody concentration ≥ 10 International Units per milliliter (IU/mL). Analysis was done in sub-cohorts 1 and 2 only. | 42 days post vaccination (At Day 42) | 
| Evaluation of Immunogenicity in Terms of Anti-measles Virus Antibody Concentrations | Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs) in mIU/mL. Analysis was done in sub-cohorts 1 and 2 only. | 42 days after vaccination (At Day 42) | 
| Evaluation of Immunogenicity in Terms of Anti-mumps Virus Antibody Concentrations | Antibody concentrations were expressed as GMCs in EU/mL. Analysis was done in sub-cohorts 1 and 2 only. | 42 days post vaccination (At Day 42) | 
| Evaluation of Immunogenicity in Terms of Anti-rubella Virus Antibody Concentrations | Antibody concentrations were expressed as GMCs in IU/mL. Analysis was done in sub-cohorts 1 and 2 only. | 42 days post vaccination (At Day 42) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anti-varicella Zoster Virus (VZV) Antibody Concentration Equal to or Above the Cut-off-value | Seroresponse was defined as post-vaccination anti-VZV antibody concentration ≥ 75 mIU/mL. Analysis was done in sub-cohort 1 only. | 42 days post vaccination (At Day 42) | 
| Evaluation of Immunogenicity in Terms of Anti-VZV Antibody Concentrations | Antibody concentrations were expressed as GMCs in mIU/mL. Analysis was done in sub-cohort 1 only. | 42 days post vaccination (At Day 42) | 
| Number of Subjects With Antibody Booster Response to Diphtheria Toxin (Anti-D) and Tetanus Toxin (Anti-T) | Booster response was defined as: For subjects with pre-vaccination antibody concentration less than (<) 0.1 IU/mL, antibody concentration ≥ 0.4 IU/ml at Day 42. For subjects with pre-vaccination antibody concentration ≥ 0.1 IU/mL: antibody concentration at Day 42 ≥ 4 fold the pre-vaccination antibody concentration. Analysis was done in sub-cohort 1 only. | 42 days post vaccination (At Day 42) | 
| Number of Subjects With Antibody Booster Response to Pertussis Toxin (PT) | Booster response was defined as: For initially seronegative subjects, antibody concentration ≥ 10.772 IU/mL at Day 42. For initially seropositive subjects with pre-vaccination antibody concentration < 10.772 IU/mL: antibody concentration at Day 42 ≥ 4 fold the pre-vaccination antibody concentration. For initially seropositive subjects with pre-vaccination antibody concentration ≥ 10.772 IU/mL: antibody concentration at Day 42 ≥ 2 fold the pre-vaccination antibody concentration. Analysis was done in sub-cohort 1 only. | 42 days post vaccination (At Day 42) | 
| Number of Subjects With Antibody Booster Response to Filamentous Hemagglutinin (FHA) | Booster response was defined as: For initially seronegative subjects, antibody concentration ≥ 8.184 IU/ml at Day 42. For initially seropositive subjects with pre-vaccination antibody concentration < 8.184 IU/mL: antibody concentration at Day 42 ≥ 4 fold the pre-vaccination antibody concentration. For initially seropositive subjects with pre-vaccination antibody concentration ≥ 8.184 IU/mL: antibody concentration at Day 42 ≥ 2 fold the pre-vaccination antibody concentration. Analysis was done in sub-cohort 1 only. | 42 days post vaccination (At Day 42) | 
| Number of Subjects With Antibody Booster Response to Pertactin (PRN) | Booster response was defined as: For initially seronegative subjects, antibody concentration ≥ 8.748 IU/mL at Day 42. For initially seropositive subjects with pre-vaccination antibody concentration < 8.748 IU/mL: antibody concentration at Day 42 ≥ 4 fold the pre-vaccination antibody concentration. For initially seropositive subjects with pre-vaccination antibody concentration ≥ 8.748 IU/mL: antibody concentration at Day 42 ≥ 2 fold the pre-vaccination antibody concentration. Analysis was done in sub-cohort 1 only. | 42 days post vaccination (At Day 42) | 
| Evaluation of Immunogenicity in Terms of Anti-D and Anti-T Antibody Concentrations | Antibody concentrations were expressed as GMCs in IU/mL. Analysis was done in sub-cohort 1 only. | 42 days post vaccination (At Day 42) | 
| Evaluation of Immunogenicity in Terms of Anti-PT, Anti-FHA and Anti-PRN Antibody Concentrations | Antibody concentrations were expressed as GMCs in EU/mL. Analysis was done in sub-cohort 1 only. | 42 days post vaccination (At Day 42) | 
| Number of Subjects With Anti-D and Anti-T Antibody Concentrations ≥ 0.1 IU/mL | Analysis was done in sub-cohort 1 only. | 42 days post vaccination (At Day 42) | 
| Number of Subjects With Anti-D and Anti-T Antibody Concentrations ≥ 1.0 IU/mL | Analysis was done in sub-cohort 1 only. | 42 days post vaccination (At Day 42) | 
| Evaluation of Immunogenicity in Terms of Anti-polio Virus Types 1, 2 and 3 Antibody Titers | Antibody titers were expressed as Geometric Mean Titers (GMTs) in ED50. Analysis was done in sub-cohort 1 only. | 42 days post vaccination (At Day 42) | 
| Number of Subjects With Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 Pain = Cried when limb was moved/spontaneously painful. Grade 3 redness and swelling = greater than 50 millimeters (m m ) i.e . > 50mm. | During the 4-day (Days 0-3) post-vaccination period | 
| Number of Subjects With Solicited General Symptoms | Assessed solicited general symptoms were drowsiness and loss of appetite. Any = occurrence of the symptom regardless of intensity grade. Grade 3 Drowsiness = Drowsiness that prevented normal activity, Grade 3 Loss of appetite = Not eating at all. Related = symptom assessed by the investigator as causally related to study vaccination. Analysis was done for sub-cohort 1 only. | During the 4-day (Days 0-3) post-vaccination period | 
| Number of Subjects Reporting Fever | Any fever = fever ≥ 38°C; Grade 3 fever = fever > 39.5°C; Related = fever assessed by the investigator as causally related to study vaccination. | During the 43-day (Days 0-42) post-vaccination period | 
| Number of Subjects Reporting MMR Specific Solicited General Symptoms | Assessed MMR specific symptoms were parotid gland swelling and any suspected signs of meningism including febrile convulsions. Any = occurrence of any general symptoms regardless of their intensity grade or relationship to vaccination. Grade 3 Parotid/salivary gland swelling = Swelling accompanied with general symptoms. Grade 3 Sign of meningism (any suspected signs including febrile convulsions) = An event which prevented normal, everyday activities. Related = symptom assessed by the investigator as causally related to study vaccination. | During the 43-day (Days 0-42) post-vaccination period | 
| Number of Subjects Reporting Investigator-confirmed Rash | Assessed any rash, varicella-like rash, measles/rubella-like rash, Grade 3, related. Any= occurrence of rash regardless of intensity grade. Grade 3 measles/rubella/varicella-like rash = Rash with more than 150 lesions. Other Grade 3 Rash = Rash that prevented normal, everyday activities. Related= Rash assessed by the investigator as causally related to study vaccination. | During the 43-day (Days 0-42) post-vaccination period | 
| Number of Subjects With New Onset Chronic Diseases (NOCDs) | NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. | During the entire study period (from Day 0 up to Day 180) | 
| Number of Subjects Reporting Adverse Events Resulting in Emergency Room (ER) Visits | The number of subjects reporting adverse events resulting in Emergency Room (ER) visits is reported. | During the entire study period (from Day 0 up to Day 180) | 
| Number of Subjects With Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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 was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | During the 43-day (Days 0-42) post-vaccination period | 
| Number of Subjects With Serious Adverse Events (SAEs) | Serious adverse events (SAEs) assessed included medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. Any SAE = occurrence of SAE regardless of intensity grade or relation to vaccination. | During the entire study period (from Day 0 up to Day 180) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Measles, mumps and rubella diseases, Immunogenicity