Immunogenicity and Safety Study of GlaxoSmithKline (GSK) Biologicals' Combined Measles-mumps-rubella (MMR) Vaccine in Children in Their Second Year of Life

Study Overview
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Brief Summary
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The purpose of this study is to evaluate end of shelf-life potency in terms of the immunogenicity and safety of GSK Biologicals' trivalent MMR vaccine, by comparing it to Merck & Co., Inc.'s MMR vaccine, which is approved for use in the United States (US).

Detailed Description
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This trial is a Phase IIIA, randomized, observer-blind, controlled, multi-center, multi-country study with four parallel groups. This study will evaluate the immunogenicity and safety of GSK Biologicals' trivalent investigational MMR vaccine (referred to as Inv_MMR vaccine, throughout this document) in contrast to the US standard of care comparator vaccine (M-M-R II, Merck and Co., Inc., referred to as Com_MMR throughout this document) in children during their second year of life. The first dose of this two-dose study is designed to establish the end of shelf-life potency of Inv_MMR vaccine. The Inv_MMR vaccine will be given as one of two lots; one of a minimum potency, designated Inv_MMR_Min; and the other at a mid-range or medium potency designated Inv_MMR_Med to two groups. The second dose for both of these Inv_MMR groups will have a potency within the release range of the marketed vaccine. The Com_MMR vaccine will consist of two lots designated Com_MMR_L1 and Com_MMR_L2 and will be analyzed as pooled lots within the study. The first MMR vaccine dose will be co-administered with Varivax, Havrix and (in the US sub-cohort only) Prevnar 13 which are routinely administered to children of this age in the US.

Official Title
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Immunogenicity and Safety Study of GSK Biologicals' Priorix Vaccine (209762) at an End of Shelf-life Potency Compared to Merck & Co., Inc.'s Measles-mumps-rubella (MMR) Vaccine When Both Are Given on a 2-dose Schedule to Healthy Children in Their 2nd Year of Life

Conditions
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Measles, Mumps, Rubella, Measles-Mumps-Rubella Vaccine

Intervention / Treatment
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* Biological: Priorix
* Biological: M-M-R II
* Biological: Varivax
* Biological: Havrix
* Biological: Prevnar 13


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female child between 12 and 15 months of age at the time of vaccination. The investigator believes that the parent(s) or Legally Acceptable Representative(s) (LAR(s)) of the child, can, and will comply with the requirements of the protocol. Written informed consent obtained from the parent(s)/LAR(s) of the child. Child is in stable health as determined by investigator's clinical examination and assessment of child's medical history. For US children only: • Child that previously received a 3-dose series of Prevnar 13 with last dose at least 60 days prior to study entry. Exclusion Criteria: Child in care. Use of any investigational or non-registered product other than the study vaccine(s) during the period starting 30 days before the day of study vaccination or planned use during the entire study period. Concurrently participating in another clinical study, in which the child has been or will be exposed to an investigational or a non-investigational product. Chronic administration of immunosuppressants, or other immune-modifying drugs during the period starting 180 days prior to the first vaccine dose or any planned administration of immunosuppressive and immune-modifying drugs during the entire study. Inhaled and topical steroids are allowed. Planned administration / administration of a vaccine not foreseen by the study protocol during the period starting 30 days prior to study vaccination at Visit 1 and ending at Visit 2 (or ending at Visit 3 for the US post-dose 2 sub-cohort). Please Note: Inactivated influenza (Flu) vaccine and Haemophilus influenzae type b conjugate vaccine (Hib) vaccines may be given at any time during the study, including the day of study vaccination (Flu and Hib vaccines must be administered at a different location than the study vaccine/s). Any age appropriate vaccine may be given starting at Visit 2 (or starting at Visit 3 for the US post-dose 2 sub-cohort), and anytime thereafter. Administration of immunoglobulins and/or any blood products during the period starting 180 days prior to study vaccination at Visit 1 or planned administration from the date of vaccination through the immunogenicity evaluation at Visit 2, or at Visit 3 for the US post-dose 2 sub-cohort. History of measles, mumps, rubella, varicella/zoster and/or hepatitis A diseases. Known exposure to measles, mumps, rubella and/or varicella/zoster during the period starting 30 days prior to the first study vaccination. Previous vaccination against measles, mumps, rubella, hepatitis A and/or varicella virus. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. A family history of congenital or hereditary immunodeficiency. History of allergic disease or reactions likely to be exacerbated by any component of the vaccines, including hypersensitivity to neomycin, latex 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 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 based on medical history. Any other condition which, in the opinion of the Investigator, prevents the child from participating in the study. For US children only: • A child that previously received a fourth dose of any pneumococcal conjugate vaccine.

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 15 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inv_MMR_Min Group<br>Subjects receive one dose of GlaxoSmithKline (GSK) Biologicals' measles, mumps, rubella (MMR) vaccine, Priorix (Inv_MMR), from a minimum potency lot (Inv_MMR_Min), co-administered with Varivax (VV) and Havrix (HAV) vaccines at Day 0. All US subjects are also co-administered Prevnar 13 (PCV-13) vaccine. Approximately 6 weeks later, at Day 42, subjects are administered a dose from a separate lot of the Inv_MMR vaccine (Inv_MMR_Release), for the second dose. Inv_MMR and VV vaccines are administered subcutaneously in the triceps region of the left and right arm, respectively. HAV and PCV-13 vaccines are administered intramuscularly in the anterolateral region of the right and left thigh, respectively. | Biological: Priorix<br>* Subjects receive one dose of either minimum (Inv_MMR_Min) or medium (Inv_MMR_Med) potency lot at Day 0 and a dose of separate potency lot (Inv_MMR_Release) at Day 42, administered subcutaneously in the triceps region of the left arm.<br>* Other names: rubella vaccine;Biological: Varivax<br>* Subjects receive one dose co-administered subcutaneously with the study vaccines (Priorix and M-M-R II), in the triceps region of right arm, at Day 0.<br>* Other names: live;Biological: Havrix<br>* Subjects receive one dose co-administered intramuscularly with the study vaccines (Priorix and M-M-R II), in the anterolateral region of the right thigh, at Day 0.<br>* Other names: inactivated;Biological: Prevnar 13<br>* US Subjects receive one dose co-administered intramuscularly with the study vaccines (Priorix and M-M-R II), in the anterolateral region of the left thigh, at Day 0.<br>* Other names: Pfizer Inc.'s pneumococcal 13-valent conjugate vaccine (diphtheria CRM197 protein);|
| Experimental: Inv_MMR_Med Group<br>Subjects receive one dose of GlaxoSmithKline (GSK) Biologicals' measles, mumps, rubella (MMR) vaccine, Priorix (Inv_MMR), from a mid-range or medium potency lot (Inv_MMR_Med), co-administered with Varivax (VV) and Havrix (HAV) vaccines at Day 0. All US subjects are also co-administered Prevnar 13 (PCV-13) vaccine. Approximately 6 weeks later, at Day 42, subjects are administered a dose from a separate lot of the Inv_MMR vaccine (Inv_MMR_Release), for the second dose. Inv_MMR and VV vaccines are administered subcutaneously in the triceps region of the left and right arm, respectively. HAV and PCV-13 vaccines are administered intramuscularly in the anterolateral region of the right and left thigh, respectively. | Biological: Priorix<br>* Subjects receive one dose of either minimum (Inv_MMR_Min) or medium (Inv_MMR_Med) potency lot at Day 0 and a dose of separate potency lot (Inv_MMR_Release) at Day 42, administered subcutaneously in the triceps region of the left arm.<br>* Other names: rubella vaccine;Biological: Varivax<br>* Subjects receive one dose co-administered subcutaneously with the study vaccines (Priorix and M-M-R II), in the triceps region of right arm, at Day 0.<br>* Other names: live;Biological: Havrix<br>* Subjects receive one dose co-administered intramuscularly with the study vaccines (Priorix and M-M-R II), in the anterolateral region of the right thigh, at Day 0.<br>* Other names: inactivated;Biological: Prevnar 13<br>* US Subjects receive one dose co-administered intramuscularly with the study vaccines (Priorix and M-M-R II), in the anterolateral region of the left thigh, at Day 0.<br>* Other names: Pfizer Inc.'s pneumococcal 13-valent conjugate vaccine (diphtheria CRM197 protein);|
| Active Comparator: Com_MMR Group<br>Subjects receive one dose of M-M-R II (Com_MMR) vaccine (Lot 1 or Lot 2), co-administered with Varivax (VV) and Havrix (HAV) vaccines at Day 0. All US subjects are also co-administered Prevnar 13 (PCV-13) vaccine. Approximately 6 weeks later, at Day 42, subjects are administered a dose of Com_MMR vaccine (Lot 1 or Lot 2), for the second dose. Com_MMR and VV vaccines are administered subcutaneously in the triceps region of the left and right arm, respectively. HAV and PCV-13 vaccines are administered intramuscularly in the anterolateral region of the right and left thigh, respectively. | Biological: M-M-R II<br>* Subjects receive two doses of either Lot 1 or Lot 2, one at Day 0 and one at Day 42, administered subcutaneously in the triceps region of the left arm.<br>* Other names: live;Biological: Varivax<br>* Subjects receive one dose co-administered subcutaneously with the study vaccines (Priorix and M-M-R II), in the triceps region of right arm, at Day 0.<br>* Other names: live;Biological: Havrix<br>* Subjects receive one dose co-administered intramuscularly with the study vaccines (Priorix and M-M-R II), in the anterolateral region of the right thigh, at Day 0.<br>* Other names: inactivated;Biological: Prevnar 13<br>* US Subjects receive one dose co-administered intramuscularly with the study vaccines (Priorix and M-M-R II), in the anterolateral region of the left thigh, at Day 0.<br>* Other names: Pfizer Inc.'s pneumococcal 13-valent conjugate vaccine (diphtheria CRM197 protein);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Anti-measles Virus Antibody Concentration Equal to or Above the Cut-off-value (by Enzyme-linked Immunosorbent Assay [ELISA]) | For measles virus, a seroresponse was defined as post-vaccination anti-measles virus antibody concentration equal or above [≥] 200 mIU/mL (ELISA) among subjects who were seronegative (antibody concentration less than [<] 150 mIU/mL) before dose 1. Criteria to demonstrate an acceptable immune response of Inv_MMR_Min/Inv_MMR_Med vaccine in terms of seroresponse rate for measles virus at Day 42: The lower limit of the two-sided 97.5% CI for the seroresponse rate of Inv_MMR_Min/Inv_MMR_Med was to be ≥ 90% for antibodies to measles virus. | At Day 42 | 
| Percentage of Subjects With Anti-mumps Virus Antibody Concentration Equal to or Above the Cut-off-value (by ELISA) | For mumps virus, a seroresponse was defined as post-vaccination anti-mumps virus antibody concentration ≥ 10 EU/mL (ELISA) among subjects who were seronegative (antibody concentration < 5 EU/mL) before dose 1. Criteria to demonstrate an acceptable immune response of Inv_MMR_Min/Inv_MMR_Med vaccine in terms of seroresponse rate for mumps virus at Day 42: The lower limit of the two-sided 97.5% CI for the seroresponse rate of Inv_MMR_Min/Inv_MMR_Med was to be ≥ 90% for antibodies to mumps virus. | At Day 42 | 
| Percentage of Subjects With Anti-mumps Virus Antibody Concentration Equal to or Above the Cut-off-value (by Plaque Reduction Neutralization Test [PRNT]) | For mumps virus as measured by PRNT, a seroresponse was defined as post-vaccination anti-mumps virus antibody concentration ≥ 4 End point Dilution 50% (ED50) (PRNT) among subjects who were seronegative (antibody concentration < 2.5 ED50) before dose 1. | At Day 42 | 
| Percentage of Subjects With Anti-rubella Virus Antibody Concentration Equal to or Above the Cut-off-value (by ELISA) | For rubella virus, a seroresponse was defined as post-vaccination anti-rubella virus antibody concentration ≥ 10 IU/mL (ELISA) among subjects who were seronegative (antibody concentration < 4 IU/mL) before dose 1. Criteria to demonstrate an acceptable immune response of Inv_MMR_Min/Inv_MMR_Med vaccine in terms of seroresponse rate for rubella virus at Day 42: The lower limit of the two-sided 97.5% CI for the seroresponse rate of Inv_MMR_Min/Inv_MMR_Med was to be ≥ 90% for antibodies to mumps virus. | At Day 42 | 
| Anti-measles Virus Antibody Concentrations (by ELISA) | Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs) in mIU/mL. | At Day 42 | 
| Anti-mumps Virus Antibody Concentrations (by ELISA) | Antibody concentrations were expressed as GMCs in EU/mL. | At Day 42 | 
| Anti-mumps Virus Antibody Concentrations (by PRNT) | Antibody concentrations were expressed as Geometric Mean Titers (GMTs). | At Day 42 | 
| Anti-rubella Virus Antibody Concentrations (by ELISA) | Antibody concentrations were expressed as GMCs in IU/mL. | At Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Anti-measles Virus Antibody Concentration Equal to or Above the Cut-off-value (by ELISA) | For measles virus, a seroresponse was defined as post-vaccination anti-measles virus antibody concentration ≥ 200 mIU/mL (ELISA) among subjects who were seronegative (antibody concentration < 150 mIU/mL) before dose 1. | At Day 84 | 
| Percentage of Subjects With Anti-mumps Virus Antibody Concentration Equal to or Above the Cut-off-value (by ELISA) | For mumps virus, a seroresponse was defined as post-vaccination anti-mumps virus antibody concentration ≥ 10 EU/mL (ELISA) among subjects who were seronegative (antibody concentration < 5 EU/mL) before dose 1. | At Day 84 | 
| Percentage of Subjects With Anti-rubella Virus Antibody Concentration Equal to or Above the Cut-off-value (by ELISA) | For rubella virus, a seroresponse was defined as post-vaccination anti-rubella virus antibody concentration ≥ 10 IU/mL (ELISA) among subjects who were seronegative (antibody concentration < 4 IU/mL) before dose 1. | At Day 84 | 
| Anti-measles Virus Antibody Concentrations (by ELISA) | Antibody concentrations were expressed as GMCs in mIU/mL. | At Day 84 | 
| Anti-mumps Virus Antibody Concentrations (by ELISA) | Antibody concentrations were expressed as GMCs in EU/mL. | At Day 84 | 
| Anti-rubella Virus Antibody Concentrations (by ELISA) | Antibody concentrations were expressed as GMCs in IU/mL. | At Day 84 | 
| Number of Subjects With Any Solicited Local Adverse Events (AEs) Post Dose 1 | Assessed solicited local AEs were pain, redness and swelling. Any = Occurrence of the AE regardless of intensity grade or relation to vaccination. | During the 4-day (Days 0-3) post-vaccination period | 
| Number of Subjects With Any Solicited Local AEs Post Dose 2 | Assessed solicited local AEs were pain, redness and swelling. Any = Occurrence of the AE regardless of intensity grade or relation to vaccination. | During the 4-day (Days 0-3) post-vaccination period | 
| Number of Subjects With Any Solicited General AEs Post Dose 1 | Assessed solicited general AEs were drowsiness, irritability/fussiness and loss of appetite. Any = Occurrence of the AE regardless of intensity grade or relation to vaccination. | During the 15-day (Days 0-14) post-vaccination period | 
| Number of Subjects Reporting Any Fever Post Dose 1 | Any fever = Fever (axillary) ≥ 38°C. | During the 43-day (Days 0-42) post-vaccination period | 
| Number of Subjects Reporting Any Fever Post Dose 2 | Any fever = Fever (axillary) ≥ 38°C. | During the 43-day (Days 0-42) post-vaccination period | 
| Number of Subjects Reporting Any Rash Post Dose 1 | Assessed were any localized or generalized rash, rash with fever, varicella-like rash and measles/rubella-like rash. Any = Occurrence of the AE regardless of intensity grade or relation to vaccination. | During the 43-day (Days 0-42) post-vaccination period | 
| Number of Subjects Reporting Any Rash Post Dose 2 | Assessed were any localized or generalized rash, rash with fever, varicella-like rash and measles/rubella-like rash. Any = Occurrence of the AE regardless of intensity grade or relation to vaccination. | During the 43-day (Days 0-42) post-vaccination period | 
| Number of Subjects Reporting Any MMR Specific Solicited General AEs Post Dose 1 | Assessed MMR specific solicited general AEs were any suspected signs of meningism including febrile convulsions and parotid/salivary gland swelling. Any = Occurrence of the AE regardless of intensity grade or relation to vaccination. | During the 43-day (Days 0-42) post-vaccination period | 
| Number of Subjects Reporting Any MMR Specific Solicited General AEs Post Dose 2 | Assessed MMR specific solicited general AEs were any suspected signs of meningism including febrile convulsions and parotid/salivary gland swelling. Any = Occurrence of the AE regardless of intensity grade or relation to vaccination. | During the 43-day (Days 0-42) post-vaccination period | 
| Number of Subjects Reporting Any Unsolicited AES Post Dose 1 | Unsolicited AE was defined as any AE reported in reported in addition to those solicited during the clinical study and any solicited AE with onset outside the specified period of follow-up for solicited AEs. Any = Occurrence of the AE regardless of intensity grade or relation to vaccination. | During the 43-day (Days 0-42) post-vaccination period | 
| Number of Subjects Reporting Any Unsolicited AES Post Dose 2 | Unsolicited AE was defined as any AE reported in reported in addition to those solicited during the clinical study and any solicited AE with onset outside the specified period of follow-up for solicited AEs. Any = Occurrence of the AE regardless of intensity grade or relation to vaccination. | During the 43-day (Days 0-42) post-vaccination period | 
| Number of Subjects Reporting Any AEs of Specific Interest | AEs of specific interest included new onset chronic disease (NOCD) (e.g., autoimmune disorders, asthma, type I diabetes, vasculitis, celiac disease, conditions associated with sub-acute or chronic thrombocytopenia and allergies) and AEs prompting emergency room (ER) visits. | From Day 0 through the end of the study (Day 222) | 
| Number of Subjects Reporting Any Serious Adverse Events (SAEs) | SAEs assessed include any untoward medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of existing hospitalization or resulted in disability/incapacity. | From Day 0 through the end of the study (Day 222) | 

 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