Safety and Immunogenicity Study of GlaxoSmithKline (GSK) Biologicals' Measles, Mumps and Rubella (MMR) Vaccine (209762) Compared to Merck & Co., Inc.'s MMR Vaccine in Healthy Children 12 to 15 Months of Age

Safety and Immunogenicity Study of GSK Biologicals' Measles-mumps-rubella (MMR) Vaccine (209762) Comparing Immunogenicity and Safety to Merck & Co., Inc.'s MMR Vaccine, in Healthy Children 12 to 15 Months of Age

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02184572

Enrollment

1742

Registered

2014-07-09

Start date

2014-08-25

Completion date

2015-12-22

Last updated

2021-01-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Measles; Mumps; Rubella, Measles-Mumps-Rubella Vaccine

Keywords

Rubella, Healthy children, Measles, Safety, Mumps, 12 to 15 months, Immunogenicity

Brief summary

The purpose of this study is to evaluate the immunogenicity and safety of GSK Biologicals' trivalent MMR (Priorix), comparing it to Merck's MMR vaccine (M-M-R II), which is approved for use in the US in healthy children 12 to 15 months of age.

Detailed description

This study will evaluate the safety of GSK's trivalent MMR vaccine (referred to as INV\_MMR vaccine) at a potency that will be used to define maximum release limits for the INV\_MMR in comparison to the US standard of care (M-M-R II/ M-M-R VaxPro vaccine referred to as COM\_MMR vaccine). In order to obtain more representative data on the comparator vaccine, the COM\_MMR used in this study will consist of two lots designated COM\_MMR\_L1 and COM\_MMR\_L2. Throughout the study COM\_MMR\_L1 and COM\_MMR\_L2 will be analyzed as pooled lots. This study is intended to support licensure of GSK's MMR vaccine in the US. All children will receive Varivax and Havrix vaccines, concomitantly with MMR containing vaccine at 12 to 15 months of age. Prevnar 13 will be administered only to US children. At the end of the study, GSK will provide a second dose of Havrix and/or varicella vaccine to participants enrolled in selected non-US countries if local health departments do not routinely provide hepatitis A and varicella vaccination. The second dose of Havrix and varicella vaccine is not part of the study procedures.

Interventions

BIOLOGICALPrevnar 13

1 dose administered intramuscularly in the anterolateral region of the left thigh at Day 0 to subjects recruited in US

BIOLOGICALPriorix

1 dose administered subcutaneously in the triceps region of left arm at Day 0

BIOLOGICALM-M-R II

1 dose administered subcutaneously in the triceps region of left arm at Day 0

BIOLOGICALVarivax

1 dose administered subcutaneously in the triceps region of right arm at Day 0

BIOLOGICALHavrix

1 dose administered intramuscularly in the anterolateral region of the right thigh at Day 0

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

12 Months to 15 Months

Healthy volunteers

Yes

Inclusion criteria

* Male or female child between 12 and 15 months of age (e.g., from the 1 year birthday until the day before age 16 months) at the time of vaccination. * Subjects' parent(s)/Legally Acceptable Representative(s) \[LAR(s)\] who, in the opinion of the investigator, 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: a child who received all routine vaccinations as per ACIP recommendations prior to study entry: completion of hepatitis B and rotavirus series and completion of the primary series of diphtheria, tetanus, pertussis, poliovirus, Haemophilus influenzae type b (Hib) and pneumococcal vaccines. The 3-dose infant series of Prevnar 13 should be completed at least 60 days prior to study vaccination.

Exclusion criteria

* Child in care. * Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) during the period starting 30 days before the day of study vaccination (i.e., 30 days prior to Day 0) 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 (pharmaceutical product or device). * Chronic administration (defined as 14 or more consecutive days) of immunosuppressants, or other immune-modifying drugs during the period starting 180 days prior to the study vaccination at Visit 1 or any planned administration of immunosuppressive and immune-modifying drugs during the entire study. * For corticosteroids, this will mean prednisone ≥0.5 mg/kg/day or equivalent. * 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 the day of study vaccination at Visit 1 and ending at Visit 2. Please Note: * Inactivated influenza (Flu) vaccine and monovalent Haemophilus influenzae type b conjugate vaccine (Hib) vaccines may be given at any time, including the day of study vaccination (Flu and Hib vaccines must be administered at a different location than the study vaccine/s). * Any other age appropriate vaccine may be given starting at Visit 2 and anytime thereafter. * Administration of immunoglobulins and/or any blood products during the period starting 180 days before the study vaccination at Visit 1 or planned administration from the date of vaccination through the immunogenicity evaluation at Visit 2. * History of measles, mumps, rubella, varicella/zoster and/or hepatitis A disease. * Known exposure to measles, mumps, rubella and/or varicella/zoster during the period starting within 30 days prior to 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 (no laboratory testing required). * Blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems. * 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. * 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 ≥38.0°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 PCV-13 vaccine.

Design outcomes

Primary

Measure	Time frame	Description
Number of Subjects Reporting Fever After MMR (Priorix or M-M-R II/M-M-R VaxPro [Lot 1 or Lot 2]) Vaccination	During Day 5 to Day 12 post-vaccination period	Fever was assessed for temperature equal to/above (≥) 38.0°C and above (\>) 39.0°C. The safety profile for fever was assessed based on the group difference (INV\_MMR minus COM\_MMR) in incidence of fever equal to or below the cut-off value.

Secondary

Measure	Time frame	Description
Anti-measles Virus Antibody Concentrations	At Day 42 post vaccination	Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs) in mIU/mL. Analyses included initially seronegative subjects only.
Percentage of Subjects With Anti-mumps Virus Antibody Concentration Equal to or Above the Cut-off-value	At Day 42 post vaccination	Seroresponse was defined as post-vaccination anti-mumps virus antibody concentration ≥ 10 ELISA Unit per milliliter \[EU/mL\] (ELISA, Pharmaceutical Product Development, Inc.\[PPD\]) among subjects who were seronegative (antibody concentration \< 5 EU/mL) before vaccination.
Anti-mumps Virus Antibody Concentrations	At Day 42 post vaccination	Antibody concentrations were expressed as GMCs in EU/mL. Analyses included initially seronegative subjects only.
Percentage of Subjects With Anti-rubella Virus Antibody Concentration Equal to or Above the Cut-off-value	At Day 42 post vaccination	Seroresponse was defined as post-vaccination anti-rubella virus antibody concentration ≥ 10 International Unit per milliliter \[IU/mL\] (ELISA, Enzygnost) among subjects who were seronegative (antibody concentration \< 4 IU/mL) before vaccination.
Anti-rubella Virus Antibody Concentrations	At Day 42 post vaccination	Antibody concentrations were expressed as GMCs in IU/mL. Analyses included initially seronegative subjects only.
Number of Subjects With Any Solicited Local Adverse Events (AEs)	During the 4-day (Days 0-3) post-vaccination period	Assessed solicited local AEs were injection site pain, redness and swelling. Any = Occurrence of AE regardless of intensity grade or relation to vaccination.
Number of Subjects With Any Solicited General AEs	During the 15-day (Days 0-14) post-vaccination period	Assessed solicited general AEs were drowsiness, irritability/fussiness and loss of appetite. Any = Occurrence of AE regardless of intensity grade or relation to vaccination.
Percentage of Subjects With Anti-measles Virus Antibody Concentration Equal to or Above the Cut-off-value	At Day 42 post vaccination	Seroresponse was defined as post-vaccination anti-measles virus antibody concentration greater than or equal to \[≥\] 200 milli International Units per milliliter \[mIU/mL\] (Enzyme-Linked Immunosorbent Assay \[ELISA\], Enzygnost) among subjects who were seronegative (antibody concentration less than \[\<\] 150 mIU/mL) before vaccination.
Number of Subjects Reporting Any Rash	During the 43-day (Days 0-42) post-vaccination period	Any rash = Occurrence of AE regardless of intensity grade or relation to vaccination.
Number of Subjects Reporting MMR Specific Solicited General AEs	During the 43-day (Days 0-42) post-vaccination period	Assessed MMR specific solicited general AEs were parotid gland swelling and any suspected signs of meningism including febrile convulsions. Any = Occurrence of AE regardless of intensity grade or relation to vaccination.
Number of Subjects Reporting Any Unsolicited AEs	During the 43-day (Days 0-42) post-vaccination period	Unsolicited AE included any AE 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 AE regardless of intensity grade or relation to vaccination.
Number of Subjects Reporting AEs of Specific Interest	Day 0 through the end of the study (Day 180)	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.
Number of Subjects Reporting Any Serious Adverse Events (SAEs)	Day 0 through the end of the study (Day 180)	SAE included any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization or resulted in disability/incapacity. Any = Occurrence of AE regardless of intensity grade or relation to vaccination.
Number of Subjects Reporting Measles-like Illness	During Day 5 to Day 12 post-vaccination period	Measles-like illness was defined as the occurrence of the following signs/symptoms in the absence of another confirmed diagnosis: maculopapular rash (includes measles/rubella-like rash), fever (≥ 38°C) and at least one of the symptoms: cough, coryza (runny nose), conjunctivitis or diarrhea, with fever or rash. Other event must be one of cough, coryza, conjunctivitis, or diarrhea.
Number of Subjects Reporting Any Fever	During the 43-day (Days 0-42) post-vaccination period	Any fever (≥ 38°C) = Occurrence of fever regardless of intensity grade or relation to vaccination.

Countries

Estonia, Finland, Puerto Rico, Taiwan, United States

Participant flow

Recruitment details

6 subjects from 1742 were allocated subject number but no study vaccine was administered. Therefore, the number of subjects started in 1736.

Pre-assignment details

US sub-cohort: Subjects recruited in US received INV\_MMR (Priorix) or COM\_MMR (M-M-R II/M-M-R VaxPro) co-administered with Varivax, Havrix & Prevnar 13 vaccines (Day 0). Non-US sub-cohort: Subjects recruited outside the US received INV\_MMR (Priorix) or COM\_MMR (M-M-R II/M-M-R VaxPro) co-administered with Varivax & Havrix vaccines (Day 0).

Participants by arm

Arm	Count
INV_MMR Subjects received 1 dose of the study vaccine Priorix co-administered with Varivax and Havrix vaccines at Day 0. Subjects recruited in the US also received Prevnar 13 at Day 0.	1,164
COM_MMR Subjects received 1 dose of the licensed vaccine M-M-R II or M-M-R VaxPro Lot 1 or Lot 2 co-administered with Varivax and Havrix vaccines at Day 0. Subjects recruited in the US also received Prevnar 13 at Day 0.	572
Total	1,736

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	2nd blooddraw & diary card incomplete	1	0
Overall Study	Family Out Of Country Until 9/29/2015	1	0
Overall Study	Loss Of Kaiser Insurance	1	0
Overall Study	Lost to Follow-up	29	21
Overall Study	Traveling Outside The Country	1	0
Overall Study	Withdrawal by Subject	14	9

Baseline characteristics

Characteristic	COM_MMR	Total	INV_MMR
Age, Continuous	12.3 Months STANDARD_DEVIATION 0.7	12.3 Months STANDARD_DEVIATION 0.7	12.3 Months STANDARD_DEVIATION 0.7
Race/Ethnicity, Customized African Heritage / African American	38 Participants	102 Participants	64 Participants
Race/Ethnicity, Customized American Indian or Alaskan Native	16 Participants	45 Participants	29 Participants
Race/Ethnicity, Customized Asian - Central/South Asian Heritage	4 Participants	13 Participants	9 Participants
Race/Ethnicity, Customized Asian - East Asian Heritage	65 Participants	196 Participants	131 Participants
Race/Ethnicity, Customized Asian - Japanese Heritage	0 Participants	2 Participants	2 Participants
Race/Ethnicity, Customized Asian - South East Asian Heritage	12 Participants	40 Participants	28 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	2 Participants	3 Participants	1 Participants
Race/Ethnicity, Customized Other	47 Participants	136 Participants	89 Participants
Race/Ethnicity, Customized White - Arabic / North African Heritage	3 Participants	6 Participants	3 Participants
Race/Ethnicity, Customized White - Caucasian / European Heritage	385 Participants	1193 Participants	808 Participants
Sex: Female, Male Female	270 Participants	821 Participants	551 Participants
Sex: Female, Male Male	302 Participants	915 Participants	613 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 1,164	0 / 572
other Total, other adverse events	980 / 1,164	477 / 572
serious Total, serious adverse events	24 / 1,164	9 / 572

Outcome results

Primary

Number of Subjects Reporting Fever After MMR (Priorix or M-M-R II/M-M-R VaxPro [Lot 1 or Lot 2]) Vaccination

Fever was assessed for temperature equal to/above (≥) 38.0°C and above (\>) 39.0°C. The safety profile for fever was assessed based on the group difference (INV\_MMR minus COM\_MMR) in incidence of fever equal to or below the cut-off value.

Time frame: During Day 5 to Day 12 post-vaccination period

Population: Analysis was performed on Total Vaccinated cohort (TVC) which included all vaccinated subjects with administration of either Priorix or M-M-R II/M-M-R VaxPro lots documented.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
INV_MMR Group	Number of Subjects Reporting Fever After MMR (Priorix or M-M-R II/M-M-R VaxPro [Lot 1 or Lot 2]) Vaccination	> 39.0°C	47 Participants
INV_MMR Group	Number of Subjects Reporting Fever After MMR (Priorix or M-M-R II/M-M-R VaxPro [Lot 1 or Lot 2]) Vaccination	≥ 38.0°C	205 Participants
COM_MMR Group	Number of Subjects Reporting Fever After MMR (Priorix or M-M-R II/M-M-R VaxPro [Lot 1 or Lot 2]) Vaccination	> 39.0°C	17 Participants
COM_MMR Group	Number of Subjects Reporting Fever After MMR (Priorix or M-M-R II/M-M-R VaxPro [Lot 1 or Lot 2]) Vaccination	≥ 38.0°C	95 Participants

Comparison: Difference between groups (INV\_MMR Group minus COM\_MMR Group) in incidence of fever \> 39.0°C.95% CI: [-0.93, 2.89]

Comparison: Difference between groups (INV\_MMR Group minus COM\_MMR Group) in incidence of fever \> 38.0°C.95% CI: [-2.89, 4.85]

Secondary

Anti-measles Virus Antibody Concentrations

Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs) in mIU/mL. Analyses included initially seronegative subjects only.

Time frame: At Day 42 post vaccination

Population: ATP cohort for immunogenicity: included all eligible subjects with pre and post-vaccination serology results available for at least one vaccine components of measles, mumps or rubella, who did not meet any elimination criteria up to the Visit 2 blood sample and who complied with the post dose blood sample schedule.

Arm	Measure	Value (GEOMETRIC_MEAN)
INV_MMR Group	Anti-measles Virus Antibody Concentrations	2751.9 mIU/mL
COM_MMR Group	Anti-measles Virus Antibody Concentrations	3133.3 mIU/mL

Secondary

Anti-mumps Virus Antibody Concentrations

Antibody concentrations were expressed as GMCs in EU/mL. Analyses included initially seronegative subjects only.

Time frame: At Day 42 post vaccination

Population: According to Protocol (ATP) cohort for immunogenicity: included all eligible subjects with pre and post-vaccination serology results available for at least one vaccine components of measles, mumps, or rubella, who did not meet any elimination criteria up to the Visit 2 blood sample and who complied with the post dose blood sample schedule.

Arm	Measure	Value (GEOMETRIC_MEAN)
INV_MMR Group	Anti-mumps Virus Antibody Concentrations	86.0 EU/mL
COM_MMR Group	Anti-mumps Virus Antibody Concentrations	82.6 EU/mL

Secondary

Anti-rubella Virus Antibody Concentrations

Antibody concentrations were expressed as GMCs in IU/mL. Analyses included initially seronegative subjects only.

Time frame: At Day 42 post vaccination

Arm	Measure	Value (GEOMETRIC_MEAN)
INV_MMR Group	Anti-rubella Virus Antibody Concentrations	45.0 IU/mL
COM_MMR Group	Anti-rubella Virus Antibody Concentrations	66.8 IU/mL

Secondary

Number of Subjects Reporting 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.

Time frame: Day 0 through the end of the study (Day 180)