Study to Assess the Safety and Immunogenicity of GSK Meningococcal Group B Vaccine When Administered Concomitantly With GSK Meningococcal MenACWY Conjugate Vaccine in Healthy Subjects of 16-18 Years of Age

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the immunogenicity, safety and tolerability of rMenB+OMV NZ and MenACWY vaccines when concomitantly administered to healthy subjects 16-18 years of age.

Detailed Description
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As per the recommendation from Center for Biologics Evaluation and Research (CBER) the study has been amended to include a new agar-overlay serum bactericidal assay using human serum complement (hSBA). Additional changes include validation of the MenB manual to measure immunogenicity of the meningococcal group B vaccine, a modification in the definition of 4-fold increase in post-vaccination hSBA titer definition when the pre-vaccination titer is below the limit of detection, and a modification in the population set to be used for safety analysis wherein the exposed set is to be used for all safety analyses.

Official Title
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A Phase IIIB, Randomized, Observer-blind, Multicenter Study to Assess the Safety and Immunogenicity of GSK's Meningococcal Group B Vaccine When Administered Concomitantly With GSK's Meningococcal MenACWY Conjugate Vaccine to Healthy Subjects of 16-18 Years of Age

Conditions
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Infections, Meningococcal

Intervention / Treatment
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* Combination Product: Meningococcal Group B Vaccine (GSK3536829A) (rMenB+OMV NZ)
* Biological: Meningococcal MenACWY Conjugate Vaccine (GSK3536820A) (MenA lyo + MenCWY liquid)
* Combination Product: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol or/and 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. Previous vaccination with 1 dose of quadrivalent meningococcal conjugate vaccine (MenACWY, Menveo or Menactra) at least 4 years prior to informed consent and assent as applicable. Written or /witnessed/thumb printed informed consent obtained from the subject/parent(s)/LAR(s) of the subject prior to performance of any study specific procedure. Written informed assent obtained from the subject (if applicable) along with informed consent from the subject's parent(s)/LAR(s) prior to performing any study specific procedure. A male or female between, and including, 16 and 18 years of age at the time of the first vaccination. Healthy subjects as established by medical history and clinical examination before entering into the study. Female subjects of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current bilateral tubal ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause. Female subjects of childbearing potential may be enrolled in the study, if the subject: has practiced adequate contraception for 30 days prior to vaccination, and has a negative pregnancy test on the day of vaccination, and has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series. Exclusion Criteria: Medical conditions Progressive, unstable or uncontrolled clinical conditions. Clinical conditions representing a contraindication to intramuscular vaccination and blood draws. Abnormal function of the immune system resulting from: Clinical conditions. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 consecutive days within 90 days prior to study vaccination. This will mean prednisone ≥ 20 mg/day (for adult subjects) or ≥ 0.5 mg/kg/day or 20 mg/day whichever is the maximum dose for paediatric subjects, or equivalent. Inhaled and topical steroids are allowed. Administration of antineoplastic or immunomodulating agents or radiotherapy within 90 days prior to informed consent. Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the subject due to participation in the study. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines. History of any reaction or hypersensitivity likely to be exacerbated by any medicinal products or medical equipment whose use is foreseen in this study. Current or previous, confirmed or suspected disease caused by N. meningitidis. Known contact to an individual with any laboratory-confirmed N. meningitidis infection within 60 days, prior to enrolment. History of neuroinflammatory or autoimmune condition. Recurrent history or un-controlled neurological disorders or seizures. Prior/Concomitant therapy Use of any investigational or non-registered product other than the study vaccine(s) during the period starting 30 days before the informed consent or planned use during the study period. Administration of immunoglobulins and/or any blood products or plasma derivatives during the period starting 180 days before the informed consent or planned administration during the study period. Previous vaccination with any group B meningococcal vaccine at any time prior to informed consent and assent as applicable. Previous vaccination with 2 doses of quadrivalent meningococcal conjugate vaccine (MenACWY, Menveo, Menactra or MenQuadfi). Prior/Concurrent clinical study experience • Subject 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 vaccine/product, will not be enrolled. Other exclusions Child in care. Pregnant or lactating female. Female planning to become pregnant or planning to discontinue contraceptive precautions. Any study personnel or immediate dependents, family, or household member.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 18 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: MenB+MenACWY Group<br>Subjects will receive 1 dose rMenB+OMV NZ given concomitantly with MenACWY at Day 1, 1 dose of rMenB+OMV NZ at Day 61 and 1 dose of placebo at Day 91. | Combination Product: Meningococcal Group B Vaccine (GSK3536829A) (rMenB+OMV NZ)<br>* rMenB+OMV will be administered intramuscularly as 1 dose each at day 1 and 61 to subjects in MenB+MenACWY group and MenB group and as 1 dose at day 91 to subjects in MenACWY group, to the deltoid region of the non-dominant arm.<br>* Other names: Bexsero;Biological: Meningococcal MenACWY Conjugate Vaccine (GSK3536820A) (MenA lyo + MenCWY liquid)<br>* MenACWY will be administered intramuscularly as 1 dose at day 1 to subjects in MenB+MenACWY group, 1 dose at day 91 for MenB group and as 1 dose at day 1 to subjects in MenACWY group, to the deltoid region of the non-dominant arm.<br>* Other names: Menveo;Combination Product: Placebo<br>* Placebo will be administered intramuscularly as 1 dose at day 91 to subjects in MenB+MenACWY group, 1 dose at day 1 to subjects in MenB group and MenACWY group, to the deltoid region of the non-dominant arm.<br>* Other names: NaCl, saline solution;|
| Experimental: MenB Group<br>Subjects will receive 1 dose of rMenB+OMV NZ and placebo concomitantly at Day 1, 1 dose of rMenB+OMV NZ at Day 61 and 1 dose of MenACWY at Day 91. | Combination Product: Meningococcal Group B Vaccine (GSK3536829A) (rMenB+OMV NZ)<br>* rMenB+OMV will be administered intramuscularly as 1 dose each at day 1 and 61 to subjects in MenB+MenACWY group and MenB group and as 1 dose at day 91 to subjects in MenACWY group, to the deltoid region of the non-dominant arm.<br>* Other names: Bexsero;Biological: Meningococcal MenACWY Conjugate Vaccine (GSK3536820A) (MenA lyo + MenCWY liquid)<br>* MenACWY will be administered intramuscularly as 1 dose at day 1 to subjects in MenB+MenACWY group, 1 dose at day 91 for MenB group and as 1 dose at day 1 to subjects in MenACWY group, to the deltoid region of the non-dominant arm.<br>* Other names: Menveo;Combination Product: Placebo<br>* Placebo will be administered intramuscularly as 1 dose at day 91 to subjects in MenB+MenACWY group, 1 dose at day 1 to subjects in MenB group and MenACWY group, to the deltoid region of the non-dominant arm.<br>* Other names: NaCl, saline solution;|
| Experimental: MenACWY Group<br>Subjects will receive 1 dose of MenACWY and placebo concomitantly at Day 1, 1 dose of rMenB+OMV NZ each at Day 61 and at Day 91. | Combination Product: Meningococcal Group B Vaccine (GSK3536829A) (rMenB+OMV NZ)<br>* rMenB+OMV will be administered intramuscularly as 1 dose each at day 1 and 61 to subjects in MenB+MenACWY group and MenB group and as 1 dose at day 91 to subjects in MenACWY group, to the deltoid region of the non-dominant arm.<br>* Other names: Bexsero;Biological: Meningococcal MenACWY Conjugate Vaccine (GSK3536820A) (MenA lyo + MenCWY liquid)<br>* MenACWY will be administered intramuscularly as 1 dose at day 1 to subjects in MenB+MenACWY group, 1 dose at day 91 for MenB group and as 1 dose at day 1 to subjects in MenACWY group, to the deltoid region of the non-dominant arm.<br>* Other names: Menveo;Combination Product: Placebo<br>* Placebo will be administered intramuscularly as 1 dose at day 91 to subjects in MenB+MenACWY group, 1 dose at day 1 to subjects in MenB group and MenACWY group, to the deltoid region of the non-dominant arm.<br>* Other names: NaCl, saline solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects with solicited local adverse events (AEs) | An adverse event is 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. Solicited local adverse events assessed are injection site pain, erythema, swelling, induration. Any erythema, swelling and swelling is defined as a symptom with a surface diameter equal or greater than 25 millimeters. | During the 7 days (including day of vaccination) after each vaccination (Administered on day 1, day 61 and day 91) | 
| Percentage of subjects with solicited systemic adverse events | Solicited systemic adverse events assessed are (i.e., fever [temperature ≥ 38.0°C/100.4°F], nausea, fatigue, myalgia, arthralgia, headache). | During the 7 days (including day of vaccination)after each vaccination (Administered on day 1, day 61 and day 91) | 
| Percentage of subjects with any unsolicited adverse events, Serious Adverse Events (SAEs), AEs leading to withdrawal and medically attended AEs | Unsolicited adverse events are defined as any AE 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 are reported as an unsolicited adverse event. Any solicited AE that has not resolved within 30 days post vaccination and is reported during clinic visits or safety follow-up calls is entered into the subject's electronic Case Report Form (eCRF) as an unsolicited AE. SAEs are any untoward medical occurrence that result in death, are life-threatening, require hospitalization or prolongation of existing hospitalization, result in disability/incapacity and is a congenital anomaly/birth defect in the offspring of a study subject Medically attended AEs are symptoms or illnesses requiring hospitalization, or emergency room visit, or visit to/by a health care provider. | During the 30 days (including day of vaccination) after each vaccination (Administered at Day 1, Day 61 and Day 91) | 
| Percentage of subjects with any SAEs, AEs leading to withdrawal and medically attended AEs. | Serious adverse events, AEs leading to withdrawal and medically attended AEs throughout the study period are assessed. | Throughout the study period (Day 1 to Day 271) | 
| Percentage of subjects with adverse events of special interest (AESI) | AESIs are predefined (serious or non-serious) adverse events of scientific and medical concern specific to the product or program, for which ongoing monitoring and rapid communication by the investigator to the sponsor can be appropriate, because such an event might warrant further investigation in order to characterize and understand it. | Throughout the study period (Day 1- Day 271) | 
| Percentage of subjects with any SAEs, AEs leading to withdrawal | SAEs are any untoward medical occurrence that result in death, are life-threatening, require hospitalization or prolongation of existing hospitalization, result in disability/incapacity and is a congenital anomaly/birth defect in the offspring of a study subject. | During safety follow-up (Day 271 to Day 451) | 
| Percentage of subjects with AESI | AESIs are predefined (serious or non-serious) adverse events of scientific and medical concern specific to the product or program, for which ongoing monitoring and rapid communication by the investigator to the sponsor can be appropriate, because such an event might warrant further investigation in order to characterize and understand it. | During safety follow-up (Day 271 to Day 451) | 
| Human Serum Bactericidal Assay Geometric Mean Titers (GMTs) against each of the N. meningitidis serogroup B strains after the second vaccination with rMenB+OMV NZ | Immune responses to rMenB+OMV NZ given with or without MenACWY, as measured by serum bactericidal assay using human complement (hSBA), are expressed as Geometric Mean Titers (GMTs) against N. meningitidis serogroup B indicator strains (M14459, 96217, NZ98/254 and M07-0241084). | At 1 month after the second vaccination with rMenB+OMV NZ in MenB+MenACWY and MenB groups (i.e. at Day 91). | 
| hSBA GMTs against each of the N. meningitidis serogroups A, C, W and Y after vaccination with MenACWY | Immune responses to MenACWY given with or without rMenB+OMV NZ, as measured by serum bactericidal assay using human complement (hSBA) are expressed as Geometric Mean Titers (GMTs) against each of the 4 serogroups A, C, W and Y | At 1 month after the vaccination with MenACWY in MenACWY and MenB+MenACWY groups (i.e. at Day 31). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| hSBA Geometric Mean Concentrations (GMCs) measured by ELISA against each of the N. meningitidis serogroups after MenACWY vaccination. | Immune response to MenACWY given with or without rMenB+OMV NZ, as measured by Enzyme-Linked Immunosorbent Assay (ELISA) GMCs against each of the serogroups A, C, W and Y. | At 1 month after the vaccination of MenACWY in MenACWY and MenB+MenACWY groups (i.e. at Day 31). | 
| hSBA GMTs against each of the serogroup B strains in both MenB+MenACWY and MenB Groups after first rMenB+OMV NZ vaccination. | Immune response to rMenB+OMV NZ given with or without MenACWY, as measured by bactericidal activity against N. meningitidis serogroup B indicator strains (M14459, 96217, NZ98/254 and M07-0241084) and expressed in GMTs. | At 1 month after first vaccination with rMenB+OMV NZ (i.e. at Day 31). | 
| Geometric mean ratios (GMRs) against each of the N. meningitidis serogroup B strains in both MenB+MenACWY and MenB Groups after the first rMenB+OMV NZ dose. | Immune response to rMenB+OMV NZ given with or without MenACWY as measured by bactericidal activity against N. meningitidis serogroup B indicator strains (M14459, 96217, NZ98/254 and M07-0241084) in terms of GMRs at one month after the first rMenB+OMV NZ vaccination compared to the baseline at Day 1/Month 0. | At 1 month after first rMenB+OMV NZ vaccination (i.e.at Day 31) compared to the baseline (Day 1). | 
| Geometric mean ratios (GMRs) against each of the N. meningitidis serogroup B strains in both MenB+MenACWY and MenB Groups after the second rMenB+OMV NZ dose | Immune response to rMenB+OMV NZ given with or without MenACWY, as measured by bactericidal activity against N. meningitidis serogroup B indicator strains (M14459, 96217, NZ98/254 and M07-0241084) in terms of GMRs at one month after the second rMenB+OMV NZ vaccination compared to the baseline at Day 1/Month 0. | At 1 month after the second rMenB+OMV NZ vaccination (i.e. at Day 91) compared to the baseline (Day 1) | 
| Percentage of subjects with hSBA titers ≥ lower limit of quantitation (LLOQ) for each of the serogroup B test strains in both MenB+MenACWY and MenB Groups after the first rMenB+OMV NZ dose. | The immune response to rMenB+OMV NZ vaccine is evaluated by measuring bactericidal activity in terms of subjects with hSBA titers ≥ LLOQ against N. meningitidis serogroup B test strains | At one month after the first rMenB+OMV NZ vaccination (i.e. Day 31). | 
| Percentage of subjects with hSBA titers ≥ lower limit of quantitation (LLOQ) for each of the serogroup B test strains in both MenB+MenACWY and MenB Groups after the second rMenB+OMV NZ dose. | The immune response to rMenB+OMV NZ vaccine is evaluated by measuring bactericidal activity in terms of subjects with hSBA titers ≥ LLOQ against N. meningitidis serogroup B test strains. | At 1 month after the second rMenB+OMV NZ vaccination (i.e. at Day 91). | 
| Percentage of subjects with 4-fold increase in hSBA titers relative to baseline in both MenB+MenACWY and MenB Groups after the first rMenB+OMV NZ dose | The immune response to rMenB+OMV NZ vaccine is evaluated by measuring bactericidal activity against each of N. meningitidis serogroup B test strains in terms of the Four-fold increase defined as: - For a pre-vaccination titer < limit of detection (LOD), a post-vaccination titer of ≥ 4-fold the LOD or ≥ LLOQ, whichever is greater, - For a pre-vaccination titer ≥LOD but <LLOQ, a post vaccination titer of at least 4-fold the LLOQ, - For a pre-vaccination titer ≥ LLOQ, a post vaccination titer of at least 4-fold the pre-vaccination titer | At 1 month after the first rMenB+OMV NZ vaccination (i.e at Day 31) relative to baseline (i.e. Day 1). | 
| Percentage of subjects with 4-fold increase in hSBA titers relative to baseline in both MenB+MenACWY and MenB Groups after the second rMenB+OMV NZ dose | The immune response to rMenB+OMV NZ vaccine is evaluated by measuring bactericidal activity against each of the N. meningitidis serogroup B test strains in terms of the Four-fold increase defined as: - For a pre-vaccination titer < limit of detection (LOD), a post-vaccination titer of ≥ 4-fold the LOD or ≥ LLOQ, whichever is greater, - For a pre-vaccination titer ≥LOD but <LLOQ, a post vaccination titer of at least 4-fold the LLOQ, - For a pre-vaccination titer ≥ LLOQ, a post vaccination titer of at least 4-fold the pre-vaccination titer. | At 1 month after the second rMenB+OMV vaccination (i.e at Day 91) relative to baseline (i.e. Day 1). | 
| Percentage of subjects with hSBA titers ≥ lower limit of quantitation (LLOQ) for each of the serogroup A, C, W and Y in both MenB+MenACWY and MenACWY Groups after MenACWY vaccination | The immune response to MenACWY vaccines is expressed in terms of percentage of subjects with hSBA titers ≥ lower limit of quantitation (LLOQ) for each of the serogroup A, C, W and Y | At one month after the MenACWY vaccination (i.e. Day 31). | 
| Geometric mean ratios (GMRs) against each of the N. meningitidis serogroup A, C, W and Y in both MenB+MenACWY and MenACWY Groups after MenACWY vaccination. | Immune response to MenACWY given with or without rMenB+OMV NZ as measured by bactericidal activity against the four serogroups A, C, W and Y in terms of GMRs at one month after MenACWY vaccination compared to the baseline at Day 1/Month 0. | At 1 month after MenACWY vaccination (i.e.at Day 31) compared to the baseline (Day 1). | 
| Percentage of subjects with 4-fold increase in hSBA titers relative to baseline in both MenB+MenACWY and MenACWY Groups after MenACWY vaccination | The immune response to MenACWY vaccine is evaluated by measuring for the four serogroups A, C, W and Y, the Four-fold increase defined as: - For a pre-vaccination titer < limit of detection (LOD), a post-vaccination titer of ≥ 4-fold the LOD or ≥ LLOQ, whichever is greater, - For a pre-vaccination titer ≥LOD but <LLOQ, a post vaccination titer of at least 4-fold the LLOQ, - For a pre-vaccination titer ≥ LLOQ, a post vaccination titer of at least 4-fold the pre-vaccination titer | At 1 month after MenACWY vaccination (i.e at Day 31) relative to baseline (i.e. Day 1). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Meningitis, Invasive meningococcal disease, Bexsero, Menveo