Antibody Persistence, and Safety and Tolerability of a Booster Dose of the Meningococcal B Vaccine After the Completion of the Vaccination Course in Study V72_28

Study Overview
=================
Brief Summary
-----------------
The aim of this extension study is to explore the antibody persistence 24 to 36 months after the last dose of vaccine, in infants that received a two or three dose primary series plus a booster dose at 11 months of age, of the Novartis meningococcal B vaccine (Bexsero®) in groups I to III of the parent V72_28 study. This study will also explore the antibody persistence 24 to 36 months after two catch-up doses of the Novartis meningococcal B vaccine (Bexsero®) administered in children (2 to 10 years old) in group IV of the parent V72_28 study.

Official Title
-----------------
A Phase IIIb, Open Label, Multi Center Extension Study of V72_28 to Assess Antibody Persistence, and the Safety and Tolerability of a Booster Dose After the Completion of the Vaccination Course in Study V72_28

Conditions
-----------------
Meningoccocal Disease, Meningococcal Meningitis

Intervention / Treatment
-----------------
* Biological: Bexsero® vaccine (1 dose at study month zero)
* Biological: Bexsero® vaccine (2 doses 1 month apart)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: For naïve subjects newly enrolled: Healthy infants and children according to the following age groups: Healthy subjects from 35 to 47 months of age, (only applicable to group K) (The age window is defined as the first day the subject turns 35 months of age up to the day before the subject turns 48 months of age), Healthy subjects 4 to 7 years of age (only applicable to group L) (The age window is defined as the first day the subject turns 4 years of age up to the day before the subject turns 8 years of age). Healthy subjects 8 to 12 years of age (only applicable to group M) (The age window is defined as the first day the subject turns 8 years of age up to the day before the subject turns 13 years of age). for whom a parent/legal guardian has given written informed consent after the nature of the study has been explained; for whom a parent/legal guardian confirmed availability for the visit scheduled in the study; in good health as determined by medical history, physical examination, clinical judgment of the investigator. For Subjects who participated in the V72_28 study (Follow-on Subjects): for whom a parent/legal guardian has given written informed consent after the nature of the study has been explained; for whom a parent/legal guardian confirmed availability for the visit scheduled in the study; in good health as determined by medical history, physical examination, clinical judgment of the investigator who have completed the vaccination course in the V72_28 study and have received their last vaccination 24 to 36 months before enrollment in V72_28E1 Exclusion Criteria: For naïve subjects newly enrolled: History of any serogroup B meningococcal vaccine administration; Previous known or suspected disease caused by N. meningitidis; Household contact with and/or intimate exposure to an individual with laboratory confirmed N. meningitidis infection or colonization; History of severe allergic reaction after previous vaccinations or hypersensitivity to any component of the vaccine; Pregnancy or nursing (breastfeeding) mothers; Females of childbearing age who have not used or do not plan to use acceptable birth control measures, for the duration of the study. Oral, injected or implanted hormonal contraceptive, barrier methods (condom or diaphragm with spermicide), intrauterine device, surgical sterilization, transdermal delivery, congenital sterility or sexual abstinence are considered acceptable forms of birth control. If sexually active the subject must have been using one of the accepted birth control methods at least two months prior to study entry; Known or suspected autoimmune disease or impairment/alteration of the immune system resulting from (for example): Receipt of any chronic immunosuppressive therapy Receipt of any chronic immunostimulants Immune deficiency disorder, or known HIV infection History of seizure, any progressive neurological disease or Guillain Barré Syndrome (exception: one self-limited febrile seizure is acceptable). Known bleeding diathesis or any condition that may be associated with a prolonged bleeding time. Subject's parent(s) or legal guardian(s) are not able to comprehend and to follow all required study procedures for the whole period of the study. Intent to participate in another clinical study during this study. Family members and household members of study staff; History or any illness/condition which, in the opinion of the investigator, might interfere with the evaluation of the study objectives or pose additional risk to the subjects due to participation in the study. Any significant chronic infection. Any serious chronic or progressive disease according to judgment of the investigator (e.g. neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease). For Subjects who participated in the V72_28 study (Follow-on Subjects): Exclusion criteria are the same as for naïve subjects, with the exception of criterion 1.

Ages Eligible for Study
-----------------
Minimum Age: 35 Months
Maximum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2H3H511_V<br>In the parent study V72_28 (NCT01339923), subjects received three primary doses and one booster dose of Bexsero® vaccine at 2.5, 3.5 and 5 months and at 11 months of age, respectively. The subjects in this group received a 5th dose of Bexsero® vaccine in the present study. | Biological: Bexsero® vaccine (1 dose at study month zero)<br> <br> |
| No Intervention: 2H3H511_NV<br>In the parent study V72_28 (NCT01339923), subjects received three primary doses and one booster dose of Bexsero® vaccine at 2.5, 3.5 and 5 months and at 11 months of age, respectively. These subjects were evaluated only for persistence. | |
| Experimental: 3H5_11_V<br>In the parent study V72_28 (NCT01339923), subjects received two primary doses and one booster dose of Bexsero® vaccine at 3.5 and 5 months and at 11 months of age, respectively. These subjects received a 4th dose of Bexsero® vaccine in the present study. | Biological: Bexsero® vaccine (1 dose at study month zero)<br> <br> |
| No Intervention: 3H5_11_NV<br>In the parent study V72_28 (NCT01339923), subjects received two primary doses and one booster dose of Bexsero® vaccine at 3.5 and 5 months and at 11 months of age, respectively. These subjects were evaluated only for persistence. | |
| Experimental: 68_11_V<br>In the parent study V72_28 (NCT01339923), subjects received two primary doses and one booster dose of Bexsero® vaccine at 6 and 8 months and at 11 months of age, respectively. These subjects received a 4th dose of Bexsero® vaccine in the present study. | Biological: Bexsero® vaccine (1 dose at study month zero)<br> <br> |
| No Intervention: 68_11_NV<br>In the parent study V72_28 (NCT01339923), subjects received two primary doses and one booster dose of Bexsero® vaccine at 6 and 8 months and at 11 months of age, respectively. These subjects were evaluated only for persistence. | |
| Experimental: 02_2_5_V<br>In the parent study V72_28 (NCT01339923), these subjects received two catch-up doses of Bexsero® vaccine, two months apart. These subjects received a 3rd dose of Bexsero® vaccine in the present study. | Biological: Bexsero® vaccine (1 dose at study month zero)<br> <br> |
| No Intervention: 02_2_5_NV<br>In the parent study V72_28 (NCT01339923), these subjects received two catch-up doses of Bexsero® vaccine, two months apart. These subjects were evaluated only for persistence. | |
| Experimental: 02_6_10_V<br>In the parent study V72_28 (NCT01339923), these subjects received two catch-up doses of Bexsero® vaccine, two months apart. These subjects received a 3rd dose of Bexsero® vaccine in the present study. | Biological: Bexsero® vaccine (1 dose at study month zero)<br> <br> |
| No Intervention: 02_6_10_NV<br>In the parent study V72_28 (NCT01339923), these subjects received two catch-up doses of Bexsero® vaccine, two months apart. These subjects were evaluated only for persistence. | |
| Experimental: NAIVE 123<br>Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study. | Biological: Bexsero® vaccine (2 doses 1 month apart)<br> <br> |
| Experimental: NAIVE_4A<br>Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study. | Biological: Bexsero® vaccine (2 doses 1 month apart)<br> <br> |
| Experimental: NAIVE_4B<br>Newly recruited naïve subjects who received two catch-up doses of Bexsero® vaccine, one month apart, in the present study. | Biological: Bexsero® vaccine (2 doses 1 month apart)<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Human Serum Bactericidal Activity Titers (hSBA) ≥ 4 or ≥ 5 Against Neisseria Meningitidis (N. Meningitidis) Serogroup B Strains | The antibody persistence in subjects, 24 to 36 months after completion of Bexsero® vaccination course in the parent study according to different schedules, is presented in terms of the percentage of subjects in each vaccine group, with hSBA titers ≥ 4 for what concerns the H44/76, 5/99 and NZ98/254 strains, and hSBA titers ≥ 5 for M10713 strain, alongside with the corresponding antibody responses in age-matched vaccine naïve subjects at baseline. The functional bactericidal antibodies directed against serogroup B meningococcal were assessed by the Serum Bactericidal Assay (SBA) using human serum as the source of exogenous complement (hSBA). | 24-36 months after booster dose in the parent study; baseline for vaccine-naïve subjects | 
| Percentage of Subjects With hSBA Titers ≥ 8 Against N.Meningitidis Serogroup B Strains | The antibody persistence in subjects, 24 to 36 months after completion of Bexsero® vaccination course in the parent study according to different schedules is presented in terms of the percentage of subjects in each vaccine group with hSBA titers ≥ 8, alongside with the corresponding antibody responses in age matched vaccine naïve subjects at baseline. | At 24-36 months after booster dose in the parent study: baseline for vaccine-naïve subjects | 
| The hSBA Geometric Mean Titers (GMTs) Against N.Meningitidis Serogroup B Strains | The hSBA antibody titers in subjects, 24 to 36 months after completion of Bexsero® vaccination course according to different schedules in the parent study, are presented in terms of vaccine-group-specific GMTs, alongside with the corresponding antibody responses in age-matched vaccine-naïve subjects at baseline. | 24-36 months after booster dose in the parent study; baseline for vaccine-naïve subjects | 
| The Geometric Mean Ratio (GMR) of hSBA GMTs Against N. Meningitidis Serogroup B, 24 to 36 Months Versus 1 Month After Completion of Bexsero® Vaccination Course According to Different Schedules in the Parent Study. | The within-subjects GMR of GMTs at 24 to 36 months versus 1 month after completion of Bexsero® vaccination course according to different schedules vaccination in parent study are reported. | At Day 1 in this study over one month after the completion of the vaccination course in the parent study | 
| The Geometric Mean Ratio (GMR) of hSBA GMTs Against N. Meningitidis Serogroup B, 24 to 36 Months Versus Visit 1 in the Parent Study. | The within-subjects GMR of GMTs at 24 to 36 months versus visit 1 in the vaccination course according to different schedules vaccination in the parent study are reported. | At Day 1 in this study over visit 1 in the vaccination course in the parent study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With hSBA Titers ≥4 or ≥ 5 Against N.Meningitidis Serogroup B, After Receiving Bexsero® Booster Vaccination in This Study. | The percentage of subjects with hSBA titers ≥ 4 against H44/76, 5/99 and NZ98/254 strains, and with hSBA titers ≥ 5 against M10713 strain, after receiving Bexsero® booster vaccination in this study (24 to 36 months after completion of vaccination course according to different schedules in parent study), alongside the corresponding response after the first dose of Bexsero® vaccine in age matched vaccine-naïve subjects. | At 24-36 months (Visit 1) and one month after booster vaccination (Day 31) | 
| Percentage of Subjects With hSBA Titers ≥ 8 Against N.Meningitidis serogroupB, After Receiving Bexsero® Booster Vaccination in This Study. | The percentage of subjects with hSBA titers ≥ 8, after receiving Bexsero® booster vaccination in this study (24 to 36 months after completion of vaccination course according to different schedules in parent study) alongside the corresponding response after the first dose of Bexsero® vaccine in age matched vaccine-naïve subjects. | At 24-36 months (Visit 1) and one month after booster vaccination (Day 31) | 
| Percentage of Subjects With Four-fold Rise in hSBA Titers, After Receiving Bexsero® Vaccination in This Study. | The percentage of subjects with a four-fold rise in hSBA titers 1 month after receiving Bexsero® booster vaccination in this study to pre vaccination at visit 1 (24 to 36 months after completion of vaccination course according to different schedules in parent study) alongside the corresponding response after the first dose of Bexsero® vaccine in age matched vaccine-naïve subjects. | One month after booster vaccination (day 31)/24-36 months (Visit 1) | 
| Percentage of Subjects With Four-fold Rise in hSBA Titers, One Month After Receiving Bexsero® Vaccination in This Study | The percentage of subjects with a four-fold rise in hSBA titers one month after receiving Bexsero® booster vaccination (visit 2) in this study to post primary visit in the parent study V72_28(1 month after last vaccination in the parent study) alongside the corresponding response after the first dose of Bexsero® vaccine in age matched vaccine-naïve subjects. | From post primary visit in the parent study to visit 2 in this extension study | 
| Percentage of Subjects With Four-fold Rise in hSBA Titers, One Month After Receiving Bexsero® Vaccination in This Study. | The percentage of subjects with a four-fold rise in hSBA titers one month after receiving Bexsero® booster vaccination in this study to pre primary visit in parent study V72_28 (Visit 1). This outcome measure was analysed only for subjects belonging to groups 02_2_5_V and 02_6_10_V | From pre primary visit in the parent study (Visit 1) to visit 2 in this extension study | 
| The GMTs Against N.Meningitidis Serogroup B, One Month After Receiving Bexsero® Booster Vaccination in the Present Study. | The hSBA antibody titers in subjects after receiving Bexsero® booster vaccination in this study (24 to 36 months after completion of vaccination course according to different schedules in parent study) alongside the corresponding response after the 1st dose of Bexsero® vaccine in age matched vaccine-naïve subjects in terms of GMTs. | At Visit 1 and one month post booster vaccination (Day 31) | 
| The Geometric Mean Ratio (GMR) of hSBA Titers, One Month After Receiving Bexsero® Booster Vaccination in the Present Study. | The within-subjects GMR of hSBA antibody titers (one month post booster vaccination versus pre vaccination) after Bexsero® booster vaccination in this study (24 to 36 months after completion of vaccination course according to different schedules in parent study) alongside the within-subject GMR for the 1st dose of rMenB+OMV NZ vaccination of age matched naïve subjects. | At Day 31 versus Day 1 | 
| The Geometric Mean Ratio (GMR) of hSBA Titers, One Month After Receiving Bexsero® Booster Vaccination in the Present Study. | The within-subjects GMR of hSBA antibody titers (one month post booster vaccination in this study versus 1 month post last vaccination visit (post-primary vaccination visit) in parent study V72_28. | Visit 2 (day 31 in extension study) versus post primary vaccination visit in parent study | 
| Percentage of Subjects With hSBA Titers ≥ 4 or ≥ 5, After Receiving Two Catch up Doses of Bexsero® Vaccination | The percentage of vaccine-naïve subjects with hSBA titers ≥ 4 against H44/76, 5/99 and NZ98/254 strains, and ≥ 5 against M10713 strain, one month after receiving two catch up doses of Bexsero® booster vaccination in this study. | At Baseline and One month post second vaccination (Day 61) | 
| Percentage of Subjects With hSBA Titers ≥ 8 , After Receiving Two Catch up Doses of Bexsero® Vaccination. | The percentage of vaccine-naïve subjects with hSBA titers ≥8, one month after receiving two catch up doses of Bexsero® booster vaccination in this study are reported. | At Baseline and One month post second vaccination (Day 61) | 
| Percentage of Subjects With Four-fold Rise in hSBA Titers, After Receiving Two Catch up Doses of Bexsero® Vaccination. | The percentage of vaccine-naïve subjects with a four-fold rise in hSBA titers from baseline, one month after receiving two catch up doses of Bexsero® booster vaccination in comparison to prevaccination in this study are reported. | One month post second vaccination (Day 61) | 
| The GMTs in Subjects Who Received Two Catch up Doses of Bexsero® Vaccination. | The hSBA antibody titers in vaccine-naïve subjects , after receiving two catch up doses of Bexsero® vaccination in this study, are reported in terms of GMTs. | At Baseline and One month post second vaccination (Day 61) | 
| The GMRs of hSBA Titers After Two Catch up Doses of Bexsero® Vaccination Versus hSBA Titers at Baseline. | The within-subject GMRs of hSBA titers at one month after receiving the second catch up dose to hSBA titers at baseline, for naïve subjects who received two catch up doses of Bexsero® vaccination in this study are reported. | At one month after receiving second vaccination (Day 61) versus baseline (Day 1) | 
| Number of Subjects (35 Months to 7 Years of Age) Reporting Solicited Local and Systemic Adverse Events After Receiving Bexsero® Booster Vaccine. | The number of subjects (35 months to 7 years of age) with solicited local and systemic adverse events after receiving Bexsero® booster vaccine in the present study. | From day 1 (6 hr) through day 7 after vaccination | 
| Number of Newly Recruited Subjects (Aged 35 Months to 7 Years) Reporting Solicited Local and Systemic Adverse Events After Receiving Catch-up Doses of Bexsero® Vaccine. | The number of newly recruited subjects (aged 35 months to 7 years) reporting solicited local and systemic adverse events after receiving two catch-up doses of Bexsero® vaccine in the present study. | From day 1 (6 hr) through day 7 after vaccination | 
| Number of Subjects (8 to 12 Years of Age) Reporting Solicited Local and Systemic Adverse Events After Receiving Bexsero® Booster Vaccine. | Number of subjects (8 to 12 years of age) reporting solicited local and systemic adverse events after receiving Bexsero® booster vaccine. | From day 1 (6 hr) through day 7 after vaccination | 
| Number of Newly Recruited naïve Subjects (Aged 8 to 12 Years of Age) Solicited Local and Systemic Adverse Events After Receiving Bexsero® Vaccine. | The number newly recruited naïve subjects (aged 8 to12 years of age) reporting solicited local and systemic adverse events after receiving two catch-up doses of Bexsero® vaccine in the present study. | From day 1(6 hr) through day 7 after vaccination | 
| Number of Subjects Reporting Unsolicited Adverse Events After Receiving Bexsero® Vaccination. | The number of subjects reporting unsolicited adverse events after receiving Bexsero® booster vaccination (24 to 36 months after completion of vaccination course according to different schedules in parent study) or two cach up schedule of Bexsero® vaccine is reported. | From day 1 through day 7 after any vaccination | 
| Number of Subjects Reporting Unsolicited Serious Adverse Events (SAEs), Medically Attended AEs and AEs Leading to Withdrawal for Entire Study Period. | The number of subjects reporting unsolicited SAEs, medically attended AEs and AEs leading to withdrawal after receiving Bexsero® booster vaccination (24 to 36 months after completion of vaccination course according to different schedules in the parent study) or two catch-up schedule of Bexsero® vaccine is reported. | Throughout the entire study period (up to 2 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Meningococcal B disease,, Antibody persistence