Evaluation of Immunogenicity and Safety of a Booster Dose of Infanrix Hexa™ in Healthy Infants Born to Mothers Vaccinated With Boostrix™ During Pregnancy or Immediately Post-delivery

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the immunogenicity and safety of the Infanrix hexa booster dose given at 11-18 months of age to infants who received primary vaccination at 6-14 weeks. All infants in this booster study were born to pregnant women who participated in the study 116945 [DTPA (BOOSTRIX)-047] and having received the full primary vaccination series as per protocol requirement in study 201330 [DTPA (BOOSTRIX)-048.

Official Title
-----------------
Immunogenicity and Safety Study of a Booster Dose of GSK Biologicals' Infanrix Hexa™ (217744) in Healthy Infants Born to Mothers Vaccinated With Boostrix™ During Pregnancy or Immediately Post-delivery

Conditions
-----------------
Diphtheria, Hepatitis B, Acellular Pertussis, Haemophilus Influenzae Type b, Tetanus, Poliomyelitis, Diphtheria-Tetanus-aPertussis-Hepatitis B-Poliomyelitis-Haemophilus Influenzae Type b Vaccines

Intervention / Treatment
-----------------
* Biological: Infanrix hexa


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects' parent(s)/Legally acceptable representatives (LAR(s)) who, in the opinion of the investigator, can and will comply, with the requirements of the protocol (e.g. completion of the diary cards, return for follow-up visits). Written informed consent obtained from the parent(s)/LAR(s) of the subject prior to performing any study specific procedure. A male or female child 9 months of age at the time of enrolment. Healthy subjects as established by medical history and clinical examination before entering into the study. Subjects born to mothers who were vaccinated in 116945 [DTPA (BOOSTRIX)-047] study and having completed their primary vaccination series as per protocol requirement in study 201330 [DTPA (BOOSTRIX)-048 PRI]. Exclusion Criteria: Child in care Concurrently participating in another clinical study, within three months prior to the booster vaccine dose and at any time during the present booster study, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product (pharmaceutical product or device). Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period within six months prior to the booster vaccine dose. For corticosteroids, this will mean prednisone ≥0.5mg/kg/day, or equivalent. Inhaled and topical steroids are allowed. Administration of long-acting immune-modifying drugs at any time during the study period (e.g. infliximab). A vaccine not foreseen by the study protocol administered during the period starting from 30 days before the booster dose of study vaccine and ending 30 days after*, with the exception of inactivated influenza vaccine and other vaccines given as a part of the national/regional immunization schedule, that are allowed at any time during the study period. In case an emergency mass vaccination for an unforeseen public health threat (e.g.: a pandemic) is organised by the public health authorities, outside the routine immunization program, the time period described above can be reduced if necessary for that vaccine provided it is licensed and used according to its SPC or Product Information (PI) and according to the local governmental recommendations and provided a written approval of the Sponsor is obtained. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required). Major congenital defects. Serious chronic illness. Administration of immunoglobulins and/or any blood products during the period within three months before the booster dose of study vaccines or planned administration during the study period. Encephalopathy defined as an acute, severe central nervous system disorder occurring within 7 days following vaccination with Infanrix hexa and generally consisting of major alterations in consciousness, unresponsiveness, generalised or focal seizures that persist more than a few hours, with failure to recover within 24 hours. History of Hib, diphtheria, tetanus, pertussis, pneumococcal, poliovirus and hepatitis B diseases since the conclusion visit of study 201330 [DTPA (BOOSTRIX)-048 PRI]. Previous booster vaccination against Hib, diphtheria, tetanus, pertussis, pneumococcus, hepatitis B and/or poliovirus since the conclusion visit of study 201330 [DTPA (BOOSTRIX)-048 PRI]. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines (e.g: antigen, excipients). Hypersensitivity to latex. History of any neurological disorders or seizures. Any condition that in the judgment of the investigator would make intramuscular injection unsafe. Acute disease and/or fever at the time of vaccination. Fever is defined as temperature ≥ 37.5°C /99.5°F for oral, axillary or tympanic route, or ≥ 38.0°C /100.4°F on rectal route. Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may be enrolled at the discretion of the investigator.

Ages Eligible for Study
-----------------
Minimum Age: 9 Months
Maximum Age: 19 Months

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dTpa Group<br>This group will consist of healthy male or female infants, aged 9 months at the time of enrollment, born to mothers who received a single dose of Boostrix during pregnancy and a dose of placebo immediately post-delivery. All enrolled subjects in this group who will come back for subsequent visit will receive a booster dose of Infanrix hexa co-administered with Prevenar 13 according to the routine national/local immunization or study procedure | Biological: Infanrix hexa<br>* All subjects will receive Infanrix hexa co-administered with Prevenar13 as a booster dose.<br>|
| Active Comparator: Control Group<br>This group will consist of healthy male or female infants, aged 9 months at the time of enrollment, born to mothers who received a dose of placebo during pregnancy and single dose of Boostrix immediately post-delivery. All enrolled subjects in this group who will come back for subsequent visit will receive a booster dose of Infanrix hexa co-administered with Prevenar 13 according to the routine national/local immunization or study procedure | Biological: Infanrix hexa<br>* All subjects will receive Infanrix hexa co-administered with Prevenar13 as a booster dose.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Seroprotected Subjects Against Anti-diphtheria (Anti-D), Anti-tetanus (Anti-T), Anti-hepatitis B (Anti-HBs), Anti-poliovirus Type 1, Anti-poliovirus Type 2, Anti-poliovirus Type 3 and Anti-polyribosyl-ribitol Phosphate (Anti-PRP) | Seroprotected subjects were defined as subjects with antibody concentrations/titres above or equal (≥) the assay cut-offs that are accepted immunological correlates of protection. 0.1 International units per milliliter (IU/ml) for anti-D and anti-T, 10 milli-International units per milliliter (mIU/mL) for anti-HB's, 8 Effective Dose 50 (ED50) for anti-polio virus (type 1,2,3) and 0.15 microgram/milliliter (µg/mL) for anti-PRP were considered as immunological correlates of protection. | At one month after the booster dose (Day 30) | 
| Number of Subjects With a Booster Response to Pertussis Antigens (Pertussis Toxoid (PT), Filamentous Haemagglutinin (FHA) and Pertactin (PRN)) | Booster response to PT, FHA and PRN antigens was defined as: for subjects with pre-vaccination antibody concentration below the assay cut-off, post-vaccination antibody concentration ≥ 4 times the assay cut-off, for subjects with pre-vaccination antibody concentration between the assay cut-off and below 4 times the assay cut-off, post-vaccination antibody concentration ≥ 4 times the pre-vaccination antibody concentration, and for subjects with pre-vaccination antibody concentration ≥ 4 times the assay cut-off, post-vaccination antibody concentration ≥ 2 times the pre-vaccination antibody concentration Seronegative (S-) subjects are those who have antibody concentration less than (<) assay cut-off. Seropositive (S+) subjects are those who have antibody concentration ≥ assay cut-off prior to vaccination. Assay cut-off was 2.693 IU/mL for anti-PT, 2.046 IU/mL for anti- FHA and 2.187 IU/mL for anti-PRN | At one month after the booster dose (Day 30) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Seroprotected Subjects Against Anti-diphtheria, Anti-tetanus, Anti-poliovirus Type 1, Anti-poliovirus Type 2, Anti-poliovirus Type 3, Anti-HBs and Anti-PRP. | Seroprotected subjects were defined as subjects with antibody concentrations/titers above or equal (≥) the assay cut-offs that are accepted immunological correlates of protection. 0.1 IU/mL for anti-D and anti-T, 10 mIU/mL for anti-HB's, 8 ED50 for anti-polio virus (type 1,2,3) and 0.15 µg/mL for anti-PRP were considered as immunological correlates of protection. | Before the booster dose (Day 0) | 
| Number of Seropositive Subjects for Anti-PT, Anti-FHA and Anti-PRN | Seropositive subjects were defined as subjects whose antibody concentration/titre was greater than or equal to the assay cut-off. Assay cut-off was 2.693 IU/mL for anti-PT, 2.046 IU/mL for anti-FHA and 2.187 IU/mL for anti-PRN | Before the booster dose (Day 0) | 
| Number of Seropositive Subjects for Anti-pneumococcal Serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) | Seropositive subjects were defined as subjects whose antibody concentration/titre was greater than or equal to the assay cut-off. Assay cut-off's for anti-pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) are 0.080 µg/mL, 0.075 µg/mL, 0.061 µg/mL, 0.198 µg/mL, 0.111 µg/mL, 0.102 µg/mL, 0.063 µg/mL, 0.66 µg/mL, 0.160 µg/mL, 0.111 µg/mL, 0.199 µg/mL, 0.163 µg/mL, 0.073 µg/mL respectively. | Before the booster dose (Day 0) | 
| Anti-D, Anti-T, Anti-PT, Anti-FHA, Anti-PRN Antibody Concentrations | Antibody concentrations are presented as Geometric Mean Concentrations (GMCs) and expressed in IU/mL. | Before the booster dose (Day 0) and One month after the booster dose (Day 30) | 
| Anti-poliovirus Type 1, 2, 3 Antibody Titres | Anti-Poliovirus type 1, 2 and 3 antibody titers were expressed as Geometric Mean Titers (GMT). | Before the booster dose (Day 0) and One month after the booster dose (Day 30) | 
| Anti-HBs Antibody Concentrations | Antibody concentrations are presented as Geometric Mean Concentrations (GMCs) and expressed in mIU/mL. | Before the booster dose (Day 0) and One month after the booster dose (Day 30) | 
| Anti-pneumococcal Serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) and Anti-PRP Antibody Concentrations | Antibody concentrations are presented as Geometric Mean Concentrations (GMCs) and expressed in µg/mL. | Before the booster dose (Day 0) and One month after the booster dose (Day 30) | 
| Number of Seropositive Subjects for Anti-PT, Anti-FHA and Anti-PRN. | Seropositive subjects were defined as subjects whose antibody concentration/titre was greater than or equal to the assay cut-off. Assay cut-off was 2.693 IU/mL for anti-PT, 2.046 IU/mL for anti- FHA and 2.187 IU/mL for anti-PRN | At one month after the booster dose (Day 30) | 
| Number of Subjects With Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness, swelling. Any redness, swelling is defined as a symptom with a surface diameter greater than 0 millimeter | During the 4-day (Day 0-Day 3) follow-up period after booster vaccination of two vaccines (Infanrix hexa and Prevenar 13) | 
| Number of Subjects With Solicited General Symptoms | Assessed solicited general symptoms were Drowsiness, Fever, Irritability/Fussiness and Loss of appetite. Fever was defined as temperature ≥37.5 degree Celsius (°C) /99.5 degree Fahrenheit (°F) for oral, axillary or tympanic route, or ≥38.0°C/100.4°F on rectal route. | During the 4-day (Day 0-Day 3) follow-up period after booster vaccination | 
| Number of Subjects With Unsolicited Adverse Events (AEs) | An AE was 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. | During the 31-day (Day 0-Day 30) follow-up period after booster vaccination | 
| Number of Subjects With Serious Adverse Events (SAEs) | SAE is any untoward medical occurrence that results in death, is life threatening, requires hospitalisation or prolongation of existing hospitalisation, resulting in disability/incapacity | From booster dose up to study end (approximately 6 or 7 months, per subject) | 
| Number of Subjects With an ASQ-3 Score (Ages & Stages Questionnaires, Third Edition) in the Black Zone | Neurodevelopmental status was measured by ASQ-3 score scale [ASQ-3, 2016] in the black zone. The ASQ-3 included a series of questions designed to assess 5 areas of development (communication, gross motor, fine motor, problem solving, and personal-social). Any subject who scored below the cut-off i.e., a score more than 2 Standard Deviations (SDs) below the mean score for the U.S. reference group (i.e., black zone in the score chart) in any of the 5 domains of the ASQ-3 was to be referred to a developmental specialist for a formal neurodevelopmental assessment (using the Bayley Scale for Infant Development, Version III [BSID-III]) | At 9 months of age, 18 months of age, and 9 or 18 months of age | 
| Number of Subjects Referred for Formal Neurodevelopmental Evaluation Using BSID-III (Bayley Scale for Infant Development, Version III) | Any subject who scored below the cut-off i.e., a score more than 2 Standard Deviations (SDs) below the mean score for the U.S. reference group (i.e., black zone in the score chart) in any of the 5 domains of the ASQ-3 was referred to a developmental specialist for a formal neurodevelopmental assessment (using the Bayley Scale for Infant Development, Version III BSID-III) | At 9 months of age, 18 months of age, and 9 or 18 months of age | 
| Estimated Proportion of Infants With at Least One of the Indicators of Neurodevelopmental Impairment Using BSID-III (Bayley Scale for Infant Development, Version III) | The estimated proportion (expressed in percentage) of infants with a BSID-III indicator of neurodevelopmental delay was based on ASQ-3 black zone indicator and subsequent BSID-III assessment using the following formula: 100 * (Number of subjects with ASQ-3 below cut off / Number of enrolled subjects with available results) * (Number of subjects with at least one indicator of neurodevelopmental delay using BSID III / Number of subjects referred for BSID III evaluation) | At 9 months of age, 18 months of age, and 9 or 18 months of age | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Immunogenicity, Poliomyelitis, Tetanus, Hepatitis B, Diptheria, Pertussis