Immunogenicity, Safety and Reactogenicity Study of GlaxoSmithKline (GSK) Biologicals' Hib-MenCY-TT (MenHibrix®) Vaccine Compared to Merck & Co, Inc. PedvaxHIB Vaccine in Healthy Infants and Toddlers 12 to 15 Months of Age

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, reactogenicity and immunogenicity of GSK Biologicals' Hib-MenCY-TT (MenHibrix®) vaccine co-administered with Rotarix, Prevnar 13 and Havrix as compared to PedvaxHIB co-administered with Rotarix, Prevnar 13 and Havrix in infants and toddlers.

Official Title
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Immunogenicity, Safety and Reactogenicity of GSK Biologicals' Hib-MenCY-TT (MenHibrix®) Vaccine 792014 Compared to Merck & Co, Inc. Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) Vaccine in Healthy Infants and Toddlers

Conditions
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Neisseria Meningitidis, Haemophilus Influenzae Type b

Intervention / Treatment
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* Biological: Hib-MenCY-TT (MenHibrix®)
* Biological: Pediarix®
* Biological: Rotarix®
* Biological: Prevnar 13®
* Biological: PedvaxHIB®
* Biological: Havrix®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. A male or female between, and including, 6 and 12 weeks of age at the time of the first vaccination. Written informed consent obtained from the parent(s)/LAR(s) of the subject. Healthy subjects as established by medical history and clinical examination before entering into the study. Born full-term (i.e. born after a gestation period of at least 37 weeks inclusive). Infants who have not received a previous dose of hepatitis B vaccine or those who have received only 1 dose of hepatitis B vaccine administered at least 30 days prior to enrollment. Exclusion Criteria: Child in care. Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the dose of study vaccine or planned use during the study period. Chronic administration of immunosuppressants or other immune-modifying drugs since birth prior to the first vaccine dose. Inhaled and topical steroids are allowed. Previous vaccination against Neisseria meningitidis, Haemophilus influenzae type b, diphtheria, tetanus, pertussis, rotavirus, pneumococcus, hepatitis A and/or poliovirus; more than one previous dose of hepatitis B vaccine. Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 30 days before and ending 30 days after the dose of vaccines. Subjects may receive inactivated influenza vaccine or pandemic influenza vaccines any time during the study according to the national recommendation. Measles, mumps, rubella and varicella vaccination are allowed 30 days before or 30 days after the final vaccination of Hib-MenCY-TT or PedvaxHIB. History of Neisseria meningitidis, Haemophilus influenzae type b, diphtheria, tetanus, pertussis, pneumococcus, hepatitis B, hepatitis A, rotavirus, and/or poliovirus disease. Any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination. History of allergic disease or reactions likely to be exacerbated by any component of the vaccines, including dry natural latex rubber. Hypersensitivity to any component of the vaccines, including gelatin or neomycin. Major congenital defects or serious chronic illnesses. History of any neurologic disorders or seizures. A single, simple febrile seizure is allowed. Subjects with history of intussusceptions or uncorrected congenital malformation of the gastrointestinal tract that would predispose for intussusceptions. Acute disease and/or fever at the time of enrollment. Administration of immunoglobulins and/or blood products since birth or planned administration during the study period.

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 12 Weeks

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HibCY Group<br>Subjects received 4 doses of Hib-MenCY-TT (MenHibrix®) vaccine at Day 0, Month 2, Month 4 and Month 10-13 , 3 doses of Pediarix® vaccine at Day 0, Month 2 and Month 4, 2 doses of Rotarix® vaccine at Day 0 and Month 2, 4 doses of Prevnar 13® vaccine at Day 0 and Month 2, Month 4 and Month 10-13 and 2 doses of Havrix® vaccine at Month 10-13 and Month 16-19. | Biological: Hib-MenCY-TT (MenHibrix®)<br>* 4 doses administered intramuscularly (IM) in the right upper anterolateral thigh at Day 0, Month 2, Month 4 and Month 10-13 in the HibCY Group.<br>Biological: Pediarix®<br>* 3 doses administered IM in the left upper anterolateral thigh at Day 0, Month 2 and Month 4. 2 doses administered IM in the left upper anterolateral thigh at Day 0 and Month 2 and 1 dose administered IM in the right upper anterolateral thigh at Month 4 in the PedHIB Group.<br>Biological: Rotarix®<br>* 2 doses administered orally at Day 0 and Month 2 each in the HibCY Group and PedHIB Group.<br>Biological: Prevnar 13®<br>* 4 doses administered IM in the left lower anterolateral thigh at Day 0, Month 2, Month 4 and Month 10-13 each in the HibCY Group and PedHIB Group.<br>Biological: Havrix®<br>* 2 doses administered IM in the left upper anterolateral thigh at Month 10-13 and Month 16-19 each in the HibCY Group and PedHIB Group.<br>|
| Active Comparator: PedHIB Group<br>Subjects received 3 doses of PedvaxHIB® vaccine at Day 0, Month 2 and Month 10-13, 3 doses of Pediarix® vaccine at Day 0, Month 2 and Month 4, 2 doses of Rotarix® vaccine at Day 0 and Month 2, 4 doses of Prevnar 13® vaccine at Day 0 and Month 2, Month 4 and Month 10-13 and 2 doses of Havrix® vaccine at Month 10-13 and Month 16-19. | Biological: Pediarix®<br>* 3 doses administered IM in the left upper anterolateral thigh at Day 0, Month 2 and Month 4. 2 doses administered IM in the left upper anterolateral thigh at Day 0 and Month 2 and 1 dose administered IM in the right upper anterolateral thigh at Month 4 in the PedHIB Group.<br>Biological: Rotarix®<br>* 2 doses administered orally at Day 0 and Month 2 each in the HibCY Group and PedHIB Group.<br>Biological: Prevnar 13®<br>* 4 doses administered IM in the left lower anterolateral thigh at Day 0, Month 2, Month 4 and Month 10-13 each in the HibCY Group and PedHIB Group.<br>Biological: PedvaxHIB®<br>* 3 doses administered IM in the right upper anterolateral thigh at Day 0, Month 2 and Month 10-13 in the PedHIB Group.<br>Biological: Havrix®<br>* 2 doses administered IM in the left upper anterolateral thigh at Month 10-13 and Month 16-19 each in the HibCY Group and PedHIB Group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Anti-Polyribosylribitol Phosphate (Anti-PRP) Antibody Concentrations Greater Than or Equal to (≥) 1.0 µg/mL | Percentage of subjects with Anti-PRP antibody concentrations≥1.0 µg/mL were assessed. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts. Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.As per an hierarchical procedure, the primary objective about Anti-PRP will first need to be met to be able to conclude on any other primary objective, and within each subsequent arm, the first primary objective will have to be reached to conclude on the second primary objective of that Epoch. | 1 month after the fourth dose for HibCY Group and 1 month after third dose for PedHIB Group [Month (M) 11-14] | 
| Anti-rotavirus Serum Immunoglobulin A (IgA) Geometric Mean Concentrations (GMCs). | Anti-rotavirus serum IgA was assessed by ELISA, tabulated as GMCs and expressed in Units per mililiter (U/mL).Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts. Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.As per a hierarchical procedure, the primary objective about Anti-PRP will first need to be met to be able to conclude on any other primary objective, and within each subsequent arm, the first primary objective will have to be reached to conclude on the second primary objective of that Epoch | 2 months post-dose 2 of Rotarix (Month 4) | 
| Anti-Streptococcus (S) Pneumoniae GMCs | Antibody concentrations against S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F were assessed by ELISA, tabulated as GMCs and expressed in µg/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.As per an hierarchical procedure, the primary objective about Anti-PRP will first need to be met to be able to conclude on any other primary objective, and within each subsequent arm, the first primary objective will have to be reached to conclude on the second primary objective of that Epoch. | 1 month post-dose 3 of Prevnar 13 (Month 5) | 
| Percentage of Subjects With Anti-Hepatitis A (Anti-Havrix) Antibody Concentrations ≥ 15mIU/mL | Percentage of subjects with Anti-Havrix (Anti-HAV) antibody concentrations was assessed. The cut-off value is ≥15 mIU/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.As per an hierarchical procedure, the primary objective about Anti-PRP will first need to be met to be able to conclude on any other primary objective, and within each subsequent arm, the first primary objective will have to be reached to conclude on the second primary objective of that Epoch | 1 month post-dose 2 of Havrix (Month 17-20) | 
| Anti-S. Pneumoniae GMCs | Antibody concentrations against S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F were assessed by ELISA, tabulated as GMCs and expressed in µg/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups.As per an hierarchical procedure, the primary objective about Anti-PRP will first need to be met to be able to conclude on any other primary objective, and within each subsequent arm, the first primary objective will have to be reached to conclude on the second primary objective of that Epoch | 1 month post-dose 4 of Prevnar 13 (Month 11-14) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Anti-PRP Antibody Concentrations ≥0.15 µg/mL. | The cut-off value for this assay was 0.15 µg/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups. | 2 months post-dose 2 [PedHib Group only (Month 4)], 1 month post-dose 3 (Month 5 for HibCY group and Months 11-14 for PedHib Group) and 1 month post-dose 4 [HibCY Group only (Month 11-14)] | 
| Anti-PRP GMCs≥ 0.15 µg/mL. | Anti-PRP antibody concentrations were assessed by Enzyme-Linked-Immunosorbent-Assay (ELISA), tabulated as Geometric Mean Concentrations (GMCs) and expressed in micrograms per mililiter (µg/mL).The cut-off value for this assay was 0.15 µg/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups. | 2 months post-dose 2 [PedHib Group only (Month 4)], 1 month post-dose 3 (Month 5 for HibCY group and Month 11-14 for PedHib Group) and 1 month post-dose 4 [HibCY Group only (Month 11-14)] | 
| Percentage of Subjects With Anti-PRP Antibody Concentrations ≥1.0 µg/mL | The cut-off value for this assay was 1.0 µg/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups. | 2 months post-dose 2 [PedHib group only (Month 4)] and 1 month postdose 3 [HibCY group only (Month 5)]. | 
| Percentage of Subjects With Serum Bactericidal Assay to N. Meningitidis Serogroup C (hSBA-MenC) and N. Meningitidis Serogroup Y (hSBA-MenY) Antibody Titers ≥1:8, ≥1:16, ≥1:32. | The cut off values are dilutions of 1:8, 1:16 and 1:32. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups. | 1 month post-dose 3 (Month 5) and 1 month post-dose 4 (Month 11-14). | 
| Geometric Mean Titres (GMTs) of Human Complement Serum Bactericidal Assay to N. Meningitidis Serogroup C (hSBA-MenC) and to hSBA-MenY | The cut-off values are dilutions of 1:8, 1:16 and 1:32. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups. | 1 month post-dose 3 (Month 5) and 1 month post-dose 4 (Month 11-14). | 
| Percentage of Subjects With Anti-rotavirus IgA Antibody Concentrations ≥ 20 Units (U)/mL | The cut-off value is 20 Units (U)/mL Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups. | 2 month post-dose 2 of Rotarix (Month 4) | 
| Percentage of Subjects With Anti-HAV Antibodies ≥ 15 mIU/mL | The cut-off value is 15 mIU/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups. | 1 month post-dose 1 of Havrix (Month 11-14) | 
| Anti-HAV GMCs ≥ 15 mIU/mL | The cut-off value is 15 mIU/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups | 1 month post-dose 1 of HAV (M11-14). | 
| GMCs for Anti-HAV Antibodies ≥15mIU/mL. | The cut-off value is 15 mIU/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups | 1 month post-dose 2 of HAV (Month 17-20). | 
| Percentage of Subjects With S. Pneumoniae Antibody Concentrations ≥ 0.15 µg/mL, ≥ 0.26 µg/mL and ≥ 0.35 µg/mL for Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F | The cut-off values are 0.15, 0.26, 0.35 µg/mL. Analysis of Immunogenicity is performed on blood sample (BS) sub-cohorts.Assignment to a BS sub-cohort depends on the date of enrolment of the subject: BS sub-cohort for the first 200 , for the next 200 subjects or for the last 200 subjects. Within each BS sub-cohort subjects have been randomized 1:1 to either HibCY or PedHIB groups | 1 month post-dose 3 (Month 5) and 1 month post-dose 4 (Month 11-14) | 
| Percentage of Subjects Reporting Any Solicited Local Adverse Events (AE). | Solicited local adverse events include pain, redness and swelling at injection site. | 4 days (Day 0 to Day 3) after all vaccines post-primary and post-fourth dose | 
| Percentage of Subjects Reporting Any Solicited General AEs. | Solicited general AEs include fever [defined as temperature ≥38.0 degrees Celsius (°C) by any method], drowsiness, irritability/fussiness and loss of appetite. | 4 days (Day 0 to Day 3) after all vaccines post-primary and post-fourth dose. | 
| Percentage of Subjects Reporting Any Unsolicited AEs. | Any adverse event (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 were reported as an unsolicited adverse event. | During 31 days (Day 0 to Day 30) after all vaccines post-primary (Dose 1-3) and post-fourth dose (Dose 4) | 
| Percentage of Subjects Reporting Any Serious Adverse Events (SAEs). | Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | During the entire study period (from Day 0 to Month 17-20) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Conjugate, Immunogenicity, Hib-MenCY-TT vaccine, Haemophilus type b, Safety, Reactogenicity