Primary & Booster Study to Evaluate the Immunogenicity and Safety of Menitorix Vaccine in Preterm Infants

Study Overview
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Brief Summary
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The purpose of this Phase IIIb study is to evaluate the immunogenicity, reactogenicity & safety of GSK Biologicals' Hib-MenC vaccine (Menitorix™) when co-administered with GSK Biologicals' DTPa-HBV-IPV vaccine (Infanrix™ penta) & Wyeth's 7-valent pneumococcal conjugate vaccine (Prevenar™) in preterm infants as a 3-dose primary vaccination course during the first 6 months of life (at 2, 4, 6 months of age) and of a booster dose of Menitorix™ when co-administered with GSK Biologicals' DTPa-IPV vaccine (Infanrix IPV) and Wyeth's Prevenar in the second year of life (16-18 months of age). The control is a group of full-term infants receiving the same vaccines. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Detailed Description
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This multicenter study is open & consists of a primary & a booster phase. The study has 2 treatment groups (Preterm & Full-term) that will receive the same vaccinations; the Full-term group will be the active control. Four blood samples will be collected from all subjects for immunogenicity analyses; 2 in the primary phase at prior to the first vaccination and one month after the third vaccination and 2 in the booster phase at prior to booster dose and one month after booster dose.

Official Title
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Immunogenicity & Safety Study in Preterm & Full-term Infants of GSK Biologicals' Hib-MenC Vaccine, Menitorix™ Co-administered With Infanrix™ Penta & Prevenar™ at 2, 4, 6 Months & as a Booster With Infanrix™ IPV & Prevenar™ at 16-18 Months

Conditions
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Haemophilus Influenzae Type b, Neisseria Meningitidis

Intervention / Treatment
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* Biological: Menitorix™
* Biological: Infanrix™ penta
* Biological: Prevenar™
* Biological: Infanrix™ IPV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects must satisfy the following criteria at study entry: Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol. A male or female between, and including, 8 and 12 weeks of age at the time of the first vaccination. Written informed consent obtained from the parent or guardian of the subject. All preterm subjects must satisfy the following criteria at study entry: Born after a gestation period of less than or equal to 36 weeks (≤258 days). Medically stable, i.e. do not require significant medical support or ongoing management for debilitating disease and have demonstrated a clinical course of sustained recovery. All full-term subjects must satisfy the following criteria at study entry: Born after a gestation period between and including 37 and 42 weeks (≥259 days and ≤294 days). Free of obvious health problems as established by medical history and clinical examination before entering into the study. Exclusion Criteria: Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period. Chronic administration of immunosuppressants or other immune-modifying drugs since birth. Planned administration/ administration of a vaccine not foreseen by the study protocol in the period starting 30 days before the first dose of vaccine until the last study visit, except measles-mumps-rubella (MMR) and varicella vaccines which may be given according to local immunisation practices and except rotavirus oral vaccine which is allowed at anytime during the study after hospital discharge as per prescribing information. Previous vaccination against diphtheria, tetanus, pertussis, polio, hepatitis B, Haemophilus influenzae type b, meningococcal serogroup C and or Streptococcus pneumoniae disease, with the exception of hepatitis B vaccine or BCG vaccine given in the first month of life according to the national recommendations (although BCG and hepatitis B vaccines should have been given outside a 30-day window from the first administration of study vaccines). History of diphtheria, tetanus, pertussis, polio, hepatitis B, H. influenzae type b, meningococcal disease and or S. pneumoniae disease. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection, based on medical history and physical examination. A family history of congenital or hereditary immunodeficiency. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine(s). Major congenital defects or serious chronic illness. History of any neurologic disorders or seizures. Acute disease at the time of enrolment. Administration of immunoglobulins (with the exception of monoclonal antibodies against respiratory syncytial virus [RSV]) and/or any blood products within one month (30 days) preceding the first dose of study vaccines. Planned administration of immunoglobulins and/or any blood products during the active phase of the study. Specific criteria for the booster part of the study (to be checked at Visit 5, study month 14): History of diphtheria, tetanus, pertussis, polio, hepatitis B, H. influenzae type b, meningococcal disease and or S. pneumoniae disease. Previous vaccination, except the study vaccines and hepatitis birth dose, against diphtheria, tetanus, pertussis, polio, hepatitis B, H. influenzae type b, meningococcal disease and or S. pneumoniae disease. Previous booster vaccination against diphtheria, tetanus, pertussis, polio, hepatitis B, H. influenzae type b, meningococcal disease and/or S. pneumoniae disease.

Ages Eligible for Study
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Minimum Age: 8 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Preterm group<br>Subjects born after a gestation period of less than or equal to 36 weeks and who received 3 doses (at 2, 4 and 6 months of age) of Menitorix™, Infanrix™ penta and Prevenar™ and a booster dose of Menitorix™, Infanrix™ IPV and Prevenar™ at 16-18 months of age. | Biological: Menitorix™<br>* Intramuscular injection, 3 doses in the primary study and 1 dose in the Booster study.<br>Biological: Infanrix™ penta<br>* Intramuscular injection, 3 doses in the primary study<br>Biological: Prevenar™<br>* Intramuscular injection, 3 doses in the primary study and 1 dose in the Booster study.<br>Biological: Infanrix™ IPV<br>* Intramuscular injection, 1 dose in the Booster study.<br>|
| Active Comparator: Full-term group<br>Subjects born after a gestation period of more than 36 weeks and who received 3 doses (at 2, 4 and 6 months of age) of Menitorix™, Infanrix™ penta and Prevenar™ and a booster dose of Menitorix™, Infanrix™ IPV and Prevenar™ at 16-18 months of age. | Biological: Menitorix™<br>* Intramuscular injection, 3 doses in the primary study and 1 dose in the Booster study.<br>Biological: Infanrix™ penta<br>* Intramuscular injection, 3 doses in the primary study<br>Biological: Prevenar™<br>* Intramuscular injection, 3 doses in the primary study and 1 dose in the Booster study.<br>Biological: Infanrix™ IPV<br>* Intramuscular injection, 1 dose in the Booster study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentration Greater Than or Equal to 0.15 Micrograms Per Milliliter (µg/mL) | Anti-PRP antibody concentration greater than or equal to 0.15 µg/mL is indicative of protection. | One month after the third vaccination | 
| Number of Subjects With Meningococcal Serogroup C Serum Bactericidal Assay Using Rabbit Complement (rSBA-MenC) Titer Greater Than or Equal to 1:8 | rSBA-MenC titer greater than or equal to 1:8 is indicative of protection. | One month after the third vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Anti-Polyribosylribitol Phosphate (Anti-PRP) Antibody Concentration Greater Than or Equal to the Cut-off Values | Anti-PRP antibody cut-off values assessed include 0.15 micrograms per milliliter (µg/mL) and 1 µg/mL. | Before vaccination (at Day 0) | 
| Number of Subject With Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentration Greater Than or Equal to 1 Microgram Per Milliliter | Anti-PRP antibody cut-off value assessed include 1 microgram per milliliter (µg/mL). | One month after the third vaccination | 
| Number of Subjects With Meningococcal Serogroup C Serum Bactericidal Assay Using Rabbit Complement (rSBA-MenC) Titer Greater Than or Equal to the Cut-off Values | rSBA-MenC titer cut-off values assessed include 1:8, 1:32 and 1:128. | Before vaccination (at Day 0) | 
| Number of Subjects With Meningococcal Serogroup C Serum Bactericidal Assay Using Rabbit Complement (rSBA-MenC) Titer Greater Than or Equal to the Cut-off Values | rSBA-MenC titer cut-off values assessed include 1:32 and 1:128. | One month after the third vaccination | 
| Number of Subjects With Anti-polysaccharide C (Anti-PSC) Antibody Concentration Greater Than or Equal to (≥) the Cut-off Values | Anti-PSC antibody cut-off values assessed include 0.3 micrograms per milliliter (µg/mL) and 2 µg/mL. | Before vaccination (at Day 0) | 
| Number of Subjects With Anti-polysaccharide C (Anti-PSC) Antibody Concentration Greater Than or Equal to (≥) the Cut-off Values | Anti-PSC antibody cut-off values assessed include 0.3 micrograms per milliliter (µg/mL) and 2 µg/mL. | One month after the third dose | 
| Number of Subjects With Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentration Greater Than or Equal to (≥) the Cut-off Values | Anti-HBs antibody cut-off values assessed include 10 milli-international units per milliliter (mIU/mL) and 100 mIU/mL. | Before vaccination (at Day 0) | 
| Number of Subjects With Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentration Greater Than or Equal to (≥) the Cut-off Values | Anti-HBs antibody cut-off values assessed include 10 milli-international units per milliliter (mIU/mL) and 100 mIU/mL. | One month after the third dose | 
| Anti-polyribosylribitol Phosphate (Anti-PRP) and Anti-polysaccharide C (Anti-PSC) Concentration | Anti-PRP and anti-PSC concentrations are given as geometric mean concentrations (GMCs) expressed micrograms per milliliter (µg/mL). | Before vaccination (at Day 0) | 
| Anti-polyribosylribitol Phosphate (Anti-PRP) and Anti-polysaccharide C (Anti-PSC) Concentration | Anti-PRP and anti-PSC concentrations are given as geometric mean concentrations (GMCs) expressed micrograms per milliliter (µg/mL). | One month after the third dose | 
| Anti-hepatitis B Surface Antigen (Anti-HBs) Concentration | Anti-HBs concentrations are given as geometric mean concentrations (GMCs) expressed in milli-international units per milliliter (mIU/mL). | Before vaccination (at Day 0) | 
| Anti-hepatitis B Surface Antigen (Anti-HBs) Concentration | Anti-HBs concentrations are given as geometric mean concentrations (GMCs) expressed in milli-international units per milliliter (mIU/mL). | One month after the third dose | 
| Meningococcal Serogroup C Serum Bactericidal Assay Using Rabbit Complement (rSBA-MenC) Titer | rSBA-MenC titers are given as geometric mean titers (GMTs). | Before vaccination (at Day 0) | 
| Meningococcal Serogroup C Serum Bactericidal Assay Using Rabbit Complement (rSBA-MenC) Titer | rSBA-MenC titers are given as geometric mean titers (GMTs). | One month after the third dose | 
| Number of Subjects Reporting Solicited Local Symptoms | Solicited local symptoms assessed include pain, redness and swelling and are presented across doses. | During the 4-day follow-up period after any primary vaccination dose | 
| Number of Subjects Reporting Solicited General Symptoms | Solicited general symptoms assessed include drowsiness, fever, irritability/fussiness and loss of appetite and are presented across doses. | During the 4-day follow-up period after any primary vaccination dose | 
| Number of Subjects Reporting Unsolicited Adverse Events (AEs) | Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. | Within 31 days after each primary vaccination | 
| Number of Subjects Reporting Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, is life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. | Throughout the entire primary vaccination phase | 
| Number of Subjects With Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentration Greater Than or Equal to 0.15 Migrogram Per Milliliter (µg/mL) | Anti-PRP antibody cut-off value assessed was 0.15 migrogram per milliliter (µg/mL). | Prior to (Month 14) and one month after the booster vaccination (Month 15) | 
| Number of Subjects With Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentration Greater Than or Equal to 1.0 Migrogram Per Milliliter (µg/mL) | Anti-PRP antibody cut-off value assessed was 1.0 migrogram per milliliter (µg/mL). | Prior to (Month 14) and one month after the booster vaccination (Month 15) | 
| Number of Subjects With Meningococcal Serogroup C Serum Bactericidal Assay Using Rabbit Complement (rSBA-MenC) Titer Greater Than or Equal to the Cut-off Values | rSBA-MenC titer cut-off values assessed include 1:8, 1:32 and 1:128. | Prior to (Month 14) and one month after the booster vaccination (Month 15) | 
| Number of Subjects With Anti-polysaccharide C (Anti-PSC) Antibody Concentration Greater Than or Equal to the Cut-off Values | Anti-PSC antibody cut-off values assessed include 0.3 micrograms per milliliter (µg/mL) and 2.0 µg/mL. | Prior to (Month 14) and one month after the booster vaccination (Month 15) | 
| Number of Subjects With Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentration Greater Than or Equal to the Cut-off Values | Anti-HBs antibody cut-off values assessed include 10 milli-international units per milliliter (mIU/mL) and 100 mIU/mL. Note: the protocol planned an analysis on HBs after the booster dose, but this analysis was not performed as the vaccines administered as booster doses did not contain HBs component. | Prior to (Month 14) the booster vaccination | 
| Anti-polyribosylribitol Phosphate (Anti-PRP) and Anti-polysaccharide C (Anti-PSC) Concentration | Anti-PRP and anti-PSC concentrations are given as geometric mean concentrations (GMCs) in micrograms per milliliter (µg/mL). | Prior to (Month 14) and one month after the booster vaccination (Month 15) | 
| Anti-hepatitis B Surface Antigen (Anti-HBs) Concentration | Anti-HBs concentrations are given as geometric mean concentrations (GMCs) in milli-international units per milliliter (mIU/mL). Note: Planned analysis in the protocol of HBs after the booster dose was not performed as booster vaccines did not contain HBs component. | Prior to (Month 14) the booster vaccination | 
| Meningococcal Serogroup C Serum Bactericidal Assay Using Rabbit Complement (rSBA-MenC) Titer | rSBA-MenC titers are given as geometric mean titers (GMTs). | Prior to (Month 14) and one month after the booster vaccination (Month 15) | 
| Number of Subjects Reporting Solicited Symptoms (Local and General) | Solicited local symptoms assessed include pain, redness and swelling. Solicited general symptoms assessed include drowsiness, fever, irritability/fussiness and loss of appetite. | During the 4-day follow-up period following booster vaccination | 
| Number of Subjects Reporting Unsolicited Adverse Events (AEs) | Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. | Within 31 days after the booster vaccination (month 15) | 
| Number of Subjects Reporting Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, is life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Period 1 is defined as 31 days after last primary vaccination until administration of booster dose (Month 14). Period 2 is defined as the administration of the booster dose until the end of the study (Month 15). | 31 days after last primary vaccination until administration of booster dose (Month 14) and from the administration of the booster dose until the end of the study (Month 15) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Persistence, Conjugate vaccine, Hib vaccine, Combination vaccine, Meningococcal vaccine, Safety, Preterm/full-term infants, Immunogenicity