Consistency & Immunogenicity Study of 3 Lots of GSK's Hib Conjugate Vaccine Versus ActHIB & Pentacel in Healthy Infants

Study Overview
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Brief Summary
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The purpose of this study is to evaluate safety, to demonstrate lot-to-lot consistency of the vaccine, to address the relevant concomitant vaccine administrations and to provide a comparison between GSK Biologicals' Hib conjugate vaccine and the licensed monovalent Hib vaccine ActHIB as well as the licensed combination product Pentacel in infants at 2, 4, 6 and 15-18 months of age. This study is designed with a primary and a booster phase.

Detailed Description
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This protocol posting has been updated following protocol amendment 3, dated 12 April 2011. The impacted section is: Eligibility Criteria (Exclusion criteria).

Official Title
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Phase III, Partially Double-blind Study to Evaluate Consistency and Immunogenicity of 3 Lots of GSK Biologicals' Hib Conjugate Vaccine 208108 Versus ActHIB and Pentacel at 2, 4, 6 and 15-18 Months of Age in Healthy Infants

Conditions
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Haemophilus Influenzae Type b

Intervention / Treatment
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* Biological: GSK Biologicals' Haemophilus influenzae type b vaccine (GSK 208108)
* Biological: ActHIB™
* Biological: Pentacel™
* Biological: Pediarix™
* Biological: Prevnar 13™
* Biological: Rotarix™
* Biological: Engerix™-B
* Biological: Infanrix™


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects for whom the investigator believes that their parent(s)/Legally Acceptable Representative(s) (LAR[s]) can and will comply with the requirements of the protocol (e.g., completion of the diary card, return for follow-up visits). 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 subject's parent/LAR. Healthy subjects as established by medical history and clinical examination before entering into the study. Born after a gestation period of minimum 36 weeks. 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: 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 (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs since birth. Planned administration of a vaccine not foreseen by the study protocol within 30 days of the first dose of study vaccine and until 30 days after the booster dose. Previous vaccination against Haemophilus influenzae type b, diphtheria, tetanus, pertussis, Pneumococcus, rotavirus and/or poliovirus; more than one previous dose of hepatitis B vaccine. History of Haemophilus influenzae type b, diphtheria, tetanus, pertussis, pneumococcal, rotavirus, poliovirus, and hepatitis B diseases. 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. Major congenital defects or serious chronic illness. History of any neurologic disorders or seizures. Acute disease at time of enrollment. All vaccines can be administered to persons with a minor illness. Administration of immunoglobulins and/or any blood products since birth or planned administration during the study period. Concurrent participation in another clinical study, up to 30 days prior to study entry or at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device). Child in care. History of intussusception. History of uncorrected congenital malformation of the gastrointestinal tract that would predispose the infant to intussusception. History of Severe Combined Immunodeficiency Disease.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hiberix Group<br>Pooled group of subjects, male or female between, and including, 6 and 12 weeks of age at the time of the first vaccination, who received 3 doses of 3 different lots of Hiberix® vaccine co-administered with 3 doses of Pediarix® and Prevnar13® vaccines at 2, 4 and 6 months of age and 2 doses of Rotarix® vaccine at 2 and 4 months of age The Hiberix® vaccine was administered intramuscularly in the right thigh. Pediarix® vaccine was administered intramuscularly in the left thigh. The Prevnar13® vaccine was administered intramuscularly in the left thigh or deltoid. The Rotarix® vaccine was administered orally. | Biological: GSK Biologicals' Haemophilus influenzae type b vaccine (GSK 208108)<br>* Three doses of 3 different manufacturing lots in primary study at 2, 4 and 6 months of age as intramuscular injection and one dose as booster vaccination.<br>* Other names: Hiberix®;Biological: Pediarix™<br>* Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection<br>Biological: Prevnar 13™<br>* Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection<br>Biological: Rotarix™<br>* Two oral doses in primary epoch at 2 and 4 months of age<br>Biological: Infanrix™<br>* One dose in the booster epoch at 15-18 months of age as intramuscular injection<br>|
| Active Comparator: ActHIB Group<br>Subjects, male or female between, and including, 6 and 12 weeks of age at the time of the first vaccination, who received 3 doses of ActHIB® vaccine co-administered with 3 doses of Pediarix® and Prevnar13® vaccines at 2, 4 and 6 months of age and 2 doses of Rotarix® vaccine at 2 and 4 months of age. The ActHIB® vaccine was administered intramuscularly in the right thigh. The Pediarix® vaccine was administered intramuscularly in the left thigh. The Prevnar13® vaccine was administered intramuscularly in the left thigh or deltoid. The Rotarix® vaccine was administered orally. | Biological: ActHIB™<br>* Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection and one dose as a booster vaccination<br>Biological: Pediarix™<br>* Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection<br>Biological: Prevnar 13™<br>* Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection<br>Biological: Rotarix™<br>* Two oral doses in primary epoch at 2 and 4 months of age<br>Biological: Infanrix™<br>* One dose in the booster epoch at 15-18 months of age as intramuscular injection<br>|
| Active Comparator: Pentacel Group<br>Subjects, male or female between, and including, 6 and 12 weeks of age at the time of the first vaccination, who received 3 doses of Pentacel® vaccine co-administered with 3 doses of Prevnar13® vaccine, 2 or 3 doses of Engerix™-B vaccine at 2, 4 and 6 months of age and 2 doses of Rotarix® vaccine at 2 and 4 months of age. The Pentacel® vaccine was administered intramuscularly in the right thigh. The Engerix™-B vaccine was administered intramuscularly in the left thigh. The Prevnar13® vaccine was administered intramuscularly in the left thigh or deltoid. The Rotarix® vaccine was administered orally. If subjects in the Pentacel Group had received a birth dose of Hepatitis B vaccine then they were to receive Engerix™-B vaccine only at 2 and 6 months of age. | Biological: Pentacel™<br>* Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection and one dose as a booster vaccination<br>Biological: Prevnar 13™<br>* Three doses in primary epoch at 2, 4 and 6 months of age as intramuscular injection<br>Biological: Rotarix™<br>* Two oral doses in primary epoch at 2 and 4 months of age<br>Biological: Engerix™-B<br>* Two or three doses in primary epoch at 2,( 4) and 6 months of age as intramuscular injection<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 Concentrations Greater Than or Equal to (≥) 0.15 Microgram Per Milliliter (µg/mL) and ≥ 1.0 µg/mL | Non-inferiority of Hiberix to ActHIB, each co-administered with Pediarix, Prevnar13 and Rotarix following 3 primary doses in terms of immune response to PRP (Anti-PRP≥ 0.15 µ g/ml and ≥1.0 µg/mL). | At 1 month after last dose of primary vaccination | 
| Number of Subjects With Anti-Protein-D (Anti-D) and Anti-Protein-T (Anti-T) Antibody Concentrations ≥ 0.1 International Units Per Milliliter (IU/mL) | Non-inferiority of Pediarix co-administered with Hiberix, Prevnar13 and Rotarix compared to Pediarix co-administered with ActHIB, Prevnar13 and Rotarix following 3 primary vaccine doses in terms of immune response to Diphtheria, Tetanus. | At 1 month after last dose of primary vaccination | 
| Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentrations | Antibody concentrations were given as Geometric Mean Concentrations (GMCs) expressed in micrograms per milliliter (µg/mL). | At 1 month after last dose of primary vaccination | 
| Anti-pertussis Toxoid (Anti-PT), Anti-pertactin (Anti-PRN) and Anti-filamentous Hemagglutinin (Anti-FHA) Antibody Concentrations | Antibody concentrations were given as geometric mean concentrations (GMCs) expressed as enzyme-linked immuno-sorbent assay (ELISA) units per milliliter i.e. EL.U/mL. | At 1 month after last dose of primary vaccination | 
| Anti-Streptococcus Pneumoniae (S.Pneumoniae) Antibody Concentrations | Antibody concentrations against S.pneumoniae were given as geometric mean concentrations (GMCs) expressed as microgram per milliliter (µg/mL). | At 1 month after last dose of primary vaccination | 
| Number of Subjects With Seroresponse (95%) to Anti-pertussis Toxoid (Anti-PT), Anti-pertactin (Anti-PRN) and Anti-filamentous Hemagglutinin (Anti-FHA) | Seroresponse (95%) was defined as the number of subjects showing a concentration above a threshold that leads to 95% seroresponse in the ActHIB group. | At 1 month after last dose of primary vaccination | 
| Number of Subjects With Anti-Polio 1,2,3 Antibody Titres Greater Than or Equal to Cut-off Value | The cut-off value was defined as a concentration ≥ 8 ED50 (ED50 is the concentration at which the protein exhibits 50% of its maximum activity). The polio testing which started at the Biomnis laboratory was stopped because the polio virus micro-neutralization assays were found to be not in line with the quality standards defined in GSK Biologicals' SOPs. As a result, polio testing was restarted at the GSK laboratory and the results were uploaded into the clinical database. | At 1 month after last dose of primary vaccination | 
| Number of Subjects With Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentrations ≥ 1.0 µg/mL | Non-inferiority of a booster dose of Hiberix co-administered with Infanrix in subjects 15-18 months of age who received 3 primary vaccine doses of Hiberix to a booster dose of ActHIB co-administered with Infanrix in subjects of 15-18 months of age who received 3 primary vaccine doses of ActHIB in terms of immune response to PRP | At 1 month after booster vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-protein-D (Anti-D) and Anti-protein-T (Anti-T) Antibody Concentrations | Antibody concentrations were given as geometric mean concentrations (GMCs) and expressed as International Units per milliliter (IU/mL). | At 1 month after last dose of primary vaccination | 
| Number of Subjects With Any Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of any symptom regardless of intensity grade. | During a 4-day follow-up period (Days 0-3) following any vaccination | 
| Number of Subjects With Any Solicited General Symptoms | Assessed solicited general symptoms were drowsiness, irritability, fever and loss of appetite. Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination. Any fever= Rectal temperature equal to or above (≥) 38 degrees Celsius (°C). | During a 4-day follow-up period (Days 0-3) following any vaccination | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs). | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | During the 31-day (Day 0-Day 30) follow-up period after primary vaccination | 
| Number of Subjects With 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. | From Day 0 until 6 months following the last primary dose | 
| Number of Subjects With AEs of Specific Interest (AESIs) | An AESI was defined as an AE including autoimmune diseases and other mediated inflammatory disorders and assessed by the investigator as specific to the treatment administration. | From Day 0 until 6 months following the last primary dose or the receipt of the booster vaccination, whichever comes first | 
| Number of Subjects With Seroresponse (90%) to Anti-PT, Anti-PRN and Anti-FHA | Seroresponse (90%) was defined as the number of subjects showing a concentration above a threshold that leads to 90% seroresponse in the ActHIB group. | At 1 month after last dose of primary vaccination | 
| Number of Subjects With Anti-PT, Anti-PRN and Anti-FHA Antibody Concentrations ≥ 5 EL.U/mL | Seroresponse was defined as the number of subjects showing a concentration above a threshold that leads to 90% seroresponse in the ActHIB group. | At 1 month after last dose of primary vaccination | 
| Number of Subjects With Anti-polyribosylribitol Phosphate (Anti-PRP) Antibody Concentrations ≥ 0.15 µg/mL and ≥ 1.0 µg/mL | Evaluation of persistence of anti-PRP antibodies induced by three primary vaccine doses of Hiberix, and ActHIB, each co-administered with Pediarix, Prevnar 13 and Rotarix, or Pentacel co-administered with Engerix-B, Rotarix and Prevnar 13 prior to the booster dose of Hiberix, ActHIB or Pentacel at 15-18 months of age and evaluation of immunogenicity of a booster dose of Hiberix co-administered with Infanrix, ActHIB co-administered with Infanrix and Pentacel in terms of the percentage of subjects with anti-PRP concentrations ≥0.15 µg/mL, ≥1.0 µg/mL and GMCs one month after the booster dose. | Prior to the booster vaccination and 1 month after the booster vaccination | 
| Anti-Hepatitis B (Anti-HBs) Antibody Concentrations | Antibody concentrations were tabulated as geometric mean concentrations (GMCs) and expressedas milli-international units per milliliter (mIU/mL). | At 1 month after last dose of primary vaccination | 
| Number of Subjects With S.Pneumoniae Antibody Concentrations ≥ 0.05 µg/mL, ≥ 0.2 µg/mL and ≥1.0 µg/mL | Evaluation of immunogenicity of a 3-dose primary vaccination course of Prevnar 13 co-administered with Hiberix, Rotarix and Pediarix, of Prevnar 13 co-administered with ActHIB, Rotarix and Pediarix and of Prevnar 13 co-administered with Pentacel, Rotarix and Engerix-B in terms of S.pneumoniae GMCs and antibody concentrations ≥ 0.05µg/mL, ≥ 0.2 µg/mL, ≥ 1.0 µg/mL at one month after the last dose of primary vaccination. | At 1 month after the last dose of primary vaccination | 
| Antibody Titers for Poliovirus Types 1, 2 and 3 | Antibody titers were given as geometric mean titers(GMTs). | At 1 month after last dose of primary vaccination | 
| Number of Subjects With Anti-HBs Antibody Concentrations Greater Than or Equal to Cut-off Values | The cut-off values were defined as a concentration≥ 3.3 mIU/mL (seropositivity) and ≥ 10 mIU/mL (seroprotection). | At 1 month after last dose of primary vaccination | 
| Anti-polyribosylribitol Phosphate (PRP) Antibody Concentrations | Antibody concentrations were given as Geometric Mean Concentrations (GMCs) expressed in micrograms per milliliter (µg/mL). | Prior to the booster vaccination and 1 month after the booster vaccination | 
| Anti-Hepatitis B (Anti-HBs) Antibody Concentrations ≥10.0 mIU/mL and ≥6.2 mIU/mL | Antibody concentrations were expressed as geometric mean concentrations (GMCs) and expressed as milli-international units per milliliter (mIU/mL). | Prior to the booster vaccination | 
| Number of Subjects With Anti-HB Antibody Concentrations ≥10.0 mlU/mL and ≥6.2mLU/mL | The cut-off values were defined as a concentration≥ 6.2 mIU/mL (seropositivity) and ≥ 10 mIU/mL (seroprotection). | Prior to booster vaccination | 
| Number of Subjects With Anti-PT, Anti-FHA and Anti-PRN Concentrations ≥ 5 EL.U/mL | Evaluation of persistence of anti-PT, anti-FHA and anti-PRN antibodies induced by Pediarix or Pentacel and Engerix-B prior to the administration of a booster dose of Hib vaccine at 15-18 months of age and evaluation of immunogenicity of a booster dose of Infanrix co-administered with Hiberix, a booster dose of Infanrix co-administered with ActHIB and a booster dose of Pentacel with respect to anti-PT, anti-FHA and anti- PRN antibodies. | Prior to the booster vaccination and 1 month after the booster vaccination | 
| Anti-poliovirus Types 1, 2, and 3 Antibody Titres and Titres ≥ 8 | Antibody concentrations were tabulated as geometric mean titers (GMTs) and expressed as titers. | Prior to the booster vaccination | 
| Number of Subjects With Anti-Polio-1,2,3 Antibody Titers ≥ 8 | Anti-polio 1,2,3 antibody titers greater or equal to the cut off value were calculated. | Prior to booster vaccination | 
| Number of Subjects With Anti-D and Anti-T Antibody Concentrations ≥ 0.1 IU/mL and ≥1.0 IU/mL, Respectively. | Evaluation of persistence of anti-D, anti-T antibodies induced by Pediarix or Pentacel and Engerix-B prior to the administration of a booster dose of Hib vaccine at 15-18 months of age and evaluation of immunogenicity of a booster dose of Infanrix co-administered with Hiberix, a booster dose of Infanrix co-administered with ActHIB and a booster dose of Pentacel with respect to anti-D and anti-T antibodies. | Prior to the booster vaccination and 1 month after the booster vaccination | 
| Number of Subjects With Any Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of any symptom regardless of intensity grade. | Within 4 days (Days 0-3) following the booster dose | 
| Number of Subjects With Any Solicited General Symptoms | Assessed solicited general symptoms were drowsiness, irritability, fever and loss of appetite. Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination. Any fever= Axillary temperature equal to or above (≥) 38 degrees Celsius (°C). | Within 4 days (Days 0-3) following the booster dose | 
| Number of Subjects With AEs of Specific Interest (AESIs) | An AESI was defined as an AE including autoimmune diseases and other mediated inflammatory disorders and assessed by the investigator as specific to the treatment administration. | From booster dose until 6 months following receipt of the booster dose | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs). | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | Within 31 days (Day 0 to Day 30) following the booster dose | 
| Number of Subjects With Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From the booster dose until 6 months following receipt of the booster dose | 
| Anti-FHA, Anti-PRN and Anti-PT Antibody Concentrations | Antibody concentrations were given as geometric mean concentrations (GMCs) expressed as enzyme-linked immuno-sorbent assay (ELISA) units per milliliter i.e. EL.U/mL. | pre-booster and one month after booster vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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primary vaccination course, Haemophilus influenzae type b, infants, children, booster vaccination, immunogenicity, safety, Gram-negative bacterial infections, vaccines, conjugate