Immune Response and Safety Comparison of 3 Lots of GSK Biologicals' DTaP-IPV Candidate Vaccine to DTaP + IPV Vaccines

Study Overview
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Brief Summary
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The aims of this trial are to demonstrate the consistency of three manufacturing lots of GSK Biologicals' DTaP-IPV candidate vaccine in terms of immunogenicity and to evaluate the non-inferiority of GSK Biologicals' DTaP-IPV vaccine with respect to immunogenicity and safety compared to the control vaccines (separate injections of GSK Biologicals' DTaP vaccine [Infanrix] and Aventis Pasteur's IPV vaccine [IPOL]) when administered as a 5th dose of DTaP and a 4th dose of inactivated poliovirus vaccine in subjects 4 to 6 years of age. Vaccines will be co-administered with the second dose of M-M-RII, which is recommended at this age. Concomitant administration of a US-licensed influenza vaccine will be allowed according to seasonal availability of vaccine and at the discretion of the investigator.

Detailed Description
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Investigational groups: 3, each receive one of 3 lots of DTaP-IPV vaccine. Control: US-licensed DTaP (Infanrix) + US-licensed IPV (IPOL) vaccines administered in separate injections. Two study visits one month apart for a subset of subjects (Safety and Immunogenicity subset) with a blood draw at each visit. All other subjects will have one visit. A telephone contact 4-6 days after vaccination for all subjects, a telephone contact 31-38 days after vaccination for the Safety only subset and a telephone contact for all subjects during the extended safety follow-up phase (5 months following the active phase).

Official Title
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Safety, Immunogenicity and Consistency of 3 Manufacturing Lots of DTaP-IPV Vaccine Versus Separate Injections of GSK Biologicals' DTaP + Aventis Pasteur's IPV Administered as Booster Doses to Healthy Children 4-6 Years, Each Co-administered With Merck's MMR Vaccine

Conditions
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Tetanus, Acellular Pertussis, Diphtheria

Intervention / Treatment
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* Biological: SB213503 lot 1
* Biological: SB213503 lot 2
* Biological: SB213503 lot 3
* Biological: Infanrix
* Biological: IPOL
* Biological: M-M-R II


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female child between and including 4 and 6 years of age at the time of vaccination. Free of obvious health problems as established by medical history and brief medical evaluation before entering into the study. Received 4 doses of Infanrix and 3 doses of IPOL during the first 2 years of life. Vaccination against measles, mumps, and rubella in the second year of life. Subjects whom the investigator believed would comply with the requirements of the protocol. Written informed consent obtained before study entry from the parent(s) or guardian(s) of the subject. Exclusion criteria: Use of any investigational or non-registered drug or vaccine other than the study vaccines within 30 days preceding the administration of study vaccines, or planned use during the study period. History of previous or intercurrent diphtheria, tetanus, pertussis, polio, measles, mumps, or rubella disease, or of vaccination against these diseases given after the second year of life. Known exposure to diphtheria, tetanus, pertussis, or polio, prior to vaccination. Poliovirus vaccination with one or more doses of OPV vaccine. Administration or planned administration of a vaccine not foreseen by the study protocol within 30 days of study vaccination and ending at Day 30. Chronic administration or administration of immunosuppressants or other immune modifying drugs within six months prior to study vaccination or planned administration during the study period ending at Day 30. Administration of immunoglobulins and/or any blood products within three months prior to study vaccination or planned administration during the study period ending at Day 30. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus infection. History of seizures or progressive neurological disorder, including infantile spasms, uncontrolled epilepsy or progressive encephalopathy. Major congenital defects or serious chronic illness. Acute disease at the time of enrollment. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine(s), including allergic reactions to 2-phenoxyethanol, formaldehyde, neomycin, polymyxin B, streptomycin, gelatin, and/or latex. History of anaphylactic reaction to egg proteins or previous doses of the vaccine(s). Encephalopathy within 7 days of administration of previous dose of Infanrix. Fever ≥ 40.5°C or 104.9°F (rectal temperature) (39.5°C or 103.1°F, oral/axillary) within 48 hours of previous dose of Infanrix not due to another identifiable cause. Collapse or shock-like state (hypotonic-hyporesponsive episode) within 48 hours of previous dose of Infanrix. Persistent, severe, inconsolable screaming or crying lasting ≥ 3 hours which occurred within 48 hours of administration of previous dose of Infanrix. Thrombocytopenia following a previous dose of M-M-RII or its component vaccines. Inability to contact a parent/guardian of the subject by telephone. Blood dyscrasias (including current thrombocytopenia), leukemia, lymphomas or other malignant neoplasms affecting the bone marrow or lymphatic systems. Family history of congenital or hereditary immunodeficiency, unless the immune competence of the subject was demonstrated.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 6 Years

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: SB213503 lot 1 + M-M-R Group<br>Subjects aged 4 to 6 years received a dose of lot 1 of SB213503 vaccine and a dose of M-M-R II vaccine. SB213503 was administered by deep intramuscular injection in the left deltoid. M-M-R II was co-administered as a subcutaneous injection in the upper right deltoid. | Biological: SB213503 lot 1<br>* SB213503 lot 1 vaccine was administered as a single dose by intramuscular injection in the deltoid at Day 0.<br>* Other names: GSK Biologicals combined diphteria, tetanus, acellular pertussis and inactivated poliovirus lot 1 vaccine;Biological: M-M-R II<br>* M-M-R II vaccine was administered as a single dose by subcutaneous injection in the deltoid at Day 0.<br>* Other names: Merck and Company licensed combined measles-mumps-rubella vaccine;|
| Experimental: SB213503 lot 2 + M-M-R Group<br>Subjects aged 4 to 6 years received a dose of lot 2 of SB213503 vaccine and a dose of M-M-R II vaccine. SB213503 was administered by deep intramuscular injection in the left deltoid. M-M-R II was co-administered as a subcutaneous injection in the upper right deltoid. | Biological: SB213503 lot 2<br>* SB213503 lot 2 vaccine was administered as a single dose by intramuscular injection in the deltoid at Day 0.<br>* Other names: GSK Biologicals combined diphteria, tetanus, acellular pertussis and inactivated poliovirus lot 2 vaccine;Biological: M-M-R II<br>* M-M-R II vaccine was administered as a single dose by subcutaneous injection in the deltoid at Day 0.<br>* Other names: Merck and Company licensed combined measles-mumps-rubella vaccine;|
| Experimental: SB213503 lot 3 + M-M-R Group<br>Subjects aged 4 to 6 years received a dose of lot 3 of SB213503 vaccine and a dose of M-M-R II vaccine. SB213503 was administered by deep intramuscular injection in the left deltoid. M-M-R II was co-administered as a subcutaneous injection in the upper right deltoid. | Biological: SB213503 lot 3<br>* SB213503 lot 3 vaccine was administered as a single dose by intramuscular injection in the deltoid at Day 0.<br>* Other names: GSK Biologicals combined diphteria, tetanus, acellular pertussis and inactivated poliovirus lot 3 vaccine;Biological: M-M-R II<br>* M-M-R II vaccine was administered as a single dose by subcutaneous injection in the deltoid at Day 0.<br>* Other names: Merck and Company licensed combined measles-mumps-rubella vaccine;|
| Active Comparator: Infanrix + IPOL + M-M-R Group<br>Subjects aged 4 to 6 years received a dose of Infanrix and a dose of IPOL vaccines separately and a dose of M-M-R II vaccine. Infanrix was administered by deep intramuscular injection in the upper left deltoid. IPOL was administered subcutaneously in the lower right deltoid. M-M-R II was co-administered as a subcutaneous injection in the upper right deltoid. | Biological: Infanrix<br>* Infanrix vaccine was administered as a single dose by intramuscular injection in the deltoid at Day 0.<br>* Other names: GSK Biologicals combined diphteria, tetanus, acellular pertussis vaccine;Biological: IPOL<br>* IPOL vaccine was administered as a single dose by subcutaneous injection in the deltoid at Day 0.<br>* Other names: Aventis Pasteur inactivated poliovirus vaccine;Biological: M-M-R II<br>* M-M-R II vaccine was administered as a single dose by subcutaneous injection in the deltoid at Day 0.<br>* Other names: Merck and Company licensed combined measles-mumps-rubella vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Concentrations (GMCs) for Anti-diphtheria (Anti-D) and Anti-tetanus (Anti-T) Antibodies in a Subset of Subjects | GMCs were measured by Enzyme-Linked Immunosorbent assay (ELISA), expressed in international units per milliliter (IU/mL). | At Month 1 (i.e. one month after vaccination) | 
| Geometric Mean Concentrations (GMCs) for Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Haemagglutinin (Anti-FHA) and Anti-pertactin (Anti-PRN) Antibodies in a Subset of Subjects | GMCs were measured by Enzyme-Linked Immunosorbent assay (ELISA), expressed in ELISA units per milliliter (EL.U/mL). | At Month 1 (i.e. one month after vaccination) | 
| Geometric Mean Titers (GMTs) for Anti-poliovirus Types 1, 2 and 3 Antibodies in a Subset of Subjects | GMTs were measured by Neutralization assay and expressed in titers. | At Month 1 (i.e. one month after vaccination) | 
| Number of Subjects With Booster Response Against Diphtheria Toxoid (D) and Tetanus Toxoid (T) Antigens in a Subset of Subjects | Vaccine response defined as: For initially seronegative subjects [pre-booster antibody concentration below (<) cut-off of 0.1 international units per milliliter (IU/mL)] with an increase of at least four times the cut-off one month after vaccination [post-booster antibody concentration greater than or equal to (≥) 0.4 IU/mL]. For initially seropositive subjects (pre-booster antibody concentration ≥ 0.1 IU/mL) with an increase of at least four times the pre-booster antibody concentration one month after vaccination. | At Month 1 (i.e. one month after vaccination) | 
| Number of Subjects With Booster Response Against Pertussis Toxoid (PT), Filamentous Haemagglutinin (FHA) and Pertactin (PRN) Antigens in a Subset of Subjects | Vaccine response defined as: For initially seronegative subjects [pre-booster antibody concentration below (<) cut-off of 5 EL.U/mL] with an increase of at least four times the cut-off one month after vaccination (post-booster antibody concentration ≥ 20 EL.U/mL). For initially seropositive subjects with pre-booster antibody concentration ≥ 5 EL.U/mL and < 20 EL.U/mL with an increase of at least 4 times the pre-booster antibody concentration one month after vaccination. For initially seropositive subjects with pre-booster antibody concentration ≥ 20 EL.U/mL with an increase of at least 2 times the pre-booster antibody concentration one month after vaccination. | At Month 1 (i.e. one month after vaccination) | 
| Number of Subjects With Circumferential Swelling at the Injection Site | Swelling (at the SB213503 & Infanrix injection sites) was categorized as an increase of > or ≤ 30 mm in mid upper arm circumference compared to baseline measurement or with an increase in mid upper arm missing; extent of swelling > or ≤ 50 % of upper arm length, or diameter of injection site missing. | Within 4 days (Day 0-3) after vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Seroprotected Subjects Against Diphteria (D) and Tetanus (T) Antigens in a Subset of Subjects | A seroprotected subject is defined as a vaccinated subject with anti-D and anti-T antibody concentration greater than or equal to (≥) 0.1 international units per milliliter (IU/mL). | At Month 1 (i.e. one month after vaccination) | 
| Number of Seroprotected Subjects Against Poliovirus Types 1, 2 and 3 Antigens in a Subset of Subjects | A seroprotected subject is defined as a vaccinated subject with anti-poliovirus types 1, 2 and 3 antibody titers greater than or equal to 1:8. | At Month 1 (i.e. one month after vaccination) | 
| Number of Seropositive Subjects Against Pertussis Toxoid (PT), Filamentous Haemagglutinin (FHA) and Pertactin (PRN) Antigens in a Subset of Subjects | A seropositive subject was defined as a vaccinated subject with anti-PT, anti-FHA and anti-PRN antibody concentrations greater than or equal to (≥) 5 ELISA units per milliliter (EL.U/mL). | At Month 1 (i.e. one month after vaccination) | 
| Number of Subjects With Anti-D and Anti-T Antibody Concentrations Greater Than or Equal to (≥) 1 IU/mL | The number of subjects with anti-D and anti-T antibody concentrations greater than or equal to (≥) 1 IU/mL is reported. | At Month 1 (i.e. one month after vaccination) | 
| Number of Subjects With Booster Response for Poliovirus Types 1, 2 and 3 Antigens in a Subset of Subjects | Vaccine response defined as: For initially seronegative subjects (pre-booster antibody titer below cut-off of 1:8), an antibody titer ≥ 1:32 at one month after vaccination. For initially seropositive subjects (pre-booster antibody titer ≥1:8), an increase at least four times the pre-booster antibody titer at one month after vaccination. | At Month 1 (i.e. one month after vaccination) | 
| Geometric Mean Titers (GMTs) for Serum Haemagglutination-inhibition (HI) Anti-H1N1, Anti-H3N2 and Anti-B Antibodies in a Subset of Subjects | GMTs were measured by hemagglutination inhibition assay and expressed in titers. | At Day 0 (i.e. before vaccination) and at Month 1 (i.e. one month after vaccination) | 
| Number of Seroconverted Subjects Against Influenza Virus Strains H1N1, H3N2, and B in a Subset of Subjects | Seroconversion was defined as a post-vaccination haemagglutination-inhibition (HI) titer of ≥ 1:40 in an initially HI antibody seronegative subject (pre-vaccination HI titer < 1:10), or a ≥ 4 fold rise in HI titer in an initially HI antibody seropositive subject (pre-vaccination HI titer ≥ 1:10) The 3 flu strains assessed were H1N1, H3N2, and B. | At Month 1 (i.e. one month after vaccination) | 
| Number of Seroprotected Subjects Against Influenza Virus Strains H1N1, H3N2, and B in a Subset of Subjects | A seroprotected subject is defined as a vaccinated subject with anti-H1N1, anti-H3N2, and anti-B antibody titers greater than or equal to (≥) 1:40. | At Day 0 (i.e. before vaccination) and at Month 1 (i.e. one month after vaccination) | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness, and swelling (at the SB213503 & Infanrix vaccination sites). Any = any symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activities. Grade 3 redness/swelling = redness/swelling spreading up to or beyond 50 mm diameter. | During the 4-day (Day 0-3) post-vaccination period | 
| Number of Subjects With Any and Grade 3 Increase in the Mid-upper Arm Circumference at the Injection Site | Assessed specific symptom was increase in mid upper arm circumference (at the SB213503 & Infanrix injection sites). Any = any symptom regardless of intensity grade. Grade 3 increase in mid upper arm circumference = mid upper arm circumference greater than 30 mm. | During the 4-day (Day 0-3) post-vaccination period | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were drowsiness, fever (orally) [≥ 37.5 degrees Celsius (°C)] and loss of appetite. Any = any solicited general symptom irrespective of intensity grade or relationship to vaccination. Grade 3 drowsiness = drowsiness that prevented normal activity. Grade 3 loss of appetite = not eating at all. Related = considered by the investigator to be related to the vaccine. Grade 3 fever = fever >39°C. | During the 4-day (Day 0-3) post-vaccination period | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms Specific to M-M-R II Vaccination | Solicited general symptoms specific to M-M-R II vaccination were fever [≥ 37.5 degrees Celsius (°C)], rash/exanthem, parotid/salivary gland swelling, and suspected signs of meningism including febrile convulsions . Any = any symptom regardless of intensity grade. Grade 3 = symptom that prevented normal everyday activity. Related = considered by the investigator to be related to the vaccine. Grade 3 fever = fever >39°C. | During the 15-day (Day 0-14) post-vaccination period | 
| 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 (Days 0-30) post-vaccination period | 
| Number of Subjects With Serious Adverse Events (SAEs) | Serious adverse events (SAEs) that were assessed included medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. | During the entire study period (from Day 0 through 6 months [minimum 182 days post-vaccination]) | 
| Number of Subjects With Onset of Chronic Illness(es) and AE(s) Leading to Emergency Room (ER) or to Physician Office Visits | Among assessed chronic illness(es) were: autoimmune disorders, asthma, type I diabetes, and allergies. AEs leading to emergency room (ER) visits or to physician office visits that were not related to well-child care, vaccination, injury or common acute illnesses such as upper respiratory tract infection, otitis media, pharyngitis, and gastroenteritis. | During the extended safety follow-up phase (i.e. 5 months following the active phase [from Day 31 up to minimum 182 days post-vaccination]) |