Prophylactic Antipyretic Treatment in Children Receiving Booster Dose of Pneumococcal Conjugate Vaccine GSK1024850A

Study Overview
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Brief Summary
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The purpose of this trial is to assess if the rate of febrile reactions following the co-administration of a booster dose of pneumococcal conjugate vaccines with standard infant vaccines is lowered when paracetamol is given prophylactically and to assess the impact of pneumococcal conjugate vaccine on pneumococcal and H. influenzae nasopharyngeal carriage compared to control group receiving meningococcal conjugate vaccine (GSK134612). This protocol posting deals with objectives & outcome measures of the booster phase. The objectives & outcome measures of the primary phase are presented in a separate protocol posting (NCT number = NCT00370318).

Detailed Description
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The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Official Title
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Prophylactic Antipyretic Treatment in Children Receiving Booster Dose of Pneumococcal Vaccine GSK1024850A and DTPa-HBV-IPV/Hib Vaccine (Infanrix Hexa) and Assessment of Impact of Pneumococcal Vaccination on Nasopharyngeal Carriage

Conditions
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Infections, Streptococcal

Intervention / Treatment
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* Biological: Pneumococcal conjugate vaccine GSK1024850A.
* Biological: Infanrix hexa.
* Biological: Meningococcal vaccine GSK134612.
* Drug: Paracetamol.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol should be enrolled in the study. A male or female between, and including, 12-15 months of age at the time of the vaccination. Written informed consent obtained from the parent or guardian of the subject. Free of obvious health problems as established by medical history and clinical examination before entering into the study. Subjects in the unprimed group • A male or female who previously participated in study 107017 and received 3 doses of pneumococcal conjugate vaccine GSK1024850A. Exclusion Criteria: For all subjects: Concurrently participating in another clinical study, 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 Indication, other than specified in the protocol, for prophylactic antipyretic treatment. Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines within one month preceding the dose of study vaccines, or planned use during the entire study period. Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within 6 months prior to the dose of study vaccines. Planned administration/administration of a vaccine not foreseen by the study protocol, during the period starting one month before the dose of study vaccines and up to one month after the dose of study vaccines. History of, or intercurrent, diphtheria, tetanus, pertussis, polio, hepatitis B, Haemophilus influenzae type b disease. History of allergic disease or reactions likely to be exacerbated by any component of the vaccines. History of seizures (this criterion does not apply to subjects who have had a single, uncomplicated febrile convulsion in the past) or progressive neurological disease. Acute disease at the time of enrolment. Any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination. A family history of congenital or hereditary immunodeficiency. Major congenital defects or serious chronic illness. Administration of immunoglobulins and/or any blood products within three months preceding administration of the dose of study vaccines or planned administration during the study period. Subjects of which both parents have a history of atopia. Subject has received systemic antibiotic therapy for acute illness within 24 hours prior to the vaccination. Subject is likely to receive antipyretic treatment as a result of a concomitant illness or has been treated with paracetamol within the past 24 hours. DTPa-HBV-IPV/Hib vaccine: Known hypersensitivity after previous administration of diphtheria, tetanus, pertussis, polio, hepatitis B and Hib vaccines or to any component of the vaccines. Encephalopathy. As with other vaccines, administration of DTPa-HBV-IPV/Hib should be postponed in subjects suffering from acute mild, moderate or severe illness. For subjects in the AP-AP, AP-NAP and NAP groups: • Administration of any pneumococcal, diphtheria, tetanus, pertussis, polio, hepatitis B and/or Haemophilus influenzae type b vaccines other than allowed and used in study 107017. For subjects in the AP-AP group: • Subject with any contraindication to treatment with paracetamol. For subjects in the unprimed group: Previous vaccination with meningococcal polysaccharide vaccine of serogroup A, C, W-135 and/or Y. Previous vaccination with meningococcal polysaccharide conjugate vaccine of serogroups A, C, W-135 and/or Y. Planned administration of a hepatitis B vaccine not foreseen by the study protocol during the period starting one month after the dose of study vaccines and up to study end. Previous vaccination with tetanus toxoid containing vaccines including T, DTP, DT, DTP-IPV, DTP-HBV-IPV and Hib-TT vaccines six months prior to study entry. History of meningococcal disease due to serogroup A, C, W, or Y. Administration of any pneumococcal vaccine since birth. Full vaccination history since birth not available.

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 15 Months

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: Synflorix I Group<br>Subjects were vaccinated with 3 primary vaccination doses of Synflorix™ vaccine with prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), and received in this study at 12-15 months of age a booster dose of Synforix™ vaccine, co-administered with Infanrix™ hexa along with prophylactic antipyretic treatment. | Biological: Pneumococcal conjugate vaccine GSK1024850A.<br>* 1 intramuscular injection.<br>Biological: Infanrix hexa.<br>* 1 intramuscular injection.<br>* Other names: DTPa-HBV-IPV/Hib;Drug: Paracetamol.<br>* Body weight of < 7 kg: none; Body weight of ≥ 7 kg to < 9 kg : 3 suppositories of 125 mg to be administered at 8h intervals after vaccination. Body weight of ≥ 9 kg: 4 suppositories of 125 mg to be administered at 6h intervals after vaccination.<br>|
| Experimental: Synflorix II Group<br>Subjects were vaccinated with 3 primary vaccination doses of Synforix™ vaccine without prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), and received in this study at 12-15 months of age a booster dose of Synforix™ vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment | Biological: Pneumococcal conjugate vaccine GSK1024850A.<br>* 1 intramuscular injection.<br>Biological: Infanrix hexa.<br>* 1 intramuscular injection.<br>* Other names: DTPa-HBV-IPV/Hib;|
| Experimental: Synflorix PRE Group<br>Subjects were vaccinated with 3 primary vaccination doses of Synforix™ vaccine without prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), and received in this study (before the implementation of the protocol amendment) at 12-15 months of age a booster dose of Synforix™ vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment. | Biological: Pneumococcal conjugate vaccine GSK1024850A.<br>* 1 intramuscular injection.<br>Biological: Infanrix hexa.<br>* 1 intramuscular injection.<br>* Other names: DTPa-HBV-IPV/Hib;|
| Experimental: Synflorix POST Group<br>Subjects were vaccinated with 3 primary vaccination doses of Synforix™ vaccine without prophylactic administration of paracetamol in study 10PN-PD-DIT-010 (107017), and received in this study (after the implementation of the protocol amendment) at 12-15 months of age a booster dose of Synforix™ vaccine, co-administered with Infanrix™ hexa without prophylactic antipyretic treatment. | Biological: Pneumococcal conjugate vaccine GSK1024850A.<br>* 1 intramuscular injection.<br>Biological: Infanrix hexa.<br>* 1 intramuscular injection.<br>* Other names: DTPa-HBV-IPV/Hib;|
| Active Comparator: Mencevax + Infanrix Hexa Group<br>Age-matched pneumococcal vaccine unprimed group receiving a single dose of Mencevax™ vaccine co-administered with Infanrix™ hexa vaccine. | Biological: Infanrix hexa.<br>* 1 intramuscular injection.<br>* Other names: DTPa-HBV-IPV/Hib;Biological: Meningococcal vaccine GSK134612.<br>* 1 intramuscular injection.<br>* Other names: Mencevax™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reported With Core Fever (Rectal Temperature) Greater Than or Equal to (≥) the Cut-off | The cut-off for core fever was 38.0 degrees Celsius (ºC). | Within 4 days (Day 0-3) after primary vaccine dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reported With Core Fever (Rectal Temperature) Greater Than (>) the Cut-off | The cut-off value for core fever (rectal temperature) was 39.0ºC. | Within 4 days (Day 0-3) after primary vaccination dose | 
| Number of Subjects Reported With Any and Grade 3 Solicited Local Symptoms. | Solicited local symptoms assessed were pain, redness and swelling. Any was defined as any occurrence of the specified symptom regardless of intensity. Grade 3 pain was defined as cried when limb was moved/spontaneously painful. Grade 3 redness/swelling was defined as redness/swelling > 30 millimeters (mm) from injection site. | During the 4-day (Days 0-3) post-primary vaccination period | 
| Number of Subjects Reported With Any, Grade 3 and Related Solicited General Symptoms | Solicited general symptoms assessed were drowsiness, fever (rectal temperature ≥ 38.5°C), irritability and loss of appetite. Any was defined as any occurrence of the specified symptom regardless of intensity and relation to vaccination. Grade 3 drowsiness was defined as drowsiness that prevented normal activity. Grade 3 fever was defined as rectal temperature >40.0°C. Grade 3 irritability was defined as crying that could not be comforted/ prevented normal activity. Grade 3 loss of appetite was defined as not eating at all. Related was defined as solicited symptoms assessed by the investigator as causally related to the study vaccination. | During the 4-day (Day 0-3) post-vaccination period | 
| Number of Subjects Reported With Unsolicited Adverse Events (AEs) | The outcome measure was not reporting statistics for all the arms in the baseline period. Results were tabulated on baseline groups except for the Synforix PRE and Synforix POST groups, for which results were presented for the Pooled Synforix PRE and POST Group. 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) after primary vaccine dose. | 
| Number of Subjects Reported 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. | Throughout the entire study period (Month 0-Month 12) | 
| Number of Subjects Reported With AEs Resulting in Rash, New Onset of Chronic Illness (NOCI), Emergency Room (ER) Visits and Non-routine Physician Office Visits. | Results were tabulated only on Mencevax + Infanrix Hexa Group, according to the outcome measure specification of the protocol. | Up to 6 months after vaccination with Mencevax™ | 
| Number of Subjects With Antibody Concentrations Against Certain Pneumococcal Serotypes ≥ the Cut Off | Certain pneumococcal serotypes includes pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F). Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F antibody concentrations were measured by 22F-inhibition Enzyme-Linked ImmunoSorbent Assay (ELISA). The seroprotection cut-off for the assay was ≥ 0.2 microgram per milliliter (μg/mL). | Prior to booster vaccination (PRE), 1 month (M1) and 12 months (M12) post-booster vaccination | 
| Antibody Concentrations Against Certain Pneumococcal Serotypes ≥ the Cut Off. | Certain pneumococcal serotypes included pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F). Anti-1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F antibody concentrations were measured by 22F-inhibition Enzyme-Linked ImmunoSorbent Assay (ELISA). Seropositivity cut-off for the assay was ≥ 0.05 microgram per milliliter (μg/mL). | Prior to booster vaccination (PRE), 1 month (M1) and 12 months (M12) post-booster vaccination | 
| Opsonophagocytic Activity (OPA) Titers Against Pneumococcal Serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F | OPA titers against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F (Opsono-1, -4, -5, -6B, -7F, -9V, -14, -18C, -19F and -23F) were calculated, expressed as geometric mean titers (GMTs) and tabulated. The seropositivity cut-off for the assay was ≥ 8. | Prior to booster vaccination (PRE), 1 month (M1) and 12 months (M12) post-booster vaccination | 
| Concentrations of Antibodies Against Protein D (Anti-PD) | The seropositivity cut-off for the assay was ≥ 100 Enzyme-Linked ImmunoSorbent Assay (ELISA) units per milliliter (EL.U/mL). | Prior to booster vaccination (PRE), 1 month (M1) and 12 months (M12) post-booster vaccination | 
| Antibody Concentrations Against Pneumococcal Serotypes 6A and 19A (Anti-6A and 19A) | Anti-6A and 19A antibody concentrations were measured by 22F-inhibition Enzyme-Linked ImmunoSorbent Assay (ELISA). | Prior to booster vaccination (PRE), 1 month (M1) and 12 months (M12) post-booster vaccination | 
| Opsonophagocytic Activity (OPA) Titers Against Pneumococcal Cross-reactive Serotypes 6A and 19A | OPA titers against pneumococcal serotypes 6A and 19A (Opsono-6A and 19A) were calculated, expressed as geometric mean titers (GMTs) and tabulated. The seropositivity cut-off for the assay was ≥ 8. | Prior to booster vaccination (PRE), 1 month (M1) and 12 months (M12) post-booster vaccination | 
| Number of Subjects With Serum Bactericidal Antibodies, Using Baby Rabbit Complement for Assay (rSBA) Titres ≥ the Cut-off Values | The cut-off values assessed were 1:8 and 1:128 for meningococcal polysaccharides A , C, W-135 and Y serum bactericidal antibodies, using baby rabbit complement for assay (rSBA-MenA, rSBA-MenC, rSBA-MenW-135 and rSBA-MenY). Results were only tabulated for subjects who received a vaccine including the respective antigens (Mencevax + Infanrix Hexa Group). | Prior to vaccination (PRE), 1 month (M1) and 12 months (M12) post-vaccination | 
| rSBA-MenA, rSBA-MenC, rSBA-MenW-135 and rSBA-MenY Titers in the Mencevax + Infanrix Hexa Group | Results were only tabulated for subjects who received a vaccine including the respective antigens (Mencevax + Infanrix Hexa Group). | Prior to vaccination(PRE), 1 month (M1) and 12 months (M12) post- vaccination. | 
| Number of Subjects With Anti-polysaccharide N (Anti-PS) Concentrations ≥ the Cut-off Values | Anti-PS assessed were anti-PS meningitidis serogroup A (anti-PSA), C (anti-PSC), W (anti-PSW-135) and Y (anti-PSY). The cut-offs for anti-PS concentrations were 0.3 μg/mL and 2.0 μg/mL, tabulated for subjects who received a vaccine including the respective antigens (Mencevax + Infanrix Hexa Group). | Prior to vaccination(PRE), 1 month (M1) and 12 months (M12) post-vaccination | 
| Geometric Mean Antibody Concentration (GMCs) for Anti-polysaccharide N (Anti-PS) Antibody Concentrations | Anti-PS assessed were Anti-PSA, anti-PSC, anti-PSW-135 and anti-PSY. Results were only tabulated for subjects who received a vaccine including the respective antigens (Mencevax + Infanrix Hexa Group). | Prior to vaccination(PRE), 1 month (M1) and 12 months (M12) post- vaccination. | 
| Anti-tetanus Toxoids (Anti-T) Antibody Concentrations in the Mencevax + Infanrix Hexa Group | The seroprotection cut-off for the assay was ≥ 0.1 international units per milliliter (IU/mL). | Prior to vaccination (Pre) | 
| Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations in the Mencevax + Infanrix Hexa Group | The seroprotection cut-off for the assay was ≥ 10 milli international units per milliliter (mIU/mL). Results were only tabulated for subjects who received a vaccine including the respective antigens (Mencevax + Infanrix Hexa Group). Dummy lower limit (LL) (0.0) and upper limit UL (99999.9) were entered when number of subjects analysed = 1. | Prior to vaccination (Pre) | 
| Concentrations of Antibodies Against Diphtheria and Tetanus Toxoids (Anti-D and T). | The seroprotection cut-off for the assay was ≥ 0.1 international units per milliliter (IU/mL). | 1 month post-vaccination (M1) | 
| Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Haemagglutinin (Anti-FHA) and Anti-pertactin (Anti-PRN) Antibody Concentrations | The seropositivity cut-off for the assay was ≥ 5 Enzyme-Linked ImmunoSorbent Assay (ELISA) units per millimiter (EL.U/mL). | 1 month post-vaccination (M1) | 
| Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations | The seroprotection cut-off for the assay was ≥ 10 mIU/mL. | 1 month post-vaccination (M1) | 
| Anti-polyribosyl-ribitol Phosphate (Anti-PRP) Antibody Concentrations | The seroprotection cut-off for the assay was ≥ 0.15 μg/mL. | 1 month post-vaccination (M1) | 
| Anti-poliovirus (Anti-Polio) Types 1, 2 and 3 Titers | The seroprotection cut-off for the assay was ≥ 8. | 1 month post-vaccination (M1) | 
| Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations | The seroprotection cut-off for the assay was ≥ 10 mIU/mL. | 12 month post-vaccination (M12) | 
| Anti-poliovirus (Anti-Polio) Type 1, 2 and 3 Titers | The seroprotection cut-off for the assay was ≥ 8. | 12 month post-vaccination (M12) | 
| Number of Nasopharyngeal Swabs With S.Pneumoniae (Vaccine Serotypes) | Results were tabulated on Pooled Synflorix Group and on Mencevax + Infanrix Hexa Group. | Prior to vaccination(Pre), 1 month post-vaccination (M1), 3 months post-vaccination (M3), 7 months post-vaccination (M7), 12 months post-vaccination (M12) and across all time points (Overall) | 
| Number of Nasopharyngeal Swabs With S.Pneumoniae (Cross-reactive Serotypes) | Results were tabulated on Pooled Synflorix Group and on Mencevax + Infanrix Hexa Group. | Prior to vaccination(Pre), 1 month post-vaccination (M1), 3 months post-vaccination (M3), 7 months post-vaccination (M7), 12 months post-vaccination (M12) and across all time points (Overall) | 
| Number of Nasopharyngeal Swabs With S.Pneumoniae (Non-vaccine and Non-cross-reactive Serotypes) | Results were tabulated on Mencevax + Infanrix Hexa Group and on Pooled Synflorix Group. | Prior to vaccination(Pre), 1 month post-vaccination (M1), 3 months post-vaccination (M3), 7 months post-vaccination (M7), 12 months post-vaccination (M12) and across all time points (Overall) | 
| Number of Nasopharyngeal Swabs With H. Influenzae | Results were tabulated on Mencevax + Infanrix Hexa Group and on Pooled Synflorix Group. | Prior to vaccination(Pre), 1 month post-vaccination (M1), 3 months post-vaccination (M3), 7 months post-vaccination (M7), 12 months post-vaccination (M12) and across all time points (Overall) | 
| Number of Nasopharyngeal Swabs With S. Pneumoniae and H. Influenzae | Results were tabulated on Mencevax + Infanrix Hexa Group and on Pooled Synflorix Group. | Prior to vaccination(Pre), 1 month post-vaccination (M1), 3 months post-vaccination (M3), 7 months post-vaccination (M7), 12 months post-vaccination (M12) and across all time points (Overall) | 
| Number of Subjects With New Acquisition Associated to S. Pneumoniae Detected in Nasopharyngeal Swabs | Results were tabulated on Mencevax + Infanrix Hexa Group and on Pooled Synflorix Group. | 1 month post-vaccination (M1), 3 months post-vaccination (M3), 7 months post-vaccination (M7), 12 months post-vaccination (M12) and across all time points (Overall) | 
| Number of Subjects With New Acquisition Associated to H. Influentzae Detected in Nasopharyngeal Swabs. | Results were tabulated on Mencevax + Infanrix Hexa Group and on Pooled Synflorix Group. | 1 month post-vaccination (M1), 3 months post-vaccination (M3), 7 months post-vaccination (M7), 12 months post-vaccination (M12) and across all time points (Overall) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Streptococcus Pneumoniae Vaccines, Meningococcal disease, Carriage, Prophylactic antipyretic, Safety, Pneumococcal vaccine, Fever, Pneumococcal disease, Immunogenicity, Meningococcal vaccine, Booster vaccination