Study Assessing the Effect of Medications to Prevent Fever on Prevenar 13®

Study Overview
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Brief Summary
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The purposes of this study are assess the immunological response (measure the amount of antibodies, i.e. proteins that fight off germs) produced by children after they have been given the 13-valent pneumococcal vaccine (13vPnC) and INFANRIX hexa at 2, 3, 4 and 12 months of age when medications to prevent fever are given on the same day as the vaccination. Also to evaluate the safety of 13-valent pneumococcal conjugate vaccine (13vPnC) in children who receive medications to prevent fever on the day of vaccination.

Official Title
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A Phase 4, Randomized, Open-Label Trial To Assess The Impact Of Prophylactic Antipyretic Medication On The Immunogenicity Of 13-Valent Pneumococcal Conjugate Vaccine Given With Routine Pediatric Vaccinations In Healthy Infants

Conditions
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Pneumococcal Vaccines

Intervention / Treatment
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* Biological: 13-valent pneumococcal conjugate vaccine
* Biological: INFANRIX hexa
* Drug: Paracetamol
* Biological: 13-valent pneumococcal conjugate vaccine
* Biological: INFANRIX hexa
* Drug: Ibuprofen
* Biological: 13-valent pneumococcal conjugate vaccine
* Biological: INFANRIX hexa
* Drug: Paracetamol
* Biological: 13-valent pneumococcal conjugate vaccine
* Biological: INFANRIX hexa
* Drug: Ibuprofen
* Biological: 13-valent pneumococcal conjugate vaccine
* Biological: INFANRIX hexa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 2 months (56 to 98 days) at time of enrollment. Healthy infant as determined by medical history, physical examination, and judgment of the investigator. Exclusion Criteria: Previous vaccination with licensed or investigational pneumococcal, diphtheria, tetanus, pertussis, polio, or Hib conjugate vaccines. A previous anaphylactic reaction to any vaccine or vaccine-related component. Allergy or contraindication to paracetamol or ibuprofen administration. Contraindication to vaccination with pneumococcal conjugate, diphtheria, tetanus, pertussis, polio, Hib, or HBV vaccines.

Ages Eligible for Study
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Minimum Age: 56 Days
Maximum Age: 98 Days

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: Group 1<br>Subjects will receive 13-valent pneumococcal vaccine and INFANRIX hexa at 2, 3, 4 and 12 months of age. They will also receive 2 doses of paracetamol on the day of each vaccination. | Biological: 13-valent pneumococcal conjugate vaccine<br>* 13vPnC will be administered by intramuscular injection at 2, 3, 4 and 12 months of age.<br>Biological: INFANRIX hexa<br>* INFANRIX hexa will be administered by intramuscular injection at 2, 3, 4 and 12 months of age.<br>Drug: Paracetamol<br>* Paracetamol suspension for oral administration will be given at a weight adjusted dose of 15mg/kg/dose. The first dose will be given 6-8 hours after each vaccination, the second dose to be given 6-8 hours after the first.<br>|
| Experimental: Group 2<br>Subjects will receive 13-valent pneumococcal vaccine and INFANRIX hexa at 2, 3, 4 and 12 months of age. They will also receive 2 doses of ibuprofen on the day of each vaccination.the first dose. | Biological: 13-valent pneumococcal conjugate vaccine<br>* 13vPnC will be administered by intramuscular injection at 2, 3, 4 and 12 months of age.<br>Biological: INFANRIX hexa<br>* INFANRIX hexa will be administered by intramuscular injection at 2, 3, 4 and 12 months of age.<br>Drug: Ibuprofen<br>* Ibuprofen suspension for oral administration will be given at a weight adjusted dose of 10mg/kg/dose. The first dose will be given 6-8 hours after each vaccination, the second dose to be given 6-8 hours after the first.<br>|
| Experimental: Group 3<br>Subjects will receive 13-valent pneumococcal vaccine and INFANRIX hexa at 2, 3, 4 and 12 months of age. They will also receive 3 doses of paracetamol on the day of each vaccination. | Biological: 13-valent pneumococcal conjugate vaccine<br>* 13vPnC will be administered by intramuscular injection at 2, 3, 4 and 12 months of age.<br>Biological: INFANRIX hexa<br>* INFANRIX hexa will be administered by intramuscular injection at 2, 3, 4 and 12 months of age.<br>Drug: Paracetamol<br>* Paracetamol suspension for oral administration will be given at a weight adjusted dose of 15mg/kg/dose. The first dose will be given at the time of each vaccination, the second dose to be given 6-8 hours after the first, and the third dose to be given 6-8 hours after the second.<br>|
| Experimental: Group 4<br>Subjects will receive 13-valent pneumococcal vaccine and INFANRIX hexa at 2, 3, 4 and 12 months of age. They will also receive 3 doses of ibuprofen on the day of each vaccination. | Biological: 13-valent pneumococcal conjugate vaccine<br>* 13vPnC will be administered by intramuscular injection at 2, 3, 4 and 12 months of age.<br>Biological: INFANRIX hexa<br>* INFANRIX hexa will be administered by intramuscular injection at 2, 3, 4 and 12 months of age.<br>Drug: Ibuprofen<br>* Ibuprofen suspension for oral administration will be given at a weight adjusted dose of 10mg/kg/dose. The first dose will be given at the time of each vaccination, the second dose to be given 6-8 hours after the first, and the third dose to be given 6-8 hours after the second.<br>|
| Experimental: Group 5<br>Subjects will receive 13-valent pneumococcal vaccine and INFANRIX hexa at 2, 3, 4 and 12 months of age. This group does not receive any antipyretic medication as part of the study. | Biological: 13-valent pneumococcal conjugate vaccine<br>* 13vPnC will be administered by intramuscular injection at 2, 3, 4 and 12 months of age.<br>Biological: INFANRIX hexa<br>* INFANRIX hexa will be administered by intramuscular injection at 2, 3, 4 and 12 months of age.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Concentration (GMC) for Serotype-specific Pneumococcal Immunoglobulin G (IgG) Antibody 1 Month After the Infant Series | Antibody geometric least squares (LS) mean concentrations (GMCs) for 13 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, 23F, 1, 3, 5, 6A, 7F and 19A) are presented. GMC (13vPnC) and corresponding 2-sided 95 percent (%) confidence interval (CI) were evaluated. Geometric means (GMs) were calculated using all participants with available data for the specified blood draw. Here 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure and 'n' signifies participants with a determinate IgG concentration to the given serotype for each arm, respectively. | 1 month after the infant series | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Concentration (GMC) for Antigen-specific Pertussis Toxin (PT), Filamentous Hemagglutinin (FHA) and Pertactin (PRN) Antibody 1 Month After the Infant Series | Geometric LS mean concentration (GMCs) were measured in Enzyme-linked Immunosorbent Assay (ELISA) units/mL (EU/mL) and corresponding 2-sided 95% CIs were evaluated for pertussis (pertussis toxin [PT], filamentous hemagglutinin [FHA] and pertactin [PRN]) antibodies. | 1 month after the infant series | 
| Geometric Mean Concentration (GMC) for Antigen-specific Tetanus and Diphtheria Antibody 1 Month After the Infant Series | Geometric LS mean concentration (GMCs) were measured in International Units/mL (IU/mL) and corresponding 2-sided 95% CIs were evaluated for tetanus and diphtheria antibodies. | 1 month after the infant series | 
| Geometric Mean Concentration (GMC) for Antigen-specific Hepatitis B Virus (HBV) Antibody 1 Month After the Infant Series | Geometric LS mean concentration (GMCs) were measured in milli international units/mL (mIU/mL) and corresponding 2-sided 95% CIs were evaluated for hepatitis B virus (HBV) antibody. | 1 month after the infant series | 
| Geometric Mean Titer (GMT) for Antigen-specific Poliomyelitis Type 1, 2 and 3 Antibodies 1 Month After the Infant Series | Geometric LS mean concentrations (GMCs) were measured as titers and corresponding 2-sided 95% CIs were evaluated for poliomyelitis type 1, 2 and 3 antibodies. | 1 month after the infant series | 
| Geometric Mean Concentration (GMC) for Antigen-specific Haemophilus Influenzae Type b (Hib) Polyribosylribitol Phosphate (PRP) Antibody 1 Month After the Toddler Dose | Geometric LS mean concentration (GMCs) were measured in mcg/mL and corresponding 2-sided 95% CIs were evaluated for Hib PRP antibody. | 1 month after the toddler dose | 
| Geometric Mean Concentration (GMC) for Antigen-specific Pertussis Toxin (PT), Filamentous Hemagglutinin (FHA) and Pertactin (PRN) Antibodies 1 Month After the Toddler Dose | Geometric LS mean concentration (GMCs) were measured in EU/mL and corresponding 2-sided 95% CIs were evaluated for pertussis (pertussis toxin [PT], filamentous hemagglutinin [FHA] and pertactin [PRN]) antibodies. | 1 month after the toddler dose | 
| Geometric Mean Concentration (GMC) for Antigen-specific Tetanus and Diphtheria Antibodies 1 Month After the Toddler Dose | Geometric LS mean concentration (GMCs) were measured in IU/mL and corresponding 2-sided 95% CIs were evaluated for tetanus and diphtheria antibodies. | 1 month after the toddler dose | 
| Geometric Mean Concentration (GMC) for Antigen-specific Hepatitis B Virus (HBV) Antibody 1 Month After the Toddler Dose | Geometric LS mean concentration (GMCs) were measured in mIU/mL and corresponding 2-sided 95% CIs were evaluated for hepatitis B virus (HBV) antibody. | 1 month after the toddler dose | 
| Geometric Mean Titer (GMT) for Antigen-specific Poliomyelitis Type 1, 2 and 3 Antibodies 1 Month After the Toddler Dose | Geometric LS mean concentration (GMCs) were measured as titers and corresponding 2-sided 95% CIs were evaluated for poliomyelitis type 1, 2 and 3 antibodies. | 1 month after the toddler dose | 
| Geometric Mean Concentration (GMC) for Antigen-specific Haemophilus Influenzae Type b (Hib) Polyribosylribitol Phosphate (PRP) Antibody 1 Month After the Infant Series | Geometric LS mean concentrations (GMCs) and corresponding 2-sided 95% CIs were evaluated for Hib PRP antibody. | 1 month after the infant series | 
| Percentage of Participants Achieving Serotype-specific Pneumococcal Immunoglobulin G (IgG) Antibody Level Greater Than or Equal to (>=)0.35 Microgram Per Milliliter (Mcg/mL) 1 Month After the Infant Series | Percentage of participants achieving predefined antibody threshold >=0.35 mcg/mL along with the corresponding 95% confidence interval (CI) for 13 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, 23F, 1, 3, 5, 6A, 7F and 19A) are presented. Exact 2-sided CI based on the observed proportion of participants. | 1 month after the infant series | 
| Geometric Mean Concentration (GMC) for Serotype-specific Pneumococcal Immunoglobulin G (IgG) Antibody 1 Month After the Toddler Dose | Antibody geometric LS mean concentrations (GMCs) for 13 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, 23F, 1, 3, 5, 6A, 7F and 19A) are presented. GMC (13vPnC) and corresponding 2-sided 95% CI were evaluated. Geometric means (GMs) were calculated using all participants with available data for the specified blood draw. Here 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure and 'n' signifies participants with a determinate IgG concentration to the given serotype for each arm respectively. | 1 month after the toddler dose | 
| Percentage of Participants Achieving Serotype-Specific Pneumococcal Opsonophagocytic Activity (OPA) Titers Greater Than or Equal to (>=) Lower Limit of Quantitation (LLOQ) 1 Month After the Infant Series | Percentage of participants achieving serotype-specific pneumococcal OPA titer >= LLOQ, along with the corresponding 95% CIs for 13 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, 23F, 1, 3, 5, 6A, 7F and 19A) are presented. Exact 2-sided CI based on the observed proportion of participants. The OPA LLOQ in titers for each serotype: 1 = 1:18; 3 = 1:12; 4 = 1:21; 5 = 1:29; 6A = 1:37; 6B = 1:43; 7F = 1:210; 9V = 1:345; 14 = 1:35; 18C = 1:31; 19A = 1:18; 19F = 1:48; 23F = 1:13. | 1 month after the infant series | 
| Geometric Mean Titer (GMT) for Serotype-specific Pneumococcal Opsonophagocytic Activity (OPA) 1 Month After the Infant Series | Antibody-mediated serum OPA against the 13 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, 23F, 1, 3, 5, 6A, 7F and 19A) was measured centrally using a pneumococcal OPA assay. Results were expressed as OPA titers. OPA titers were logarithmically transformed for analysis; geometric means calculated and expressed as geometric mean titers (GMTs). | 1 month after the infant series | 
| Percentage of Participants Achieving Pre-specified Criteria for the Concomitant Antigens Contained in INFANRIX Hexa 1 Month After the Infant Series | Percentage of participants achieving pre-specified criteria for concomitant antigens contained in INFANRIX hexa (Hib polyribosylribitol phosphate [PRP] >=0.15 mcg/mL; Hib PRP >=1 mcg/mL; Pertussis PT >=14.6 EU/mL, FHA >=16.1 EU/mL, PRN >=24.0 EU/mL; Tetanus >=0.1 IU/mL; Diphtheria >=0.1 IU/mL; HBV >=10 mIU/mL; Poliomyelitis Type 1, 2, 3 >=1:8 titer) along with the corresponding 95% CIs were presented. Exact 2-sided CI based on the observed proportion of participants. Pre-specified criteria for pertussis was the level that 95% of the participants achieved in 13vPnC + INFANRIX hexa group. | 1 month after the infant series | 
| Percentage of Participants Achieving Pre-specified Criteria for the Concomitant Antigens Contained in INFANRIX Hexa 1 Month After the Toddler Dose | Percentage of participants achieving pre-specified criteria for concomitant antigens contained in INFANRIX hexa (Hib polyribosylribitol phosphate [PRP] >=0.15 mcg/mL; Hib PRP >=1 mcg/mL; Pertussis PT >=14.8 EU/mL, FHA >=46.5 EU/mL, PRN >=43.5 EU/mL; Tetanus >=0.1 IU/mL; Diphtheria >=0.1 IU/mL; HBV >=10 mIU/mL; Poliomyelitis Type 1, 2, 3 >=1:8 titer) along with the corresponding 95% CIs were presented. Exact 2-sided CI based on the observed proportion of participants. Pre-specified criteria for pertussis was the level that 95% of the participants achieved in 13vPnC + INFANRIX hexa group. | 1 month after the toddler dose | 
| Percentage of Participants Reporting Fever Within 4 Days: Infant Series Dose 1 | Participants' core (rectal) temperature was collected for 4 days after each vaccination using an electronic diary. Participants' temperature was collected at 6 to 8 hours after vaccination, 6 to 8 hours following that and coincidentally with antipyretic administration for groups receiving antipyretics. Temperature was recorded at bedtime daily for 3 following days (Day 2 to Day 4) and at any time during the 3 days when fever was suspected. The highest temperature for each day was recorded in the e-diary. Incidences of fever were presented in following categories: >=38 but <=39 degree Celsius (degree C), greater than (>) 39 but <=40 degree C and >40 degree C. | Within 4 days after infant series Dose 1 | 
| Percentage of Participants Reporting Fever Within 4 Days: Infant Series Dose 2 | Participants' rectal temperature was collected for 4 days after each vaccination using an electronic diary. Participants' temperature was collected at 6 to 8 hours after vaccination, 6 to 8 hours following that and coincidentally with antipyretic administration for groups receiving antipyretics. Temperature was recorded at bedtime daily for 3 following days (Day 2 to Day 4) and at any time during the 3 days when fever was suspected. The highest temperature for each day was recorded in the e-diary. Incidences of fever were presented in following categories: >=38 but <=39 degree C, >39 but <=40 degree C and >40 degree C. | Within 4 days after infant series Dose 2 | 
| Percentage of Participants Reporting Fever Within 4 Days: Infant Series Dose 3 | Participants' rectal temperature was collected for 4 days after each vaccination using an electronic diary. Participants' temperature was collected at 6 to 8 hours after vaccination, 6 to 8 hours following that and coincidentally with antipyretic administration for groups receiving antipyretics. Temperature was recorded at bedtime daily for 3 following days (Day 2 to Day 4) and at any time during the 3 days when fever was suspected. The highest temperature for each day was recorded in the e-diary. Incidences of fever were presented in following categories: >=38 but <=39 degree C, >39 but <=40 degree C and >40 degree C. Report of fever >40 degrees C after 13vPnC Infant Series Dose 3 was confirmed as data entry error. | Within 4 days after infant series Dose 3 | 
| Percentage of Participants Reporting Fever Within 4 Days: Toddler Dose | Participants' rectal temperature was collected for 4 days after each vaccination using an electronic diary. Participants' temperature was collected at 6 to 8 hours after vaccination, 6 to 8 hours following that and coincidentally with antipyretic administration for groups receiving antipyretics. Temperature was recorded at bedtime daily for 3 following days (Day 2 to Day 4) and at any time during the 3 days when fever was suspected. The highest temperature for each day was recorded in the e-diary. Incidences of fever were presented in following categories: >=38 but <=39 degree C, >39 but <=40 degree C and >40 degree C. | Within 4 days after toddler dose | 
| Number of Participants With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs): Infant Series | An AE was any untoward medical occurrence in a participant who received vaccine without regard to possibility of causal relationship. SAE: an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial/prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent events for infant series were events between infant series Dose 1 and up to 1 month (28 to 42 days) after infant series that were absent before treatment or that worsened relative to pre-treatment state. Reported non-SAEs included AEs other than SAEs collected using electronic diary (fever, systematic assessment) and events spontaneously collected on case report form at each visit (non-systematic assessment). | Baseline up to 1 Month (28 to 42 days) after infant series | 
| Number of Participants With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs): After the Infant Series | An AE was any untoward medical occurrence in a participant who received vaccine without regard to possibility of causal relationship. SAE: an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial/prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent events after the infant series were events between 1 month (28 to 42 days) after infant series to toddler dose that were absent before treatment or that worsened relative to pre-treatment state. Reported non-SAEs included AEs other than SAEs spontaneously collected on case report form (non-systematic assessment). | 1 Month (28 to 42 days) after infant series Dose 3 up to toddler dose | 
| Number of Participants With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs): Toddler Dose | An AE was any untoward medical occurrence in a participant who received vaccine without regard to possibility of causal relationship. SAE: an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial/prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent events for toddler dose were events between toddler dose and up to 1 month (28 to 42 days) after toddler dose that were absent before treatment or that worsened relative to pre-treatment state. Reported non-SAEs included AEs other than SAEs collected using electronic diary (fever, systematic assessment) and events spontaneously collected on case report form at each visit (non-systematic assessment). | Toddler dose up to 1 Month (28 to 42 days) after toddler dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prevenar 13, 13vPnC, Antipyretic medication, Healthy subjects