Evaluation of a Vaccine for Reducing Ear and Lung Infections in Children

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to 1) demonstrate the protective efficacy against acute otitis media (AOM), 2) assess safety of the GlaxoSmithKline (GSK) Biologicals' pneumococcal vaccine GSK2189242A in Native American infants aged less than 24 months, living in the southwestern US, in and around the Navajo and White Mountain Apache reservations, and 3) evaluate the impact on acute lower respiratory tract infections (ALRI) up to the second year of life.

Detailed Description
-----------------
The study will also evaluate the impact of the pneumococcal vaccine GSK2189242A on nasopharyngeal carriage in a subgroup of children called Carriage subgroup. Immunogenicity and reactogenicity of the pneumococcal vaccine GSK2189242A will be evaluated in another subgroup of children called Immuno/reacto subgroup. Protocol Posting has been updated following Protocol Amendment 3, April 2012, leading to the addition of a secondary outcome measure. Protocol Posting has been updated following Protocol Amendment 7, March 2017, to add serological testing for antibodies against the Hib polysaccharide PRP on samples collected 12 months following booster dose (Month 22) in the Immuno/reacto sub-cohort, in order to evaluate the long term persistence of immune responses to co-administered PedvaxHIB vaccine.

Official Title
-----------------
Study to Determine Protective Efficacy Against Otitis Media and Assess Safety of an Investigational Pneumococcal Vaccine 2189242A in Healthy Infants

Conditions
-----------------
Infections, Streptococcal

Intervention / Treatment
-----------------
* Biological: Pneumococcal vaccine GSK2189242A
* Biological: Placebo
* Biological: Prevnar 13®
* Biological: PedvaxHIB®


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject who the investigator believes that their parent(s)/Legally Authorized Representative(s) (LARs) can and will comply with the requirements of the protocol. A male or female American Indian infant between, and including, 6 and 12 weeks (42-90 days) of age at the time of the first vaccination. Voluntary, written informed consent obtained from the parents/LAR(s) of the subject. Where parent(s)/LAR(s) are illiterate, the consent form will be countersigned by a witness. Healthy subject as established by medical history and clinical examination before entering into the study. Born after a gestation period of more than 35 6/7 weeks. Exclusion Criteria: For all infants: Child in care. Use of any investigational or non-registered product 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 starting from 30 days before each dose and ending 30 days after each dose of study vaccines, with the exception of licensed inactivated influenza vaccines and recommended pediatric vaccines. 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. Previous vaccination against S. pneumoniae. Obstruction or anomalies of the nasopharyngeal space. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. Family history of congenital or hereditary immunodeficiency. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine(s) including latex. Major congenital defects or serious chronic illness. History of any neurological disorders or seizures. Acute disease and/or fever at the time of enrollment. Administration of immunoglobulins and/or any blood products since birth or planned administration during the study period. Any medical or social condition which might interfere with the assessment of the study objectives in the opinion of the investigator. For infants in the Immuno/reacto subgroup only: • Previous vaccination against H. influenzae type b.

Ages Eligible for Study
-----------------
Minimum Age: 6 Weeks
Maximum Age: 12 Weeks

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dPly-PhtD Group<br>Healthy Native American infants between, and including, 6 and 12 weeks (42-90 days) of age at the time of the first vaccination, receiving GSK2189242A (dPly-PhtD) vaccine co-administered with Prevenar13™: 3 primary doses at 2, 4, 6 months of age and a booster dose at 12-15 months of age. PedvaxHIB was given as study vaccine to a subset of subjects at 2, 4 and 12-15 months. At the primary epoch, the dPly-PhtD vaccine was administered intramuscularly into the right anterolateral thigh and at the booster epoch, the dPly-PhtD vaccine was administered into the right deltoid or anterolateral thigh if the deltoid muscle size was not adequate. At the primary epoch, the co-administered Prevenar13™ and PedvaxHIB vaccines were administered intramuscularly into the left anterolateral thigh and at the booster epoch, the Prevenar13™ and PedvaxHIB vaccines were administered into the left deltoid or anterolateral thigh if the deltoid muscle size was not adequate. | Biological: Pneumococcal vaccine GSK2189242A<br>* 4 doses administered intramuscularly<br>Biological: Prevnar 13®<br>* 4 doses administered intramuscularly<br>Biological: PedvaxHIB®<br>* 4 doses administered intramuscularly<br>|
| Placebo Comparator: Control Group<br>Healthy Native American infants between, and including, 6 and 12 weeks (42-90 days) of age at the time of the first vaccination, receiving Placebo vaccine co-administered with Prevenar13™: 3 primary doses at 2, 4, 6 months of age and a booster dose at 12-15 months of age. PedvaxHIB was given as study vaccine to a subset of subjects at 2, 4 and 12-15 months. At the primary epoch, the Placebo vaccine was administered intramuscularly into the right anterolateral thigh and at the booster epoch, the Placebo vaccine was administered into the right deltoid or anterolateral thigh if the deltoid muscle size was not adequate. At the primary epoch, the co-administered Prevenar13™ and PedvaxHIB vaccines were administered intramuscularly into the left anterolateral thigh and at the booster epoch, the Prevenar13™ and PedvaxHIB vaccines were administered into the left deltoid or anterolateral thigh if the deltoid muscle size was not adequate. | Biological: Placebo<br>* 4 doses administered intramuscularly<br>Biological: Prevnar 13®<br>* 4 doses administered intramuscularly<br>Biological: PedvaxHIB®<br>* 4 doses administered intramuscularly<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Occurrence of Any Acute Otitis Media (AOM) Diagnosed and Verified Against American Academic of Pediatrics (AAP) Criteria | Time to occurrence of any episode of AOM is expressed in terms of rate: Person-year rate = number of episodes (n)/sum of follow-up expressed in years (T[year)]). Definition of clinical AOM diagnosed and verified against AAP criteria required meeting three criteria based on the guidelines from the AAP [AAP, 2004], as per the judgment of a treating physician or equivalent licensed medical professional: A history of acute (recent, usually abrupt) onset of signs and symptoms of middle-ear inflammation and middle-ear effusion (MEE).AND The presence of MEE indicated by any of the following: a) Bulging of tympanic membrane; b) Limited or absent mobility of tympanic membrane; c) Air-fluid level behind tympanic membrane; d) Otorrhea AND Signs or symptoms of middle-ear inflammation as indicated by either: a) Distinct erythema of tympanic membrane or b) Distinct otalgia (discomfort clearly referable to the ear[s] that resulted in interference with or precluded normal activity or sleep). | Any time from 2 weeks after the administration of dose 3 up to Month 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Occurrence of Any Episodes of AOM Diagnosed by Healthcare-provider | Time to occurrence of any episode of AOM is expressed in terms of rate: Person-year rate = number of episodes (n)/sum of follow-up expressed in years (T[year)]). A healthcare-provider-diagnosed clinical AOM case was defined as an AOM event diagnosed by a treating physician or equivalent licensed medical professional with or without clinical symptoms documented in the routine medical record. | Any time from 2 weeks after the administration of dose 3 up to Month 22 | 
| Time to Occurrence of Any Clinical Acute Otitis Media (AOM) Diagnosed and Verified Against Modified American Academic of Pediatrics (AAP) Criteria | Time to occurrence of any episode of AOM is expressed in terms of rate: Person-year rate = number of episodes (n)/sum of follow-up expressed in years (T[year)]). Definition of clinical AOM diagnosed and verified against modified AAP criteria required a history of acute disease (i.e. AAP criterion 1) together with abnormal tympanic membrane (i.e. one of the AAP criteria 2 or 3a), as per the judgment of a treating physician or equivalent licensed medical professional: 1. A history of acute (recent, usually abrupt) onset of signs and symptoms of middle-ear inflammation and middle-ear effusion (MEE).AND 2. The presence of MEE that is indicated by any of the following: a) Bulging of tympanic membrane, b) Limited or absent mobility of tympanic membrane, c) Air-fluid level behind tympanic membrane, d) Otorrhea OR 3. Signs or symptoms of middle-ear inflammation as indicated by: a) Distinct erythema of tympanic membrane. | Any time from 2 weeks after the administration of dose 3 up to Month 22 | 
| Number of Subjects With Any Recurrent Healthcare Provider Diagnosed Acute Otitis Media (AOM) | Recurrent AOM was defined as at least 3 AOM episodes diagnosed by a physician or equivalent licensed medical professional and occurring within 6 months or at least 4 episodes within one year, regardless of the etiology. | From the administration of dose 1 up to Month 22 | 
| Time to Occurrence of Any Draining Acute Otitis Media (AOM) | Time to occurrence of any episode of AOM is expressed in terms of rate: Person-year rate = number of episodes (n)/sum of follow-up expressed in years (T[year)]). Draining AOM was defined as AOM with otorrhea or with spontaneously perforated tympanic membrane. In this case, middle ear fluid (MEF) was to be swabbed with no tympanocentesis needed and tested for the presence of S. pneumoniae and other pathogens as part of the routine clinical practice. Draining pneumococcal AOM were defined as draining AOM cases with S. pneumoniae identified in MEF. | Any time from 2 weeks after the administration of dose 3 up to Month 22 | 
| Time to Occurrence of Any Draining Pneumococcal Acute Otitis Media (AOM) | Time to occurrence of any episode of AOM is expressed in terms of rate: Person-year rate = number of episodes (n)/sum of follow-up expressed in years (T[year)]). Draining AOM was defined as AOM with otorrhea or with spontaneously perforated tympanic membrane. In this case, middle ear fluid (MEF) was to be swabbed with no tympanocentesis needed and tested for the presence of S. pneumoniae and other pathogens as part of the routine clinical practice. Draining pneumococcal AOM were defined as draining AOM cases with S. pneumoniae identified in MEF. | Any time from 2 weeks after the administration of dose 3 up to Month 22 | 
| Number of Subjects With Any Acute Otitis Media (AOM) With Temporally Related Carriage | AOM with temporally related carriage was defined as AOM with nasopharyngeal swab taken within 3 days before or after an AOM episode. | From the administration of dose 1 up to Month 22 | 
| Time to Occurrence of Medically Attended Acute Lower Respiratory Tract Infection (ALRI) | Time to occurrence of any episode of AOM is expressed in terms of rate: Person-year rate = number of episodes (n)/ sum of follow-up expressed in years (T[year)]). ALRI was defined by the presence of tachypnea (respiratory rate >50 amongst children 2 to 12 months of age, and respiratory rate >40 in children over 1 year of age) and at least two of the following signs and symptoms: cough; fever documented at visit or reported within preceding 3 days (Fever was defined as temperature ≥100.4°F (38.0°C) regardless of the route of measurement); increased work of breathing: grunting, nasal flaring, and intercostal and/or subcostal retractions; auscultatory abnormalities: wheezing, crackles, rhonchi, decreased breath sounds. | Any time from 2 weeks after the administration of dose 3 up to Month 22 | 
| Time to Occurrence of Medically Attended ALRI With Fever Documented at the Visit or History of Fever Within 3 Days Preceding a Given Episode | Time to occurrence of any episode of AOM is expressed in terms of rate: Person-year rate = number of episodes (n)/ sum of follow-up expressed in years (T[year)]). ALRI was defined by the presence of tachypnea (respiratory rate >50 amongst children 2 to 12 months of age, and respiratory rate >40 in children over 1 year of age) and at least two of the following signs and symptoms: cough; fever documented at visit or reported within preceding 3 days (Fever is defined as temperature ≥100.4°F (38.0°C) regardless of the route of measurement); increased work of breathing: grunting, nasal flaring, and intercostal and/or subcostal retractions; auscultatory abnormalities: wheezing, crackles, rhonchi, decreased breath sounds. | Any time from 2 weeks after the administration of dose 3 up to Month 22 | 
| Time to Occurrence of Any Medically Attended Healthcare-provider-diagnosed ALRI With Fever Documented at the Visit or History of Fever Within 3 Days Preceding a Given Episode. | Time to occurrence of any episode of AOM is expressed in terms of rate: Person-year rate = number of episodes (n)/ sum of follow-up expressed in years (T[year)]). A healthcare-provider-diagnosed ALRI with fever case was defined as, but not limited to, chest infection, bronchiolitis, pneumonia, bronchopneumonia, pleural effusion or empyema diagnosed by a treating physician or equivalent licensed medical professional with fever documented at the time of visit or history of fever within 3 days preceding a given episode and with or without other clinical symptoms documented in the routine medical record. | Any time from 2 weeks after the administration of dose 3 up to Month 22 | 
| Number of Subjects With S. Pneumoniae (Any and Serotype Specific) in the Nasopharynx - Carriage Sub-cohort | Positive cultures of S. pneumoniae (any and serotype specific) identified in the nasopharynx were analyzed. | At 7 months of age (Month 5), 12-15 months of age (Month 10),18-22 months of age (Month 16) and 24-27 months of age (Month 22) | 
| Antibody Concentrations Against Pneumococcal Pneumolysin Toxoid (Ply) and Pneumococcal Histidine Triad Protein D (PhtD) Proteins - Immuno/Reacto Sub-cohort | Anti-Ply and anti-PhtD antibody concentrations were measured by Enzyme-linked immunosorbent assay (ELISA) immunoassay and expressed as geometric mean concentrations (GMCs), in ELISA Units per milliliter (EL.U/mL). Cut-off of the assay were concentrations equal to (=) 12 EL.U/mL for anti-Ply antibodies and = 17 EL.U/mL for anti-PhtD antibodies. | One month post-dose 3 [PIII(Month 5)], prior to booster dose [PIII(Month 10)] and one and twelve months post-booster dose [Post-booster(Month 11) and Post-booster(Month 22)], respectively | 
| Concentrations of Antibodies Inhibiting Pneumococcal Pneumolysin Toxoid (Ply) Haemolysis Activity, or Hem-Ply Antibodies | Inhibition of Ply hemolysis activity was not evaluated due to assay stability issues. | One month post-dose 3 [PIII(Month 5)], prior to booster dose [PIII(Month 10)] and one and twelve months post-booster dose [Post-booster(Month 11) and Post-booster(Month 22)], respectively | 
| Concentrations of Antibodies Against Polyribosyl Ribitol Phosphate (Anti-PRP) - Immuno/Reacto Sub-cohort | Seroprotection rate = Anti-PRP antibody concentrations ≥ 0.15 µg/mL. | 1 month post-dose 3 [PIII(Month 5)], prior to booster dose [PIII(Month 10)], 1 month post-booster dose [Post-booster(Month 11)], 12 months post-booster dose [Post-booster(Month 22)] | 
| Antibody Concentrations Against Vaccine Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F | Antibody concentrations were measured by Electro-chemiluminescence assay (ECL), expressed as geometric mean concentrations (GMCs), in micrograms per milliliter (µg/mL). The cut-off of the assay was a serotype-specific antibody concentration higher than or equal to (≥) LLOQ (Lower Limit of Quantification) expressed in µg/mL: 0.08 for Anti-1; 0.075 for anti-3; 0.061 for Anti-4; 0.198 for Anti-5; 0.111 for Anti-6A and Anti-18C; 0.102 for Anti-6B; 0.063 for Anti-7F; 0.066 for Anti-9V; 0.160 for Anti-14; 0.199 for Anti-19A; 0.163 for Anti-19F; 0.073 for Anti-23F. | One month post-dose 3 [PIII(Month 5)], prior to booster dose [PIII(Month 10)] and one month post-booster dose [Post-booster(Month 11)] | 
| Antibody Concentrations Against Vaccine-related Serotypes 6C | No analysis was performed on antibody concentrations against vaccine-related serotype 6C as no specific qualified/validated assay was available. | One month post-dose 3 [PIII(Month 5)], prior to booster dose [PIII(Month 10)] and one month post-booster dose [Post-booster(Month 11)] | 
| Titers for Opsonophagocytic Activity Against Pneumococcal Serotypes | Titers for opsonophagocytic activity assessed for this outcome measure were those for opsonophagocytic activity against the vaccine pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F (OPA-1, -3, -4, -5, -6A, -6B, -7F, -9V, -14, -18C, -19A, -19F and -23F). The cut-off of the assay was a titer for opsonophagocytic activity higher than or equal to (≥) LLOQ: 8 for OPA-1, OPA-3 and OPA-6B; 33 for OPA-4, and OPA-14; 50 for OPA-5; 151 for OPA-6A; 330 for OPA-7F; 275 for OPA-9V; 11 for OPA-18C; 143 for OPA-19A; 36 for OPA-19F; 101 for OPA-23F. | One month post-dose 3 [PIII(Month 5)] and one month post-booster dose [Post-booster(Month 11)] | 
| Titers for Opsonophagocytic Activity Against Pneumococcal Serotypes 6C | Titers for opsonophagocytic activity assessed for this outcome measure were those for opsonophagocytic activity against the vaccine-related pneumococcal serotypes 6C (OPA-6C). The cut-off of the assay was a titer for opsonophagocytic activity higher than or equal to (≥) 145. | One month post-dose 3 [PIII(Month 5)] and one month post-booster dose [Post-booster(Month 11)] | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms, After Primary Vaccination - Immuno/Reacto Sub-cohort | Assessed local symptoms were pain, redness and swelling. Any = Occurrence of the specified solicited local symptom, regardless of intensity. Grade 3 Pain = Crying when limb was moved/spontaneously painful. Grade 3 Redness/Swelling = Redness/swelling at injection site larger than (>) 30 millimeters (mm). The Immuno /reacto sub-cohort was composed of 200 vaccinated subjects from each study group. | Within the 4-day (Days 0-3) post-primary vaccination period following each dose | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms, After Booster Vaccination - Immuno/Reacto Sub-cohort | Assessed local symptoms were pain, redness and swelling. Any = Occurrence of the specified solicited local symptom, regardless of intensity. Grade 3 Pain = Crying when limb was moved/spontaneously painful. Grade 3 Redness/Swelling = Redness/swelling at injection site larger than (>) 30 millimeters (mm). The Immuno /reacto sub-cohort was composed of 200 vaccinated subjects from each study group. | Within the 4-day (Days 0-3) post-booster vaccination period | 
| Number of Subjects With Any and Grade 3 Solicited General Symptoms and With Solicited General Symptoms With Relationship to Vaccination, After Primary Vaccination - Immuno/Reacto Sub-cohort | Assessed solicited general symptoms were Drowsiness, Irritability/Fussiness (Irr./Fuss.), Loss of appetite (Loss Appet.) and Fever (axillary route - temperature equal or higher than [≥] 38.0 degrees Celsius [°C]),. Any = Occurrence of the specified solicited general symptom, regardless of intensity or relationship to vaccination. Grade 3 Drowsiness = Drowsiness that prevented normal activity. Grade 3 Irr./Fuss. = Crying that could not be comforted/prevented normal activity. Grade 3 Loss of appetite = Subject did not eat at all. Grade 3 Fever = (axillary) temperature higher than (>) 40.0°C. Related = Occurrence of the specified symptom assessed by the investigator as causally related to vaccination. The Immuno /reacto sub-cohort was composed of 200 vaccinated subjects from each study group. | Within the 4-day (Days 0-3) post-primary vaccination period following each dose | 
| Number of Subjects With Any and Grade 3 Solicited General Symptoms and With Solicited General Symptoms With Relationship to Vaccination, After Booster Vaccination - Immuno/Reacto Sub-cohort | Assessed solicited general symptoms were Drowsiness, Irritability/Fussiness (Irr./Fuss.), Loss of appetite (Loss Appet.) and Fever (axillary route - temperature equal or higher than [≥] 38.0 degrees Celsius [°C]),. Any = Occurrence of the specified solicited general symptom, regardless of intensity or relationship to vaccination. Grade 3 Drowsiness = Drowsiness that prevented normal activity. Grade 3 Irr./Fuss. = Crying that could not be comforted/prevented normal activity. Grade 3 Loss of appetite = Subject did not eat at all. Grade 3 Fever = (axillary) temperature higher than (>) 40.0°C. Related = Occurrence of the specified symptom assessed by the investigator as causally related to vaccination. The Immuno /reacto sub-cohort was composed of 200 vaccinated subjects from each study group. | Within the 4-day (Days 0-3) post-booster vaccination period | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) After Primary Vaccination - Immuno/Reacto Sub-cohort | An unsolicited AE was defined as 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. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For the marketed products administered in the study, this also included failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse of the product. Any = Occurrence of an unsolicited AE, regardless of intensity or relationship to vaccination. The Immuno/reacto sub-cohort was composed of 200 vaccinated subjects from each study group. | Within the 31-day (Days 0-30) period post primary vaccination, across doses | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) After Booster Vaccination - Immuno/Reacto Sub-cohort | An unsolicited AE was defined as 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. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For the marketed products administered in the study, this also included failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse of the product. Any = Occurrence of an unsolicited AE, regardless of intensity or relationship to vaccination. The Immuno /reacto sub-cohort was composed of 200 vaccinated subjects from each study group. | Within the 31-day (Days 0-30) period post booster vaccination | 
| Number of Subjects With Any Serious Adverse Events (SAEs) | An SAE was defined as any medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity in a subject. AE(s) considered as SAE(s) also included invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalization, as per the medical or scientific judgement of the physician. Any = Occurrence of an SAE, regardless of relationship to vaccination. | From Day 0 to Month 22 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
immunogenicity, US, Pneumococcal vaccine, efficacy, Streptococcus pneumoniae, infants, nasopharyngeal carriage, safety