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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
1,806
4 doses administered intramuscularly
4 doses administered intramuscularly
4 doses administered intramuscularly
GSK Investigational Site
Chinle, Arizona, United States
GSK Investigational Site
Fort Defiance, Arizona, United States
GSK Investigational Site
Whiteriver, Arizona, United States
GSK Investigational Site
Gallup, New Mexico, United States
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).
Time frame: Any time from 2 weeks after the administration of dose 3 up to Month 22
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.
Time frame: 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.
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4 doses administered intramuscularly
GSK Investigational Site
Shiprock, New Mexico, United States
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: From Day 0 to Month 22