Safety, Tolerability, and Immunogenicity of V114 in Healthy Infants (V114-025)

Study Overview
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Brief Summary
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This study will evaluate the safety and tolerability and immunogenicity of V114 when administered to 2-month old infants. The primary hypotheses are: 1) V114 is non-inferior to Prevenar 13™ for the 13 shared serotypes between V114 and Prevenar 13™ based on response rates at 30 days post toddler dose (PTD); 2) V114 is superior to Prevenar 13™ for the 2 serotypes unique to V114 based on the response rates at 30 days PTD; 3) V114 is non-inferior to Prevenar 13™ for the 13 shared serotypes between V114 and Prevenar 13™ based on anti-pneumococcal polysaccharide (PnPs) serotype-specific Immunoglobin G (IgG) geometric mean concentrations (GMCs) at 30 days PTD; and 4) V114 is superior to Prevenar 13™ for the 2 serotypes unique to V114 based on anti-PnPs serotype-specific IgG GMCs at 30 days PTD.

Official Title
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A Phase 3, Multicenter, Randomized, Double-blind, Active-comparator-controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in Healthy Infants (PNEU-PED-EU-1)

Conditions
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Pneumococcal Infections

Intervention / Treatment
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* Drug: Rotarix™
* Drug: Infanrix™ hexa
* Drug: V114
* Drug: Prevenar 13™


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Healthy Has a legally acceptable representative who understands the study procedures, alternate treatments available, and risks involved with the study and voluntarily agrees to participate by giving written informed consent Exclusion Criteria History of invasive pneumococcal disease [(IPD); positive blood culture, positive cerebrospinal fluid culture, or other sterile site] or known history of other culture positive pneumococcal disease Has a known or suspected impairment of immunological function Has a history of congenital or acquired immunodeficiency Has, or his/her mother has, a documented human immunodeficiency virus (HIV) infection Has, or his/her mother has, a documented hepatitis B surface antigen - positive test Has known or history of functional or anatomic asplenia Has failure to thrive based on the clinical judgement of the Investigator Has a bleeding disorder contraindicating intramuscular vaccination Has a history of autoimmune disease (including but not limited to systemic lupus erythematosus, antiphospholipid syndrome, Behcet's disease, autoimmune thyroid disease, polymyositis and dermatomyositis, scleroderma, Type 1 diabetes mellitus, or other autoimmune disorders) Has a known neurologic or cognitive behavioral disorder, including encephalitis/myelitis, acute disseminating encephalomyelitis, pervasive development disorder, and related disorders Has received a dose of any pneumococcal vaccine prior to study entry Has received >1 dose of monovalent hepatitis B vaccine or hepatitis B-based combination vaccine prior to study entry Has received a dose of any acellular pertussis- or whole cell pertussis-based combination vaccines, Haemophilus influenzae type b conjugate vaccine, poliovirus vaccine, rotavirus vaccine, or any other combination thereof, prior to study entry Has received a blood transfusion or blood products, including immunoglobulins Has participated in another clinical study of an investigational product before the beginning or anytime during the duration of the current clinical study. Participants enrolled in observational studies may be included; these will be reviewed on a case-by-case basis for approval by the Sponsor Is or has an immediate family member (eg, parent/legal guardian or sibling) who is investigational site or Sponsor staff directly involved with this study

Ages Eligible for Study
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Minimum Age: 42 Days
Maximum Age: 90 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: V114<br>Full-term infants received a 0.5 mL intramuscular injection of V114 at approximately 2, 4, and 11-15 months of age (Study Day 1, Month 2, and Month 9-13). Preterm infants received a 0.5 mL intramuscular injection of V114 at approximately 2, 3, 4, and 11-15 months of age (Study Day 1, Month 1, Month 2, and Month 9-13). All infants also received intramuscular injection of 0.5 mL Infanrix™ hexa at approximately 2, 3, 4, and 11-15 months of age and 1.5 mL oral dose of Rotarix™ at 2 and 4 months of age. | Drug: Rotarix™<br>* Single 1.5 mL oral dose at 2 and 4 months of age (Study Day 1 and Month 2)<br>Drug: Infanrix™ hexa<br>* Single 0.5 mL intramuscular injection at 2, 3, 4, and 11-15 months of age (Study Day 1, Month 1, Month 2, and Month 9-13)<br>Drug: V114<br>* 15-valent pneumococcal conjugate vaccine (PCV) containing 13 serotypes present in Prevenar 13™ (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) and 2 unique serotypes (22F and 33F) in each 0.5 mL intramuscular administration,<br>* Other names: Pneumococcal 15-Valent Conjugate Vaccine;|
| Active Comparator: Prevenar 13™<br>Full-term infants received a 0.5 mL intramuscular injection of Prevenar 13™ at approximately 2, 4, and 11-15 months of age (Study Day 1, Month 2, and Month 9-13). Preterm infants received a 0.5 mL intramuscular injection of Prevenar 13™ at approximately 2, 3, 4, and 11-15 months of age (Study Day 1, Month 1, Month 2, and Month 9-13). All infants also received intramuscular injection of 0.5 mL Infanrix™ hexa at approximately 2, 3, 4, and 11-15 months of age and 1.5 mL oral dose of Rotarix™ at 2 and 4 months of age. | Drug: Rotarix™<br>* Single 1.5 mL oral dose at 2 and 4 months of age (Study Day 1 and Month 2)<br>Drug: Infanrix™ hexa<br>* Single 0.5 mL intramuscular injection at 2, 3, 4, and 11-15 months of age (Study Day 1, Month 1, Month 2, and Month 9-13)<br>Drug: Prevenar 13™<br>* 13-valent PCV containing 13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) in each 0.5 mL intramuscular administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants That Report at Least 1 Solicited Injection-site Adverse Event (AE) | An AE is any untoward medical occurrence in a participant temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease (new or exacerbated) temporally associated with the use of a study intervention. Injection-site AEs solicited on the Vaccine Report Card (VRC) consisted of erythema (redness), induration (hard lump), pain (tenderness) and swelling. | Up to 14 days post any vaccination (up to approximately study month 13) | 
| Percentage of Participants That Report at Least 1 Solicited Systemic AE | An AE is any untoward medical occurrence in a participant temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease (new or exacerbated) temporally associated with the use of a study intervention. Systemic AEs solicited on the VRC consisted of decreased appetite (loss of appetite), irritability, somnolence (drowsiness) and urticaria (hive/welts). | Up to 14 days post any vaccination (up to approximately study month 13) | 
| Percentage of Participants That Report at Least 1 Vaccine-related Serious Adverse Event (SAE) | A serious adverse event (SAE) is an AE that results in death, is life threatening, results in a persistent or significant disability or incapacity, results in or prolongs an existing hospitalization, is a congenital anomaly or birth defect, is a cancer, is an overdose, or is another important medical event. The relatedness of a vaccine to a SAE is determined by an investigator who is a qualified physician. | Up to 6 months post last vaccination (up to approximately study month 20) | 
| Anti-pneumococcal Polysaccharide (PnPs) Serotype-specific Immunoglobin G (IgG) Geometric Mean Concentrations (GMC) for Each Serotype at 30 Days Post Toddler Dose (PTD) | Sera from participants was used to measure vaccine-induced anti-PnPs serotype-specific IgG for each serotype using pneumococcal electrochemiluminescence (PnECL). The Geometric Mean Concentration (GMC) for each of the 13 serotypes shared by both V114 and Prevenar 13™ (Serotypes 1 to 23F); and the 2 serotypes unique to V114 (Serotypes 22F and 33F) was assessed. Per protocol, within-group CIs were not calculated. | 30 days PTD (Up to approximately study month 14) | 
| Percentage of Participants Who Meet Serotype-specific IgG Threshold Value of ≥0.35 μg/mL for Each Serotype at 30 Days PTD | Sera from participants was used to measure vaccine-induced anti-PnPs serotype-specific IgG for the 15 serotypes using pneumococcal electrochemiluminescence (PnECL). The percentage of participants that achieve the threshold value of ≥0.35 μg/mL for each of the 13 serotypes shared by both V114 and Prevenar 13™ (Serotypes 1 to 23F); and the 2 serotypes unique to V114 (Serotypes 22F and 33F) was assessed. | 30 days PTD (Up to approximately study month 14) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Meet Antigen-Specific Threshold Value for Each Antigen in Infanrix™ Hexa at 30 Days PTD | Sera from participants was used to measure vaccine-induced responses to 10 pre-specified Infanrix™ hexa antigens with the following threshold (% ≥) values: Diphtheria toxoid-0.1 international unit (IU)/mL;Tetanus toxoid-0.1 IU/mL; Pertussis pertussis toxin (PT)-5 endotoxin unit (EU)/mL; Pertussis filamentous hemagglutinin (FHA)-5 EU/mL; Pertussis pertactin (PRN)-5 EU/mL; Haemophilus influenzae type b (Hib) polyribosylribitol phosphate (PRP)-0.15 μg/mL; hepatitis B surface antigen (HBsAg)-10 mIU/mL; Poliovirus 1,2 and 3-1:8 neutralizing antibodies (NAb) dilution. | 30 days PTD (Up to approximately study month 14) | 
| Anti-rotavirus Immunoglobulin A (IgA) Geometric Mean Titers (GMTs) at 30 Days Post Primary Series (PPS) of Rotarix™ | Sera from participants was used to measure vaccine-induced antibodies in response to vaccination with Rotarix™ by assessing the GMT for IgA. Per protocol, within-group CIs were not calculated. | 30 days PPS (Up to approximately study month 3) | 
| Anti-PnPs Serotype-specific IgG GMCs for Each Serotype at 30 Days PPS | Sera from participants was used to measure vaccine-induced anti-PnPs serotype-specific IgG for each serotype using PnECL. The GMC for each of the 13 serotypes shared by both V114 and Prevenar 13™ (Serotypes 1 to 23F); and the 2 serotypes unique to V114 (Serotypes 22F and 33F) was assessed. Per protocol, within-group CIs were not calculated. | 30 days PPS (Up to approximately study month 3) | 
| Percentage of Participants Who Meet Serotype-specific IgG Threshold Value of ≥0.35 μg/mL for Each Serotype at 30 Days PPS | Sera from participants was used to measure vaccine-induced anti-PnPs serotype-specific IgG for the 15 serotypes using PnECL. The percentage of participants that achieve the threshold value of ≥0.35 μg/mL for each of the 13 serotypes shared by both V114 and Prevenar 13™ (Serotypes 1 to 23F); and the 2 serotypes unique to V114 (Serotypes 22F and 33F) was assessed. | 30 days PPS (Up to approximately study month 3) | 
| Anti-PnPs Serotype-specific Opsonophagocytic Activity (OPA) GMTs for Each Serotype at 30 Days PTD | Sera from participants was used to measure vaccine-induced anti-PnPs serotype-specific OPA using the multiplexed opsonophagocytic assay (MOPA). The GMT for each of the 13 serotypes shared by both V114 and Prevenar 13™ (Serotypes 1 to 23F); and the 2 serotypes unique to V114 (Serotypes 22F and 33F) was assessed. The within-group CIs were obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. | 30 days PTD (Up to approximately study month 14) | 
| Percentage of Participants Who Meet Serotype-specific OPA Threshold Value for Each Serotype at 30 Days PTD | Sera from participants was used to measure vaccine-induced anti-PnPs serotype-specific OPA using the MOPA. The threshold dilution (% ≥) for each of the 13 serotypes shared by both V114 and Prevenar 13™ (Serotypes 1 to 23F) were as follows: 1:9, 1:19, 1:34, 1:27, 1:232, 1:40, 1:61, 1:151, 1:62, 1:115, 1:31, 1:113, 1:55. For Serotypes 22F and 33F the threshold dilution was 1:15 and 1:20 respectively. The within-group CIs were based on the exact binomial method of Clopper and Pearson. | 30 days PTD (Up to approximately study month 14) | 
| Percentage of Participants Who Achieved the IgG Serotype-Specific Threshold Value of ≥0.35 μg/mL For Protocol Pre-Specified Serotypes at 30 Days PTD | Sera from participants was used to measure vaccine-induced anti-PnPs serotype-specific IgG for the 15 serotypes using PnECL. As pre-specified in the protocol the percentage of participants from the two serotypes unique to V114 (Serotypes 22F and 33F) are presented, as well as the percentage of participants with the lowest response rate from any of the 13 shared serotypes randomized to Prevenar 13™ (Serotype 3). | 30 days PTD (Up to approximately study month 14) |