A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 When Administered Concomitantly With Influenza Vaccine in Healthy Adults 50 Years of Age or Older (V114-021/PNEU-FLU)

Study Overview
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Brief Summary
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This study was designed to evaluate the safety and tolerability of a single dose of V114 when administered concomitantly and non-concomitantly (i.e., 30 days after) with influenza vaccine. It also evaluated whether V114 can be administered concomitantly with influenza vaccine without impairing the antibody response to the 15 serotypes contained in V114 and to the 4 influenza viruses contained in the seasonal inactivated quadrivalent influenza vaccine (QIV). The primary hypotheses state that immune responses to V114 and to QIV are non-inferior when administered concomitantly as compared with non-concomitant administration as measured by serotype-specific opsonophagocytic activity (OPA) and hemagglutination inhibition (HAI) geometric mean titers (GMTs) at 30 days postvaccination. This study will also contribute to the overall safety database and immunogenicity data for V114 to support initial licensure in adults.

Official Title
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A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 When Administered Concomitantly With Influenza Vaccine in Healthy Adults 50 Years of Age or Older (PNEU-FLU)

Conditions
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Pneumococcal Infections

Intervention / Treatment
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* Biological: V114
* Biological: QIV
* Biological: Matching Placebo for V114


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In good health. Any underlying chronic illness must be documented to be in stable condition. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: a) not a woman of childbearing potential (WOCBP) OR b) a WOCBP who agrees to use 1 of the contraceptive methods as defined in the protocol during the treatment period and for at least 6 weeks after the last dose of study intervention. Exclusion Criteria: History of invasive pneumococcal disease (IPD, positive blood culture, positive cerebrospinal fluid culture, or positive culture at another sterile site) or known history of other culture-positive pneumococcal disease within 3 years before Visit 1 (Day 1) Known hypersensitivity to any component of pneumococcal polysaccharide vaccine, pneumococcal conjugate vaccine (PCV), or any diphtheria toxoid-containing vaccine Known hypersensitivity to any component of influenza vaccines, including egg protein, or following a previous dose of any influenza vaccine. Known or suspected impairment of immunological function Experienced Guillain-Barré syndrome within 6 weeks of receiving a previous influenza vaccination Coagulation disorder contraindicating intramuscular vaccinations. History of malignancy ≤5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer A WOCBP who has a positive urine or serum pregnancy test before the first vaccination at Visit 1 (Day 1) Prior administration of any PCV (e.g., Prevnar 13®) or is expected to receive any pneumococcal vaccine during the study outside of the protocol. Prior administration of PNEUMOVAX®23 ≤12 months before Visit 1 (Note: individuals who received PNEUMOVAX®23 >12 months prior to Visit 1 are eligible for this study.) Previous receipt of influenza vaccine during the 2018/2019 flu season or expected to receive any influenza vaccine during the study outside of the protocol Received systemic corticosteroids (≥20 mg/day prednisone equivalent) for ≥14 consecutive days and has not completed intervention at least 30 days before study entry. Received systemic corticosteroids exceeding physiologic replacement doses (approximately 5 mg/day prednisone equivalent) within 14 days before vaccination (Note: Topical, ophthalmic, intra-articular or soft-tissue [e.g., bursa, tendon steroid injections], and inhaled/nebulized steroids are permitted). Receiving immunosuppressive therapy, including chemotherapeutic agents used to treat cancer or other conditions, and interventions associated with organ or bone marrow transplantation, or autoimmune disease Received a blood transfusion or blood products, including immunoglobulin within the 6 months before receipt of study vaccine or is scheduled to receive a blood transfusion or blood product within 30 days of receipt of study vaccine. Autologous blood transfusions are not considered an exclusion criterion. Is currently participating in or has participated in an interventional clinical study with an investigational compound or device within 2 months of participating in this current study. Is a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence as assessed by the study investigator. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study.

Ages Eligible for Study
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Minimum Age: 50 Years

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Concomitant Vaccination<br>Participants will receive a single 0.5 mL intramuscular (IM) injection of V114 and a single 0.5 mL IM injection of QIV on Day 1 and a single 0.5 mL injection of placebo on Day 30 | Biological: V114<br>* Single 0.5 mL injection<br>Biological: QIV<br>* Single 0.5 mL injection<br>* Other names: Fluarix Quadrivalent (Influenza Vaccine);Biological: Matching Placebo for V114<br>* Single 0.5 mL injection<br>|
| Experimental: Non-concomitant Vaccination<br>Participants will receive a single 0.5 mL IM injection of QIV and a single 0.5 mL IM injection of placebo on Day 1 and a single 0.5 mL injection of V114 on Day 30 | Biological: V114<br>* Single 0.5 mL injection<br>Biological: QIV<br>* Single 0.5 mL injection<br>* Other names: Fluarix Quadrivalent (Influenza Vaccine);Biological: Matching Placebo for V114<br>* Single 0.5 mL injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Solicited Injection-site Adverse Event | An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of 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. Solicited injection-site AEs included injection-site erythema /redness, pain /tenderness, swelling. | Up to Day 5 after vaccination | 
| Percentage of Participants With a Solicited Systemic Adverse Event | An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of 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. Solicited systemic AEs included myalgia/muscle pain, arthralgia/joint pain, headache, and fatigue/tiredness. | Up to Day 14 after any vaccination | 
| Percentage of Participants With a Vaccine-Related Serious Adverse Event | A serious adverse event (SAE) is an AE that results in death, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment. Relatedness of an SAE to the study vaccine was determined by the investigator. | Up to 7 months | 
| Geometric Mean Titer (GMT) Ratio of Pneumococcal Serotype-specific Opsonophagocytic Activity (OPA) | Serotype-specific OPA GMTs (estimated) and GMT ratios with 95% confidence intervals (CIs) and 1-sided p-values were calculated using a constrained longitudinal data analysis (cLDA) method utilizing data from both vaccination groups. Per the statistical analysis plan, the only CIs calculated were the between-group CIs (for the GMT ratios); within-group CIs were not calculated. | 30 days after V114 vaccination (Day 30 for concomitant vaccination group and Day 60 for non-concomitant vaccination group) | 
| GMT of Influenza Strain-Specific Hemagglutination Inhibition | Activity for the 4 strains contained in QIV vaccine was determined using an hemagglutination inhibition (HAI) assay. Serotype-specific HAI GMTs (estimated) and GMT ratios with 95% confidence intervals (CIs) and 1-sided p-values were calculated using a constrained longitudinal data analysis (cLDA) method utilizing data from both vaccination groups. Per the statistical analysis plan, the only CIs calculated were the between-group CIs (for the GMT ratios); within-group CIs were not calculated. | Day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Concentration (GMC) of Pneumococcal Serotype-specific Immunoglobulin G (IgG) | Serotype-specific IgG GMC ratios (estimated) and GMC ratios with 95% confidence intervals (CIs) were calculated using a constrained longitudinal data analysis (cLDA) method utilizing data from both vaccination groups. Per the statistical analysis plan, the only CIs calculated were the between-group CIs (for the GMC ratios); within-group CIs were not calculated. | 30 days after V114 vaccination (Day 30 for concomitant vaccination group and Day 60 for non-concomitant vaccination group) | 
| Geometric Mean Fold Rise (GMFR) in Pneumococcal Serotype-Specific OPA | Activity for the 15 serotypes contained in V114 vaccine will be determined using a Multiplex Opsonophagocytic Assay. GMFR is the geometric mean of fold rise from baseline to postvaccination. | Baseline and 30 days after V114 vaccination (Day 1 and Day 30 for concomitant vaccination group, and Day 30 and Day 60 for non-concomitant vaccination group, respectively) | 
| GMFR in Pneumococcal Serotype-Specific IgG | Immunoglobulin G for the 15 serotypes contained in V114 vaccine will be determined using an electrochemiluminescence assay. GMFR is the geometric mean of fold rise from baseline to postvaccination. | Baseline and 30 days after V114 vaccination (Day 1 and Day 30 for concomitant vaccination group, and Day 30 and Day 60 for non-concomitant vaccination group, respectively) | 
| Percentage of Participants With GMFR ≥4 in Pneumococcal Serotype-specific OPA | Activity for the 15 serotypes contained in V114 vaccine will be determined using a Multiplex Opsonophagocytic Assay. GMFR is the geometric mean of fold rise from baseline to postvaccination. The percentage of participants who had ≥ 4-fold rise in GMFR were calculated from baseline to postvaccination. | Baseline and 30 days after V114 vaccination (Day 1 and Day 30 for concomitant vaccination group, and Day 30 and Day 60 for non-concomitant vaccination group, respectively) | 
| Percentage of Participants With GMFR ≥4 in Pneumococcal Serotype-specific IgG | Immunoglobulin G for the 15 serotypes contained in V114 vaccine will be determined using an electrochemiluminescence assay. GMFR is the geometric mean of fold rise from baseline to postvaccination. The percentage of participants who had ≥ 4-fold rise in GMFR are calculated from baseline to postvaccination. | Baseline and 30 days after V114 vaccination (Day 1 and Day 30 for concomitant vaccination group, and Day 30 and Day 60 for non-concomitant vaccination group, respectively) | 
| GMFR of Influenza Strain-Specific HAI | Activity for the 4 strains contained in QIV vaccine will be determined using an HAI assay. GMFR is the geometric mean of fold rise from baseline to postvaccination. | Baseline (Day 1) and Day 30 | 
| Percentage of Participants With Influenza Strain-specific HAI Titer ≥1:40 | Activity for the 4 strains contained in QIV vaccine will be determined using an HAI assay. Seroconversion is defined as achieving a 4-fold rise from baseline to postvaccination among participants who are seropositive at baseline (HAI titer ≥ 1:10) or a titer of ≥ 1:40 at postvaccination among participants who are seronegative at baseline (HAI titer < 1:10). | Day 30 | 
| Percentage of Participants Who Seroconvert for Influenza Strain-specific HAI | Activity for the 4 strains contained in QIV vaccine will be determined using an HAI assay. Seroconversion for HAI responses is defined as achieving either 1) a 4-fold rise in influenza strain-specific HAI titer from Baseline to Day 30 among participants who are seropositive at Baseline (HAI titer ≥1:10) or 2) a influenza strain-specific HAI titer of ≥1:40 at Day 30 among participants who are seronegative at Baseline (HAI titer <1:10). | Baseline (Day 1) and Day 30 |