Evaluation of the Immunogenicity and Safety of GlaxoSmithKline (GSK) Biologicals' Quadrivalent Influenza Vaccine Influsplit™ Tetra (Fluarix™ Tetra) (GSK2321138A) When Co-administered With Pneumovax™ 23 in Adults 50 Years of Age and Older

Study Overview
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Brief Summary
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The purpose of this study is to investigate the immunogenicity and safety when GSK Biologicals' influenza vaccine Influsplit™ Tetra (Fluarix™ Tetra) is co-administered with Merck & Co. Inc.'s pneumococcal vaccine (Pneumovax™23/Pneumovax) in adults 50 years of age and older at risk for complications from influenza and pneumococcal infections.

Official Title
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Immunogenicity and Safety Study of GSK Biologicals' Quadrivalent Split Virion Influenza Vaccine 2014/2015 Influsplit™ Tetra (Fluarix™ Tetra) (GSK2321138A) When Co-administered With Pneumovax™ 23 in Adults 50 Years of Age and Older

Conditions
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Influenza

Intervention / Treatment
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* Biological: Influsplit™ Tetra (Fluarix™ Tetra)
* Biological: Pneumovax™ 23
* Biological: Placebo (Saline)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g. completion of the diary cards, return for follow-up visits). A male or female aged 50 years or above at the time of the first vaccination at risk for complications from influenza and/or pneumococcal infections, meeting their respective countries' recommendations for vaccination against influenza and pneumococcal disease. At risk subjects include adults with chronic respiratory, heart, kidney, liver or neurological disease; human immunodeficiency virus (HIV) disease on combination antiretroviral therapy (cART) with cluster of differentiation 4 (CD4) T-cell counts greater than 350 cells/mm3; sickle cell disease or coeliac syndrome that may lead to splenic dysfunction (all other asplenics are excluded). The decision to enrol should be based on the investigators clinical judgement. Written informed consent obtained from the subject. Female subjects of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current tubal ligation, hysterectomy, ovariectomy or post-menopause. Female subjects of childbearing potential may be enrolled in the study, if the subject: has practiced adequate contraception for 30 days prior to vaccination, and has a negative pregnancy test on the day of vaccination, and has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series. Exclusion Criteria: Use of any investigational or non-registered product other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period. Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose. Inhaled, topical and low-dose intra-articular steroids are allowed. Planned administration/administration of a vaccine not foreseen by the study protocol within the period starting 30 days before the first dose and 30 days after the last dose of vaccine. Administration of such a vaccine has to be documented in the Concomitant vaccination of the electronic Case Report Form (eCRF). Administration of long-acting immune-modifying drugs/treatment within six months prior to the first vaccine dose or expected administration at any time during the study period. These immunosuppressant drugs/treatment/Biologics include: Methotrexate Leflunomide Azathioprine and 6-mercaptopurine Cyclosporin A Cyclophosphamide Tacrolimus, everolimus, sirolimus, temsirolimus Mycophenolate mofetil Antilymfocytaire immunoglobulins Tumor Necrosis Factor (TNF) inhibitors: Adalimumab (Humira®), certolizumab (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®) and infliximab(Remicade®) Monoclonal antibodies and other biologicals: Rituximab (Mabthera®), Abatacept (Orencia®), tocilizumab (RoActemra®), basiliximab (Simulect®), Natalizumab (Tysabri®) cluster of differentiation 3 (CD3), … Antitumor agents: alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, microtubule inhibitors and other anti-tumor agents Lenalidomide Revlimid® Tasonermin: Beromun® Proleukin® (aldesleukin; Novartis, …) Tyrosine kinase inhibitor (Glivec®)Omalizumab Xolair® Eculizumab Soliris® The above list is compiled from: [Federal Public Service Belgium: Health, Food Chain Safety and Environment]. Any immunosuppressive treatment which in the opinion of the investigator will not allow an adequate immune response. Inhaled, topical and low-dose intra-articular steroids are allowed. 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 vaccine/product. Previous vaccination with a pneumococcal vaccine within the last five years. Previous vaccination with an influenza vaccine within the last six months. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. HIV infected subjects on cART with CD4 T-cell counts above 350 cells/mm3 can be enrolled. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines. Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥ 38.0°C (100.4°F). The preferred route for recording temperature in this study will be axillary. Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever [≥ 38.0°C (100.4°F)] may be enrolled at the discretion of the investigator. Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period. Pregnant or lactating female. Female planning to become pregnant or planning to discontinue contraceptive precautions. Any condition which, in the opinion of the investigator, prevents the subject from participating in the study or would make intramuscular (IM) injection unsafe. Asplenia or dysfunction of the spleen. This excludes homozygous sickle cell disease or coeliac syndrome that may lead to splenic dysfunction. Acute clinically significant (i.e. a medically significant change from baseline condition in the past 30 days) pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests. History of chronic alcohol consumption and/or drug abuse. History of Guillain-Barré syndrome. A history of anaphylaxis following ANY vaccination.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Co-Ad Group<br>Subjects received 1 dose of Influsplit™ Tetra vaccine and 1 dose of Pneumovax™ 23 vaccine at Day 0 and 1 dose of placebo at Day 28. | Biological: Influsplit™ Tetra (Fluarix™ Tetra)<br>* Intramuscular injection, 1 dose each in Control and Co-Ad groups.<br>* Other names: GSK2321138A;Biological: Pneumovax™ 23<br>* Intramuscular injection, 1 dose each in Control and Co-Ad groups.<br>Biological: Placebo (Saline)<br>* Intramuscular injection, 1 dose each in Control and Co-Ad groups.<br>|
| Experimental: Control Group<br>Subjects received 1 dose of Influsplit™ Tetra vaccine and 1 dose of placebo at Day 0 and 1 dose of Pneumovax™ 23 vaccine at Day 28. | Biological: Influsplit™ Tetra (Fluarix™ Tetra)<br>* Intramuscular injection, 1 dose each in Control and Co-Ad groups.<br>* Other names: GSK2321138A;Biological: Pneumovax™ 23<br>* Intramuscular injection, 1 dose each in Control and Co-Ad groups.<br>Biological: Placebo (Saline)<br>* Intramuscular injection, 1 dose each in Control and Co-Ad groups.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Humoral Immune Response in Terms of Haemagglutination Inhibition (HI) Antibodies Titers Against the 4 Vaccine Strains. | HI antibody titres were expressed as geometric mean titers (GMTs) and adjusted GMT ratios (Control Group/Co-Ad Group). The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), FluA/Texas/50/2012 (H3N2), Flu B/Brisbane/60/2008 (Victoria) and Flu B/Massachusetts/2/2012 (Yamagata). | At Day 28 post Influsplit™ Tetra vaccination | 
| Pneumococcal Vaccine Response in Terms of Anti-pneumococcal Antibody Concentrations Against 6 Pneumococcal Serotypes (1, 3, 4, 7F, 14 and 19A). | Anti-pneumococcal antibody concentrations were expressed as adjusted geometric mean concentrations (GMCs) and adjusted GMC ratio (Control Group/Co-Ad Group). | At 28 days after Pneumovax™ 23 vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reporting Solicited Local Adverse Events (AEs) | Solicited local symptoms assessed were pain, redness and swelling. Any = occurrence of the specified solicited local symptom regardless of its intensity. Grade 3 pain = significant pain at rest and pain that prevented normal everyday activities. Grade 3 redness and swelling = greater than 50 millimeters (mm) i.e. > 100mm. | Within 7 days (Days 0 - 6) after each dose and across doses. | 
| Number of Subjects Reporting Solicited General Adverse Events (AEs) | Solicited general symptoms assessed were fatigue, gastrointestinal symptoms*, headache, joint pain, muscle aches, shivering, sweating and fever. Any was defined as any solicited general symptom reported irrespective of intensity and relationship to vaccination. Grade 3 was defined as symptoms that prevented normal everyday activities. Related was defined as symptoms assessed by the investigator to have a causal relationship to vaccination. Grade 3 fever was defined as temperature greater than (>)39.0°C. *Gastrointestinal (GI) symptoms included nausea, vomiting, diarrhoea and/or abdominal pain | Within 7 days (Days 0 - 6) after each dose and across doses. | 
| Duration of Local Adverse Events | Duration was defined as number of days with any grade of local symptoms. | During the 7-day (Days 0-6) post-vaccination period | 
| Duration of Solicited General AEs. | Duration was defined as number of days with any grade of general symptoms. | During the 7-day (Days 0-6) post-vaccination period | 
| Number of Subjects Reporting the Occurrence of Medically Attended Adverse Events (MAEs) | MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Any was defined as any occurrence of MAE(s) regardless of intensity grade or relationship to vaccination. Related was defined as MAE assessed by the investigator to be causally related to the study vaccination. | Throughout the study period (Days 0-180) | 
| Number of Subjects Reporting the Occurrence of Potential Immune Mediated Diseases (pIMDs) | Potential immune-mediated diseases (pIMDs) were defined as a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology. Any was defined as any occurrence of pIMD(s) regardless of intensity grade or relationship to vaccination. Related was defined as pIMD assessed by the investigator to be causally related to the study vaccination. | During the entire study period (Days 0-180) | 
| Number of Subjects Reporting Any, Grade 3 and Related Unsolicited Adverse Events (AEs). | An unsolicited AE was defined as an untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as occurrence of any unsolicited symptom regardless of intensity grade or relation to vaccination. | Within the 28-day (Days 0-27) post-vaccination period | 
| Number of Subjects Reporting Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Any was defined as occurrence of any symptom regardless of intensity grade or relation to vaccination and related was an event assessed by the investigator as causally related to the study vaccination. | Throughout the study period (Days 0-180) | 
| Humoral Immune Response in Terms of Haemagglutination Inhibition (HI) Antibodies in Subjects by Calculating Serum Antihaemagglutination (HA) Antibody Titers Against the 4 Influenza Vaccine Strains | HI antibody titres were expressed as Geometric mean titers (GMTs). The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Brisbane/60/2008 (Victoria) and Flu B/Massachusetts/02/2012 (Yamagata). | At Day 0 and Day 28 | 
| Number of Subjects Who Were Seroprotected for Haemagglutination Inhibition (HI) Antibodies Against Each of the Four Vaccine Influenza Strains. | A seroprotected subject was defined as a vaccinated subject with a serum HI titer greater than or equal to (≥) 1:40 that usually is accepted as indicating protection in adults. The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Brisbane/60/2008 (Victoria) and Flu B/Massachusetts/2/2012 (Yamagata). | At Day 0 and Day 28 | 
| Number of Seroconverted Subjects for Anti-Haemagglutination Inhibition (HI) Antibodies Against Each of the Four Vaccine Influenza Strains. | A seroconverted subject was defined as a vaccinated subject with either a pre-vaccination titer less than (<) 1:10 and a post-vaccination titer greater than or equal to (≥) 1:40, or a pre-vaccination titer ≥ 1:10 and at least a 4-fold increase in post-vaccination titer. The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Brisbane/60/2008 (Victoria) and Flu B/Massachusetts/02/2012 (Yamagata). | At Day 28 | 
| Mean Geometric Increase (MGI) for Haemagglutination Inhibition (HI) Antibody Titer Against Each of the Four Vaccine Influenza Strains. | MGI was defined as the fold increase in serum haemagglutination inhibition (HI) GMTs post-vaccination compared to pre-vaccination (Day 0). The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Brisbane/60/2008 (Victoria) and Flu B/Massachusetts/02/2012 (Yamagata). | At Day 28 | 
| Number of Subjects With Anti-pneumococcal Antibody Concentrations for the Following Serotypes: 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F | The pneumococcal antigen testing was performed, as determined by ELISA cut-offs of ≥0.05 µg/mL and a seroprotection cut-off of ≥ 0.2 µg/ml. PRE = Pre-vaccination i.e. at Day 0 for Co-Ad Group and at Day 28 for Control Group. POST = Post-vaccination i.e. at Day 28 for Co-Ad Group and at Day 56 for Control Group. | At Days 0 (Co-Ad group only), 28 (both groups), and 56 (Control group only) | 
| Pneumococcal Vaccine Response in Terms of Anti-pneumococcal Antibody Concentrations Against 12 Pneumococcal Serotypes (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) | Anti-pneumococcal antibody concentrations were expressed as adjusted geometric mean concentrations (GMCs) PRE = Pre -vaccination i.e. at Day 0 for Co-Ad Group and at Day 28 for Control Group. POST = Post-vaccination i.e. at Day 28 for Co-Ad Group and at Day 56 for Control Group. | At Days 0 (Co-Ad group only), 28 (both groups), and 56 (Control group only) | 
| Number of Subjects Whose N Antibody Titers Were at Least 2 or 4-fold Higher Than Their Pre-vaccination Titer by Anti-pneumococcal Serotype Subjects. | Fold antibody concentration increases post-vaccination/pre-vaccination ≥ 2 and ≥ 4. The anti-pneumococcal serotypes assessed were 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. | At 28 days post-vaccination with Pneumovax™ 23 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunogenicity, Influsplit Tetra (Fluarix Tetra) 2014/2015 season, Safety, Adults, Pneumovax 23/Pneumovax, Co-administration, Elderly, Seasonal influenza, Pneumococcal infection