A Study to Evaluate the Safety, Reactogenicity and Immunogenicity of the Investigational GSK Biologicals' GSK3277511A Vaccine in Adults.

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, reactogenicity and immunogenicity of the investigational GSK Biologicals' GSK3277511A vaccine in adults

Official Title
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An Observer-blind Study to Evaluate the Safety, Reactogenicity and Immunogenicity of the Investigational GSK Biologicals' GSK3277511A Vaccine in Adults.

Conditions
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Respiratory Disorders

Intervention / Treatment
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* Biological: Formulation 1 (plain): NTHi/Mcat vaccine GSK3277513A
* Biological: Formulation 2 (adjuvanted): NTHi/Mcat vaccine GSK3277513A
* Biological: Formulation 3 (adjuvanted): NTHi/Mcat vaccine GSK3339036A
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: applicable for both Step 1 ((healthy volunteers) and Step 2 ([ex-]smokers) Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol 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, 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 vacci-nation, and has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series. only applicable for Step 1 A male or female between, and including, 18 and 40 years of age at the time of the Screening Visit. Healthy subjects without acute or chronic, clinically sig-nificant pulmonary, cardiovascular, hepatic or renal func-tional abnormality, as determined by physical examination or laboratory screening tests. only applicable for Step 2 A male or female between, and including, 50 and 70 years of age at the time of the screening visit. Subjects without medical history, clinical finding or laboratory finding which in the opinion of the investigator could pose a safety concern or interfere with the protocol. Current or former smoker with a cigarette smoking history ≥ 10 pack-years. Exclusion Criteria: applicable for both Step 1 and Step 2 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. 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 any vaccine containing NTHi and/or Mcat antigens. Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs within 6 months prior to the first vaccine dose. For corticosteroids, this will mean prednisone ≥20 mg/day, or equivalent. Only topical steroids are allowed. Administration of long-acting immune-modifying drugs at any time during the study period. Administration of immunoglobulins and/or any blood products within the 3 months preceding the first dose of study vaccine or planned administration during the study period. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. History of or current autoimmune disease. Acute disease and/or fever at the time of enrolment. Fever is defined as temperature >= 37.5°C for oral or axillary route. The preferred route for recording temperature in this study will be oral. Subjects with a minor illness without fever may, be enrolled at the discretion of the investigator. Current alcoholism and/or drug abuse. History of or current condition preventing intramuscular injection as bleeding or coagulation disorder. Malignancies within previous 5 years or lymphoproliferative disorders. Pregnant or lactating female. Female planning to become pregnant or planning to discontinue contraceptive precautions. Any other condition that the investigator judges may interfere with study findings. only applicable for Step 1 Planned administration/ administration of a vaccine not foreseen by the study protocol in the period starting 30 days before the first dose and ending 30 days after the last dose of vaccine, with the exception of any influenza vaccine which may be administered ≥ 15 days preceding or following any study vaccine dose. Laboratory evidence of clinically significant haematological (complete blood cell count [RBC, WBC], WBC differential count [lymphocytes, neutrophils and eosinophils], platelets count or haemoglobin level) and biochemical (alanine aminotransferase [ALT], aspartate aminotransferase [AST] or creatinine) abnormalities as per the opinion of the investigator. only applicable for Step 2 Planned administration/ administration of a vaccine not foreseen by the study protocol in the period starting 30 days before the first dose and ending 30 days after the last dose of vaccine, with the exception of any influenza or pneumococcal licensed vaccine which may be admin-istered ≥ 15 days preceding or following any study vaccine dose. Post-bronchodilator FEV1 < 80% of predicted normal value. Diagnosed with a respiratory disorder (e.g. asthma, COPD, sarcoidosis, tuberculosis, bronchiectasis, lung fi-brosis, pulmonary embolism, pneumothorax, or physi-cian confirmed lung cancer). Please note that subjects with mild pulmonary obstruction (i.e. FEV1/ FVC ratio < 0.7 with FEV1 ≥ 80% of normal predicted values [GOLD grade 1]) can be enrolled. Has contraindication for spirometry testing (such as recent eye surgery, recent thoracic or abdominal surgery procedures, unstable cardiovascular status, recent myo-cardial infection or pulmonary embolism). Laboratory evidence of clinically significant haematological (complete blood cell count [RBC, WBC], WBC differential count [lymphocytes, neutrophils and eosinophils], platelets count or haemoglobin level) and biochemical (ALT, AST or creatinine) abnormalities. Has significant disease, in the opinion of the investigator, likely to interfere with the study and/or likely to cause death within the study duration.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK3277513A F1 Group<br>Subjects, 18 - 40 years, receiving two doses of the non adjuvanted GSK Biologicals' NTHi Mcat investigational vaccine (GSK3277513A ) containing formulation 1 (F1) of PD, PE-PilA and UspA2 during Step 1 of the study. Intramuscular injection should be done in the deltoid of the non-dominant arm. In case it is not possible to inject in the non dominant arm, an injection in the dominant arm may be performed. | Biological: Formulation 1 (plain): NTHi/Mcat vaccine GSK3277513A<br>* 2 doses at Day 0 and Day 60, Intramuscular vaccination in the deltoid region of the non-dominant arm according to protocol schedule<br>|
| Experimental: GSK3277513A F2 Group<br>Subjects, 50 - 70 years, receiving two doses of the GSK Biologicals' NTHi-Mcat investigational vaccine(GSK3277513A) containing formulation 2 (F2) (adjuvanted) of PD, PE-PilA and UspA2 during Step 2 of the study. Intramuscular injection should be done in the deltoid of the non-dominant arm. In case it is not possible to inject in the non dominant arm, an injection in the dominant arm may be performed. | Biological: Formulation 2 (adjuvanted): NTHi/Mcat vaccine GSK3277513A<br>* 2 doses at Day 0 and Day 60, Intramuscular vaccination in the deltoid region of the non-dominant arm according to protocol schedule<br>|
| Experimental: GSK3277513A F3 Group<br>Subjects, 50 - 70 years, receiving two doses of the GSK Biologicals' NTHi-Mcat investigational vaccine(GSK3277513A) containing formulation 3 (F3) (adjuvanted) of PD, PE-PilA and UspA2 during Step 2 of the study. Intramuscular injection should be done in the deltoid of the non-dominant arm. In case it is not possible to inject in the non dominant arm, an injection in the dominant arm may be performed. | Biological: Formulation 3 (adjuvanted): NTHi/Mcat vaccine GSK3339036A<br>* 2 doses at Day 0 and Day 60, Intramuscular vaccination in the deltoid region of the non-dominant arm according to protocol schedule<br>|
| Placebo Comparator: Placebo Group<br>Subjects, 18 - 40 years, receiving two doses of placebo (saline solution) during Step 1 of the study and subjects, 50 - 70 years, receiving two doses of placebo (saline solution) during Step 2 of the study. Intramuscular injection should be done in the deltoid of the non-dominant arm. In case it is not possible to inject in the non dominant arm, an injection in the dominant arm may be performed. | Drug: Placebo<br>* 2 doses at Day 0 and Day 60, Intramuscular vaccination in the deltoid region of the non-dominant arm according to protocol schedule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Any Solicited Local Adverse Events (AEs) | Assessed solicited local symptoms are pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. | During a 7-day follow-up period (Day 0 to Day 6) after first dose. | 
| Number of Subjects With Any Solicited Local Adverse Events (AEs) | Assessed solicited local symptoms are pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. | During a 7-day follow-up period (Day 60 to Day 66) after second dose | 
| Number of Subjects With Any Solicited General Adverse Events (AEs) | Assessed solicited general symptoms are fatigue, gastrointestinal symptoms, headache, myalgia, fever [defined as oral temperature equal to or above 37.5 degrees Celsius (°C)]. | During a 7-day follow-up period (Day 0 to Day 6) after first dose. | 
| Number of Subjects With Any Solicited General Adverse Events (AEs) | Assessed solicited general symptoms are fatigue, gastrointestinal symptoms, headache, myalgia, fever [defined as oral temperature equal to or above 37.5 degrees Celsius (°C)]. | During a 7-day follow-up period (Day 60 to Day 66) after second dose. | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs). | Assessed unsolicited AEs cover 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 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 is defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | During a 30-day follow-up period (Day 0 to Day 29) after first dose. | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) | Assessed unsolicited AEs cover 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 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 is defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | During a 30-day follow-up period (Day 60 to Day 89) after second dose | 
| Number of Subjects With Any Haematological and Biochemical Laboratory Abnormalities, After Vaccination. | Assessed haematological parameters are complete blood cell count: Erythrocytes (RBC [red blood cells]), Leukocytes (WBC [white blood cells]), differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase [ALT], aspartate aminotransferase [AST] or creatinine below or above the normal laboratory ranges tabulated by time point. | At Day 7, post-dose 1. | 
| Number of Subjects With Any Haematological and Biochemical Laboratory Abnormalities After Vaccination | Assessed haematological parameters are complete blood cell count: Erythrocytes (RBC [red blood cells]), Leukocytes (WBC [white blood cells]), differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase [ALT], aspartate aminotransferase [AST] or creatinine below or above the normal laboratory ranges tabulated by time point. | At Day 60, post-dose 1. | 
| Number of Subjects With Any Haematological and Biochemical Laboratory Abnormalities After Vaccination | Assessed haematological parameters are complete blood cell count: Erythrocytes (RBC [red blood cells]), Leukocytes (WBC [white blood cells]), differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase [ALT], aspartate aminotransferase [AST] or creatinine below or above the normal laboratory ranges tabulated by time point. | At Day 67, post-dose 2. | 
| Number of Subjects With Any Haematological and Biochemical Laboratory Abnormalities After Vaccination | Assessed haematological parameters are complete blood cell count: Erythrocytes (RBC [red blood cells]), Leukocytes (WBC [white blood cells]), differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase [ALT], aspartate aminotransferase [AST] or creatinine below or above the normal laboratory ranges tabulated by time point. | At Day 210, post-dose 2. | 
| Number of Subjects With Any Haematological and Biochemical Laboratory Abnormalities After Vaccination | Assessed haematological parameters are complete blood cell count: Erythrocytes (RBC [red blood cells]), Leukocytes (WBC [white blood cells]), differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelets count, and hemoglobin level below or above the normal laboratory ranges tabulated by time point. Assessed biochemical parameters are alanine aminotransferase [ALT], aspartate aminotransferase [AST] or creatinine below or above the normal laboratory ranges tabulated by time point. | At Day 420, post-dose 2. | 
| Number of Subjects With Any Serious Adverse Events (SAEs) | Assessed SAEs include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From first vaccination up to study conclusion (Day 0 to Day 420) | 
| Number of Subjects With Any Potential Immune-mediated Diseases (pIMDs) | Potential immune-mediated diseases (pIMDs) are 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. | From first vaccination up to study conclusion (Day 0 to Day 420) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of Antibodies Against the NTHi-Mcat Anti-PD (Protein D of Haemophilus Influenzae) Vaccine Component | Antibody concentrations are measured by enzyme-linked immunosorbent assay (ELISA) and expressed as geometric mean concentrations (GMCs) in ELISA units per millilitre (EL.U/mL). The cut-off of the assay is 153 EL.U/mL for anti-PD antibodies. | At Day 0 (pre-dose 1); at Day 30 and Day 60 (post-dose 1); at Day 90, Day 210 and Day 420 (post-dose2). | 
| Concentration of Antibodies Against the NTHi-Mcat Anti-PE (Protein E of Haemophilus Influenzae) Vaccine Component | Antibody concentrations are measured by enzyme-linked immunosorbent assay (ELISA) and expressed as geometric mean concentrations (GMCs) in ELISA units per millilitre (EL.U/mL). The cut-off of the assay is 25 EL.U/mL for anti-PE antibodies. | At Day 0 (pre-dose 1); at Day 30 and Day 60 (post-dose 1); at Day 90, Day 210 and Day 420 (post-dose2). | 
| Concentration of Antibodies Against the NTHi-Mcat Anti-PilA (Type IV Pili Subunit of Non-typeable Haemophilus Influenzae) Vaccine Component | Antibody concentrations are measured by enzyme-linked immunosorbent assay (ELISA) and expressed as geometric mean concentrations (GMCs) in ELISA units per millilitre (EL.U/mL). The cut-off of the assay is 7 EL.U/mL for anti-PilA antibodies. | At Day 0 (pre-dose 1); at Day 30 and Day 60 (post-dose 1); at Day 90 (post-dose2). | 
| Concentration of Antibodies Against the NTHi-Mcat Anti-PilA (Type IV Pili Subunit of Non-typeable Haemophilus Influenzae) Vaccine Component | Antibody concentrations are measured by enzyme-linked immunosorbent assay (ELISA) and expressed as geometric mean concentrations (GMCs) in ELISA units per millilitre (EL.U/mL). The cut-off of the assay is 16 EL.U/mL for anti-PilA antibodies. | At Day 210 and Day 420 (post-dose2). | 
| Concentration of Antibodies Against the NTHi-Mcat Anti-UspA2 (Ubiquitous Surface Protein A2 of Moraxella Catarrhalis) Vaccine Component | Antibody concentrations are measured by enzyme-linked immunosorbent assay (ELISA) and expressed as geometric mean concentrations (GMCs) in ELISA units per millilitre (EL.U/mL). The cut-off of the assay is 38 EL.U/mL for anti-UspA2 antibodies. | At Day 0 (pre-dose 1); at Day 30 and Day 60 (post-dose 1); at Day 90, Day 210 and Day 420 (post-dose2). | 
| Frequency of Specific Cluster of Differentiation (CD)4+ T-cells Against NTHi-Mcat Antigens Collected for the Evaluation of Cell-mediated Immune Response | Frequency of specific CD4+ T-cells are measured by flow cytometry intracellular cytokine staining (ICS) expressing two or more markers (such as Interleukin [IL]-2, IL-13, IL-17, Interferon gamma [FN-γ], Tumour necrosis factor alpha [TNF-α] and CD40L). The frequency of specific CD4+ T-cells are summarised [descriptive statistics: Mean and standard deviation (SD)] against each antigen (PD, PE, PilA and UspA2), by group in Step 2 at each time point during which blood samples are collected for CMI. | At Day 0 (pre-dose 1); at Day 60 (post-dose 1); at Day 90, Day 210 and Day 420 (post-dose2). | 
| Frequency of Specific CD8+ T-cells Against NTHi-Mcat Antigens Collected for the Evaluation of Cell-mediated Immune Response | Frequency of specific CD8+ T-cells are measured by flow cytometry intracellular cytokine staining (ICS) expressing two or more markers (such as IL-2, IL-13, IL-17, IFN-γ, TNF-α and CD40L). The frequency of specific CD8+ T-cells are summarised [descriptive statistics: Mean and standard deviation (SD)] against each antigen (PD, PE, PilA and UspA2), by group in Step 2 at each time point during which blood samples are collected for CMI. | At Day 0 (pre-dose 1); at Day 60 (post-dose 1); at Day 90, Day 210 and Day 420 (post-dose2). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Immunogenicity, Reactogenicity