A Study to Evaluate the Safety, Reactogenicity and Immunogenicity of GlaxoSmithkline (GSK) Biologicals' Investigational Vaccine GSK2838504A When Administered to Chronic Obstructive Pulmonary Disease (COPD) Patients With Persistent Airflow Obstruction.

Study Overview
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Brief Summary
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The purpose of this Phase II study is to assess the safety, reactogenicity and immunogenicity of the investigational Non-typeable Haemophilus influenzae (NTHi) vaccine in patients with moderate and severe persistent airflow obstruction.

Official Title
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An Observer-blind Study to Evaluate the Safety, Reactogenicity and Immunogenicity of GSK Biologicals' Investigational Vaccine GSK2838504A When Administered to Chronic Obstructive Pulmonary Disease (COPD) Patients

Conditions
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Respiratory Disorders

Intervention / Treatment
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* Biological: NTHi-10-AS01E
* Drug: NaCl Placebo


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. A male or female between, and including, 40 and 80 years of age at the time of the first vaccination. Written informed consent obtained from the subject. Confirmed diagnosis of COPD with forced expiratory volume in 1 second (FEV1) over forced vital capacity (FVC) ratio (FEV1/FVC) < 0.7, AND FEV1 < 80% and ≥ 30% predicted. Current or former smoker with a cigarette smoking history of ≥ 10 pack-years. Stable COPD patient with documented history of at least 1 moderate or severe acute exacerbation of COPD within the 12 months before Screening. Regular sputum producer. Capable to comply with the daily electronic Diary Card completion throughout the study period, according to investigator's judgement at Visit 1. Female subjects of non-childbearing potential may be enrolled in the study. 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: 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. Use of any investigational or non-registered product other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period. 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 vaccine which may be administered ≥ 15 days preceding or following any study vaccine dose. Previous vaccination with any vaccine containing NTHi antigens. Administration of immunoglobulins or any blood products within the 3 months preceding the first dose of study vaccine or planned administration during the study period. Chronic administration of non-steroid immunosuppressants or other immune-modifying drugs within 6 months prior to the first vaccine dose. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. History of immune-mediated disease other than COPD. Administration of systemic corticosteroids within the 30 days before Screening. Administration of systemic antibiotics within the 30 days before Screening. Chronic use of antibiotics for prevention of acute exacerbations of COPD (AECOPD). Receiving oxygen therapy. Planned lung transplantation. Planned/ underwent lung resection surgery. Diagnosis of α-1 antitrypsin deficiency as the underlying cause of COPD. Diagnosed with a respiratory disorder other than COPD, or chest X-ray/ CT scan revealing evidence of clinically significant abnormalities not believed to be due to the presence of COPD. Subjects with allergic rhinitis can be enrolled. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines and/ or the bronchodilator used for spirometry assessment during the study. Contraindication for spirometry testing. Clinically significant abnormality in haematology or biochemistry parameter. Acute cardiac insufficiency. Malignancies within the previous 5 years or lymphoproliferative disorder. Any known disease or condition likely to cause death during the study period. Acute disease and/ or fever at the time of Screening. Fever is defined as oral or axillary temperature ≥ 37.5°C. The preferred route for recording temperature in this study will be oral. Subjects with acute disease and/ or fever at the time of Screening may be enrolled at a later date if enrolment is still open. Subjects with a minor illness without fever may be enrolled at the discretion of the investigator. Pregnant or lactating female. Current alcoholism and/or drug abuse. Other condition which the investigator judges may put the safety of the subject at risk through study participation or which may interfere with the study findings. Planned move to a location that will complicate participation in the trial through study end.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: 10-AS01E group<br>Subjects in this group will receive the investigational NTHi vaccine. | Biological: NTHi-10-AS01E<br>* Intramuscular vaccination in the deltoid region of the non-dominant arm according to protocol schedule.<br>|
| Placebo Comparator: Control group<br>Subjects in this group will receive placebo. | Drug: NaCl Placebo<br>* 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 were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. | During a 7-day follow-up period (from Day 0 to Day 6) after first dose. | 
| Number of Subjects With Any Solicited Local AEs. | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. | During a 7-day follow-up period (from Day 60 to Day 66) after second dose. | 
| Number of Subjects With Any Solicited General AEs. | Assessed solicited general symptoms are fatigue, gastrointestinal symptoms (included nausea, vomiting, diarrhoea and/or abdominal pain), headache, fever [defined as oral temperature equal to or above 37.5 degrees Celsius (°C)]. Any = occurrence of the symptom regardless of intensity grade. | During a 7-day follow-up period (from Day 0 to Day 6) following the first dose. | 
| Number of Subjects With Any Solicited General AEs | Assessed solicited general symptoms are fatigue, gastrointestinal symptoms (included nausea, vomiting, diarrhoea and/or abdominal pain), headache, fever (defined as oral temperature equal to or above 37.5 °C). Any = occurrence of the symptom regardless of intensity grade. | During a 7-day follow-up period (from Day 60 to Day 66) following the second dose. | 
| Number of Subjects With Any Unsolicited AEs. | Assessed unsolicited AEs covered 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. 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. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination. | During the 30-day follow-up period (from Day 0 to Day 29) following the first dose. | 
| Number of Subjects With Any Unsolicited AEs | Assessed unsolicited AEs covered 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. 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. Any = occurrence of the symptom regardless of intensity grade or relation to vaccination. | During the 30-day follow-up period (from Day 60 to Day 89) following the second dose. | 
| Number of Subjects With Each Haematological/ Biochemical Laboratory Abnormality. | Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], 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 0. | 
| Number of Subjects With Each Haematological/ Biochemical Laboratory Abnormality. | Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], 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. | 
| Number of Subjects With Each Haematological/ Biochemical Laboratory Abnormality. | Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], 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 30. | 
| Number of Subjects With Each Haematological/ Biochemical Laboratory Abnormality. | Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], 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. | 
| Number of Subjects With Each Haematological/ Biochemical Laboratory Abnormality. | Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], 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. | 
| Number of Subjects With Each Haematological/ Biochemical Laboratory Abnormality. | Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], 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 90. | 
| Number of Subjects With Each Haematological/ Biochemical Laboratory Abnormality. | Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], 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 270. | 
| Number of Subjects With Each Haematological/ Biochemical Laboratory Abnormality. | Assessed haematological parameters are complete blood cell count: Leukocytes [white blood cells (WBC)], 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 450. | 
| Number of Subjects Reporting Any Potential Immune-mediated Diseases (pIMDs). | 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 (Day 0) up to study conclusion (Day 450). | 
| Number of Subjects With Any Serious Adverse Events (SAEs). | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity or are a congenital anomaly/ birth defect in the offspring of a study subject. | From first vaccination (Day 0) up to study conclusion (Day 450). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of Anti Protein D (Anti-PD) Total Immunoglobulin G (IgG) Antibodies Against the NTHi Vaccine Antigens. | Antibody concentrations were 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 was 153 EL.U/mL for anti-PD. | At Day 0, Day 30, Day 60, Day 90, Day 270 and at Day 450. | 
| Concentration of Anti Protein E (Anti-PE) Total IgG Antibodies Against the NTHi Vaccine Antigens. | Antibody concentrations were measured by ELISA and expressed as GMCs in EL.U/mL. The cut-off of the assay was 8 EL.U/mL for anti-PE. | At Day 0, Day 30, Day 60, Day 90, Day 270 and at Day 450 | 
| Concentration of Anti-PilA Total IgG Antibodies Against the NTHi Vaccine Antigens. | Antibody concentrations were measured by ELISA and expressed as GMCs in EL.U/mL. The cut-off of the assay was 7 EL.U/mL for anti-PilA. | At Day 0, Day 30, Day 60, Day 90, Day 270 and at Day 450. | 
| Frequency of Specific Cluster of Differentiation 4 (CD4+) T-cells Against NTHi Antigens Collected for Evaluation of Cell-mediated Immune Response. | Frequency of specific CD4+ T-cells were measured by flow cytometry intracellular cytokine staining (ICS) expressing two or more markers [such as Interleukin-2 (IL-2), IL-13, IL-17, Interferon-γ (IFN-γ), Tumor Necrosis Factor-α (TNF-α) and Cluster of Differentiation 40 Ligand (CD40L)].The frequency of specific CD4+ T-cells are summarised [descriptive statistics: Mean and standard deviation (SD)] against each antigen (PD, PE and PilA), by group at each time point during which blood samples are collected for CMI. | At Day 0, Day 90, Day 270 and at Day 450. | 
| Frequency of Specific CD8+ T-cells Against NTHi Antigens Collected for Evaluation of Cell-mediated Immune Response. | Frequency of specific CD8+ T-cells were measured by flow cytometry 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 and PilA), by group at each time point during which blood samples are collected for CMI. | At Day 0, Day 90, Day 270 and at Day 450. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunogenicity, Observer-blind, Reactogenicity, Chronic Obstructive Pulmonary Disease, Safety