A Study to Test if a Third Dose of the Vaccine is Safe in Current and Former Smokers Aged 40 to 80 Years Old and to Gather Information on the Immune Response Following the Third Dose of the Vaccine

Study Overview
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Brief Summary
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The purpose of this study is to test two different vaccine schedules to be used for administering the investigational NTHi Mcat vaccine that will be targeting patients with chronic obstructive pulmonary disease (COPD) to prevent acute exacerbations. An acute exacerbation is when the breathlessness in COPD patients will get even worse than it normally already is, sometimes to the point where oxygen therapy is required. In previous studies, study participants have received two doses of the vaccine according to a 0, 2 month vaccination schedule, in addition to standard care. The current study will find out if a third dose of the study vaccine against NTHi/Mcat is safe and working well. The study will also investigate if the third dose of vaccine works best when given after 6 months or after 12 months.

Detailed Description
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The purpose of this Phase 2 study is to evaluate two vaccine schedules of the investigational NTHi-Mcat vaccine. As the prevalence of COPD increases with age and as age has an influence on both the immunogenicity and reactogenicity of a vaccine, subjects 40-80 years old will be enrolled. As cigarette smoking is the most commonly encountered risk factor for COPD, adults with a smoking history of at least 10 pack-years will be selected in order to immunologically match the COPD population as much as possible. Literature data indeed suggest that alterations of the immune system start early on in smokers, before the COPD disease is recognized [Barcelo et al 2008; Droemann et al, 2005; Takanashi et al, 1999]. Several formulations of a vaccine containing the NTHi antigens (10 or 30 µg) either non-adjuvanted or combined with different adjuvants (aluminium [Al], adjuvant system [AS]01E and AS04C) were already evaluated in two previous Phase 1 clinical trials (NTHI-002 in healthy adults aged 18 - 40 years and NTHI-003 in current and former healthy smokers of 50-70 years old). The investigational vaccines were well-tolerated, with an acceptable safety and reactogenicity profile. These studies allowed the dose selection of the NTHi antigens (10 µg) and the adjuvant system (AS01E) evaluated for the first time in moderate and severe COPD patients aged 40-80 years in the Phase 2 study NTHI-004. The safety, reactogenicity and immunogenicity of different formulations of the NTHi-Mcat investigational vaccine have been evaluated in the Phase 1 study in healthy adults aged 18-40 years and in current and former smokers aged 50-70 years (study NTHI MCAT-001). Based on results obtained up to 30 days post-Dose 2 from this study, the AS01E-adjuvanted formulation containing 10 µg of NTHi proteins PD and PE-PilA and 3.3 µg of UspA2 has been selected for evaluation in the current NTHI MCAT-008 study. The current study will evaluate the impact of a 3rd dose (following a 0-2 month vaccination schedule), either given at 6 months or at 12 months after the first dose. The primary aim is to assess the safety of the additional dose. The study will also investigate how the two schedules improve the persistence of antibody response. To this end, adults aged 40 to 80 years with a smoking history of at least 10 pack-years, will receive 2 doses of the NTHi-Mcat investigational vaccine at 0 and 2 months in both study arms. Following these 2 doses, one study arm will receive a 3rd dose of the investigational NTHi-Mcat vaccine at 6 months and a placebo control at 12 months (Schedule 1) and the other study arm will receive a placebo control at 6 months and a 3rd dose of the investigational NTHi-Mcat vaccine at 12 months (Schedule 2).

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

Conditions
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Respiratory Disorders

Intervention / Treatment
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* Biological: NTHi Mcat investigational vaccine (GSK3277511A)
* Biological: 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. Written informed consent obtained from the subject prior to performing any study specific procedure. A male or female between, and including, 40 and 80 years of age at the time of the first vaccination. Current or former smoker with a cigarette smoking history of ≥ 10 pack-years. Female subjects of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current bilateral tubal ligation or occlusion, hysterectomy, bilateral 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 (drug or vaccine) other than the study vaccines during the period starting 30 days before the first dose of study vaccines (Day -29 to Day 1), or planned use during the study period. Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe. Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose. For corticosteroids, this will mean prednisone ≥20 mg/day, or equivalent. Inhaled and topical steroids are allowed. Administration of long-acting immune-modifying drugs at any time 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 and ending 30 days after the last dose of vaccine administration, with the exception of any influenza or pneumococcal vaccine which may be administered ≥ 15 days preceding or following any study vaccine dose. 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. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. History of or current autoimmune disease. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine. Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥37.5°C. The preferred location for measuring temperature in this study will be the oral cavity or the axilla. Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may be enrolled at the discretion of the investigator. Administration of immunoglobulins and/or any blood products during the period starting 3 months before the first dose of study vaccine or planned administration during the study period. Pregnant or lactating female. Current alcoholism and/or drug abuse. Female planning to become pregnant or planning to discontinue contraceptive precautions. Diagnosed with a respiratory disorder. 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. Malignancies within previous 5 years or lymphoproliferative disorders. Any other condition that the investigator judges may interfere with study findings.

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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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: Schedule 0-2-6 Group<br>Subjects between, and including, 40 and 80 years of age at the time of the first vaccination, receiving three doses of the GSK3277511A investigational vaccine at Day 1 (Month 0), Day 61 (Month 2) and Day 181 (Month 6) and one dose of placebo at Day 361 (Month 12). | Biological: NTHi Mcat investigational vaccine (GSK3277511A)<br>* Two doses administered intramuscularly at Day 1 and Day 61 in the deltoid region of the non-dominant arm and a third dose administered at either Day 181 or Day 361, according to each vaccination scheduling defined per protocol.<br>Biological: Placebo<br>* One dose administered intramuscularly at either Day 181 or Day 361 in the deltoid region of the non-dominant arm.<br>|
| Experimental: Schedule 0-2-12 Group<br>Subjects between, and including, 40 and 80 years of age at the time of the first vaccination, receiving three doses of the GSK3277511A investigational vaccine at Day 1 (Month 0), Day 61 (Month 2) and Day 361 (Month 12) and one dose of placebo at Day 181 (Month 6). | Biological: NTHi Mcat investigational vaccine (GSK3277511A)<br>* Two doses administered intramuscularly at Day 1 and Day 61 in the deltoid region of the non-dominant arm and a third dose administered at either Day 181 or Day 361, according to each vaccination scheduling defined per protocol.<br>Biological: Placebo<br>* One dose administered intramuscularly at either Day 181 or Day 361 in the deltoid region of the non-dominant arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reported With Each Solicited Local Adverse Event (AE) (Any and Grade 3) Within Each Vaccination Schedule | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 100 millimeters (mm) injection site. | During the 7-day follow-up period (the day of vaccination + 6 days) after each vaccination administered at Day 1, Day 61, Day 181 and Day 361 | 
| Number of Subjects Reported With Each Solicited General Adverse Event (AE) (Any and Grade 3) Within Each Vaccination Schedule | Assessed solicited general symptoms were chills, gastrointestinal symptoms (including nausea, vomiting, diarrhoea and/or abdominal pain), fatigue, myalgia, headache and fever [defined Oral cavity or axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)]. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever ≥ 39.0 °C. | During the 7-day follow-up period (the day of vaccination + 6 days) after each vaccination administered at Day 1, Day 61, Day 181 and Day 361 | 
| Number of Subjects Reported With Any Unsolicited Adverse Event (AE) Within Each Vaccination Schedule | An AE is 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. Unsolicited AE is any AE reported in addition to those solicited during the clinical study. Also any 'solicited' symptom with onset outside the specified period of follow-up for solicited symptoms was reported as an unsolicited adverse event. | During the 30-day follow-up period (the day of vaccination + 29 days) after each vaccination administered at Day 1, Day 61, Day 181 and Day 361 | 
| Number of Subjects Reported With Any Serious Adverse Event (SAE) Within Each Vaccination Schedule | An SAE is defined as any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity in a subject or was a congenital anomaly/birth defect in the offspring of a study subject. AE(s) considered as SAE(s) also include invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, as per the medical or scientific judgement of the physician. | From first vaccination (Day 1) up to Day 541 (an average of 18 months) | 
| Number of Subjects Reported With Any Potential Immune-mediated Diseases (pIMDs) Within Each Vaccination Schedule | 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 (Day 1) up to Day 541 (an average of 18 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reported With Any SAE Within Each Vaccination Schedule | An SAE is defined as any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity in a subject or was a congenital anomaly/birth defect in the offspring of a study subject. AE(s) considered as SAE(s) also include invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, as per the medical or scientific judgement of the physician. | From Day 541 up to Day 721 (an average of 6 months) | 
| Number of Subjects Reported With Any pIMDs Within Each Vaccination Schedule | 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 Day 541 up to Day 721 (an average of 6 months) | 
| Anti-Protein D (PD) Antibody Concentrations, as Measured by ELISA, Within Each Vaccination Schedule | Anti-Protein D (PD) antibody concentrations as determined by Enzyme-linked Immunosorbent Assay (ELISA), and expressed as geometric mean concentrations (GMCs) in ELISA unit per milliliter (EU/mL). Calculation of the GMCs are performed by taking the anti-logarithm in base 10 (anti-log10) of the mean of the log10 concentration transformations. Antibody concentrations below the assay cut-off (153 EU/mL) is given an arbitrary value of half the assay cut-off for the purpose of GMC calculation. | At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721 | 
| Anti-Protein E (PE) Antibody Concentrations, as Measured by ELISA, Within Each Vaccination Schedule | Anti-Protein E (PE) antibody concentrations as determined by ELISA, and expressed in EU/mL. Calculation of the GMCs are performed by taking the anti-logarithm in base 10 (anti-log10) of the mean of the log10 concentration transformations. Antibody concentrations below the assay cut-off (16 EU/mL) is given an arbitrary value of half the assay cut-off for the purpose of GMC calculation. | At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721 | 
| Anti-Type IV Pili Subunit (PilA) Antibody Concentrations, as Measured by ELISA, Within Each Vaccination Schedule | Anti-type IV pili subunit (PilA) antibody concentrations as determined by ELISA, and expressed in EU/mL. Calculation of the GMCs are performed by taking the anti-logarithm in base 10 (anti-log10) of the mean of the log10 concentration transformations. Antibody concentrations below the assay cut-off (8 EU/mL) is given an arbitrary value of half the assay cut-off for the purpose of GMC calculation. | At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721 | 
| Anti-Ubiquitous Surface Protein A2 of Moraxella Catarrhalis (UspA2) Antibody Concentrations, as Measured by ELISA, Within Each Vaccination Schedule | Anti-ubiquitous surface protein A2 of Moraxella catarrhalis (UspA2) antibody concentrations as determined by ELISA, and expressed in EU/mL. Calculation of the GMCs are performed by taking the anti-logarithm in base 10 (anti-log10) of the mean of the log10 concentration transformations. Antibody concentrations below the assay cut-off (28 EU/mL) is given an arbitrary value of half the assay cut-off for the purpose of GMC calculation. | At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721 | 
| Number of Seropositive Subjects for Anti-PD Antibody, as Measured by ELISA, Within Each Vaccination Schedule | A Seropositive subject is defined as a subject whose antibody concentration is greater than or equal to the assay cut off (i.e. the ELISA lower limit of quantification = 153 EU/mL).Antibody concentrations as determined by Enzyme-linked Immunosorbent Assay (ELISA), and expressed in EU/mL. | At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721 | 
| Number of Seropositive Subjects for Anti-PE Antibody, as Measured by ELISA, Within Each Vaccination Schedule | A Seropositive subject is defined as a subject whose antibody concentration is greater than or equal to the assay cut off (i.e. the ELISA lower limit of quantification = 16 EU/mL). Antibody concentrations as determined by Enzyme-linked Immunosorbent Assay (ELISA), and expressed in EU/mL. | At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721 | 
| Number of Seropositive Subjects for Anti- PilA Antibody, as Measured by ELISA, Within Each Vaccination Schedule | A Seropositive subject is defined as a subject whose antibody concentration is greater than or equal to the assay cut off (i.e. the ELISA lower limit of quantification = 8 EU/mL).Antibody concentrations as determined by Enzyme-linked Immunosorbent Assay (ELISA), and expressed in EU/mL. | At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721 | 
| Number of Seropositive Subjects for Anti- UspA2 Antibody, as Measured by ELISA, Within Each Vaccination Schedule | A Seropositive subject is defined as a subject whose antibody concentration is greater than or equal to the assay cut off (i.e. the ELISA lower limit of quantification = 28 EU/mL).Antibody concentrations as determined by Enzyme-linked Immunosorbent Assay (ELISA), and expressed in EU/mL. | At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721 | 
| Frequency of Specific Cluster of Differentiation 4 (CD4+) T-cells Producing 2 or More Markers Upon in Vitro Stimulation With the Antigen, by NTHi and Mcat Antigens | 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 summarized with following descriptive statistics: Mean and standard deviation (SD) against each antigen (PD, PE,PilA and UspA2), by group and at each time point for which blood samples were collected for Cell-Mediated Immunity (CMI). The CMI sub-cohort subjects were selected from sites able to process the blood samples according to GSK procedures for peripheral blood mononuclear cell (PBMC) preparation. | At Day 1, Day 91, Day 181, Day 211, Day 361 and Day 391 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-typeable Haemophilus influenzae, Moraxella catarrhalis, Safety, Third vaccine dose, Vaccination, Immunogenicity