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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

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ClinicalTrials.gov Identifier: NCT03443427
Recruitment Status : Active, not recruiting
First Posted : February 23, 2018
Last Update Posted : June 5, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:

The purpose of this study is to test two schedules of how a vaccine will be given to patients with chronic obstructive pulmonary disease (COPD) to prevent acute exacerbations. An acute exacerbation is when during an infection, 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.


Condition or disease Intervention/treatment Phase
Respiratory Disorders Biological: NTHi Mcat investigational vaccine (GSK3277511A) Biological: Placebo Phase 2

Detailed Description:

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).


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

By observer-blind, it is meant that during the course of the study, the vaccine recipient and those responsible for the evaluation of any study endpoint (e.g. safety, reactogenicity) will all be unaware of whether vaccine or placebo was administered. Each study site is responsible for having a blinding plan. To work in an observer-blind manner, vaccine preparation and administration will be done by authorised medical personnel (e.g. study nurse) who will not participate in any of the study clinical evaluation assays. Two teams of study personnel will hence be set up:

  • A team of unblinded personnel (responsible for the preparation and the administration of the vaccines)
  • A team of blinded personnel (responsible for the clinical evaluation of the subjects).

The laboratory in charge of the laboratory testing will be blinded to the treatment, and codes will be used to link the subject and study (without any link to the treatment attributed to the subject) to each sample.

Primary Purpose: Prevention
Official Title: An Observer-blind Study to Evaluate the Safety, Reactogenicity and Immunogenicity of the Investigational GSK Biologicals' COPD Vaccine (GSK3277511A) in Adults
Actual Study Start Date : March 20, 2018
Estimated Primary Completion Date : May 19, 2020
Estimated Study Completion Date : June 2, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Schedule 1
100 planned subjects receiving three doses of the GSK3277511A investigational vaccine at Visit 1 (Day 1), Visit 3 (Day 61) and Visit 5 (Day 181) and one dose of placebo at Visit 7 (Day 361).
Biological: NTHi Mcat investigational vaccine (GSK3277511A)
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 Day 181 or Day 361, according each vaccination scheduling defined per protocol.

Biological: Placebo
One dose administered intramuscularly at Day 181 or Day 361 in the deltoid region of the non-dominant arm.

Experimental: Schedule 2
100 planned subjects receiving three doses of the GSK3277511A investigational vaccine at Visit 1 (Day 1), Visit 3 (Day 61) and Visit 7 (Day 361) and one dose of placebo at Visit 5 (Day 181).
Biological: NTHi Mcat investigational vaccine (GSK3277511A)
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 Day 181 or Day 361, according each vaccination scheduling defined per protocol.

Biological: Placebo
One dose administered intramuscularly at Day 181 or Day 361 in the deltoid region of the non-dominant arm.




Primary Outcome Measures :
  1. Number of subjects reported with each solicited local adverse event (AE) (any and grade 3) within each vaccination schedule. [ Time Frame: During the 7-day follow-up period (Days 1-7) after each vaccination. ]
    The number and percentage of subjects with at least one local solicited AE, regardless of intensity, during the 7-day follow-up period after each vaccination, will be reported after each vaccination by study group. The same computations will be done for Grade 3 solicited AEs. Assessed local symptoms are pain, redness and swelling. Grade 3 Pain = Significant pain at rest -Prevents normal every day activities. Grade 3 Redness/Swelling = Redness/swelling at injection site larger than (>) 100 millimeters (mm).

  2. Number of subjects reported with each solicited general adverse event (AE) (any and grade 3) within each vaccination schedule. [ Time Frame: During the 7-day follow-up period (Days 1-7) after each vaccination. ]
    The number and percentage of subjects with at least one general solicited AE, regardless of intensity, during the 7-day follow-up period after each vaccination, will be reported after each vaccination by study group. The same computations will be done for Grade 3 solicited AEs. Assessed solicited general symptoms are Fatigue, Gastrointestinal symptoms (nausea, vomiting, diarrhoea and/or abdominal pain), Myalgia, Chills and Fever (oral cavity or axillary route - temperature equal or higher than [≥] 37.5 degrees Celsius [°C]). Grade 3 Fatigue, gastrointestinal symptoms, Myalgia and Chills = Symptoms that prevent normal activity. Grade 3 Fever = temperature higher than (>) 39.0°C.

  3. Number of subjects reported with any unsolicited adverse event (AE) within each vaccination schedule. [ Time Frame: During the 30-day follow-up period (Days 1-30) after each vaccination. ]
    The percentage of subjects with at least one unsolicited AE, regardless of intensity or relationship to vaccination, during the 30 day follow-up period after any study vaccination will be reported for each group and by MedDRA Preferred Term. 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 will be reported as an unsolicited adverse event.

  4. Number of subjects reported with any serious adverse event (SAE) within each vaccination schedule. [ Time Frame: From first vaccination at Day 1 up to Day 541 (an average of 18 months). ]
    The percentage of subjects with at least one SAE, regardless of intensity or relationship to vaccination, from first vaccination (Day 1) up to and including Day 541, will be reported for each group and by MedDRA Preferred Term. An SAE is defined as any untoward medical occurrence that results in death, was life-threatening, requires hospitalization or prolongation of hospitalization, results in disability/incapacity in a subject or is 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.

  5. Number of subjects reported with any Potential Immune-mediated diseases (pIMDs) within each vaccination schedule. [ Time Frame: From first vaccination at Day 1 up to Day 541 (an average of 18 months). ]
    The number of subjects who experienced any pIMD from first vaccination up to Day 541 will be reported. 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.


Secondary Outcome Measures :
  1. Number of subjects reported with any serious adverse event (SAE) within each vaccination schedule. [ Time Frame: From Day 541 up to Day 721(an average of 6 months). ]
    The percentage of subjects with at least one SAE, regardless of intensity or relationship to vaccination, from Day 541 up to Day 721, will be reported for each group and by MedDRA Preferred Term. An SAE is defined as any untoward medical occurrence that results in death, was life-threatening, requires hospitalization or prolongation of hospitalization, results in disability/incapacity in a subject or is 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.

  2. Number of subjects reported with any Potential Immune-mediated diseases (pIMDs) within each vaccination schedule. [ Time Frame: From Day 541 up to Day 721 (an average of 6 months). ]
    The number of subjects who experienced any pIMD from Day 541 to Day 721 will be reported. 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.

  3. Anti-Protein D (PD) antibody concentrations, as measured by ELISA, within each vaccination schedule. [ Time Frame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721. ]
    Geometric Mean Concentrations (GMC) and their 95% CI will be calculated (the GMCs are computed by taking the anti-log of the mean of the log concentration transformations).

  4. Anti-Protein E (PE) antibody concentrations, as measured by ELISA, within each vaccination schedule. [ Time Frame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721. ]
    Geometric Mean Concentrations (GMC) and their 95% CI will be calculated (the GMCs are computed by taking the anti-log of the mean of the log concentration transformations).

  5. Anti-type IV pili subunit (PilA) antibody concentrations, as measured by ELISA, within each vaccination schedule. [ Time Frame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721. ]
    Geometric Mean Concentrations (GMC) and their 95% CI will be calculated (the GMCs are computed by taking the anti-log of the mean of the log concentration transformations).

  6. Anti-ubiquitous surface protein A2 of Moraxella catarrhalis (UspA2) antibody concentrations, as measured by ELISA, within each vaccination schedule. [ Time Frame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721. ]
    Geometric Mean Concentrations (GMC) and their 95% CI will be calculated (the GMCs are computed by taking the anti-log of the mean of the log concentration transformations).

  7. Number of seropositive subjects for anti-PD antibody, as measured by ELISA, within each vaccination schedule. [ Time Frame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721. ]
    A seropositive subject is defined as a subject whose anti-PD antibody concentration is greater than or equal to the assay cut-off value.

  8. Number of seropositive subjects for anti-PE antibody, as measured by ELISA, within each vaccination schedule. [ Time Frame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721. ]
    A seropositive subject is defined as a subject whose anti-PE antibody concentration is greater than or equal to the assay cut-off value.

  9. Number of seropositive subjects for anti- PilA antibody, as measured by ELISA, within each vaccination schedule. [ Time Frame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721. ]
    A seropositive subject is defined as a subject whose anti- PilA antibody concentration is greater than or equal to the assay cut-off value.

  10. Number of seropositive subjects for anti- UspA2 antibody, as measured by ELISA, within each vaccination schedule. [ Time Frame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721. ]
    A seropositive subject is defined as a subject whose anti- UspA2 antibody concentration is greater than or equal to the assay cut-off value.

  11. NTHi-specific and Mcat-specific cell-mediated immune responses as measured by flow cytometry Intracellular Cytokine Staining (ICS) (frequency of specific CD4+ T-cells), in a sub-cohort of subjects and within each vaccination schedule. [ Time Frame: At Day 1, Day 91, Day 181, Day 211, day 361 and Day 391. ]
    The ICS staining assay will be used to assess Cell-Mediated Immune response (CMI) responses, using an adaptation of previously described methods [Moris , 2011]. After PBMC stimulation with the relevant antigens, CMI induced by the NTHi-Mcat candidate vaccine will be evaluated, presenting the frequencies (including mean, medium, minimum and maximum) of antigen-specific Cluster of Differentiation (CD)4+ T cells per 106 cells. The specific CD4+T cells being identified as the CD4+ T cells expressing at least 2 different cytokines/activation markers among CD40 Ligand (CD40L), interleukin (IL)-2, IL-13, IL-17, tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), upon in vitro stimulation. A descriptive statistics (Minimum, Q1, Median, Q3 & Maximum) will be reported for each group at Day 1, Day 91, Day 181, Day 211, Day 361 and Day 391.

  12. NTHi-specific and Mcat-specific cell-mediated immune responses as measured by flow cytometry Intracellular Cytokine Staining (ICS) (frequency of specific CD8+ T-cells), in a sub-cohort of subjects and within each vaccination schedule. [ Time Frame: At Day 1, Day 91, Day 181, Day 211, day 361 and Day 391. ]
    The ICS staining assay will be used to assess Cell-Mediated Immune response (CMI) responses, using an adaptation of previously described methods [Moris , 2011]. After PBMC stimulation with the relevant antigens, CMI induced by the NTHi-Mcat candidate vaccine will be evaluated, presenting the frequencies (including mean, medium, minimum and maximum) of antigen-specific Cluster of Differentiation (CD)8+ T cells per 106 cells. The specific CD8+/T cells being identified as the CD8+ T cells expressing at least 2 different cytokines/activation markers among CD40 Ligand (CD40L), interleukin (IL)-2, IL-13, IL-17, tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), upon in vitro stimulation. A descriptive statistics (Minimum, Q1, Median, Q3 & Maximum) will be reported for each group at Day 1, Day 91, Day 181, Day 211, Day 361 and Day 391.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03443427


Locations
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Canada, Nova Scotia
GSK Investigational Site
Truro, Nova Scotia, Canada, B2N 1L2
Canada, Quebec
GSK Investigational Site
Sherbrooke, Quebec, Canada, J1H 2G2
Germany
GSK Investigational Site
Wuerzburg, Bayern, Germany, 97070
GSK Investigational Site
Goch, Nordrhein-Westfalen, Germany, 47574
United Kingdom
GSK Investigational Site
Chesterfield, Derbyshire, United Kingdom, S40 4AA
GSK Investigational Site
Wellingborough, Northamptonshire, United Kingdom, NN8 4RW
GSK Investigational Site
Axbridge, Somerset, United Kingdom, BS26 2BJ
GSK Investigational Site
Chippenham, United Kingdom, SN15 2SB
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03443427     History of Changes
Other Study ID Numbers: 207759
2017-002941-31 ( EudraCT Number )
First Posted: February 23, 2018    Key Record Dates
Last Update Posted: June 5, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:
Non-typeable Haemophilus influenzae
Moraxella catarrhalis
Safety
Third vaccine dose
Vaccination
Immunogenicity

Additional relevant MeSH terms:
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Respiration Disorders
Respiratory Tract Diseases
Vaccines
Immunologic Factors
Physiological Effects of Drugs