A Study to Test if the Vaccine is Working Well in Chronic Obstructive Pulmonary Disease (COPD) Patients Aged 40 to 80 Years Old to Reduce Episodes of Worsening Symptoms and to Gather Further Information on Safety and Immune Response.

NCT ID: NCT03281876

Last Updated: 2021-01-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 606 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-27
• Study Completion Date: 2020-03-26

Brief Summary

The purpose of this study is to test if the vaccine is working well in COPD patients aged 40 to 80 years old to reduce episodes of worsening symptoms ("exacerbations") and to gather further information on safety and immune response.

In the current study, COPD patients with a history of acute exacerbations will receive 2 doses of the investigational vaccine or placebo intramuscularly according to a 0, 2 month vaccination schedule, in addition to standard care.

The effect of vaccination against two pathogens known to cause exacerbations (Non-typeable Haemophilus influenza [NTHi] and Moraxella catarrhalis [Mcat]) will be evaluated at pre-defined timepoints (scheduled study visits).

In addition to the scheduled study visits, additional study visit(s) and/ or phone contact(s) will take place for each acute exacerbation of COPD occurring from first vaccination up to study conclusion.

Detailed Description

The purpose of this Phase IIB proof-of-concept (POC) study in moderate to very severe COPD patients (i.e. GOLD grade 2, 3 and 4) aged 40 to 80 years with a history of moderate or severe acute exacerbations of COPD (AECOPD) in the previous 12 months is to evaluate whether the NTHi-Mcat vaccine can reduce the frequency of AECOPD in this population and to assess the vaccine's safety, reactogenicity and immunogenicity.

Several formulations of a vaccine containing the NTHi antigens (low or high formulation) either non-adjuvanted or combined with different adjuvants (aluminium [Al], adjuvant system) were already evaluated in two previous Phase I 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 (low formulation) and the adjuvant system currently evaluated for the first time in moderate and severe COPD patients aged 45 - 81 years in the Phase II study NTHI-004.

The safety, reactogenicity and immunogenicity of different formulations of the NTHi-Mcat investigational vaccine have been evaluated in the Phase I study in healthy adults aged 19 - 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 adjuvanted formulation containing NTHi proteins PD and PE-PilA and of UspA2 has been selected for evaluation in the current NTHI MCAT-002 study. Placebo will be used as a control. The NTHi-Mcat investigational vaccine and placebo will be given on top of standard of care to subjects in the respective study groups.

In the current study, moderate, severe and very severe COPD patients (i.e. GOLD grade 2, 3 and 4) with a history of AECOPD will receive 2 doses of the NTHi-Mcat investigational vaccine or placebo intramuscularly (IM) according to a 0, 2 month vaccination schedule, in addition to standard care.

Scheduled study visits, during which the effect of immunisation against NTHi and Mcat will be evaluated, will take place at pre-defined timepoints.

In addition to the scheduled study visits, ad hoc AECOPD-driven study visit(s) and/ or phone contact(s) will take place for each AECOPD occurring from first vaccination up to study conclusion:

• An AECOPD visit will be scheduled as soon as possible after the onset of the AECOPD symptoms (maximum 96 hours after the onset of the symptoms).
• Follow-up visit(s) and/or phone call(s) will take place to determine the end of the AECOPD.

Rationale for the protocol amendment:

• CD8+ T cell component was removed from the secondary endpoint, but kept in the exploratory/tertiary endpoint. Previous clinical studies have shown that the investigational NTHi and NTHi-Mcat vaccines do not induce CD8+ T cell responses. This was observed in all studies performed with the NTHi vaccine and seen in the interim analysis of NTHi Mcat-001 study.
• An exclusion criterion was updated to clarify that only subjects with clinically significant respiratory diseases other than COPD (e.g. clinically significant lung fibrosis, clinically significant pulmonary embolism) need to be excluded from study participation.
• The polymerase chain reaction (PCR) assay for sputum samples was not designed to discriminate amongst Haemophilus influenzae (Hi) serotypes. Results from AERIS epidemiological study [Wilkinson, 2017] showed that more than 99% of these bacteria would be Non-Typeable Haemophilus influenzae (NTHi). Therefore, the protocol was updated to clarify that the presence of Hi bacteria in sputum during exacerbation will be used to determine AECOPD associated to NTHi.
• The list of potential immune mediated diseases was updated (effective June 30th 2017).
• The 87% confidence interval (CI) was removed from all secondary analyses. This confidence interval will only be maintained for the primary analysis because the 95% CIs are underpowered for this study. All other sensitivity analyses on different cohorts will be described using 95% CIs. As the primary objective will have both 87% and 95%, the sensitivity analyses can be interpreted with 95% CIs.
• A Full-Analysis Set (FAS) that corresponds to an intent-to-treat analysis was added. The FAS will include all randomized subjects who will receive at least 1 vaccine administration and, as per intention-to-treat principle, a subject in the FAS will be analysed "as randomized" (i.e. according to the vaccine a subject was planned to receive irrespectively of his/her real exposure).
• Cut-off values for anti-PE, anti-PilA and anti-UspA2 antibody ELISAs were updated following the re-set up of the assays.
• Additional minor updates were based on the scientific and operational experience gained from current COPD studies.

Conditions

Respiratory Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

GSK3277511A Group

Healthy males and females, 40 to 80 years of age, who received two doses of the adjuvanted GSK3277511A investigational vaccine containing surface protein D (PD), protein E- type IV pilus assembly protein (PE-PilA,) and ubiquitous surface protein A2 (UspA2) at Day 1 and Day 61.

Group Type: EXPERIMENTAL

NTHi Mcat investigational vaccine (GSK3277511A)

Intervention Type: BIOLOGICAL

Two doses administered intramuscularly at Day 1 and Day 61 in the deltoid region of the non-dominant arm.

CONTROL Group

Healthy males and females, 40 to 80 years of age, who received two doses of placebo vaccine at Day 1 and Day 61.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: BIOLOGICAL

Two doses administered intramuscularly at Day 1 and Day 61 in the deltoid region of the non-dominant arm.

Interventions

NTHi Mcat investigational vaccine (GSK3277511A)

Two doses administered intramuscularly at Day 1 and Day 61 in the deltoid region of the non-dominant arm.

Intervention Type: BIOLOGICAL

Placebo

Two doses administered intramuscularly at Day 1 and Day 61 in the deltoid region of the non-dominant arm.

Intervention Type: BIOLOGICAL

Eligibility 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.
• 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% predicted (GOLD 2, 3 and 4).
• 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 AECOPD within the 12 months before Screening.

• Patient for whom the last episode of AECOPD is resolved for at least 30 days at the time of first vaccination.

• A documented history of a COPD exacerbation is a medical record of worsening COPD symptoms that required systemic/oral corticosteroids and/or antibiotics (for a moderate exacerbation) or hospitalization (for a severe exacerbation). Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnea, sputum volume, or sputum purulence. Subject verbal reports are not acceptable.
• Capable of complying 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. 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 other than the study vaccine during the period starting 30 days before the first dose of study vaccine (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.
• 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.
• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
• 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.
• 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.
• Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose (e.g. methotrexate).
• Administration of systemic corticosteroids within the 30 days before first vaccination.

Subjects who received systemic corticosteroids within this period may be enrolled at a later date if enrolment is still open.

Inhaled and topical steroids are allowed.

• Administration of systemic antibiotics within the 30 days before first vaccination.

Subjects who received systemic antibiotics within this period may be enrolled at a later date if enrolment is still open.

• Chronic use of antibiotics for prevention of AECOPD (e.g. azithromycin).
• Acute disease and/or fever at the time of first vaccination. 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.

• Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy >3L/min (Oxygen use ≤3L/min flow is not exclusionary).
• Planned lung transplantation.
• Lung resection: Subjects with planned lung volume reduction surgery during the study or within the 12 months prior to first vaccination.
• Diagnosis of α-1 antitrypsin deficiency as the underlying cause of COPD.
• Diagnosed with a respiratory disorder other than COPD at time of enrolment (such as sarcoidosis, active tuberculosis, clinically significant bronchiectasis, clinically significant lung fibrosis, clinically significant pulmonary embolism, clinically significant pneumothorax, current diagnosis of asthma in the opinion of the investigator), 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 do not need to be excluded and may be enrolled at the discretion of the investigator.
• History of immune-mediated disease other than COPD. If the subject has any condition on the non-exhaustive list of potential immune-mediated diseases defined in the protocol, they must be excluded unless the aetiology is clearly documented to be non-immune mediated.
• Previous vaccination with any vaccine containing NTHi and/ or Mcat antigens.
• 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.
• Unstable or life threatening cardiac disease: subjects with any of the following at Screening (Visit 1) would be excluded:

Myocardial infarction or unstable angina in the last 6 months. Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months NYHA Class IV Heart failure

• Malignancies within the previous 5 years or lymphoproliferative disorder.
• Any known disease or condition likely to cause death during the study period.
• 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.

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Mesa, Arizona, United States

GSK Investigational Site

Phoenix, Arizona, United States

GSK Investigational Site

Phoenix, Arizona, United States

GSK Investigational Site

Palm Springs, California, United States

GSK Investigational Site

Clearwater, Florida, United States

GSK Investigational Site

Jacksonville, Florida, United States

GSK Investigational Site

Jacksonville, Florida, United States

GSK Investigational Site

Council Bluffs, Iowa, United States

GSK Investigational Site

Wichita, Kansas, United States

GSK Investigational Site

Missoula, Montana, United States

GSK Investigational Site

Neptune City, New Jersey, United States

GSK Investigational Site

Charlotte, North Carolina, United States

GSK Investigational Site

Mooresville, North Carolina, United States

GSK Investigational Site

Winston-Salem, North Carolina, United States

GSK Investigational Site

Columbus, Ohio, United States

GSK Investigational Site

Corvallis, Oregon, United States

GSK Investigational Site

Medford, Oregon, United States

GSK Investigational Site

Erie, Pennsylvania, United States

GSK Investigational Site

Gaffney, South Carolina, United States

GSK Investigational Site

Mt. Pleasant, South Carolina, United States

GSK Investigational Site

Spartanburg, South Carolina, United States

GSK Investigational Site

Union, South Carolina, United States

GSK Investigational Site

Abingdon, Virginia, United States

GSK Investigational Site

Richmond, Virginia, United States

GSK Investigational Site

Wenatchee, Washington, United States

GSK Investigational Site

Brussels, , Belgium

GSK Investigational Site

Genk, , Belgium

GSK Investigational Site

Ghent, , Belgium

GSK Investigational Site

Kortrijk, , Belgium

GSK Investigational Site

Leuven, , Belgium

GSK Investigational Site

Liège, , Belgium

GSK Investigational Site

Edmonton, Alberta, Canada

GSK Investigational Site

Vancouver, British Columbia, Canada

GSK Investigational Site

Halifax, Nova Scotia, Canada

GSK Investigational Site

Truro, Nova Scotia, Canada

GSK Investigational Site

Montreal, Quebec, Canada

GSK Investigational Site

Québec, Quebec, Canada

GSK Investigational Site

Saint-Charles-Borromée, Quebec, Canada

GSK Investigational Site

Brest, , France

GSK Investigational Site

Créteil, , France

GSK Investigational Site

Marseille, , France

GSK Investigational Site

Montpellier, , France

GSK Investigational Site

Frankfurt am Main, Hesse, Germany

GSK Investigational Site

Frankfurt am Main, Hesse, Germany

GSK Investigational Site

Immenhausen, Hesse, Germany

GSK Investigational Site

Großhansdorf, Schleswig-Holstein, Germany

GSK Investigational Site

Lübeck, Schleswig-Holstein, Germany

GSK Investigational Site

Magdeburg, , Germany

GSK Investigational Site

Cona (FE), Emilia-Romagna, Italy

GSK Investigational Site

Parma, Emilia-Romagna, Italy

GSK Investigational Site

Milan, Lombardy, Italy

GSK Investigational Site

Milan, Lombardy, Italy

GSK Investigational Site

Monza, Lombardy, Italy

GSK Investigational Site

Negrar, Veneto, Italy

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Centelles (Barcelona), , Spain

GSK Investigational Site

Elda, , Spain

GSK Investigational Site

La Roca Del Valles (Barcelona), , Spain

GSK Investigational Site

Madrid, , Spain

GSK Investigational Site

Pozuelo de Alarcón/Madrid, , Spain

GSK Investigational Site

Vic, , Spain

GSK Investigational Site

Portsmouth, Hampshire, United Kingdom

GSK Investigational Site

Bradford, , United Kingdom

GSK Investigational Site

Dundee, , United Kingdom

GSK Investigational Site

Edinburgh, , United Kingdom

GSK Investigational Site

High Heaton, Newcastle Upon Tyne, , United Kingdom

GSK Investigational Site

Southampton, , United Kingdom

Countries

United States; Belgium; Canada; France; Germany; Italy; Spain; United Kingdom

References

Arora AK, Chinsky K, Keller C, Mayers I, Pascual-Guardia S, Vera MP, Lambert C, Lombardi S, Rondini S, Tian S, Ulloa-Montoya F, Moraschini L, Casula D; NTHi-Mcat-002 study group. A detailed analysis of possible efficacy signals of NTHi-Mcat vaccine against severe COPD exacerbations in a previously reported randomised phase 2b trial. Vaccine. 2022 Sep 29;40(41):5924-5932. doi: 10.1016/j.vaccine.2022.08.053. Epub 2022 Sep 6.

Reference Type: DERIVED

PMID: 36068109 (View on PubMed)

Andreas S, Testa M, Boyer L, Brusselle G, Janssens W, Kerwin E, Papi A, Pek B, Puente-Maestu L, Saralaya D, Watz H, Wilkinson TMA, Casula D, Di Maro G, Lattanzi M, Moraschini L, Schoonbroodt S, Tasciotti A, Arora AK, Maltais F; NTHi-Mcat-002 study group. Non-typeable Haemophilus influenzae-Moraxella catarrhalis vaccine for the prevention of exacerbations in chronic obstructive pulmonary disease: a multicentre, randomised, placebo-controlled, observer-blinded, proof-of-concept, phase 2b trial. Lancet Respir Med. 2022 May;10(5):435-446. doi: 10.1016/S2213-2600(21)00502-6. Epub 2022 Jan 10.

Reference Type: DERIVED

PMID: 35026180 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2017-000880-34

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

207489

Identifier Type: -

Identifier Source: org_study_id