Clinical trial NCT03443427: 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
Official title: An Observer-blind Study to Evaluate the Safety, Reactogenicity and Immunogenicity of the Investigational GSK Biologicals' COPD Vaccine (GSK3277511A) in Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Respiratory Disorders
Keywords: Non-typeable Haemophilus influenzae
Moraxella catarrhalis
Safety
Third vaccine dose
Vaccination
Immunogenicity
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2018-02-23
Enrollment: 200
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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).

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.
* 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.

Primary outcomes:
measure: Number of Subjects Reported With Each Solicited Local Adverse Event (AE) (Any and Grade 3) Within Each Vaccination Schedule
timeFrame: 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
measure: Number of Subjects Reported With Each Solicited General Adverse Event (AE) (Any and Grade 3) Within Each Vaccination Schedule
timeFrame: 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
measure: Number of Subjects Reported With Any Unsolicited Adverse Event (AE) Within Each Vaccination Schedule
timeFrame: 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
measure: Number of Subjects Reported With Any Serious Adverse Event (SAE) Within Each Vaccination Schedule
timeFrame: From first vaccination (Day 1) up to Day 541 (an average of 18 months)
measure: Number of Subjects Reported With Any Potential Immune-mediated Diseases (pIMDs) Within Each Vaccination Schedule
timeFrame: From first vaccination (Day 1) up to Day 541 (an average of 18 months)
Secondary outcomes:
measure: Number of Subjects Reported With Any SAE Within Each Vaccination Schedule
timeFrame: From Day 541 up to Day 721 (an average of 6 months)
measure: Number of Subjects Reported With Any pIMDs Within Each Vaccination Schedule
timeFrame: From Day 541 up to Day 721 (an average of 6 months)
measure: Anti-Protein D (PD) Antibody Concentrations, as Measured by ELISA, Within Each Vaccination Schedule
timeFrame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721
measure: Anti-Protein E (PE) Antibody Concentrations, as Measured by ELISA, Within Each Vaccination Schedule
timeFrame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721
measure: Anti-Type IV Pili Subunit (PilA) Antibody Concentrations, as Measured by ELISA, Within Each Vaccination Schedule
timeFrame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721
measure: Anti-Ubiquitous Surface Protein A2 of Moraxella Catarrhalis (UspA2) Antibody Concentrations, as Measured by ELISA, Within Each Vaccination Schedule
timeFrame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721
measure: Number of Seropositive Subjects for Anti-PD Antibody, as Measured by ELISA, Within Each Vaccination Schedule
timeFrame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721
measure: Number of Seropositive Subjects for Anti-PE Antibody, as Measured by ELISA, Within Each Vaccination Schedule
timeFrame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721
measure: Number of Seropositive Subjects for Anti- PilA Antibody, as Measured by ELISA, Within Each Vaccination Schedule
timeFrame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721
measure: Number of Seropositive Subjects for Anti- UspA2 Antibody, as Measured by ELISA, Within Each Vaccination Schedule
timeFrame: At Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721
measure: 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
timeFrame: At Day 1, Day 91, Day 181, Day 211, Day 361 and Day 391
Other outcomes:
Locations:
city: Truro
country: Canada
facility: GSK Investigational Site
state: Nova Scotia
city: Sherbrooke
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Wuerzburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Goch
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Chesterfield
country: United Kingdom
facility: GSK Investigational Site
state: Derbyshire
city: Wellingborough
country: United Kingdom
facility: GSK Investigational Site
state: Northamptonshire
city: Axbridge, Somerset
country: United Kingdom
facility: GSK Investigational Site
city: Chippenham
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Galgani I, Annaratone M, Casula D, Di Maro G, Janssens M, Tasciotti A, Schwarz T, Ferguson M, Arora AK. Safety and immunogenicity of three doses of non-typeable Haemophilus influenzae-Moraxella catarrhalis (NTHi-Mcat) vaccine when administered according to two different schedules: a phase 2, randomised, observer-blind study. Respir Res. 2022 May 4;23(1):114. doi: 10.1186/s12931-022-02019-4.