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.
Condition: Respiratory Disorders
MeSH terms: Respiration Disorders; Respiratory Tract Diseases
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): NTHi Mcat investigational vaccine (GSK3277511A); Placebo
Intervention type(s): Biological; Biological
Intervention description(s): Two doses administered intramuscularly at Day 1 and Day 61 in the deltoid region of the non-dominant arm.; Two doses administered intramuscularly at Day 1 and Day 61 in the deltoid region of the non-dominant arm.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Phase IIB, randomised, observer-blind, placebo-controlled, multi-centric study with two parallel groups.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Immunogenicity; Vaccination; Chronic Obstructive Pulmonary Disease; Non-typeable Haemophilus influenzae; Acute exacerbation of COPD; Moraxella catarrhalis; Efficacy; Safety