Exploring Asthma Exacerbations in Mepolizumab Treated Patients
Condition: Asthma Brittle
MeSH terms: Asthma
Study type: Observational

Summary: 
      This is a multicentre, observational study focusing on exacerbation events in patients with
      severe eosinophilic asthma on Mepolizumab.

      Mepolizumab is an anti-IL5 (Interleukin 5) monoclonal antibody which blocks the eosinophilic
      activation pathways associated with decreasing asthma control. The pre-licensing studies have
      shown that Mepolizumab decreases asthma exacerbation events by approximately 50%, this study
      seeks to understand the underlying mechanisms of the remaining 50% of exacerbations.

      The study will enrol patients within GINA classification 4 and 5 who are known to difficult
      asthma services across four UK sites. Some patients will recently have been commenced on
      Mepolizumab, whilst others will be commenced on the drug on entry to the study. The patients
      will have baseline measurements of biomarkers, lung function, sputum analysis and quality of
      life questionnaires on study entry, after which patients will be asked to contact the clinic
      at the first signs of worsening asthma symptoms to arrange a clinic visit prior to commencing
      rescue treatment. They will be clinically assessed with review of peak flow and symptom
      diaries, measurements taken at baseline will be repeated and a decision on the nature of the
      exacerbation and treatment required will be made.

      This is an observational study, all outcomes will be exploratory.
    

Detailed description: 
      Background:

      Around 15% of the United Kingdom (UK) have asthma, of these, 10-20% have asthma which is
      difficult to control using current therapies and with high levels of morbidity resulting.
      These patients consume 50-60% of the UK healthcare costs of asthma and as such, there is much
      interest in developing novel treatments for this group.

      The heterogeneity of inflammatory pathways underlying asthma are of great interest with
      development of biomarkers useful for phenotyping asthmatic patients and allowing more
      accurate assessment of their response to treatment. Traditionally, oral corticosteroids are
      used in eosinophilic 'T2-high' asthmatic patients with good therapeutic effect, however,
      there are a group of T2-high patients who have refractory type-2 cytokine driven inflammation
      and airway eosinophilia despite oral corticosteroids. As such, there are several novel
      biological agents being engineered to block type 2 cytokine pathways including antagonists to
      IL5, IL13 and IL4 (Interleukin 5, 13, 4).

      Mepolizumab is a humanised monoclonal antibody against IL5. Through a selective inhibition of
      eosinophilic inflammation, the agent reduces the number of eosinophils in sputum and blood,
      with important clinical outcomes such as a reduction of asthma exacerbations and a need for
      systemic glucocorticoids. The pre-licencing clinical trials have shown that selective
      inhibition of IL5 and presumptive removal of eosinophils reduces exacerbations by 50%, but
      while this is a significant reduction, patients with severe asthma continue to have severe
      exacerbations requiring systemic corticosteroid administration.

      Therefore, the point of interest is eliciting the inflammatory phenotype and physiological
      characteristics of the remaining 50% of exacerbations and ascertaining whether systemic
      corticosteroids have a role when the IL-5 pathway has been blocked by Mepolizumab.

      Purpose/ Aim This is an observational study designed to phenotype exacerbations or worsening
      asthma control when participants are established on Mepolizumab. The study will look for
      changes in lung function, biomarkers and patient symptoms scores.

      The hypothesis is as follows: In patients with severe refractory eosinophilic asthma, who
      have been established on mepolizumab:

      - increased asthma symptoms (exacerbations) will have no evidence of airway eosinophilia and
      will be clinically mild events associated with small reductions in lung function which may
      not require rescue oral corticosteroids.

      Outline plan of investigation This will be an open observational multi-centre, cohort study
      in participants with severe asthma (Global Initiative for Asthma (GINA) Steps 4 and 5
      classification of asthma severity) who are initiated on Mepolizumab in line with the NICE/SMC
      (National institute foe Health and Care Excellence) Clinical Guidelines.

      The study is exploratory and will assess deteriorations in asthma control to characterise the
      clinical severity of each exacerbation and the airway and systemic inflammatory phenotype
      associated with these events. Clinical assessment and management of each exacerbation will be
      in line with standard clinical guidelines (SIGN 153 (Scottish Intercollegiate Guidelines
      Network), British Guideline on the Management of Asthma, September 2016).

      The study design incorporates a proportion of participants already established on Mepolizumab
      as well as participants who will be commenced on Mepolizumab on entry to the study. A
      baseline assessment of medical history, clinical examination, lung function and
      sputum/blood/urine for analysis will be undertaken along with quality of life questionnaires.
      Those newly started on Mepolizumab, will be assessed in a similar manner 3 months into the
      study.

      Subjects will be given an electronic peak flow recorder, symptoms diary and action plan for
      change in baseline symptoms. Participants will be asked to contact the clinic when they feel
      there has been a decline in asthma control and before they take rescue treatment, a clinic
      visit will be arranged. At this visit, all participants will have full medical assessment and
      clinical management based on detailed medical history, clinical findings and lung function
      measurement. Blood will be taken as part of this clinical assessment as outlined in the
      schedule of study procedures including biobanking of samples for whole blood gene expression,
      serum, plasma, sputum and urine. These samples will be stored for validation of additional
      biomarkers, aligned with the RASP-UK (Refractory Asthma Stratification Programme-UK)
      biomarker corticosteroid optimisation study.

      Number in study:

      This is a study will take place across 4 NHS sites within the UK, namely Belfast, Glasgow,
      Oxford and Leicester.

      The study design incorporates a proportion of participants already established on Mepolizumab
      and also participants starting on Mepolizumab, allowing recruitment of up to 150 participants
      in a 6 - 9 month window (all sites have large numbers of patients on the waiting list for the
      drug). Assuming a conservative 0.7 exacerbations per patient per year on mepolizumab (ca 160
      events in an 18 month period) and a minimum rate of attendance of 65% this is 102 observed
      episodes. The study will be terminated when 100 clinical assessments at exacerbation in total
      have been completed across all sites for participants on Mepolizumab prior to initiation of
      rescue treatment. The expected duration of study per participant is 24 months.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients known to Difficult Asthma services within the NHS, who are eligible for
        Mepolizumab treatment as per NICE guidelines.
      
Biospecimen description: 
      Whole blood, sputum, urine.
    
Keywords: Monoclonal antibody; Mepolizumab; Eosinophil