The aim of the project is to study the persistence of inflammation after addition of an interleukin-5 (IL-5) blocker in severe eosinophilic asthma as a study of untreated pathways in these patients.

Mepolizumab, a humanized monoclonal antibody (mAb) antagonizes IL-5 and through a selective inhibition of eosinophilic inflammation, reduces the number of eosinophils in sputum and blood, leading to a reduction in asthma exacerbations and a need for systemic glucocorticoids. Once this therapy has been initiated for severe eosinophilic asthma, the additional role of oral corticosteroids is questionable as their main target is reduction of eosinophils and hence responsiveness to oral corticosteroids in patients in a stable state of asthma may reduce.

Using two weeks of high dose prednisolone versus placebo in a crossover design after 12 weeks of mepolizumab therapy will allow an understanding of the pathways that remain steroid responsive following IL-5 suppression.

This is an exploratory study with no single primary end point. The objective of the study is to assess the change in airway inflammation following oral corticosteroids versus placebo and the airway inflammation while on mepolizumab in stable state of asthma.

Note: Mepolizumab is not an intervention in this study; it is initiated as part of usual NHS care.

Inclusion Criteria:

• Age ≥ 18 and ≤ 80 years at consent.
• Able and willing to provide written informed consent and to comply with the study protocol.
• Severe asthma diagnosis confirmed after assessment by an asthma specialist.
• Suitable for mepolizumab as per NICE/SMC Clinical Guidelines.

Exclusion Criteria:

• Maintenance oral corticosteroid treatment within the past four weeks.
• Acute exacerbation requiring oral corticosteroids in the four weeks prior to consent.
• Other clinically significant medical disease or uncontrolled concomitant disease despite treatment that is likely, in the opinion of the investigator, to require a change in therapy or impact the ability to participate in the study or be significantly worsened by oral corticosteroids.
• History of current alcohol, drug, or chemical abuse or past abuse that would impair or risk the subject's full participation in the study, in the opinion of the investigator.
• Treatment with an investigational agent within 30 days of Visit 1 (or five half-lives of the investigational agent, whichever is longer).
• Women of child-bearing potential who are pregnant, lactating, planning pregnancy during the study period or are unwilling to use a highly effective form of contraception.
• Known hypersensitivity to prednisolone or its excipients.
• Previous psychiatric adverse reactions to steroid therapy in the past.
• Concomitant medication with systemic anti-fungals such as ketoconazole, retinoids, tetracycline, other systemic immunosuppressants e.g. ciclosporin, azathioprine, mycophenolate and live vaccines during the crossover trial.