A Pragmatic Trial of Corticosteroid Optimisation in Severe Asthma

Inclusion Criteria: 1. Age ≥ 18 and ≤ 80 years at screening visit 2. Able and willing to provide written informed consent and to comply with the study protocol 3. Baseline FeNO\< 45 ppb at screening 4. Severe asthma confirmed after assessment by an asthma specialist. Diagnosed with asthma at least 12 months prior to screening 5. Current asthma treatment with LABA plus high doses of inhaled corticosteroids (≥1000 µg FP daily or equivalent) 6. Patients on an ICS/LABA single inhaler strategy must be switched to fixed dosing ICS/LABA for 4 weeks prior to screening 7. Documented history of reversibility of ≥12% change in FEV1 within the past 24 months or during screening period, as demonstrated by: * Documented airflow obstruction (forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC ) \<70%), where FEV1 has varied by ≥12% either spontaneously or in response to oral corticosteroid (OCS) therapy or bronchodilators either between or during clinic visits Or * A 20% drop in FEV1 (PC20) to methacholine \<8 mg/mL or a 15% fall in FEV1 (PD15) after inhaling a cumulative dose of mannitol of ≤635 mg indicating the presence of airway hyperresponsiveness. If sites customarily use histamine to perform tests of airway responsiveness, this may be used in place of methacholine. Exclusion Criteria: 1. Acute exacerbation requiring oral corticosteroids in previous 4 weeks before screening. 2. Known severe or clinically significant immunodeficiency, including, but not limited to, human immunodeficiency virus (HIV) infection. 3. Currently receiving or have historically received intravenous immunoglobulin for treatment for immunodeficiency. 4. If recently commenced on a leukotriene receptor antagonist or theophylline, stable on treatment for 4 weeks prior to screening 5. Known current malignancy or current evaluation for a potential malignancy or history of malignancy within 5 years prior to baseline. With the exception of basal-cell and squamous-cell carcinomas of the skin and carcinoma in situ of the cervix uteri that have been excised and cured. 6. 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 7. 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 8. Current self-reported history of smoking (including electronic inhaled nicotine products) or former smoker with a smoking history of \>15 pack-years * A current smoker is defined as someone who has smoked one or more cigarettes per day (or marijuana or pipe or cigar) for ≥ 30 days within the 24 months prior to the screening visit (Day -14) and / or cotinine positive at screening * Any individual who smokes (cigarettes, marijuana, pipe, or cigar) occasionally, even if for \< 30 days within the 24 months prior to the screening visit (Day -14), must agree to abstain from all smoking from the time of consent through completion of study * A former smoker is defined as someone who has smoked one or more cigarettes per day (or marijuana or pipe or cigar) for ≥ 30 days in his or her lifetime (as long as the 30-day total did not include the 24 months prior to the screening visit \[Day -14\]). * A pack-year is defined as the average number of packs per day times the number of years of smoking. 9. Current use of an immunomodulatory/immunosuppressive therapy or past use within 3 months or five drug half-lives (whichever is longer) prior to the screening visit 10. Use of a biologic therapy including Omalizumab at any time during the 6 months prior to the screening visit. 11. Bronchial thermoplasty within prior 6 months of the screening visit 12. Initiation of or change in allergen immunotherapy within 3 months prior to the screening visit. 13. Treatment with an investigational agent within 30 days of the screening visit (or five half lives of the investigational agent, whichever is longer). 14. Female patients who are pregnant or lactating. \-