A Pragmatic Trial of Corticosteroid Optimisation in Severe Asthma

A Randomised Pragmatic Trial Of Corticosteroid Optimisation In Severe Asthma Using A Composite Biomarker Algorithm To Adjust Corticosteroid Dose Versus Standard Care

This study explores if a composite biomarker strategy predicts exacerbation risk in patients with asthma on high dose inhaled corticosteroid (+/-long-acting beta agonist) treatment and to evaluate the utility of this composite score to facilitate personalised biomarker specific titration of corticosteroid therapy in this population.

Asthma affects an estimated 300 million people worldwide with a population prevalence of ca 15% in the UK. The WHO has estimated UK disability adjusted life-years per 100,000 population for asthma to be greater than diabetes and breast cancer. Much of this excessive disability is in the 10-20% of patients with asthma which is difficult to control despite currently available therapies. This high morbidity and disproportionate use of health care resources reflects the considerable unmet need in this patient group, and their significance for health care providers.

Asthma has been traditionally 'stratified' on the basis of response to 'step-wise' incremental treatment with inhaled corticosteroid (ICS) therapy forming the cornerstone of this approach. However, more recently, asthma has been stratified on the basis of inflammatory phenotype to better understand disease heterogeneity with a view to developing biomarkers of therapeutic response and for the better targeting of both new and existing treatments.

Investigators have recently examined the predictive value of a composite biomarker strategy using FeNO, blood eosinophils and serum periostin together to predict exacerbation risk in the placebo arms of clinical trials. Investigators propose to examine if this composite biomarker strategy predicts exacerbation risk in patients with asthma on high dose ICS (+/-long-acting beta agonist) treatment and to evaluate the utility of this composite score to facilitate personalised biomarker specific titration of corticosteroid therapy in this population. This study will examine subjects with FeNO<45 ppb and the scoring system will potentially allow identification of a 'low-risk' group who can safely reduce corticosteroid dose. This study will address a second important question of estimating the proportion of patients with severe disease who develop typical (T2)-driven eosinophilic inflammation on progressive corticosteroid withdrawal.

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.

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