Clinical trial NCT02717689: A Pragmatic Trial of Corticosteroid Optimisation in Severe Asthma
Official title: A Randomised Pragmatic Trial Of Corticosteroid Optimisation In Severe Asthma Using A Composite Biomarker Algorithm To Adjust Corticosteroid Dose Versus Standard Care
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Severe Persistent Asthma
Lead sponsor: Belfast Health and Social Care Trust
Sponsor class: OTHER
Collaborators: name: Medical Research Council
name: Hoffmann-La Roche
name: Aerocrine AB
First posted: 2016-03-24
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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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Primary outcomes:
measure: Proportion of patients with any reduction in corticosteroid dose
timeFrame: 48 weeks
Secondary outcomes:
measure: Rate of protocol-defined severe exacerbations per patient per year
timeFrame: 48 weeks
measure: Time to first severe exacerbation from randomisation
timeFrame: 48 weeks
measure: Dose of inhaled steroid at end of study
timeFrame: Week 48
measure: Cumulative dose of inhaled corticosteroid during study
timeFrame: 48 weeks
measure: Proportion of patients on oral corticosteroids at the end of the study
timeFrame: Week 48
measure: Proportion of patients who decline to progress to oral corticosteroids despite composite biomarker score of 2
timeFrame: 48 weeks
measure: Frequency of hospital admission for asthma
timeFrame: 48 weeks
measure: Change in Asthma Control Questionnaire (ACQ-7)
timeFrame: Week 48
measure: Change in FEV1 (volume)
timeFrame: Week 48
measure: Change in exhaled breath nitric oxide level
timeFrame: Week 48
measure: Change in blood eosinophil count
timeFrame: Week 48
measure: Change in serum periostin levels
timeFrame: Week 48
measure: Change in Asthma Quality of Life Questionnaire (AQLQ)
timeFrame: Week 48
Other outcomes:
measure: Exploratory biomarker analysis using whole blood gene expression
timeFrame: 48 weeks
measure: Exploratory serum biomarker analysis
timeFrame: 48 weeks
measure: Exploratory plasma biomarker analysis
timeFrame: 48 weeks
measure: Exploratory urinary biomarker analysis
timeFrame: 48 weeks
Locations:
city: Belfast
country: United Kingdom
facility: Belfast Health and Social Care Trust
state: Northern Ireland
city: Birmingham
country: United Kingdom
facility: Heart of England NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
city: London
country: United Kingdom
facility: Royal Brompton & Harefield NHS Foundation Hospital
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation
city: Manchester
country: United Kingdom
facility: University Hospitals of South Manchester NHS Trust
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle upon Tyne Hospitals NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Trust
city: Southampton
country: United Kingdom
facility: University Hospital of Southampton NHS Foundation Trust
Study officials:
affiliation: Queen's University, Belfast
name: Liam Heaney, MBBCh MRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: McDowell PJ, Busby J, Hanratty CE, Djukanovic R, Woodcock A, Walker S, Hardman TC, Arron JR, Choy DF, Bradding P, Brightling CE, Chaudhuri R, Cowan D, Mansur AH, Fowler SJ, Diver SE, Howarth P, Lordan J, Menzies-Gow A, Harrison T, Robinson DS, Holweg CTJ, Matthews JG, Pavord ID, Heaney LG. Exacerbation Profile and Risk Factors in a Type-2-Low Enriched Severe Asthma Cohort: A Clinical Trial to Assess Asthma Exacerbation Phenotypes. Am J Respir Crit Care Med. 2022 Sep 1;206(5):545-553. doi: 10.1164/rccm.202201-0129OC.
citation: Busby J, Matthews JG, Chaudhuri R, Pavord ID, Hardman TC, Arron JR, Bradding P, Brightling CE, Choy DF, Cowan DC, Djukanovic R, Hanratty CE, Harrison TW, Holweg CT, Howarth PH, Fowler SJ, Lordan JL, Mansur AH, Menzies-Gow A, Niven RM, Robinson DS, Walker SM, Woodcock A, Heaney LG; investigators for the MRC Refractory Asthma Stratification Programme. Factors affecting adherence with treatment advice in a clinical trial of patients with severe asthma. Eur Respir J. 2021 Sep 24;59(4):2100768. doi: 10.1183/13993003.00768-2021. Print 2022 Apr.
citation: Heaney LG, Busby J, Hanratty CE, Djukanovic R, Woodcock A, Walker SM, Hardman TC, Arron JR, Choy DF, Bradding P, Brightling CE, Chaudhuri R, Cowan DC, Mansur AH, Fowler SJ, Niven RM, Howarth PH, Lordan JL, Menzies-Gow A, Harrison TW, Robinson DS, Holweg CTJ, Matthews JG, Pavord ID; investigators for the MRC Refractory Asthma Stratification Programme. Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial. Lancet Respir Med. 2021 Jan;9(1):57-68. doi: 10.1016/S2213-2600(20)30397-0. Epub 2020 Sep 8.
citation: Hanratty CE, Matthews JG, Arron JR, Choy DF, Pavord ID, Bradding P, Brightling CE, Chaudhuri R, Cowan DC, Djukanovic R, Gallagher N, Fowler SJ, Hardman TC, Harrison T, Holweg CT, Howarth PH, Lordan J, Mansur AH, Menzies-Gow A, Mosesova S, Niven RM, Robinson DS, Shaw DE, Walker S, Woodcock A, Heaney LG; RASP-UK (Refractory Asthma Stratification Programme) Consortium. A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised trial. Trials. 2018 Jan 4;19(1):5. doi: 10.1186/s13063-017-2384-7.