A Pragmatic Trial of Corticosteroid Optimisation in Severe Asthma

NCT02717689 | Completed DMC

• 1 other identifier: 001
• Study Type: interventional
• Target: 300
• Locations: 1 country
• Sites: 11

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.

Conditions

Severe Persistent Asthma

Outcome Measures

Primary Outcomes (1)

• Proportion of patients with any reduction in corticosteroid dose

  Proportion of patients with any reduction in oral or inhaled corticosteroid dose at any point over the 48 weeks of the study

  48 weeks

Secondary Outcomes (13)

• Rate of protocol-defined severe exacerbations per patient per year

  48 weeks

• Time to first severe exacerbation from randomisation

  48 weeks

• Dose of inhaled steroid at end of study

  Week 48

• Cumulative dose of inhaled corticosteroid during study

  48 weeks

• Proportion of patients on oral corticosteroids at the end of the study

  Week 48

Other Outcomes (4)

• Exploratory biomarker analysis using whole blood gene expression

  48 weeks

• Exploratory serum biomarker analysis

  48 weeks

• Exploratory plasma biomarker analysis

  48 weeks

Study Arms (2)

Biomarker arm

EXPERIMENTAL

Biomarker based adjustment of corticosteroid dose.

Other: Biomarker based adjustment of corticosteroid dose

Standard care

NO INTERVENTION

The subject's corticosteroid dose will be adjusted based upon asthma symptom control and lung function

Interventions

Biomarker based adjustment of corticosteroid dose OTHER

The subject's corticosteroid dose will be adjusted based upon biomarker results (FeNO, eosinophils and periostin)

Biomarker arm

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 and ≤ 80 years at screening visit
• Able and willing to provide written informed consent and to comply with the study protocol
• Baseline FeNO\< 45 ppb at screening
• Severe asthma confirmed after assessment by an asthma specialist. Diagnosed with asthma at least 12 months prior to screening
• Current asthma treatment with LABA plus high doses of inhaled corticosteroids (≥1000 µg FP daily or equivalent)
• Patients on an ICS/LABA single inhaler strategy must be switched to fixed dosing ICS/LABA for 4 weeks prior to screening
• 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.

You may not qualify if:

• Acute exacerbation requiring oral corticosteroids in previous 4 weeks before screening.
• Known severe or clinically significant immunodeficiency, including, but not limited to, human immunodeficiency virus (HIV) infection.
• Currently receiving or have historically received intravenous immunoglobulin for treatment for immunodeficiency.
• If recently commenced on a leukotriene receptor antagonist or theophylline, stable on treatment for 4 weeks prior to screening
• 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.
• 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
• 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
• 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.
• 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
• Use of a biologic therapy including Omalizumab at any time during the 6 months prior to the screening visit.
• Bronchial thermoplasty within prior 6 months of the screening visit

Sponsors & Collaborators

• Belfast Health and Social Care Trust: lead
• Medical Research Council: collaborator
• Hoffmann-La Roche: collaborator
• Aerocrine AB: collaborator

Study Sites (11)

Belfast Health and Social Care Trust

Belfast, Northern Ireland, BT9 7AB, United Kingdom

Location

Heart of England NHS Foundation Trust

Birmingham, United Kingdom

Location

NHS Greater Glasgow and Clyde

Glasgow, United Kingdom

Location

University Hospitals of Leicester NHS Trust

Leicester, United Kingdom

Location

Royal Brompton & Harefield NHS Foundation Hospital

London, United Kingdom

Location

University College London Hospitals NHS Foundation

London, United Kingdom

Location

University Hospitals of South Manchester NHS Trust

Manchester, United Kingdom

Location

Newcastle upon Tyne Hospitals NHS Foundation Trust

Newcastle upon Tyne, United Kingdom

Location

Nottingham University Hospitals NHS Foundation Trust

Nottingham, United Kingdom

Location

Oxford University Hospitals NHS Trust

Oxford, United Kingdom

Location

University Hospital of Southampton NHS Foundation Trust

Southampton, United Kingdom

Location

Related Publications (4)

• 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.

  PMID: 35549845 DERIVED

• 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.

  PMID: 34561291 DERIVED

• 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.

  PMID: 32916135 DERIVED

• 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.

  PMID: 29301585 DERIVED

Study Officials

• Liam Heaney, MBBCh MRCP

  Queen's University, Belfast

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Respiratory Medicine

Study Record Dates

• First Submitted: March 16, 2016
• First Posted: March 24, 2016
• Study Start: January 1, 2016
• Primary Completion: June 19, 2019
• Study Completion: June 19, 2019
• Last Updated: June 25, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will not share

Locations

GB (11)