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

Abstract

Background: Patients with difficult-to-control asthma consume 50-60% of healthcare costs attributed to asthma and cost approximately five-times more than patients with mild stable disease. Recent evidence demonstrates that not all patients with asthma have a typical type 2 (T2)-driven eosinophilic inflammation. These asthmatics have been called 'T2-low asthma' and have a minimal response to corticosteroid therapy. Adjustment of corticosteroid treatment using sputum eosinophil counts from induced sputum has demonstrated reduced severe exacerbation rates and optimized corticosteroid dose. However, it has been challenging to move induced sputum into the clinical setting. There is therefore a need to examine novel algorithms to target appropriate levels of corticosteroid treatment in difficult asthma, particularly in T2-low asthmatics. This study examines whether a composite non-invasive biomarker algorithm predicts exacerbation risk in patients with asthma on high-dose inhaled corticosteroids (ICS) (± long-acting beta agonist) treatment, and evaluates the utility of this composite score to facilitate personalized biomarker-specific titration of corticosteroid therapy.

Methods/design: Patients recruited to this pragmatic, multi-centre, single-blinded randomised controlled trial are randomly allocated into either a biomarker controlled treatment advisory algorithm or usual care group in a ratio of 4:1. The primary outcome measure is the proportion of patients with any reduction in ICS or oral corticosteroid dose from baseline to week 48. Secondary outcomes include the rate of protocol-defined severe exacerbations per patient per year, time to first severe exacerbation from randomisation, dose of inhaled steroid at the end of the study, cumulative dose of inhaled corticosteroid during the study, proportion of patients on oral corticosteroids at the end of the study, proportion of patients who decline to progress to oral corticosteroids despite composite biomarker score of 2, frequency of hospital admission for asthma, change in the 7-item Asthma Control Questionnaire (ACQ-7), Asthma Quality of Life Questionnaire (AQLQ), forced expiratory volume in 1 s (FEV1), exhaled nitric oxide, blood eosinophil count, and periostin levels from baseline to week 48. Blood will also be taken for whole blood gene expression; serum, plasma, and urine will be stored for validation of additional biomarkers.

Discussion: Multi-centre trials present numerous logistical issues that have been addressed to ensure minimal bias and robustness of study conduct.

Trial registration: ClinicalTrials.gov, NCT02717689 . Registered on 16 March 2016.

Keywords: Asthma; Biomarkers; Corticosteroids; Personalized medicine; Steroid titration; T2-low.

Conflict of interest statement

Authors’ information

See title page for institution affiliations and email addresses.

Ethics approval and consent to participate

Queens University Belfast is the principal sponsor for this study (Ref. 15062LH-AS). The protocol has been reviewed and centrally approved for all sites by the Office for Research Ethics Northern Ireland (Ref. 15/NI0158). This approval can be viewed in an Additional file. The trial has been registered with ClinicalTrials.gov (NCT02717689).

Consent for publication

All authors and their institutions/companies have given consent for publication. Consent for publication from patients is not applicable as this is a protocol.

Competing interests

JGM is an employee of Genentech, Inc., a member of the Roche Group, and has received stock options as part of his standard employment compensation, and his employer may have patents or pending patent applications relating to subject matter of this manuscript. JRA is an employee of Genentech, Inc., holds stock and stock options in the Roche Group, and is a named inventor on patents pending relating to diagnosis and treatment of asthma. DFC is an employee and holds stocks and options in Genetech Inc, a member of the Roche Group. He is an inventor of planned or filed patents related to the diagnosis and treatment of respiratory diseases. IDP has received speaker’s honoraria for speaking at sponsored meetings from Astra Zeneca and Aerocrine, and payment for organizing an educational event from Astra Zeneca. He has received honoraria for attending advisory panels with Genentech and Astra Zeneca. PB has received grant funding from Genentech, acts as a consultant for Roche and GlaxoSmithKline, and has received speaker fees for Astra Zeneca and support to attend conferences from GlaxoSmithKline. CEB has received grants or consultancy fees via his Institution from Astra Zeneca and Roche/Genentech Inc. RC has been paid to attend Advisory Board meetings by AstraZeneca and received educational grants for research from Aerocrine. RD has given lectures at symposia organised by pharma companies and has consulted companies as a member of advisory boards. CTH is an employee of Genentech Inc., a member of the Roche Group. PHH has participated on advisory boards for Roche. He has received sponsorship to attend international scientific meetings from Astra Zeneca. AM-G has attended advisory boards and or received lecture fees from Astra Zeneca and Hoffman La Roche, and has participated in clinical studies for which his institution has been reimbursed by Hoffman La Roche. RMN has received funds for attending advisory boards, speaking on a fee-paid basis, and received travel support for attending internal education conferences from Astra Zeneca. LGH has received grant funding and has taken part in advisory boards and given lectures at meetings supported by Hoffman la Roche/Genentech Inc. and Aerocrine AB. He has taken part in asthma clinical trials sponsored by Hoffman la Roche/Genentech Inc., for which his institution was remunerated. LGH is Academic Lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma which involves industrial partnerships with a number of pharmaceutical companies, including Hoffman la Roche and Aerocrine AB. The remaining authors declare that they have no competing interests.

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Figures

Fig. 1

CONSORT diagram displaying flow of patients through the RASP-UK biomarker study

Fig. 2

Schedule of study procedures. ACQ-7 7-item Asthma Control Questionnaire, AE adverse event, AQLQ Asthma Quality of Life Questionnaire; BMI body mass index, BP blood pressure, (e-)CRF (electronic) case report form, FeNO fractional exhaled nitric oxide, SAE serious adverse event, Temp temperature

Fig. 3

Schedule of study procedures: unscheduled exacerbation visit. ACQ-7 7-item Asthma Control Questionnaire, BP blood pressure, CRP C-reactive peptide, FeNO fractional exhaled nitric oxide, Temp temperature