Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial

David B Price, Roland Buhl, Adrian Chan, Daryl Freeman, Elizabeth Gardener, Clifford Godley, Kevin Gruffydd-Jones, Lorcan McGarvey, Ken Ohta, Dermot Ryan, Jörgen Syk, Ngiap Chuan Tan, TzeLee Tan, Mike Thomas, Sen Yang, Priyanka Raju Konduru, Marcus Ngantcha, Martina Stagno d'Alcontres, Therese S Lapperre

Research output: Contribution to journalArticle

29 Citations (Scopus)
6 Downloads (Pure)

Abstract

BACKGROUND: Chronic non-specific respiratory symptoms are difficult to manage. This trial aimed to evaluate the association between baseline fractional exhaled nitric oxide (FeNO) and the response to inhaled corticosteroids in patients with non-specific respiratory symptoms.

METHODS: In this double-blind randomised placebo-controlled trial, we enrolled undiagnosed patients, aged 18-80 years, with cough, wheeze, or dyspnoea and less than 20% bronchodilator reversibility across 26 primary care centres and hospitals in the UK and Singapore. Patients were assessed for 2 weeks before being randomly assigned (1:1) to 4 weeks of treatment with extrafine inhaled corticosteroids (QVAR 80 μg, two puffs twice per day, equivalent to 800 μg per day beclomethasone dipropionate) or placebo. Randomisation was stratified by baseline FeNO measurement: normal (≤25 parts per billion [ppb]), intermediate (>25 tp <40 ppb), and high (≥40 ppb). The primary endpoint was change in Asthma Control Questionnaire (ACQ7) mean score. We used generalised linear modelling to assess FeNO as a predictor of response, estimating an interaction effect between FeNO and treatment on change in ACQ7. We did our primary and secondary analyses in the per-protocol set, which excluded patients with non-completion of the primary endpoint, non-compliance to treatment (ascertained by patient report), and study visits made outside the predefined visit windows. This study is registered on ClinicalTrials.gov, number NCT02294279.

FINDINGS: Between Feb 4, 2015, and July 12, 2016, we randomly assigned 294 patients to extrafine inhaled corticosteroid treatment (n=148) or placebo (n=146). Following exclusions due to protocol violations, we analysed 214 patients (114 extrafine inhaled corticosteroids and 100 placebo). We observed a significant interaction between baseline FeNO and treatment group for every 10 ppb increase in baseline FeNO, with the change in ACQ7 greater in the extrafine inhaled corticosteroids group than in the placebo group (difference between groups 0·071, 95% CI 0·002 to 0·139; p=0·044). The most common adverse events were nasopharyngitis (18 [12%] patients in the treatment group vs 13 [9%] in the placebo group), infections and infestations (25 [17%] vs 21 [14%]), and respiratory, thoracic, and mediastinal disorders (13 [9%] vs 17 [12%]).

INTERPRETATION: FeNO measurement is an easy and non-invasive tool to use in clinical practice in patients with non-specific respiratory symptoms to predict response to inhaled corticosteroids. Further research is needed to examine its role in patients with evidence of other airway diseases, such as chronic obstructive pulmonary disease.

FUNDING: Sponsored by OPRI with partial funding by Circassia and study drugs provided by TEVA.

Original languageEnglish
Pages (from-to)29-39
Number of pages11
JournalThe Lancet. Respiratory medicine
Volume6
Issue number1
Early online date3 Nov 2017
DOIs
Publication statusPublished - Jan 2018

Fingerprint

Bronchodilator Agents
Adrenal Cortex Hormones
Nitric Oxide
Randomized Controlled Trials
Placebos
Nasopharyngitis
Therapeutics
Beclomethasone
Singapore
Random Allocation
Cough
Dyspnea
Chronic Obstructive Pulmonary Disease
Primary Health Care
Thorax
Asthma

Keywords

  • Journal Article

Cite this

Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility : a randomised controlled trial. / Price, David B; Buhl, Roland; Chan, Adrian; Freeman, Daryl; Gardener, Elizabeth; Godley, Clifford; Gruffydd-Jones, Kevin; McGarvey, Lorcan; Ohta, Ken; Ryan, Dermot; Syk, Jörgen; Tan, Ngiap Chuan; Tan, TzeLee; Thomas, Mike; Yang, Sen; Konduru, Priyanka Raju; Ngantcha, Marcus; d'Alcontres, Martina Stagno; Lapperre, Therese S.

In: The Lancet. Respiratory medicine, Vol. 6, No. 1, 01.2018, p. 29-39.

Research output: Contribution to journalArticle

Price, DB, Buhl, R, Chan, A, Freeman, D, Gardener, E, Godley, C, Gruffydd-Jones, K, McGarvey, L, Ohta, K, Ryan, D, Syk, J, Tan, NC, Tan, T, Thomas, M, Yang, S, Konduru, PR, Ngantcha, M, d'Alcontres, MS & Lapperre, TS 2018, 'Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial', The Lancet. Respiratory medicine, vol. 6, no. 1, pp. 29-39. https://doi.org/10.1016/S2213-2600(17)30424-1
Price, David B ; Buhl, Roland ; Chan, Adrian ; Freeman, Daryl ; Gardener, Elizabeth ; Godley, Clifford ; Gruffydd-Jones, Kevin ; McGarvey, Lorcan ; Ohta, Ken ; Ryan, Dermot ; Syk, Jörgen ; Tan, Ngiap Chuan ; Tan, TzeLee ; Thomas, Mike ; Yang, Sen ; Konduru, Priyanka Raju ; Ngantcha, Marcus ; d'Alcontres, Martina Stagno ; Lapperre, Therese S. / Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility : a randomised controlled trial. In: The Lancet. Respiratory medicine. 2018 ; Vol. 6, No. 1. pp. 29-39.
@article{693ccfdb69e8436e9d77e4d0b77f87b8,
title = "Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial",
abstract = "BACKGROUND: Chronic non-specific respiratory symptoms are difficult to manage. This trial aimed to evaluate the association between baseline fractional exhaled nitric oxide (FeNO) and the response to inhaled corticosteroids in patients with non-specific respiratory symptoms.METHODS: In this double-blind randomised placebo-controlled trial, we enrolled undiagnosed patients, aged 18-80 years, with cough, wheeze, or dyspnoea and less than 20{\%} bronchodilator reversibility across 26 primary care centres and hospitals in the UK and Singapore. Patients were assessed for 2 weeks before being randomly assigned (1:1) to 4 weeks of treatment with extrafine inhaled corticosteroids (QVAR 80 μg, two puffs twice per day, equivalent to 800 μg per day beclomethasone dipropionate) or placebo. Randomisation was stratified by baseline FeNO measurement: normal (≤25 parts per billion [ppb]), intermediate (>25 tp <40 ppb), and high (≥40 ppb). The primary endpoint was change in Asthma Control Questionnaire (ACQ7) mean score. We used generalised linear modelling to assess FeNO as a predictor of response, estimating an interaction effect between FeNO and treatment on change in ACQ7. We did our primary and secondary analyses in the per-protocol set, which excluded patients with non-completion of the primary endpoint, non-compliance to treatment (ascertained by patient report), and study visits made outside the predefined visit windows. This study is registered on ClinicalTrials.gov, number NCT02294279.FINDINGS: Between Feb 4, 2015, and July 12, 2016, we randomly assigned 294 patients to extrafine inhaled corticosteroid treatment (n=148) or placebo (n=146). Following exclusions due to protocol violations, we analysed 214 patients (114 extrafine inhaled corticosteroids and 100 placebo). We observed a significant interaction between baseline FeNO and treatment group for every 10 ppb increase in baseline FeNO, with the change in ACQ7 greater in the extrafine inhaled corticosteroids group than in the placebo group (difference between groups 0·071, 95{\%} CI 0·002 to 0·139; p=0·044). The most common adverse events were nasopharyngitis (18 [12{\%}] patients in the treatment group vs 13 [9{\%}] in the placebo group), infections and infestations (25 [17{\%}] vs 21 [14{\%}]), and respiratory, thoracic, and mediastinal disorders (13 [9{\%}] vs 17 [12{\%}]).INTERPRETATION: FeNO measurement is an easy and non-invasive tool to use in clinical practice in patients with non-specific respiratory symptoms to predict response to inhaled corticosteroids. Further research is needed to examine its role in patients with evidence of other airway diseases, such as chronic obstructive pulmonary disease.FUNDING: Sponsored by OPRI with partial funding by Circassia and study drugs provided by TEVA.",
keywords = "Journal Article",
author = "Price, {David B} and Roland Buhl and Adrian Chan and Daryl Freeman and Elizabeth Gardener and Clifford Godley and Kevin Gruffydd-Jones and Lorcan McGarvey and Ken Ohta and Dermot Ryan and J{\"o}rgen Syk and Tan, {Ngiap Chuan} and TzeLee Tan and Mike Thomas and Sen Yang and Konduru, {Priyanka Raju} and Marcus Ngantcha and d'Alcontres, {Martina Stagno} and Lapperre, {Therese S}",
note = "Funding: Sponsored by OPRI with partial funding by Circassia and study drugs provided by TEVA.",
year = "2018",
month = "1",
doi = "10.1016/S2213-2600(17)30424-1",
language = "English",
volume = "6",
pages = "29--39",
journal = "The Lancet. Respiratory medicine",
issn = "2213-2600",
publisher = "Elsevier Limited",
number = "1",

}

TY - JOUR

T1 - Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility

T2 - a randomised controlled trial

AU - Price, David B

AU - Buhl, Roland

AU - Chan, Adrian

AU - Freeman, Daryl

AU - Gardener, Elizabeth

AU - Godley, Clifford

AU - Gruffydd-Jones, Kevin

AU - McGarvey, Lorcan

AU - Ohta, Ken

AU - Ryan, Dermot

AU - Syk, Jörgen

AU - Tan, Ngiap Chuan

AU - Tan, TzeLee

AU - Thomas, Mike

AU - Yang, Sen

AU - Konduru, Priyanka Raju

AU - Ngantcha, Marcus

AU - d'Alcontres, Martina Stagno

AU - Lapperre, Therese S

N1 - Funding: Sponsored by OPRI with partial funding by Circassia and study drugs provided by TEVA.

PY - 2018/1

Y1 - 2018/1

N2 - BACKGROUND: Chronic non-specific respiratory symptoms are difficult to manage. This trial aimed to evaluate the association between baseline fractional exhaled nitric oxide (FeNO) and the response to inhaled corticosteroids in patients with non-specific respiratory symptoms.METHODS: In this double-blind randomised placebo-controlled trial, we enrolled undiagnosed patients, aged 18-80 years, with cough, wheeze, or dyspnoea and less than 20% bronchodilator reversibility across 26 primary care centres and hospitals in the UK and Singapore. Patients were assessed for 2 weeks before being randomly assigned (1:1) to 4 weeks of treatment with extrafine inhaled corticosteroids (QVAR 80 μg, two puffs twice per day, equivalent to 800 μg per day beclomethasone dipropionate) or placebo. Randomisation was stratified by baseline FeNO measurement: normal (≤25 parts per billion [ppb]), intermediate (>25 tp <40 ppb), and high (≥40 ppb). The primary endpoint was change in Asthma Control Questionnaire (ACQ7) mean score. We used generalised linear modelling to assess FeNO as a predictor of response, estimating an interaction effect between FeNO and treatment on change in ACQ7. We did our primary and secondary analyses in the per-protocol set, which excluded patients with non-completion of the primary endpoint, non-compliance to treatment (ascertained by patient report), and study visits made outside the predefined visit windows. This study is registered on ClinicalTrials.gov, number NCT02294279.FINDINGS: Between Feb 4, 2015, and July 12, 2016, we randomly assigned 294 patients to extrafine inhaled corticosteroid treatment (n=148) or placebo (n=146). Following exclusions due to protocol violations, we analysed 214 patients (114 extrafine inhaled corticosteroids and 100 placebo). We observed a significant interaction between baseline FeNO and treatment group for every 10 ppb increase in baseline FeNO, with the change in ACQ7 greater in the extrafine inhaled corticosteroids group than in the placebo group (difference between groups 0·071, 95% CI 0·002 to 0·139; p=0·044). The most common adverse events were nasopharyngitis (18 [12%] patients in the treatment group vs 13 [9%] in the placebo group), infections and infestations (25 [17%] vs 21 [14%]), and respiratory, thoracic, and mediastinal disorders (13 [9%] vs 17 [12%]).INTERPRETATION: FeNO measurement is an easy and non-invasive tool to use in clinical practice in patients with non-specific respiratory symptoms to predict response to inhaled corticosteroids. Further research is needed to examine its role in patients with evidence of other airway diseases, such as chronic obstructive pulmonary disease.FUNDING: Sponsored by OPRI with partial funding by Circassia and study drugs provided by TEVA.

AB - BACKGROUND: Chronic non-specific respiratory symptoms are difficult to manage. This trial aimed to evaluate the association between baseline fractional exhaled nitric oxide (FeNO) and the response to inhaled corticosteroids in patients with non-specific respiratory symptoms.METHODS: In this double-blind randomised placebo-controlled trial, we enrolled undiagnosed patients, aged 18-80 years, with cough, wheeze, or dyspnoea and less than 20% bronchodilator reversibility across 26 primary care centres and hospitals in the UK and Singapore. Patients were assessed for 2 weeks before being randomly assigned (1:1) to 4 weeks of treatment with extrafine inhaled corticosteroids (QVAR 80 μg, two puffs twice per day, equivalent to 800 μg per day beclomethasone dipropionate) or placebo. Randomisation was stratified by baseline FeNO measurement: normal (≤25 parts per billion [ppb]), intermediate (>25 tp <40 ppb), and high (≥40 ppb). The primary endpoint was change in Asthma Control Questionnaire (ACQ7) mean score. We used generalised linear modelling to assess FeNO as a predictor of response, estimating an interaction effect between FeNO and treatment on change in ACQ7. We did our primary and secondary analyses in the per-protocol set, which excluded patients with non-completion of the primary endpoint, non-compliance to treatment (ascertained by patient report), and study visits made outside the predefined visit windows. This study is registered on ClinicalTrials.gov, number NCT02294279.FINDINGS: Between Feb 4, 2015, and July 12, 2016, we randomly assigned 294 patients to extrafine inhaled corticosteroid treatment (n=148) or placebo (n=146). Following exclusions due to protocol violations, we analysed 214 patients (114 extrafine inhaled corticosteroids and 100 placebo). We observed a significant interaction between baseline FeNO and treatment group for every 10 ppb increase in baseline FeNO, with the change in ACQ7 greater in the extrafine inhaled corticosteroids group than in the placebo group (difference between groups 0·071, 95% CI 0·002 to 0·139; p=0·044). The most common adverse events were nasopharyngitis (18 [12%] patients in the treatment group vs 13 [9%] in the placebo group), infections and infestations (25 [17%] vs 21 [14%]), and respiratory, thoracic, and mediastinal disorders (13 [9%] vs 17 [12%]).INTERPRETATION: FeNO measurement is an easy and non-invasive tool to use in clinical practice in patients with non-specific respiratory symptoms to predict response to inhaled corticosteroids. Further research is needed to examine its role in patients with evidence of other airway diseases, such as chronic obstructive pulmonary disease.FUNDING: Sponsored by OPRI with partial funding by Circassia and study drugs provided by TEVA.

KW - Journal Article

U2 - 10.1016/S2213-2600(17)30424-1

DO - 10.1016/S2213-2600(17)30424-1

M3 - Article

C2 - 29108938

VL - 6

SP - 29

EP - 39

JO - The Lancet. Respiratory medicine

JF - The Lancet. Respiratory medicine

SN - 2213-2600

IS - 1

ER -