Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD

A Randomized Clinical Trial

Graham Devereux, Seonaidh Cotton, Shona Fielding, Nicola McMeekin, Peter J Barnes, Andrew Briggs, Graham Burns, Rekha Chaudhuri, Henry Chrystyn, Lisa Davies, Anthony De Soyza, Simon Gompertz, John Haughney, Karen Innes, Joanna Kaniewska, Amanda Lee, Alyn Morice, John Norrie, Anita Sullivan, Andrew Wilson & 1 others David Price

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Importance: Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD.

Objective: To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD.

Design, Setting, and Participants: The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites.

Interventions: Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787).

Main Outcomes and Measures: The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period.

Results: Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%).

Conclusions and Relevance: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations.

Trial Registration: isrctn.org Identifier: ISRCTN27066620.

Original languageEnglish
Pages (from-to)1548-1559
Number of pages12
JournalJAMA
Volume320
Issue number15
DOIs
Publication statusPublished - 16 Oct 2018

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Theophylline
Chronic Obstructive Pulmonary Disease
Adrenal Cortex Hormones
Randomized Controlled Trials
Placebos
Disease Progression
Anti-Bacterial Agents
Ideal Body Weight
Secondary Care
Vital Capacity
Forced Expiratory Volume
Nausea
Headache
Primary Health Care
Anti-Inflammatory Agents
Smoking
Outcome Assessment (Health Care)
Incidence
Therapeutics

Cite this

Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD : A Randomized Clinical Trial. / Devereux, Graham; Cotton, Seonaidh; Fielding, Shona; McMeekin, Nicola; Barnes, Peter J; Briggs, Andrew; Burns, Graham; Chaudhuri, Rekha; Chrystyn, Henry; Davies, Lisa; De Soyza, Anthony; Gompertz, Simon; Haughney, John; Innes, Karen; Kaniewska, Joanna; Lee, Amanda; Morice, Alyn; Norrie, John; Sullivan, Anita; Wilson, Andrew; Price, David (Corresponding Author).

In: JAMA, Vol. 320, No. 15, 16.10.2018, p. 1548-1559.

Research output: Contribution to journalArticle

Devereux, G, Cotton, S, Fielding, S, McMeekin, N, Barnes, PJ, Briggs, A, Burns, G, Chaudhuri, R, Chrystyn, H, Davies, L, De Soyza, A, Gompertz, S, Haughney, J, Innes, K, Kaniewska, J, Lee, A, Morice, A, Norrie, J, Sullivan, A, Wilson, A & Price, D 2018, 'Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial', JAMA, vol. 320, no. 15, pp. 1548-1559. https://doi.org/10.1001/jama.2018.14432
Devereux, Graham ; Cotton, Seonaidh ; Fielding, Shona ; McMeekin, Nicola ; Barnes, Peter J ; Briggs, Andrew ; Burns, Graham ; Chaudhuri, Rekha ; Chrystyn, Henry ; Davies, Lisa ; De Soyza, Anthony ; Gompertz, Simon ; Haughney, John ; Innes, Karen ; Kaniewska, Joanna ; Lee, Amanda ; Morice, Alyn ; Norrie, John ; Sullivan, Anita ; Wilson, Andrew ; Price, David. / Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD : A Randomized Clinical Trial. In: JAMA. 2018 ; Vol. 320, No. 15. pp. 1548-1559.
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abstract = "Importance: Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD.Objective: To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD.Design, Setting, and Participants: The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites.Interventions: Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787).Main Outcomes and Measures: The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period.Results: Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54{\%} (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98{\%}) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95{\%} CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95{\%} CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95{\%} CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95{\%} CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4{\%} vs 3.4{\%}; gastrointestinal, 2.7{\%} vs 1.3{\%}; and adverse reactions such as nausea (10.9{\%} vs 7.9{\%}) and headaches (9.0{\%} vs 7.9{\%}).Conclusions and Relevance: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations.Trial Registration: isrctn.org Identifier: ISRCTN27066620.",
author = "Graham Devereux and Seonaidh Cotton and Shona Fielding and Nicola McMeekin and Barnes, {Peter J} and Andrew Briggs and Graham Burns and Rekha Chaudhuri and Henry Chrystyn and Lisa Davies and {De Soyza}, Anthony and Simon Gompertz and John Haughney and Karen Innes and Joanna Kaniewska and Amanda Lee and Alyn Morice and John Norrie and Anita Sullivan and Andrew Wilson and David Price",
note = "The study was funded by the NIHR HTA program (project number 11/58/15). The study was cosponsored by the University of Aberdeen and NHS Grampian.",
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TY - JOUR

T1 - Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD

T2 - A Randomized Clinical Trial

AU - Devereux, Graham

AU - Cotton, Seonaidh

AU - Fielding, Shona

AU - McMeekin, Nicola

AU - Barnes, Peter J

AU - Briggs, Andrew

AU - Burns, Graham

AU - Chaudhuri, Rekha

AU - Chrystyn, Henry

AU - Davies, Lisa

AU - De Soyza, Anthony

AU - Gompertz, Simon

AU - Haughney, John

AU - Innes, Karen

AU - Kaniewska, Joanna

AU - Lee, Amanda

AU - Morice, Alyn

AU - Norrie, John

AU - Sullivan, Anita

AU - Wilson, Andrew

AU - Price, David

N1 - The study was funded by the NIHR HTA program (project number 11/58/15). The study was cosponsored by the University of Aberdeen and NHS Grampian.

PY - 2018/10/16

Y1 - 2018/10/16

N2 - Importance: Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD.Objective: To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD.Design, Setting, and Participants: The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites.Interventions: Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787).Main Outcomes and Measures: The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period.Results: Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%).Conclusions and Relevance: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations.Trial Registration: isrctn.org Identifier: ISRCTN27066620.

AB - Importance: Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD.Objective: To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD.Design, Setting, and Participants: The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites.Interventions: Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787).Main Outcomes and Measures: The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period.Results: Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%).Conclusions and Relevance: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations.Trial Registration: isrctn.org Identifier: ISRCTN27066620.

U2 - 10.1001/jama.2018.14432

DO - 10.1001/jama.2018.14432

M3 - Article

VL - 320

SP - 1548

EP - 1559

JO - JAMA

JF - JAMA

SN - 0098-7484

IS - 15

ER -