Determinants of Response to Roflumilast in Severe Chronic Obstructive Pulmonary Disease. Pooled Analysis of Two Randomized Trials

Martínez, Fernando J.; Rabe, Klaus F.; Calverley, Peter M.A.; Fabbri, Leonardo M.; Sethi, Sanjay; Pizzichini, Emílio; McIvor, Andrew; Anzueto, Antonio; Alagappan, Vijay; Siddiqui, Shahid; Reisner, Colin; Zetterstrand, Sofia; Román, Jonas; Purkayastha, Debasree; Bagul, Nitin; Rennard, Stephen I.

doi:10.1164/rccm.201712-2493oc

Cited by 60 publications

(63 citation statements)

References 25 publications

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“…Given that adjustments for multiple comparisons were not performed, it is possible that this finding could be due to type I error. However, in light of a recent report that another phosphodiesterase inhibitor (roflumilast) is most beneficial in people with prior COPD hospitalization for exacerbation and greater exacerbation frequency, 36 this finding warrants further investigation.…”

Section: Discussionmentioning

confidence: 93%

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

Devereux

Cotton

Fielding

et al. 2018

JAMA

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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 (FEV 1 /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.

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Section: Discussionmentioning

confidence: 93%

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

Devereux

Cotton

Fielding

et al. 2018

JAMA

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“…This finding led to the execution of studies that specifically recruited patients with chronic bronchitis, in which roflumilast reduced the exacerbation rate versus placebo by 17% ( p = 0.0003) [ 13 ]. Furthermore, in patients with chronic bronchitis, the benefit of roflumilast increased with increasing baseline blood eosinophil count [ 16 ], and administration of roflumilast significantly reduced eosinophil cell counts in bronchial biopsy samples and induced sputum, suggesting that the efficacy of roflumilast could be due at least in part to an impact on lung eosinophils [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of CHF6001, a novel inhaled PDE4 inhibitor in COPD: the PIONEER study

Singh

Emirova

Francisco³

et al. 2020

Respir Res

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Background This study evaluated the efficacy, safety and tolerability of the novel inhaled phosphodiesterase-4 inhibitor CHF6001 added-on to formoterol in patients with chronic obstructive pulmonary disease (COPD). Methods Randomised, double-blind, placebo- and active-controlled, parallel-group study. Eligible patients had symptomatic COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 30–70% predicted, and history of ≥1 moderate/severe exacerbation. Patients were randomised to extrafine CHF6001 400, 800, 1200 or 1600 μg twice daily (BID), budesonide, or placebo for 24 weeks. Primary objectives: To investigate CHF6001 dose-response for pre-dose FEV1 after 12 weeks, and to identify the optimal dose. Moderate-to-severe exacerbations were a secondary endpoint. Results Of 1130 patients randomised, 91.9% completed. Changes from baseline in pre-dose FEV1 at Week 12 were small in all groups (including budesonide), with no CHF6001 dose-response, and no significant treatment–placebo differences. For moderate-to-severe exacerbations, CHF6001 rate reductions versus placebo were 13–28% (non-significant). In post-hoc analyses, CHF6001 effects were larger in patients with a chronic bronchitis phenotype (rate reductions versus placebo 24–37%; non-significant), and were further increased in patients with chronic bronchitis and eosinophil count ≥150 cells/μL (49–73%, statistically significant for CHF6001 800 and 1600 μg BID). CHF6001 was well tolerated with no safety signal (including in terms of gastrointestinal adverse events). Conclusions CHF6001 had no effect in the primary lung function analysis, although was well-tolerated with no gastrointestinal adverse event signal. Post-hoc analyses focused on exacerbation risk indicate specific patient subgroups who may receive particular benefit from CHF6001. Trial registration ClinicalTrials.gov (NCT02986321). Registered 8 Dec 2016.

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“…A predefined pooled analysis of the phosphodiesterase-4 (PDE4) inhibitor roflumilast trials (REACT/RE 2 SPOND) found that a combination of BEC ≥300 cells/µL and ≥1 prior hospitalization for COPD exacerbation was associated with a 43% reduction in moderate to severe exacerbations for patients receiving roflumilast vs. placebo compared with a reduction of 12% for the overall population ( Table 1) (53). The ROBERT study demonstrated a significant reduction in eosinophils in sputum and bronchial biopsy samples, but not in the blood, with roflumilast treatment, providing evidence for PDE4 inhibition acting through modulation of lung eosinophil numbers (54).…”

Section: Phosphodiesterase-4 Inhibitorsmentioning

confidence: 99%

Blood Eosinophil Counts in Clinical Trials for Chronic Obstructive Pulmonary Disease

Singh

Bafadhel

Brightling

et al. 2020

Am J Respir Crit Care Med

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Determinants of Response to Roflumilast in Severe Chronic Obstructive Pulmonary Disease. Pooled Analysis of Two Randomized Trials

Cited by 60 publications

References 25 publications

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

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

Efficacy and safety of CHF6001, a novel inhaled PDE4 inhibitor in COPD: the PIONEER study

Blood Eosinophil Counts in Clinical Trials for Chronic Obstructive Pulmonary Disease

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