Use of a 4-week up-titration regimen of roflumilast in patients with severe COPD

Watz, Henrik; Bagul, Nitin; Rabe, Klaus F.; Rennard, Stephen I.; Alagappan, Vijay; Román, Jonas; Facius, Axel; Calverley, Peter M.A.

doi:10.2147/copd.s154012

Cited by 23 publications

(54 citation statements)

References 27 publications

(52 reference statements)

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“…The study took place between 10 July 2017 and 7 February 2018 in 47 study centres across six countries (Bulgaria [8], Czech Republic [2], Germany [16], Poland [13], Romania [7], and United Kingdom [1]). We recruited 616 patients, of whom 405 were eligible to be randomly assigned to medication, with 375 (93%) completing the study (Fig.…”

Section: Resultsmentioning

confidence: 99%

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A dose-ranging study of the inhaled dual phosphodiesterase 3 and 4 inhibitor ensifentrine in COPD

et al. 2020

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Background: Many patients with chronic obstructive pulmonary disease (COPD) still experience daily symptoms, exacerbations, and accelerated lung function decline, even when receiving maximal combined treatment with inhaled long-acting bronchodilators and corticosteroids. Novel treatment options are needed for these patients. Phosphodiesterases (PDEs) are enzymes that impact a range of cellular functions by modulating levels of cyclic nucleotides, and there is evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive (or perhaps synergistic) effects. This study investigated the efficacy and safety of ensifentrine, a first-in-class dual inhibitor of PDE 3 and 4, in patients with COPD.Methods: This randomised, double-blind, placebo-controlled, parallel-group, dose-ranging study recruited patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV 1 ) 40-80% predicted and FEV 1 /forced vital capacity ratio ≤ 0.7. Patients were randomised equally to inhale nebulised ensifentrine 0.75, 1.5, 3 or 6 mg or placebo, all twice daily. Primary outcome: placebo-adjusted difference in peak FEV 1 (assessed over 3 h) at Week 4. Results: The study took place between July 2017 and February 2018. Of 405 patients randomly assigned to medication, 375 (92.6%) completed the study. For peak FEV 1 at Week 4, all four ensifentrine doses were superior to placebo (p ≤ 0.0001) with least squares mean differences of 146 (95% CI 75-216), 153 (83-222), 200 (131-270) and 139 (69-210) mL for ensifentrine 0.75, 1.5, 3 and 6 mg, respectively. Respiratory symptoms (assessed using the Evaluating Respiratory Symptoms questionnaire) were also significantly improved with all ensifentrine doses at Week 4. Adverse events were reported by 33.3, 44.4, 35.4 and 36.3% patients with ensifentrine 0.75, 1.5, 3 and 6 mg, respectively, and 39.2% with placebo. Conclusions:In this four-week Phase IIb study, all four ensifentrine doses significantly improved bronchodilation and symptoms, with a dose-ranging effect from 0.75 to 3 mg twice daily, and all doses well tolerated. The study supports the continuing development of ensifentrine in COPD.

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Section: Resultsmentioning

confidence: 99%

“…In patients with COPD, lung function and safety data had previously been obtained from up to 6 days treatment, although with no evaluation of symptoms [15]. Delivery of ensifentrine by inhalation aims to minimise the systemic adverse effects that have been associated with oral administration of PDE inhibitors [16].…”

Section: Introductionmentioning

confidence: 99%

A dose-ranging study of the inhaled dual phosphodiesterase 3 and 4 inhibitor ensifentrine in COPD

et al. 2020

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“…In multivariate analysis, the OR for discontinuation with 500 μg was 2.87. Similar results were reported in a multicenter, double-blind trial [31]. COPD patients (n = 1,321) were randomly assigned to groups treated with roflumilast 250 μg once daily, 500 μg every other day, or 500 μg once daily for 4 weeks.…”

Section: Adverse Effectsmentioning

confidence: 56%

Role of phosphodiesterase-4 inhibitors in chronic obstructive pulmonary disease

Rhee

Kim

2020

Korean J Intern Med

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Phosphodiesterase-4 inhibitors (PDE4Is) are potent anti-inf lammatory agents and roflumilast has been used to prevent acute exacerbation of chronic obstructive pulmonary disease (COPD). Roflumilast decreases neutrophil migration, restores cystic fibrosis transmembrane conductance regulator activity, and recovers glucocorticoid effects. A forced expiratory volume in 1 second of < 50%, a chronic bronchitis phenotype, high blood eosinophil levels, and a history of hospitalization are biomarkers for predicting responses to roflumilast. Adverse effects are common in clinical practice. An inhaled PDE4I has recently been developed and is under clinical trial. CHF6001 and RPL554 exhibit promise and may be future treatment options for COPD.

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“… 26 – 28 Results from the OPTIMIZE study have confirmed this by demonstrating a 34% reduction in the odds of discontinuing therapy when an initial dose of roflumilast 250 μg OD is taken for 4 weeks before uptitration to 500 μg OD. 29 These strategies were not in effect at the time of DINO and DACOTA.…”

Section: Discussionmentioning

confidence: 99%

Health status in patients with COPD treated with roflumilast: two large noninterventional real-life studies: DINO and DACOTA

Kardos¹,

Mokros²,

R³

et al. 2018

COPD

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PurposeDINO and DACOTA were prospective, noninterventional studies assessing the health status and quality of life of patients with COPD newly treated with roflumilast 500 μg once-daily add-on therapy.Patients and methodsPatients were evaluated over 6 months. Clinical COPD questionnaire (CCQ) and COPD assessment test (CAT) scores were recorded at baseline and after 3 and 6 months. In DACOTA, post-bronchodilator FEV1 was recorded at each time point.ResultsOf 5,462 and 3,645 patients recruited into DINO and DACOTA, respectively, 3,274 patients in DINO and 916 patients in DACOTA completed the 6-month visit. Almost all patients had severe or very severe airway obstruction; mean baseline CCQ total score was 3.9 in DINO and 3.7 in DACOTA. Overall, 33.8% of patients in DACOTA and 30.6% in DINO discontinued treatment prematurely. Significant and clinically relevant improvements in CCQ total scores were observed in both studies (mean change from baseline of 1.36 in DINO and 0.91 in DACOTA at Month 6 [all P<0.001]). Changes in CAT total score from baseline to Month 6 indicated that the average clinical impact of COPD was reduced from a severe (score: 21–30) to a moderate (score: 11–20) impairment. In DACOTA, mean change in post-bronchodilator FEV1 was 202 mL (P<0.001). Diarrhea, nausea, and weight decrease were the most frequently reported adverse drug reactions.ConclusionIn real-life clinical practice, roflumilast treatment as an add-on therapy is associated with clinically relevant improvements in health status and quality of life.

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Use of a 4-week up-titration regimen of roflumilast in patients with severe COPD

Cited by 23 publications

References 27 publications

A dose-ranging study of the inhaled dual phosphodiesterase 3 and 4 inhibitor ensifentrine in COPD

A dose-ranging study of the inhaled dual phosphodiesterase 3 and 4 inhibitor ensifentrine in COPD

Role of phosphodiesterase-4 inhibitors in chronic obstructive pulmonary disease

Health status in patients with COPD treated with roflumilast: two large noninterventional real-life studies: DINO and DACOTA

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