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

Abstract

Background

The oral selective phosphodiesterase-4 inhibitor roflumilast (ROF) reduces exacerbations in patients with severe COPD. Adverse events (AEs) can cause early ROF discontinuation. Alternative dosing strategies may help patients continue their therapy.

Methods

In this multicenter, double-blind trial, 1,321 patients with severe COPD were randomized 1:1:1 to 4 weeks’ treatment with ROF 250 µg once daily (OD), 500 µg every other day (EOD), or 500 µg OD, each followed by ROF 500 µg OD for 8 weeks, plus standard therapy. The primary end point was the percentage of patients prematurely discontinuing study treatment.

Results

Patients in the 250 µg OD/500 µg OD group had significantly fewer treatment discontinuations (odds ratio [OR] 0.66 [95% CI 0.47–0.93], p=0.017) and lower rates of AEs of interest such as diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain (OR 0.63 [95% CI 0.47–0.83], p=0.001) compared with those in the 500 µg OD group. Although rates of discontinuation and AEs of interest were numerically lower with ROF 500 µg EOD/500 µg OD, the difference was not significant (OR 0.76, p=0.114, and OR 0.78, p=0.091, respectively) compared with ROF 500 µg OD.

Conclusion

A dose of ROF 250 µg OD for 4 weeks before escalation to the approved maintenance dose of 500 µg OD resulted in reduced treatment discontinuation and improved tolerability.

Keywords:

• roflumilast
• COPD
• discontinuation
• adverse event

Acknowledgments

Ken Nip (Takeda) provided additional statistical assistance, and Udo-Michael Goehring provided study interpretation. Ella Palmer, PhD (Synergy Vision, London, UK, supported by AstraZeneca) provided writing and editorial assistance with the preparation of this manuscript, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). This study was funded by Takeda Pharmaceutical Company and AstraZeneca. Data from the OPTIMIZE study were presented as an abstract (PA308) at the European Respiratory Society International Congress, 3–7 September 2016, London, UK. Additionally, the pharmacokinetic and pharmacodynamics data from this study were presented as an abstract (A1337) at the American Thoracic Society 2017 International Conference, 19–14 May 2017, Washington DC, USA.

Disclosure

NB was employed by Takeda Development Centre Europe Ltd, London, UK. The authors report no other conflicts of interest in this work.