Roflumilast: a review of its use in the treatment of COPD

Figures & data

Figure 1 Schematic of the frequent exacerbator phenotype.

Notes: Reproduced from BioMed Central. © 2013 Wedzicha et al; licensee BioMed Central Ltd. Wedzicha JA, Brill SE, Allinson JP, Donaldson GC. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 2013;11:181. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/legalcode.¹⁰
Abbreviations: CRP, C-reactive protein; FEV₁, forced expiratory volume in 1 second; IL-6, interleukin-6.

Table 1 Randomized double-blind trials evaluating roflumilast in patients with COPD

Study	N	Patient characteristics	Study design	Treatment	Outcomes
					Pre-BD FEV1a(mL)	Post-BD FEV1a(mL)	Post-BD FVCa(mL)	Moderate/severe exacerbationsb
M2-107^Citation33	1,157	COPD > 12 mo; 10y pack history; age >40 y; FEV1 30%–80% of predicted FVC <70%	R, MC, DB, PC, PG	ROF 250 µg QD (n=578)	64‡	74§	71*
				ROF 500 µg QD (n=555) PLA QD (n=280)	88§	97§	114‡
M2-111/M2-112^Citation34	1,514	COPD; 10y pack history; age >40 y; FEV1, ≤50%; FEV1,:FVC ratio ≤0.7	R, MC, DB, PC, PG	ROF 500 µg QD (n= 1,327)	51§	53§		−14.3%*
				PLA QD(n= 1,359)
M2-124^Citation31	1,525	COPD; 20y pack history; age >40 y; FEV1, ≤50%; FEV1,:FVC ratio ≤0.7; chronic cough and sputum production; ≥ 1 COPD exacerbation in last year	R, MC, DB, PC, PG	ROF 500 µg QD (n=766)	39‡	49§	101§	−15%*
				PLA QD (n=759)
M2-125^Citation31	1,571	COPD; 20y pack history; age >40 y; FEV1, ≤50%; FEV1,:FVC ratio ≤0.7; chronic cough and sputum production; ≥ 1 COPD exacerbation in last year	R, MC, DB, PC, PG	ROF 500 µg QD (n=773)	58§	61§	103§	−18%#
				PLA QD (n=798)
M2-127^Citation32	935	COPD; 10y pack history; FEV1, 40%–70%; FEV1,:FVC ratio ≤0.7	R, MC, DB, PC, PG	ROF 500 µg QD + salmeterol (n=467)	49§	60§	58#	−40%#
				PLA QD + salmeterol (n=468)
M2-128^Citation32	744	COPD; 10y pack history; FEV1, 40%–70%; FEV1,:FVC ratio ≤0.7, chronic cough and sputum production; frequent (≥28 puffs/week) short-acting β2-agonist; background tiotropium	R, MC, DB, PC, PG	ROF 500 µg QD + tiotropium (n=372)	80§	81§	101‡	−27%
				PLA QD + tiotropium (n=372)
ACROSS^Citation36	626	COPD; Chinese, Malay, or Indian ethnicity; ≥ 10y pack history; age 40–80 y; FEV1, ≤50%; FEV1,:FVC ratio ≤0.7	R, MC, DB, PC, PG	ROF 500 µg QD (n=313)	49‡	45‡	101‡
REACT^Citation35	1,945	COPD; 20y pack history; age >40 y; FEV1, ≤50%; FEV1,:FVC ratio ≤0.7; symptoms of chronic bronchitis; ≥2 COPD exacerbations in last year	R, MC, DB, PC, PG	PLAQD(n=3l3) ROF 500 µg QD + ICS/LABA (n=973)		56§	92§	−14%*,c −13%d
				PLA QD + ICS/LABA (n=972)

Notes:

* P<0.05,

# P<0.0l,

‡ P<0.00l,

§ P<0.000l (all versus PLA).

a Change versus placebo.

b Percent difference versus PLA.

c Negative binomial regression analysis.

d Poisson regression analysis (P=0.0529).

Abbreviations: BD, bronchodilator; DB, double-blind; FEV₁ forced expiratory volume in 1 second; FVC, forced vital capacity; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonists; MC, multicenter; mo, month; PC, placebo-controlled; PG, parallel group; PLA, placebo; QD, once daily; R, randomized; ROF, roflumilast; y, year.

Figure 2 Effect of roflumilast on the mean rate of moderate or severe exacerbations with or without a LABA.

Notes: Reproduced with permission of the European Respiratory Society^©. Eur Respir J, September 2011 38(3):553–560; doi:10.1183/09031936.00178710. Bateman ED, Rabe KF, Calverley PM, et al. Roflumilast with long-acting β₂-agonists for COPD: influence of exacerbation history. Eur Respir J. 2011;38(3):553–560.³⁸
Abbreviations: CI, confidence interval; LABA, long-acting β₂-agonist.

Figure 3 Mean rate of serious exacerbations or exacerbations leading to hospital admission per patient per year in the REACT study.

Notes: Reprinted from The Lancet, Vol. 385, number 9971, Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial, Pages 857–866, Copyright (2015), with permission from Elsevier.³⁵
Abbreviation: CI, confidence interval.

Table 2 Adverse reactions (≥2%) associated with roflumilast from four 1-year placebo-controlled trials and four 6-month trials

Adverse reaction, % (n)	Roflumilast (n=4,438)	Placebo (n=4,192)
Diarrhea	9.5 (420)	2.7 (113)
Weight loss	7.5 (331)	2.1 (89)
Nausea	4.7 (209)	1.4 (60)
Back pain	3.2 (142)	2.2 (92)
Influenza	2.8 (124)	2.7 (112)
Insomnia	2.4 (105)	1.0 (41)
Decreased appetite	2.1 (91)	0.4 (15)

Notes: Reprinted by permission from Macmillan Publishers Ltd: Clin Pharmacol Ther. Michalski JM, Golden G, Ikari J, et al. PDE4: a novel target in the treatment of chronic obstructive pulmonary disease. Clin Pharmacol Ther. 2012;91(1):134–142, copyright 2012.⁵⁰

Figure 4 Changes in mean glycated hemoglobin (HbA_1c) levels over 12 weeks in patients with newly diagnosed, treatment-naïve type 2 diabetes mellitus.

Notes: Bars represent confidence intervals. Republished with permission of the Endocrine Society, from Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus. Wouters EF, Bredenbroker D, Teichmann P, et al. J Clin Endocrinol Metab. 2012;97(9):E1720–E1725. Copyright 2012; permission conveyed through Copyright Clearance Center, Inc.⁵⁶

Figure 5 Pooled analysis of the incidence rate of the composite of MACE (nonfatal MI, nonfatal stroke, and CV death) for patients receiving roflumilast (n=6,563) or placebo (n=5,491).

Notes: Adapted with permission from the American College of Chest Physicians. White WB, Cooke GE, Kowey PR, et al. Cardiovascular safety in patients receiving roflumilast for the treatment of COPD. Chest. 2013;144(3):758–765.⁵⁷
Abbreviations: CV, cardiovascular; MACE, major adverse cardiovascular events; MI, myocardial infarction.

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