Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol

Peter M A Calverley, Fernando J Martinez, Leonardo M Fabbri, Udo-Michael Goehring, Klaus F Rabe, Peter M A Calverley, Fernando J Martinez, Leonardo M Fabbri, Udo-Michael Goehring, Klaus F Rabe

Abstract

Background: Many patients with chronic obstructive pulmonary disease (COPD) continue to suffer exacerbations, even when treated with maximum recommended therapy (eg, inhaled combinations of long-acting β2-agonist and high dose inhaled corticosteroids, with or without a long-acting anticholinergic [long-acting muscarinic antagonist]). Roflumilast is approved to treat severe COPD in patients with chronic bronchitis--and a history of frequent exacerbations--as an add-on to bronchodilators.

Purpose: The REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment) study (identification number RO-2455-404-RD, clinicaltrials. gov identifier NCT01329029) will investigate whether roflumilast further reduces exacerbations when added to inhaled combination therapy in patients still suffering from frequent exacerbations.

Patients and methods: REACT is a 1-year randomized, double-blind, multicenter, phase III/IV study of roflumilast 500 μg once daily or placebo on top of a fixed long-acting β2-agonist/inhaled corticosteroid combination. A concomitant long-acting muscarinic antagonist will be allowed at stable doses. The primary outcome is the rate of moderate or severe COPD exacerbations. Using a Poisson regression model with a two-sided significance level of 5%, a sample size of 967 patients per treatment group is needed for 90% power. COPD patients with severe to very severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year will be recruited.

Conclusion: It is hypothesized that because roflumilast (a phosphodiesterase-4 inhibitor) has a different mode of action to bronchodilators and inhaled corticosteroids, it may provide additional benefits when added to these treatments in frequent exacerbators. REACT will be important to determine the role of roflumilast in COPD management. Here, the design and rationale for this important study is described.

Keywords: ICS; LABA; chronic obstructive pulmonary disease; exacerbation; protocol; roflumilast.

Figures

Figure 1
Figure 1
REACT (Roflumilast in the Prevention of Chronic Obstructive Pulmonary Disease Exacerbations While Taking Appropriate Combination Treatment) study design. Abbreviations: ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; R, randomization; Vend, last visit.

References

    1. Almagro P, Salvado M, Garcia-Vidal C, et al. Recent improvement in long-term survival after a COPD hospitalisation. Thorax. 2010;65(4):298–302.
    1. Kessler R, Stahl E, Vogelmeier C, et al. Patient understanding, detection, and experience of COPD exacerbations: an observational, interview-based study. Chest. 2006;130(1):133–142.
    1. Decramer M, Celli B, Kesten S, Liu D, Tashkin DP. Frequency of exacerbations adversely impacts the course of COPD. Am J Respir Crit Care Med. 2010;181:A1526.
    1. Donaldson GC, Hurst JR, Smith CJ, Hubbard RB, Wedzicha JA. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest. 2010;137(5):1091–1097.
    1. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370(9589):786–796.
    1. Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60(11):925–931.
    1. Postma D, Anzueto A, Calverley P, et al. A new perspective on optimal care for patients with COPD. Prim Care Respir J. 2011;20(2):205–209.
    1. Perera WR, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J. 2007;29(3):527–534.
    1. Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax. 2000;55(2):114–120.
    1. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374(9691):685–694.
    1. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374(9691):695–703.
    1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of COPD. Dec, 2011. [Accessed April 19, 2012]. Available from: .
    1. Rennard SI, Calverley PM, Goehring UM, Bredenbroker D, Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor roflumilast – the importance of defining different subsets of patients with COPD. Respir Res. 2011;12:18.
    1. Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete failure time data by modeling marginal distributions. J Am Stat Assoc. 1989;84(408):1065–1073.
    1. Calverley PM, Rennard SI. What have we learned from large drug treatment trials in COPD? Lancet. 2007;370(9589):774–785.
    1. Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med. 2005;142(4):233–239.
    1. McGarvey LP, John M, Anderson JA, Zvarich MT, Wise RA. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax. 2007;62(5):411–415.
    1. Calverley PM, Spencer S, Willits L, Burge PS, Jones PW. Withdrawal from treatment as an outcome in the ISOLDE study of COPD. Chest. 2003;124(4):1350–1356.
    1. Keene ON, Calverley PM, Jones PW, Vestbo J, Anderson JA. Statistical analysis of exacerbation rates in COPD: TRISTAN and ISOLDE revisited. Eur Respir J. 2008;32(1):17–24.
    1. Suissa S. Statistical treatment of exacerbations in therapeutic trials of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173(8):842–846.
    1. Gamble E, Grootendorst DC, Brightling CE, et al. Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003;168(8):976–982.
    1. Grootendorst DC, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax. 2007;62(12):1081–1087.
    1. Bourbeau J, Christodoulopoulos P, Maltais F, Yamauchi Y, Olivenstein R, Hamid Q. Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial. Thorax. 2007;62(11):938–943.
    1. Hattotuwa K, Gizycki MJ, Ansari TW, Jeffrey PK, Barnes NC. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Am J Respir Crit Care Med. 2002;165(12):1592–1596.
    1. Compton CH, Gubb J, Nieman R, et al. Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study. Lancet. 2001;358(9278):265–270.
    1. Rabe KF, Bateman ED, O’Donnell D, Witte S, Bredenbroker D, Bethke TD. Roflumilast – an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2005;366(9485):563–571.
    1. Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176(2):154–161.
    1. 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.
    1. Iversen KK, Kjaergaard J, Akkan D, et al. Chronic obstructive pulmonary disease in patients admitted with heart failure. J Intern Med. 2008;264(4):361–369.
    1. Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;160(6):1856–1861.
    1. Martinez FJ, Rabe KF, Wouters EFM, et al. Time course and reversibility of weight decrease with roflumilast, a phosphodiesterase 4 inhibitor. Am J Respir Crit Care Med. 2010;181:A4441.
    1. Choudhury AB, Dawson CM, Kilvington HE, et al. Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial. Respir Res. 2007;8:93.
    1. Bredenbroker D, Syed J, Leichtl S, Rathgeb F, Wurst W. Safety of once-daily roflumilast, a new, orally active selective phosphodiesterase 4 inhibitor, in patients with COPD. Am J Respir Crit Care Med. 2002;165:A595.

Source: PubMed

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