Randomized double-blind controlled trial of roflumilast at acute exacerbations of

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1 Page 1 of 12 AJRCCM Articles in Press. Published on 01-February-2017 as /rccm LE Randomized double-blind controlled trial of roflumilast at acute exacerbations of COPD Authors: Alex J Mackay 1,2 *, Anant RC Patel 2, Richa Singh 1,3, Raymond J Sapsford 3, Gavin C Donaldson 3, Niyati Prasad 4,5, Udo-Michael Goehring 5, Tsz Keung Nip 5, Jadwiga A Wedzicha 3 1 Dept of Respiratory Medicine, The Royal London Hospital, Barts Health NHS Trust, London, UK 2 Centre for Respiratory Medicine, UCL, London, UK 3 Airways Disease Section, National Heart and Lung Institute, Imperial College, London, UK 4 Vertex Pharmaceuticals (Europe) Ltd, London, UK 5 Takeda Development Centre Europe Ltd, London, UK * Corresponding author: ; alexandermackay@nhs.net, telephone; At the time the study was conducted Running title: Roflumilast at acute COPD exacerbation Word count: 1073

2 AJRCCM Articles in Press. Published on 01-February-2017 as /rccm LE Page 2 of 12 COMPETING INTERESTS Alex Mackay reports grants and non-financial support from Takeda during the conduct of the study, and lecture fees from Takeda and GlaxoSmithKline outside the submitted work. Jadwiga Wedzicha reports board membership fees from GlaxoSmithKline, Novartis, Pfizer, Takeda, Boehringer Ingelheim, Almirall, Johnson and Johnson, Napp, and Vifor Pharma, consultancy fees from Novartis, grants from GlaxoSmithKline, Novartis, Takeda, Johnson and Johnson, and Vifor Pharma, payment for lectures including service on speakers bureaus from Boehringer Ingelheim, GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Almirall, and Chiesi, outside the submitted work. Gavin Donaldson reports personal fees from MiCom SRL, Milan, Italy, outside the submitted work. Richa Singh reports personal lecture fees from Chiesi, outside the submitted work. Tsz Keung Nip is an employee of Takeda Pharmaceuticals. Udo-Michael Goehring and Niyati Prasad were employees of Takeda Pharmaceuticals at the time of the study. Anant Patel and Raymond Sapsford have nothing to disclose. FUNDING All funding for this study was provided by Takeda Pharmaceuticals. AUTHOR CONTRIBUTIONS AJM, GCD, UMG and JAW conceived the idea for the study; data collection and laboratory analysis was undertaken by AJM, ARCP, RS, RJS and data analysis by TKN; all authors contributed to data interpretation and the writing of the paper. KEY WORDS Disease exacerbation, COPD, inflammation, phosphodiesterase 4 inhibitors, roflumilast

3 Page 3 of 12 AJRCCM Articles in Press. Published on 01-February-2017 as /rccm LE INTRODUCTION Chronic obstructive pulmonary disease (COPD) exacerbations are critical events that lead to poor health status [1], lung function decline [2], and mortality [3]. However, treatment options for acute exacerbations remain limited. Treatment failure with the current standard of care is 27% at 30 days [4] and rises to 37% at 90 days [5]. Thus, new therapies for the management of acute exacerbations are urgently needed. Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor and a non-steroid, anti-inflammatory agent, designed to target both the systemic and pulmonary inflammation associated with COPD. Roflumilast reduces neutrophilic airway inflammation [6], improves lung function and reduces exacerbations in stable COPD patients [7-9], but has not previously been studied as an acute exacerbation therapy. Therefore, we conducted a randomized, double-blind, placebo-controlled study to test the hypothesis that roflumilast reduces neutrophilic inflammation during exacerbations of COPD when added to usual medication. Faster resolution of neutrophilic inflammation is associated with shorter clinical recovery [10]. Thus, this study served as a proof-of-mechanism study to examine whether roflumilast can improve clinical recovery following COPD exacerbations.

4 AJRCCM Articles in Press. Published on 01-February-2017 as /rccm LE Page 4 of 12 METHODS Treatment with Roflumilast at ExAcerbaTion (TREAT) was a randomized, double-blind, placebo-controlled, parallel-group, single-center, phase II trial. This study was registered with ClinicalTrials.gov (NCT ). Patients were recruited from the London COPD patient cohort if they experienced an acute exacerbation of COPD with bronchitic symptoms (increased sputum volume or change in sputum color) that required additional systemic therapy. Patients requiring hospitalization at exacerbation presentation were not recruited. Patients were randomized at exacerbation presentation to either oral roflumilast 500 µg or placebo, once daily. The double-blind treatment period was 4 weeks followed by a follow-up period of a further 4 weeks. All patients received standardized exacerbation treatment (30 mg prednisolone for 10 days and amoxicillin 500 mg three times per day [clarithromycin/doxycycline in event of penicillin allergy] for 7 days). Clinic visits were performed at Days 1 (exacerbation presentation), 7, 14, 28 and 56 (Figure 1A). The primary endpoint was change in sputum neutrophil counts from Day 1 to Day 14 post exacerbation. Treatment comparison was evaluated using an analysis of covariance model with Day 1 result as covariate and 2-sided significance level of Key secondary endpoints included change in forced expiratory volume in one second (FEV 1 ) and in other sputum inflammatory markers from Day 1 to each post randomization visit, and were evaluated using Mixed Model Repeated Measurement (MMRM) model with baseline value, treatment group, visit, and treatment group-by-visit interaction.

5 Page 5 of 12 AJRCCM Articles in Press. Published on 01-February-2017 as /rccm LE RESULTS The study included 38 patients randomized to the roflumilast group and 43 patients randomized to the placebo group (Table 1). See Figure 1B for a CONSORT diagram showing the flow of patients. Roflumilast Placebo N=38 N=43 Mean±SD Mean±SD Age (years) 72.9± ±9.3 FEV 1 (L) 1.3± ±0.6 FEV 1 (% predicted) 48.6± ±18.0 FVC (L) 2.7± ±1.0 FEV 1 / FVC ratio (%) 46.7± ±13.3 Smoking pack years 53.1± ±27.1 BMI (kg/m 2 ) 26.8± ±5.8 Exacerbations in year prior to enrolment 1.4± ±1.3 N (%) N (%) Male gender 22 (57.9) 28 (65.1) Current smokers 8 (21.1) 11 (25.6) Chronic bronchitis 24 (63.2) 26 (60.5) Frequent exacerbators ( 2 HCU exacerbations in year prior to enrolment) 10 (26.3) 15 (34.9) Table 1. Baseline clinical characteristics. Stable state clinical characteristics of patients included. FEV 1 = forced expiratory volume in one second; FVC=forced vital capacity; BMI=body mass index; HCU=health care utilization; SD=standard deviation.

6 AJRCCM Articles in Press. Published on 01-February-2017 as /rccm LE Page 6 of 12 Primary outcome: change in sputum neutrophil count from Day 1 (exacerbation presentation) to Day 14. There was no significant difference in change in absolute sputum neutrophil count (10 6 cells/g sputum) from Day 1 to Day 14 between the roflumilast group and the placebo group (Figure 1C). Least squares (LS) mean change in sputum neutrophil count from Day 1 to Day 14 for roflumilast was (95% confidence interval (CI) -23.2, -14.2) and for placebo was (95% CI -24.1, -16.1); the between treatment difference did not reach statistical significance (1.4 [95% CI -4.7, 7.5]; p=0.649). Secondary outcomes: lung function Compared with placebo, change in FEV 1 from Day 1 was numerically greater in the roflumilast-treated group at Day 7 and at Day 14 by approximately 50 ml, although this did not meet the threshold for statistical significance. At the end of treatment at Day 28, there was a non-statistically significant greater increase in FEV 1 in the roflumilast group by 94 ml (95% CI -2, 191; p=0.055) (Figure 1D). Secondary outcomes: airway inflammation Compared with placebo, roflumilast use significantly reduced airway inflammation as shown by change from Day 1 to Day 28 in % sputum neutrophils (-13.9% [95% CI -27.8, -0.09]; p=0.049), and sputum myeloperoxidase (MPO) concentration ( ng/ml [95% CI , ]; p=0.018).

7 Page 7 of 12 AJRCCM Articles in Press. Published on 01-February-2017 as /rccm LE Adverse events Adverse events (AEs) with suggested relationship to the investigational medicinal product were reported in 33 (86.8%) and 16 (37.2%) patients in the roflumilast and placebo groups respectively; serious AEs were reported by 4 (10.5%) patients and 1 (2.3%) patient in the roflumilast and placebo groups respectively. The most frequently reported AEs were diarrhea (reported in 25 [65.8%] and 10 [23.3%] patients in roflumilast and placebo groups respectively), COPD exacerbations (reported in 17 [44.7%] and 14 [32.6%] patients in roflumilast and placebo groups respectively), and insomnia (reported in 12 [31.6%] and 2 [4.7%] patients in roflumilast and placebo groups respectively). Events led to withdrawal from the study in 10 (26.3%) patients in the roflumilast group compared with 2 (4.7%) patients in the placebo group. No deaths occurred over the entire course of the study. Weight assessment Between Day 1 and Day 28, patients in the roflumilast group lost 2.0 kg (SD: 1.6) in body weight; whilst in the placebo group, patients gained 0.1 kg (SD: 0.9).

8 AJRCCM Articles in Press. Published on 01-February-2017 as /rccm LE Page 8 of 12 DISCUSSION Roflumilast, when given in addition to standard therapy, did not accelerate reduction of sputum neutrophils from exacerbation onset to 2 weeks post exacerbation, which was the study s primary outcome. However in exploratory analyses, at 4 weeks, patients treated with roflumilast experienced a statistically significant greater reduction in percentage sputum neutrophils and sputum MPO concentration. Moreover, roflumilast use led to trends in benefits in lung function. Patients treated with roflumilast had over 40 ml improvement at 1 week, over 50 ml improvement at 2 weeks, and almost 100 ml additional improvement in FEV 1 at 4 weeks, compared with patients treated with antibiotics and steroids alone. However, these differences were not statistically significant. AEs and withdrawal rates in this study were higher in the roflumilast group. Additionally, 2.0 kg weight loss over 28 days in the roflumilast group is concerning, as it is similar to that seen over a year in studies of patients in the stable state [7, 9]. Further studies would be required to confirm the positive effects on lung function recovery seen in this study, and accurately define the optimum use of roflumilast as an acute exacerbation treatment. This study suggests days post exacerbation may be the most advantageous time to administer roflumilast as this is when improved outcomes are observed. However, the high AE rates seen in this study may limit the tolerability and applicability of roflumilast in clinical practice in the acute setting.

9 Page 9 of 12 AJRCCM Articles in Press. Published on 01-February-2017 as /rccm LE ACKNOWLEDGEMENTS Editorial assistance provided by Alexis Pashiardis, Synergy Vision (London, UK), was funded by Takeda and AstraZeneca.

10 AJRCCM Articles in Press. Published on 01-February-2017 as /rccm LE Page 10 of 12 REFERENCE LIST 1. Seemungal TAR, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of Exacerbation on Quality of Life in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 1998;157: Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57: Soler-Cataluna JJ, Martinez-Garcia MÁ, Sánchez PR, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005;60: Aaron SD, Vandemheen KL, Hebert P, Dales R, Stiell IG, Ahuja J, Dickinson G, Brison R, Rowe BH, Dreyer J, Yetisir E, Cass D, Wells G. Outpatient oral prednisone after emergency treatment of chronic obstructive pulmonary disease. N Engl J Med 2003;348: Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross NJ, Light RW, Anderson P, Morgan NA. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med 1999;340: Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF. Reduction in sputum neutrophil and eosinophil

11 Page 11 of 12 AJRCCM Articles in Press. Published on 01-February-2017 as /rccm LE numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007;62: Calverley PMA, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374: Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, Bundschuh D, Brose M, Martinez FJ, Rabe KF. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009;374: Martinez FJ, Calverley PMA, 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. Lancet 2015;385: Perera WR, Hurst JR, Wilkinson TMA, Sapsford RJ, Mullerova H, Donaldson GC, Wedzicha JA. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J 2007;29:

12 AJRCCM Articles in Press. Published on 01-February-2017 as /rccm LE Page 12 of 12 FIGURE LEGENDS Figure 1A. Clinical trial design. od=once daily. Figure 1B. Study profile. Enrolment did not reach the original intended power calculation (140 patients) because recruitment was curtailed early by the scientific oversight committee. Figure 1C. Change in sputum neutrophil count from Day 1 14 (10 6 cells/g sputum). Lines represent 95% lower confidence intervals. Figure 1D. Change in FEV 1 from exacerbation presentation. Data are least squares means ± standard error in the intention-to-treat population. Least squares means are from the MMRM. Covariates for MMRM are baseline value, treatment, visit, and treatment by visit interaction. Covariance structure = unstructured. LS=least squares. FEV 1 = forced expiratory volume in one second. MMRM=mixed model repeated measurement.