68 Suppl. 2: 3-57 REVIEW ARTICLE 0012-6667/08/0002-0003/$53.45/0

Drugs 2008; 68 Suppl. 2: 3-57 REVIEW ARTICLE 0012-6667/08/0002-0003/$53.45/0

The Efficacy and Safety of Cilomilast in COPD Stephen Rennard,1 Katharine Knobil,2 Klaus F. Rabe,3 Andrea Morris,2 Neil Schachter,4 Nicholas Locantore,2 Walter G. Canonica,5 Yuanjue Zhu6 and Frank Barnhart2 1 Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA 2 GlaxoSmithKline, Research Triangle Park, North Carolina, USA 3 Leiden University Medical Centre, Leiden, the Netherlands 4 Mount Sinai School of Medicine, New York City, New York, USA 5 Medical University of Genoa, Genoa, Italy 6 Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China

Contents Abstract ...... 5 1. Introduction ...... 6 1.1 Chronic Obstructive Pulmonary Disease (COPD) ...... 6 1.2 Potential Shortcomings of Pharmacotherapy in COPD ...... 6 1.3 Phosphodiesterase Inhibitors ...... 7 1.4 Clinical Studies with Cilomilast ...... 8 2. Evidence of Anti-Inflammatory Activity of Cilomilast in Induced Sputum and Bronchial Biopsies from COPD Patients ...... 8 2.1 Study Objectives ...... 8 2.2 Methods ...... 9 2.2.1 Patients ...... 9 2.2.2 Study Design ...... 9 2.2.3 Statistical Methods ...... 11 2.3 Results ...... 11 2.3.1 Study Population ...... 11 2.3.2 Primary Efficacy Measures ...... 11 2.3.3 Secondary Efficacy Endpoints ...... 12 2.4 Safety Results ...... 13 2.4.1 Adverse Events ...... 13 2.4.2 Adverse Events Leading to Withdrawal ...... 14 2.4.3 Other Safety Assessments ...... 14 2.5 Summary ...... 15 3. Efficacy and Safety of Cilomilast in the Pivotal Phase III Studies ...... 17 3.1 Study Objectives ...... 17 3.2 Materials and Methods ...... 17 3.2.1 Study Design ...... 17 3.2.2 Patients ...... 17 3.2.3 Study Procedures ...... 18 3.2.4 Statistical Analysis ...... 19 3.2.5 Sample Sizes ...... 20 3.3 Results ...... 20 3.3.1 Patient Disposition ...... 20 3.3.2 Baseline Characteristics ...... 21 4 Rennard et al.

3.3.3 Primary Efficacy Endpoints ...... 22 3.3.4 Secondary Endpoints ...... 22 3.4 Safety and Tolerability ...... 24 3.5 Summary ...... 25 4. Long-Term Tolerability and Safety of Cilomilast in Patients with COPD ...... 26 4.1 Study Objectives ...... 26 4.2 Materials and Methods ...... 26 4.2.1 Study Design ...... 26 4.2.2 Assessments ...... 27 4.2.3 Statistical Analysis ...... 28 4.3 Results ...... 28 4.3.1 Baseline Characteristics; Studies 040 and 041 ...... 28 4.3.2 Baseline Characteristics; Study 157 ...... 29 4.4 Safety and Tolerability Measurements ...... 29 4.4.1 Adverse Events ...... 29 4.4.2 Deaths ...... 30 4.4.3 Withdrawals ...... 30 4.4.4 Laboratory Safety and Vital Signs ...... 31 4.5 Efficacy Evaluations ...... 31 4.5.1 COPD Exacerbations ...... 31 4.5.2 Lung Function ...... 32 4.6 Summary ...... 32 5. Cardiovascular Safety and Tolerability of Cilomilast ...... 33 5.1 Study Objective ...... 33 5.2 Methods ...... 33 5.2.1 Patients ...... 33 5.2.2 Study Design ...... 34 5.2.3 Statistical Methods ...... 34 5.3 Results ...... 35 5.3.1 Study Population ...... 35 5.3.2 Holter Monitoring ...... 36 5.3.3 Electrocardiograms ...... 36 5.4 Other Safety Results ...... 37 5.5 Efficacy Results ...... 38 5.6 Summary ...... 38 6. Effect of Cilomilast on Hyperinflation ...... 40 6.1 Study Objectives ...... 40 6.2 Methods ...... 41 6.2.1 Patients ...... 41 6.2.2 Study Design ...... 41 6.2.3 Statistical Methods ...... 42 6.3 Results ...... 42 6.3.1 Study Population ...... 42 6.3.2 Primary Efficacy Measures of Hyperinflation ...... 43 6.3.3 Secondary Efficacy Endpoints ...... 43 6.4 Safety Results ...... 44 6.4.1 Adverse Events ...... 44 6.4.2 Other Safety Assessments ...... 45 6.5 Summary ...... 45 7. Efficacy and Safety of Cilomilast in Chinese Patients with COPD ...... 46 7.1 Study Objective ...... 46 7.2 Materials and Methods ...... 46 7.2.1 Study Design ...... 46 7.2.2 Patients ...... 46 7.2.3 Study Procedures ...... 47

7.2.4 Statistical Analysis ...... 47 7.3 Results ...... 47 7.3.1 Patient Disposition ...... 47 7.3.2 Baseline Characteristics ...... 47 7.3.3 Primary Efficacy Endpoint; Trough FEV1 ...... 48 7.3.4 Secondary Endpoints ...... 48 7.4 Safety and Tolerability ...... 49 7.5 Summary ...... 50 8. Discussion ...... 50 8.1 Anti-Inflammatory Effects of Cilomilast ...... 50 8.2 FEV1 ...... 50 8.3 Forced Vital Capacity ...... 51 8.4 Hyperinflation ...... 51 8.5 Health Status ...... 52 8.6 Exacerbations ...... 52 8.7 Dyspnoea ...... 53 8.8 Safety ...... 53 8.8.1 Adverse Events ...... 53 8.8.2 Adverse Events Leading to Withdrawal ...... 53 8.8.3 Deaths ...... 53 8.8.4 Laboratory Data and Vital Signs ...... 53 8.8.5 Cardiovascular Findings ...... 54 8.8.6 Summary ...... 54 9. Conclusion ...... 54

Abstract The aim of this review is to present the clinical data on the efficacy and safety of cilomilast in patients with chronic obstructive pulmonary disease (COPD). Over 6000 COPD patients received cilomilast during an extensive clinical development programme performed by GlaxoSmithKline (GSK). Five phase III randomized, double-blind, placebo-controlled, parallel-group pivotal studies were conducted in poorly reversible patients (<15% or <200 mL improvement over baseline in forced expiratory volume in 1 second (FEV1) after salbutamol). Patients were randomized to receive oral cilomilast 15 mg (n = 2088) or placebo (n = 1408) twice daily for 24 weeks. The co-primary efficacy variables were changes from baseline in trough (predose) FEV1 and in total score of the St George’s Respiratory Questionnaire (SGRQ). Additional studies were performed to investigate the anti-inflammatory actions of cilomilast by measuring inflammatory cells and mediators in biopsies and induced sputum; to assess the long-term effects of cilomilast; to assess the cardiac safety of cilomilast; and to assess the efficacy of cilomilast on hyperinflation. Results from one of the phase III and from one supportive study have been previously published. In the phase III pivotal studies, when averaged over 24 weeks, the mean change from baseline in FEV1 in the cilomilast group showed improvement compared with placebo in all studies (range 24–44 mL treatment difference). When averaged over 24 weeks, there was a similar improvement in the mean total SGRQ score in both treatment groups with a decrease ranging from –1.8 to –4.2 units in the cilomilast group and 0.4 to –4.9 units in the placebo group. Only one study, however, showed both a statistically and clinically meaningful difference between

the two treatment groups (treatment difference –4.1 units; p < 0.001). Although cilomilast was shown to reduce COPD exacerbations in some of these studies, there was no effect on the incidence of COPD exacerbations in a study specifically powered to detect a difference compared with placebo. No significant change was found in the primary endpoints of the anti- inflammatory studies, although some anti-inflammatory activity was detected, including a reduction in tissue CD8+ T lymphocytes and CD68+ macrophages in airway biopsies. In addition, studies did not demonstrate a consistent significant effect of cilomilast on hyperinflation. In all studies, adverse events associated with the gastrointestinal body system were reported more frequently in the cilomilast group than the placebo group and predominantly occurred within the first 2 weeks of initiating cilomilast therapy. During the cilomilast development programme a number of different endpoints were investigated to characterize the efficacy and safety of this second-generation phosphodiesterase 4 inhibitor. Safety assessments throughout the late-phase programme did not reveal any evidence of serious safety concerns with the use of cilomilast. Previous studies in phase II and early phase III had shown improvements in efficacy endpoints and some evidence of an anti-inflammatory mechanism of action. However, subsequent phase III studies failed to definitively confirm the earlier programme results, which led to termination of the development of cilomilast.

1. Introduction throughout airways, parenchyma and pulmonary vasculature is believed to have a central role.[3,4] The aim of this review is to ensure that the clinical data for the efficacy and safety of cilomilast 1.2 Potential Shortcomings of in chronic obstructive pulmonary disease (COPD) Pharmacotherapy in COPD are available in the public domain. To accomplish Inflammatory processes have been implicated in this, data from 18 trials that evaluated cilomilast are both the bronchiolar and alveolar damage seen in summarized. These trials include two studies, re- COPD and are thought to underlie the accelerated [1,2] sults from which have been published. yearly decline in forced expiratory volume in 1 second (FEV1) that is characteristic of COPD.[5] The 1.1 Chronic Obstructive Pulmonary inflammation seen in COPD is clearly different from Disease (COPD) that seen in asthma with a predominantly neutrophil- ic rather than eosinophilic bronchitis.[6,7] The preva- COPD is a common disease which is usually lent T cells in COPD are the CD8+ cells, which are characterized by partially reversible airflow limita- found in increased numbers in the airway epitheli- tion, progressive loss of lung function and an abnor- um.[7] There is also an increase in alveolar macro- mal inflammatory response in the lung to noxious phages, neutrophils, B cells and CD8+ T lympho- substances, the most common of which is cigarette cytes in various parts of the lung, which is usually smoke.[3] The disease is associated with increased associated with a decline in lung function.[8-10] Air- frequency of exacerbations and deterioration of way wall inflammation is present even in the early health status, as well as the development of non- stages of COPD.[11] pulmonary complications.[3] The pathogenesis of There is a need for a novel anti-inflammatory COPD remains unclear but chronic inflammation treatment, as experimental data indicate that the

inflammatory process in COPD, particularly those gastric parietal cell stimulation.[24,25] Newer PDE4 that are neutrophil mediated, may be resistant to the inhibitors such as cilomilast have been developed in anti-inflammatory effects of corticosteroids.[12,13] recent years as an attempt to improve the therapeutic Novel anti-inflammatory therapies are therefore be- index of the first generation of PDE4 inhibitors. ing developed as potential therapeutic agents, in- Cilomilast (Ariflo®, GlaxoSmithKline [GSK]) is an cluding selective phosphodiesterase (PDE) inhibi- orally active second-generation PDE4 inhibitor with tors.[14] a half-life of 7 hours and a better side-effect profile than the first-generation PDE4 inhibitors.[20] 1.3 Phosphodiesterase Inhibitors Cilomilast is a potent and selective PDE4 inhibi- Phosphodiesterase 4 (PDE4) inhibitors act by tor which modulates pathophysiological processes inhibiting the degradation of the intracellular second of direct relevance to COPD. In preclinical studies, messenger, cyclic adenosine monophosphate cilomilast relaxed airway smooth muscle, inhibited (cAMP).[14] cAMP mediates a broad suppression of immune and inflammatory cell activation and inhib- [26-28] immune and inflammatory cell activity[15] and medi- ited cellular infiltration and mediator release. ates the relaxation of airway smooth muscle through The effect of cilomilast on airway cells was evalu- the activation of protein kinase A.[15] It is degraded ated using bronchial epithelial cells and induced- by the PDE enzymes, which are widely distributed sputum cells (squamous and immune cells) from [29] in a variety of tissues.[16] Currently, there are at least COPD patients, normal controls and smokers. α 11 distinct families of PDE isoenzymes identi- Cilomilast significantly reduced TNF release by fied.[16-18] Of these, PDE4 is the predominant PDE bronchial epithelial and sputum cells, and GM-CSF [29] isoenzyme in nearly all immune and inflammatory release by sputum cells. Supernatants of sputum cells and is a major regulator of cAMP content in and bronchial epithelial cells treated with cilomilast airway smooth muscle.[15,19] Inactivation of cAMP also demonstrated significantly reduced neutrophil [29] by PDE4 increases the level of cAMP, which in turn chemotaxis. Furthermore, cilomilast attenuated leads to inhibition of proinflammatory mediator re- the inhaled lipopolysaccharide-induced pulmonary lease, augmentation of the release of anti-inflamma- neutrophilia and oedema with equivalent effective- tory mediators and bronchodilation.[20] ness to that of high-dose, orally administered pred- [30] PDE4 inhibitors have a high therapeutic potential nisolone in an animal model. This suggested a as nonsteroidal disease controllers in inflammatory possible beneficial role for cilomilast on the neutro- airway diseases such as asthma, COPD and rhini- philic inflammation in COPD. tis.[15,19,20] PDE4 inhibition leads to the suppression The anti-inflammatory effects of cilomilast dem- of two very important cytokines, tumour necrosis onstrated in both in vitro and in vivo preclinical factor (TNF)-α and granulocyte-macrophage studies have also been observed in patients with colony-stimulating factor (GM-CSF), which may COPD. In a study designed to evaluate the effects of play a role in COPD.[21,22] cilomilast on inflammation in patients with COPD, In airway diseases, control of inflammation by although 12 weeks’ treatment with cilomilast did not specific PDE4 inhibition is expected to decrease the significantly reduce neutrophils in induced sputum, adverse effects observed with the initial nonselec- which was the primary endpoint, cilomilast signifi- tive PDE inhibitors such as theophylline.[23] The cantly reduced subepithelial CD68+ macrophages first-generation PDE4 inhibitors such as rolipram and CD8+ lymphocytes in biopsies when compared were shown to have efficacy but, unfortunately, with placebo.[1] At the time, this was the first dem- their beneficial actions were significantly offset by onstration of a reduction of airway tissue inflamma- their potent adverse effects including nausea and tory cells in COPD by any therapy and it was vomiting, which resulted from central nervous stim- suggested that the clinical benefits of cilomilast may ulation and increased gastric acid secretion due to be due primarily to anti-inflammatory effects.

1.4 Clinical Studies with Cilomilast serial electrocardiograms and 24-hour Holter monitoring. Cilomilast was studied in an extensive clinical Five pivotal, randomized, double-blind, placebo- programme, with over 6000 patients exposed to controlled, multicentre, parallel-group studies of cilomilast. Two phase II clinical trials were conduct- similar design were conducted evaluating the effect ed in outpatients with moderate COPD to evaluate of cilomilast (15 mg twice daily) for 24 weeks in the safety, tolerability and efficacy of orally admin- patients with COPD. Additional phase III and long- istered cilomilast. In one of these studies (study term safety studies were conducted to provide sup- 032), patients were randomized to receive either porting data (table I). Data from these studies are cilomilast (5, 10 or 15 mg twice daily) or placebo for found in the subsequent sections of this review. An 6 weeks.[31] At the highest dose, cilomilast produced overall discussion and conclusion of all data is a progressive and statistically significant increase in found in section 8. trough (predose) FEV1, and at the end of week 6 Despite early promise from the phase II studies cilomilast had improved trough FEV1 by 11% com- and some of the early pivotal phase III studies, data pared with placebo.[31] Similar improvements at from the other phase III studies were disappointing. week 6, relative to placebo, were observed for the A lack of consistency of results was observed which 15 mg twice-daily dose in forced vital capacity did not support the use of cilomilast in COPD and (FVC), peak expiratory flow rate (PEFR), exertional therefore the clinical programme was terminated. dyspnoea and rescue bronchodilator use. Lower doses of cilomilast produced negligible improve- 2. Evidence of Anti-Inflammatory ments in lung function, which was confirmed in a Activity of Cilomilast in Induced Sputum [32] similar multicentre 4-week study (study 038). and Bronchial Biopsies from Quality-of-life assessments using the St George’s COPD Patients Respiratory Questionnaire (SGRQ) were also recorded before and after therapy with cilomilast (15 mg twice daily) or placebo.[31] Consistent im- 2.1 Study Objectives provements approaching that defined as clinically meaningful in the total and composite scores of the Three studies were conducted to assess the anti- SGRQ were recorded for patients who received inflammatory properties of cilomilast. cilomilast 15 mg when compared with the placebo In study SB207499/076 (076)[1] and study group, although this did not reach statistical signifi- SB207499/110 (110),[33] the primary objectives cance.[32] were to examine the effects of cilomilast and place- The improvement in lung function and health bo on the inflammatory cell profile and inflamma- status demonstrated in the phase II trial resulted in a tory mediator concentrations in induced sputum and, commitment to a comprehensive phase III develop- in addition, to further evaluate the clinical efficacy ment programme evaluating the efficacy, safety and of cilomilast in terms of pulmonary function. In mechanism of action of cilomilast at the maximum study 076 a further objective was to examine the tolerated dose of 15 mg twice daily. effects on tissue histology and morphology in pa- During the preclinical development of cilomilast, tients with COPD by using bronchoscopic bronchial gastrointestinal (GI) effects were noted as a poten- biopsy. Study 076 has been previously published.[1] tial safety concern. Extensive monitoring of GI ad- In study SB207499/181 (181)[34] the primary ob- verse events was therefore undertaken throughout jective was to compare the numbers of inflammatory the clinical programme including testing for faecal cells of distinct immuno and ultrastructural pheno- occult blood. The cilomilast clinical development types after treatment with cilomilast and placebo in programme also evaluated the safety of patients by patients with COPD, using bronchial biopsy. The examination of laboratory parameters, vital signs, secondary objective was to compare the relative

Table I. Phase II and III studies in the cilomilast development programmea,b Study number Type of study Patient numbers receiving cilomilast Treatment duration 032 Phase II dose ranging 318 6 wk 038 Phase II dose ranging 138 4 wk 076 Mechanism of action 30 12 wk 110 Mechanism of action 31 12 wk 181 Mechanism of action (biopsy) 65 13 wk 039 Phase III pivotal 431 24 wk 042 Phase III pivotal 474 24 wk 091 Phase III pivotal 469 24 wk 156 Phase III pivotal 418 24 wk 657 Phase III pivotal 296 24 wk 040 Long-term safety extension 723 Up to 3 y 041 Long-term safety extension 355 Up to 3 y 157 Exacerbation study 455 52 wk 168 Holter monitoring 188 12 wk 125 Seretide® add-on study 162 12 wk 111 Hyperinflation 79 12 wk 180 Hyperinflation 97 18 wk 121 Chinese efficacy and safety 678 24 wk a See clinicaltrials.gov for summaries of study details and results. b Studies 107 and 122 were additional studies which were conducted for the Japanese authorities in the local language. Data from these studies has not been included in the review. numbers (i.e. percentage) of distinct inflammatory cally significant GI conditions and uncontrolled dis- cells after treatment in induced sputum. orders of major body systems.[1] For study 110,[33] patients entered the study in ten 2.2 Methods centres in the US during a study period from July 1999 to June 2000. The entry criteria were the same as for study 076 except that the requirement for the 2.2.1 Patients post-salbutamol FEV1 was ≥1.0 L and there was no For study 076, patients (aged 40–80 years) en- requirement for hypoxaemia. tered the study in seven centres in the UK, Germany, For study 181,[34] patients entered the study in 27 Italy, Spain and the Netherlands during a study centres in 12 countries during a study period from [1] period from September 1999 to September 2000. March 2003 to April 2004. The entry criteria were To be eligible for enrolment patients had to meet the the same as for study 076 except that all patients following criteria: a clinical diagnosis of COPD, a were required to have an FEV1 ≥40% and ≤70% of ≥ cigarette-smoking history of 10 pack-years, a pre- predicted normal and a poor reversibility after ad- ≤ salbutamol FEV1 to FVC ratio 0.7, post- ministration of salbutamol 400 µg (i.e. ≤10% of ≤ ≤ salbutamol reversibility 15% or 200 mL and post- predicted normal FEV1 or ≤200 mL increase). ≥ ≥ ≤ salbutamol FEV1 1.2 L and 30% and 70% The protocols were approved by an institutional ≥ ≤ (FEV1 40% and 70% for one centre) of predicted review board at all sites and all patients provided normal. In selected centres, an additional inclusion written informed consent prior to any study proce- criterion was patients without hypoxaemia. The dures. study excluded patients with a primary diagnosis of asthma, poorly controlled COPD, active pulmonary 2.2.2 Study Design disease (other than COPD), those receiving treat- Studies 076[1] and 110[33] were multicentre, ran- ment with long-term oxygen therapy, and with clini- domized, double-blind, placebo-controlled, parallel-

group studies consisting of a 4-week single-blind placebo run-in period and 12 weeks of active treatment with a 1-week safety follow-up visit. In study 076, patients were required to attend the clinic for at least 9 visits over the 16-week period with visits at weeks 1, 2, 4, 8, 10 and 12 during treatment. In study 110, patients were required to attend the clinic for at [34] least 8 visits over the 16-week period with visits at weeks 1, 2, 4, 8 and 12 during treatment. At the end

Study 181 of the 4-week run-in phase, patients were randomized in a ratio of 1 : 1 to receive cilomilast 15 mg twice daily or placebo for 12 weeks. All COPD medications except salbutamol or ipratropium and mucolytics were not allowed during the study period. In both studies, the key efficacy variable was the change from baseline at endpoint in neutrophils as a percentage of total cells in induced sputum. An [33] induced sputum sample was taken at screening, baseline and after 2, 4, 8 and 12 weeks of treatment.

Study 110 Other endpoints in study 076 included tissue histology and morphology assessed by bronchoscopic bronchial biopsy. In study 110, secondary efficacy endpoints included changes from baseline in subepithelial CD8+ lymphocytes per area tissue, subepithelial neutrophils per area tissue, subepithelial macrophages (CD68+) per area tissue and epithelial neutrophils per area tissue. In both studies,

[1] bronchial biopsies were performed at week –2 (baseline sample) and week 10. Study 181[34] was a multicentre, randomized, placebo (n = 30) cilomilast (n = 29) placebo (n = 34) cilomilast (n = 31) placebo (n = 62) cilomilast (n = 65) = forced vital capacity. double-blind, placebo-controlled, parallel-group

FVC study consisting of a 4-week single-blind placebo run-in period and 13 weeks of active treatment with a 1-week safety follow-up visit. Patients were required to attend the clinic for at least 8 visits over the 18-week period with visits at weeks 4, 8, 12 and 13 during treatment. The primary efficacy endpoint was the measurement of subepithelial CD68+

[mean (SD)] 54.2 (12.1) 58.2 (8.2)(macrophages) 54.8 (12.4) and 53.2 (11.0) subepithelial 59.8 (11.7) 62.0 (10.1) CD8+ (cytotoxic b 1 T lymphocytes) in biopsy tissue with secondary endpoints of inflammatory cells measured in in- Summary of demographic characteristics at screening (all randomized patients) duced sputum. Bronchial biopsies were performed (L) [mean (SD)] 1.61 (0.42) 1.81 (0.41) 1.64 (0.57) 1.63 (0.42) 1.61 (0.50) 1.70 (0.40) a /FVC ratio [mean (SD)] = forced expiratory volume in 1 second; 0.54 (0.10) 0.56 (0.09) 0.55 (0.11) 0.52 (0.10) 0.54 (0.10) 0.55 (0.10) 1 1 1 prior to randomization and after 12 weeks of treat- Baseline reversibility (%) [mean (SD)]FEV 8.0 (5.9) 7.0 (6.2) 6.7 (6.7) 6.7 (9.0) 4.6 (3.8) 4.2 (3.3) % Predicted FEV Table II. CharacteristicSex, male [no. (%)]Race, Caucasian [no. (%)]Age (y) [mean (SD)]Current smoker [no. (%)]Smoking history (pack-years) [mean (SD)]FEV 46.3 (17.7) 29 (97) Study 076 25 (83) 46.3 (20.4)a 17 (57) 61.7 (7.6) 29 (100) Pre-salbutamol inhalation. b 25 (86) 52.6 (23.9) Post-salbutamol inhalation. FEV 61.8 (11.1) 15 (52)ment. 33 (97) 60.8 (27.5) 23 (68) 64.4 (8.1) Six 12 (35) 41.3 (22.1)biopsies 29 (93) 66.1 (8.1) 26 (84) 46.3 (28.2) of 13 (42) 60 (97) 63.4 (9.1)adequate 47 (76) 61.4 (8.4) 28 (45) 62 (95) size 47 (72) (2mm) 32 (49) were

20 Cilomilast ables were based on an analysis of variance model Placebo 15 with effects for centre and treatment group. Least 10 squares means along with associated 95% confi- 5 dence intervals were calculated for each treatment 0 –5 group. Treatment differences were assessed using t- –10 tests on the least squares means.

sputum neutrophils (%) –15

Mean change from baseline, 2.3 Results –20 BL 2 4 8 12 EP Week 2.3.1 Study Population Fig. 1. Mean (SEM) change from baseline (BL) in sputum neutro- In study 076, 59 patients were randomized to phil counts by week in study 076.[1] EP = endpoint. receive placebo (n = 30) or cilomilast (n = 29) and in study 110, 65 patients were randomized to receive performed on the right side beginning at the sub- placebo (n = 34) or cilomilast (n = 31). In study 181, carinae in the right lower lobe (2 biopsies), then the 127 patients were randomized to receive placebo right middle lobe (2 biopsies) and finally the right (n = 62) or cilomilast (n = 65). In general, there were upper lobe (2 biopsies). no marked differences in the baseline characteristics Prior to biopsy, patients were required to have a of the two treatment groups in any study and the pre-salbutamol FEV1 40–80% predicted normal demographic and baseline characteristics of COPD value, no history of bleeding diathesis and a normal for all studies are shown in table II. platelet count. Sputum induction was carried out at 2.3.2 Primary Efficacy Measures baseline and after 13 weeks of treatment. In study 076, there was no evidence for a differ- In all studies, safety assessments included evalu- ence in sputum neutrophils as a percentage of the ation of adverse events (including additional moni- total cells between cilomilast and placebo at any toring for GI adverse events), vital signs, electrocar- timepoint (figure 1). At endpoint, the mean differ- diograms (studies 076 and 110) and clinical labora- ence was 2.1% (p = 0.697).[1] tory tests including faecal occult blood tests. In study 110, there were changes in percentage sputum neutrophils that favoured cilomilast (figure 2.2.3 Statistical Methods 2). When compared with placebo, cilomilast de- Studies 076 and 110 intended to have at least creased the mean percentage of sputum neutrophils 90% power to detect a significant difference in at endpoint (–14.9%), although this difference was sputum neutrophils assuming a 20% treatment dif- not statistically significant (p = 0.065). It should be ference, a standard deviation (SD) of 15% and a noted that samples from a number of patients result- significance level of 0.05. It was therefore estimated that 30 patients per group be evaluable (i.e. without 20 Cilomilast protocol violations) at endpoint. 15 Placebo Study 181 had 90% power to detect an approxi- 10 mate difference of 175 cells/mm2 (assumed SD of 5 230 cells/mm2) in CD8+ cells and a difference of 80 0 cells/mm2 (assumed SD 75 cells/mm2) in CD68+ –5 between cilomilast and placebo at significance level –10

sputum neutrophils (%) –15

of 2.5%. Mean change from baseline, –20 The primary population of interest in these stud- BL 2 4 8 12 EP ies was the per protocol population excluding pa- Week tients with protocol violations. Descriptive assess- Fig. 2. Mean (SEM) change from baseline (BL) in sputum neutro- ment of treatment differences for the efficacy vari- phil counts by week in study 110.[33] EP = endpoint.

ab )

) placebo and cilomilast groups, respectively. Reduc- 2 2 250 150 tions from baseline at endpoint in CD8+ cells were 200 similar in both groups (75.3 cells/mm2 in the cilomilast group and 69.8 cells/mm2 in the placebo group) 100 150 which was not statistically significant (p = 0.690). 100 The reductions from baseline in the level of CD8+ T 50 lymphocytes were 37% and 33% in the cilomilast 50 and placebo treatment groups, respectively (figure 3).

0 CD8+ T lymphocytes (cells/mm 0 CD68+ macrophages (cells/mm BL EP BL EP BL EP BL EP Placebo Cilomilast Placebo Cilomilast 2.3.3 Secondary Efficacy Endpoints Fig. 3. Mean (SEM) change from baseline (BL) in (a) CD68+ In study 076, a statistically significant mean de- macrophages and (b) CD8+ lymphocytes in study 181.[34] EP = crease from baseline in subepithelial macrophages endpoint. CD68+ per area tissue at endpoint was shown (–42.8 cells/mm2 for cilomilast, 33.2 cells/mm2 for place- ed in inadequate sputum slides (e.g. due to the bo; p = 0.005). The mean change from baseline in presence of too few cells, squamous contamination subepithelial CD8+ lymphocytes per area tissue being too high or cell degradation) in both treatment showed some improvement (cilomilast group groups. –132.4 compared with 24.4 for placebo group), but In study 181, at endpoint there was a smaller did not reach statistical significance (p = 0.055).[1] reduction from baseline in CD68+ cells in the There was no difference between cilomilast and cilomilast group than in the placebo group (20.8 vs placebo for the other endpoints (table III). 50.0 cells/mm2) which was not statistically signif- In study 110, there were no statistically significant (p = 0.093). This represented a 35% and 17% icant differences between the cilomilast and placebo decrease from baseline levels of CD68+ cells in the groups for sputum macrophages, sputum total cell

Table III. Mean change from baseline to endpoint in secondary efficacy endpoints in study 076[1] Variable Placebo Cilomilast Subepithelial CD8+ lymphocytes/area tissue n = 21 n = 16 Baseline 304.7 328.3 Mean (SE) change from baseline 24.4 (55.8) –132.4 (66.5) Mean difference (95% CI) –156.8 (–316.8, 3.3) p-Value vs placebo 0.055 Subepithelial neutrophils/area tissue n = 21 n = 16 Baseline 53.4 57.7 Mean (SE) change from baseline 4.4 (18.9) –17.9 (22.5) Mean difference (95% CI) –22.3 (–76.4, 31.8) p-Value vs placebo 0.406 Subepithelial CD68+ macrophages/area tissue n = 20 n = 16 Baseline 59.4 102.1 Mean (SE) change from baseline 33.2 (17.8) –42.8 (21.0) Mean difference (95% CI) –76.0 (–126.6, –25,4) p-Value vs placebo 0.005 Epithelial neutrophils/area tissue n = 21 n = 16 Baseline 7.3 4.3 Mean (SE) change from baseline –1.7 (2.6) –0.0 (3.1) Mean difference (95% CI) 1.7 (–5.7, 9.1) p-Value vs placebo 0.645

Table IV. Change from baseline to endpoint in secondary efficacy endpoints in study 110[33] Variable Placebo Cilomilast Sputum macrophages (%) n = 20 n = 19 Baseline 22.9 18.2 Mean (SE) change from baseline –9.1 (5.5) 2.3 (5.9) Mean difference (95% CI) 11.4 (–2.9, 25.6) p-Value vs placebo 0.114 Sputum eosinophils (%) n = 20 n = 19 Baseline 2.19 1.17 Mean (SE) change from baseline –0.32 (0.83) 1.31 (0.88) Mean difference (95% CI) 1.63 (–0.52, 3.77) p-Value vs placebo 0.132 Sputum lymphocytes (%) n = 20 n = 19 Baseline 1.58 1.26 Mean (SE) change from baseline –0.82 (0.37) –0.30 (0.40) Mean difference (95% CI) 0.52 (–0.44, 1.49) p-Value vs placebo 0.277 Sputum total cell count (×106) n = 22 n = 20 Baseline 1.48 4.31 Mean (SE) change from baseline 2.79 (2.71) –1.69 (2.72) Mean difference (95% CI) –4.48 (–11.1, 2.15) p-Value vs placebo 0.178 counts, sputum eosinophils or sputum lymphocytes 2.4 Safety Results (table IV). In study 181, there were reductions in the total 2.4.1 Adverse Events cell count in both groups (cilomilast 5.3 × 106/mL; In study 076, during the double-blind phase, 20 placebo 8.0 × 106/mL), but the difference was not patients (67%) in the placebo group had adverse statistically significant (p = 0.439). Other results events, compared with 22 patients (76%) in the were generally similar in both groups and there were cilomilast group. There was a higher incidence of adverse events relating to the GI and central/peri- no statistically significant differences between treat- pheral nervous system body systems in the cilomi- ments (table V). For biopsy endpoints, there was a last group compared with placebo (GI 52% cilomi- reduction from baseline in the number of subepithe- last, 27% placebo; CNS/peripheral 24% cilomilast, lial neutrophils per unit area of biopsy tissue at 7% placebo) [table VII]. Most of the events in the endpoint in the cilomilast and placebo groups (2.2 central/peripheral nervous system body system were and 21.6 cells/mm2, respectively). The reduction headaches. In study 110, the overall incidence of was significantly larger in the placebo group (p = adverse events was lower in the placebo group 0.019). Reduction in cell numbers per area of biopsy (59%) than in the cilomilast group (77%). The most tissue were seen for CD4+ lymphocytes, interleu- common adverse events in the cilomilast group were back pain, diarrhoea, dyspepsia, viral infection and kin-8 mRNA positive cells, TNFα mRNA positive nausea (all 13%) and in the placebo group a COPD cells and CD45 positive cells in both treatment exacerbation (15%) [table VII]. In study 181, the groups. There were no statistically significant differ- overall incidence of adverse events was similar in ences between the treatments, although in most both treatment groups and the most frequently re- cases the reductions in cell numbers were smaller in ported events in both groups were headache and the cilomilast group (table VI). nasopharyngitis. There was a higher incidence of

Table V. Change from baseline to endpoint in sputum secondary efficacy endpoints in study 181[34] Variable Placebo Cilomilast Sputum total cell count (×106/mL) n = 42 n = 43 Baseline 14.5 9.4 Mean (SE) change from baseline –8.0 (2.7) –5.3 (2.5) Mean difference (95% CI) 2.7 (–4.2, 9.6) p-Value vs placebo 0.439 Sputum macrophages (%) n = 33 n = 33 Baseline 44.3 44.5 Mean (SE) change from baseline –3.9 (5.4) 4.8 (5.1) Mean difference (95% CI) 8.6 (–5.6, 22.8) p-Value vs placebo 0.226 Sputum eosinophils (%) n = 33 n = 33 Baseline 3.5 3.6 Mean (SE) change from baseline 0.4 (2.5) –0.5 (2.3) Mean difference (95% CI) –0.9 (–7.4, 5.6) p-Value vs placebo 0.782 Sputum lymphocytes (%) n = 33 n = 33 Baseline 0.89 0.60 Mean (SE) change from baseline 0.01 (0.32) –0.00 (0.30) Mean difference (95% CI) –0.01 (–0.85, 0.83) p-Value vs placebo 0.980 Sputum neutrophil elastase (ng/mL) n = 40 n = 41 Baseline 49 781 61 218 Mean (SE) change from baseline –9012 (36 206) 5054 (34 216) Mean difference (95% CI) 14066 (–80 707, 108 839) p-Value vs placebo 0.767 Sputum interleukin-8 elastase (ng/mL) n = 40 n = 41 Baseline 71.9 45.8 Mean (SE) change from baseline –21.6 (9.7) –18.6 (9.2) Mean difference (95% CI) 2.9 (–22.5, 28.4) p-Value vs placebo 0.818 adverse events relating to the GI body system in the ing to adverse events, four (6%) in the cilomilast cilomilast group compared with placebo (31% vs group and one (2%) in the placebo group. The 16%) with events such as nausea, diarrhoea and events leading to withdrawal were atrial flutter, gas- vomiting occurring more frequently in the cilomilast tritis, gastro-oesophageal reflux disease, nausea and group (table VII). enteritis (cilomilast) and an exacerbation of COPD (placebo). No deaths occurred in any of the three 2.4.2 Adverse Events Leading to Withdrawal studies. In study 076, adverse events leading to withdrawal occurred in four patients in the cilomilast group 2.4.3 Other Safety Assessments and no patients in the placebo group. The adverse events leading to withdrawal that had a suspected or Overall, in all studies the mean changes from probable relationship to study medication were ab- baseline in clinical laboratory parameters and vital dominal pain, dyspepsia and nausea. No patient was signs were small and comparable between the treat- withdrawn because of an adverse event in study 110, ment groups. There were small changes in ECG and in study 181 five patients were withdrawn ow- parameters in studies 076 and 110 from baseline to

endpoint in both treatment groups, with no clinically COPD by any therapy.[1] Although no significant relevant differences noted within or between groups. change was found in the primary endpoint, spu- In study 076, 4% of patients receiving placebo (1 tum neutrophil count, a substantial reduction in of 25) and 16% receiving cilomilast (4 of 25, one of tissue CD8+ T lymphocytes and CD68+ macro- whom had a positive test at baseline) had positive faecal occult blood results. In study 110, overall, phages was demonstrated. 3.4% (1 of 29) of patients who received placebo and • Study 110 did not provide definitive evidence of 3.7% (1 of 27) who received cilomilast had a posi- activity of cilomilast on the cellular and bio- tive faecal occult blood result during double-blind chemical indices of inflammation in patients with treatment. In study 181, 7.3% of patients receiving COPD. cilomilast (3 of 41, one of whom had a positive test at baseline) and 12.5% receiving placebo (5 of 40, • Study 181 did not provide any definitive evi- two of whom had a positive test at baseline) had dence of activity of cilomilast on the cellular and positive faecal occult blood results. biochemical indices of inflammation in patients with COPD. 2.5 Summary • No clinically relevant safety issues in laboratory • Study 076 was the first study to demonstrate a values including faecal occult bloods, vital signs reduction of airway tissue inflammatory cells in or ECGs were revealed in these studies.

Table VI. Change from baseline to endpoint in biopsy secondary efficacy endpoints in study 181[34] Variable Placebo (n = 49) Cilomilast (n = 54) Subepithelial neutrophils (cells/mm2) Baseline 46.9 38.0 Mean (SE) change from baseline –21.6 (6.5) –2.2 (5.8) Mean difference (95% CI) 19.4 (3.3, 35.6) p-Value vs placebo 0.019 Subepithelial CD4+ (cells/mm2) Baseline 122.9 102.3 Mean (SE) change from baseline –21.6 (12.0) –8.1 (10.6) Mean difference (95% CI) 13.6 (–16.2, 43.3) p-Value vs placebo 0.367 Subepithelial interleukin-8 mRNA+ (cells/mm2) Baseline 44.4 36.1 Mean (SE) change from baseline –24.8 (4.7) –13.2 (4.2) Mean difference (95% CI) 11.6 (–0.1, 23.3) p-Value vs placebo 0.052 Subepithelial tumour necrosis factor-α mRNA+ (cells/mm2) Baseline 70.3 63.5 Mean (SE) change from baseline –42.5 (5.7) –34.9 (5.1) Mean difference (95% CI) 7.6 (–6.6, 21.8) p-Value vs placebo 0.289 Subepithelial CD45+ (cells/mm2) Baseline 393.1 396.1 Mean (SE) change from baseline –90.7 (18.8) –99.4 (16.6) Mean difference (95% CI) –8.6 (–55.2, 37.9) p-Value vs placebo 0.713

© 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 Suppl. 2 16 Rennard et al. [34] Study 181 [33] Study 110 10% patients in any group study) ≥ [1] placebo (n = 30) cilomilast (n = 29) placebo (n = 34) cilomilast (n = 31) placebo (n = 62) cilomilast (n = 65) Patients with the most frequently reported adverse events ( = chronic obstructive pulmonary disease. Table VII. Preferred term [no. (%)]Total patients with at least one adverseevent 20 (67)Diarrhoea Study 076 Exacerbation of COPD 22 (76)DyspepsiaHeadache 20 (59)Upper respiratory tract infection 4 (13)Vomiting 24 (77) 4 (13)Nausea 1 (3) 5 (17)Abdominal pain 1 (3) 6 (21) 36 (58)Coughing 1 (3) 4 (14)Dyspnoea 5 (15) 5 (17) 41 (63) 2 (6)Back pain 0 5 (17) 4 (12)Infection viral 1 (3) 0 2 (7) 0Hypertension 4 (13)Sinusitis 3 (10) 1 (3) 4 (14) 3 (10) 1 (2) 3 (10)Nasopharyngitis 3 (10) 5 (17) 2 (3) 4 (13)COPD 1 (3) 3 (10) 2 (3) 2 (7) 0 0 0 1 (3) 1 (3) 1 (3) 1 (3) 0 5 (8) 0 12 (19) 1 (2) 1 (3) 0 0 0 4 (13) 0 3 (10) 0 0 9 (14) 3 (5) 0 0 4 (7) 1 (3) 0 2 (3) 1 (2) 1 (3) 1 (3) 0 4 (13) 2 (3) 6 (9) 1 (3) 4 (13) 0 5 (8) 0 1 (3) 3 (10) 0 3 (5) 0 0 3 (10) 0 0 2 (3) 0 8 (13) 1 (2) 0 8 (12) 0

Table VIII. Study details Study number Dates conducted Participating countries SB207499/039[2] Nov 1998 to Mar 2000 102 centres in the US, Canada and Mexico SB207499/042[38] Nov 1998 to Dec 1999 98 centres in Australia, New Zealand, Germany, Spain, South Africa and the UK SB207499/091[37] Dec 1998 to Mar 2000 110 centres in 9 European countries SB207499/156[35] Dec 2000 to Jul 2002 132 centres in the US and Canada CIL103657[36] Nov 2004 to Jan 2007 103 centres in the US

3. Efficacy and Safety of Cilomilast in optional open-label extension (see section 4) or who the Pivotal Phase III Studies withdrew prior to the end of the study. The local ethics committee or institutional review board approved the study protocol at each centre and 3.1 Study Objectives all patients gave written informed consent to participate. The primary objective of the pivotal studies was Patients were assessed for eligibility at the to assess the clinical efficacy of oral cilomilast screening visit. After the 4-week run-in period, eli- 15 mg twice daily by assessment of trough FEV1 gible patients were randomized in a 2 : 1 ratio (stud- and total score of the SGRQ over 24 weeks in ies 039, 042 and 091) or 1 : 1 ratio (studies 156 and patients with COPD. Secondary objectives included 657) to receive twice-daily oral treatment with either assessment of the efficacy of cilomilast on COPD cilomilast 15 mg or placebo during a 24-week dou- exacerbation rates, FVC, and post-exercise breath- ble-blind phase. lessness. Patients attended the clinic weekly up to week 2, every 2 weeks up to week 4 of treatment and then at 3.2 Materials and Methods 4-weekly intervals. A final follow-up visit occurred 1 week after treatment completion (figure 4). The 3.2.1 Study Design co-primary endpoints in these studies were the Five pivotal, multicentre, randomized, double- change from baseline in FEV1 measured at trough blind, placebo-controlled, parallel-group studies of drug concentrations, and health status measured us- similar design were conducted evaluating the effect ing the SGRQ. Secondary efficacy endpoints includ- of cilomilast (15 mg twice daily) for 24 weeks in ed FVC, incidence of COPD exacerbations and patients with COPD. Three studies were conducted post-exercise dyspnoea assessed by the modified in North America (studies SB207499/039,[2] Borg Dyspnoea scale.[39] Immediately after exercise, SB207499/156[35] and CIL103657;[36] patients were asked to rate their breathlessness on a NCT00103922) and two studies were conducted in scale from 0 (nothing at all) to 10 (maximal) in all Europe and the rest of the world (studies SB207499/ studies except study 657.[36] Safety was measured by 091[37] and SB207499/042[38]) [table VIII]. Study the assessment of adverse events, vital signs, clinical 039 was the first pivotal phase III study completed laboratory tests including faecal occult blood tests, and has been previously published.[2] The studies ECGs and 24-hour Holter readings (in a subset of had the same study design with a 4-week, single- patients in studies 091, 039 and 042). blind, placebo run-in period followed by 24 weeks of double-blind treatment (figure 4). One tablet of 3.2.2 Patients cilomilast 15 mg or matched placebo was taken The studies generally had the same patient selec- immediately after breakfast and after the evening tion criteria (table IX). The cilomilast pivotal devel- meal, in order to improve GI tolerability. The treat- opment programme was restricted to patients with ment period was followed by a 1-week safety fol- poor reversibility to bronchodilator (<15% or low-up period for patients who did not enter an 200 mL improvement over baseline in FEV1).

Run-in Treatment Follow-up Single-blind phase Double-blind phase Cilomilast 15 mg bid

Placebo bid

2 2 1 1 2 4 4 4 4 4 1 Weeks Weeks Week Week Weeks Weeks Weeks Weeks Weeks Weeks Week

V1V2* V3 V3a V4 V5V6 V7 V8 V9 V10 Wk –4Wk –2 Wk 0 Wk 1 Wk 2 Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24 Wk 25

Screen Baseline/randomization End of double-blind phase Fig. 4. Study schematic of a 24-week phase III pivotal study. * No visit (V) 2 in study 657. bid = twice daily.

To be eligible for participation, patients had to be 3.2.3 Study Procedures diagnosed with COPD (by American Thoracic Patients were asked to refrain from taking any Society or European Respiratory Society defini- respiratory medication for at least 2 hours and re- tion), be aged 40–80 years, have a pre-bronchodi- frain from smoking for at least 2 hours before each lator FEV1 to FVC ratio of ≤0.7, a post-bronchodi- clinic visit. Trough (predose) FEV1 was performed lator FEV1 between ≥30% and ≤70% of predicted using standardized spirometry equipment supplied normal (except study 657, which had no lower limit) by GSK at all centres within each study. and have a cigarette smoking history of ≥10 pack- Overall and post-exercise (6-minute walk) years. Randomization criteria required a total symp- dyspnoea were assessed using the modified Borg tom score (cough, sputum production and breath- Dyspnoea scale at baseline and at each visit after lessness) of ≥3 on at least 5 of 10 days prior to randomization (except study 657). The SGRQ, a baseline for studies 039, 091 and 042. There were no disease-specific health status tool, was administered symptom score requirements for study 156. at weeks 0, 12 and 24. COPD exacerbations, defined as a worsening of COPD symptoms requiring Study 657 was designed to achieve a more symp- changes to normal treatment, including anti- tomatic population to optimize the potential of microbial therapy, short courses of oral steroids and cilomilast to show an improvement in SGRQ and other bronchodilator therapy, were recorded exacerbations. The criteria were therefore amended throughout the study. COPD exacerbations were to include at least one exacerbation requiring either categorized as level 1, 2 or 3, based on the treatment antibiotics or oral corticosteroids or hospitalization received by the patient for the exacerbation. Level 1 ≥ in the year prior to screening, a symptom score of 4 (mild) was defined as an acute worsening of COPD on at least 5 of 10 days prior to randomization and that was self-managed by the patient at home by removal of the lower end FEV1 requirement (pre- increasing usual COPD medications, level 2 (mod- vious studies had 30–70% predicted requirement). erate) for those who required additional treatment Patients were provided with salbutamol metered (e.g. a short course of oral steroids or antibiotics dose inhalers for use on an as-needed basis and were prescribed by the physician) and level 3 (severe) as permitted to continue inhaled short-acting anticho- requiring hospitalization. linergics and mucolytics at a stable dose throughout At all visits during the double-blind study period, the study. No other COPD medications were al- patients were assessed for compliance with the med- lowed except for the short-term treatment of exacer- ication as well as for use of concomitant medica- bations. tions.

Table IX. Main inclusion and exclusion criteria used in the pivotal phase III studies Inclusion Exclusion Male or female (aged 40–80 years)a Women who were pregnant or lactating Diagnosed with COPD as defined by ATS or ERS guidelines Patients with asthma as the main component of their obstructive airways disease Patients with a cigarette smoking history of ≥10 pack-years Patients with poorly controlled COPD, defined as the occurrence of (1 pack-year = 20 cigarettes smoked per day for 1 year or the any of the following in the 2 weeks prior to visit 1: acute worsening equivalent). Both current smokers and ex-smokers were eligible of COPD managed by the patient at home by self-treatment with corticosteroids or antibiotics, that required treatment prescribed by a physician, or for which the patient was hospitalized

Patients with a pre-salbutamol FEV1 to FVC ratio ≤0.7 at visit 1 Patients with active tuberculosis, lung cancer or clinically overt bronchiectasis Patients with fixed airway obstruction, defined by ≤15% or Patients with clinically significant cardiovascular, neurological, renal, ≤200 mL (or both) increase in FEV1 after administration of endocrine or haematological abnormalities that were uncontrolled salbutamol 180 µg (studies 039, 657, 156) or 360 µg (studies 042, on permitted therapy 091) via MDI with a spacer at visit 1

Patients with a post-salbutamol FEV1 between ≥30% and ≤70% of Patients with clinically significant gastrointestinal or hepatic predicted normal for height, age and gender at visit 1.a Patients abnormalities were assessed 15 to 30 (± 5) minutes after receiving salbutamol 180 µg via MDI Patients who gave their signed written informed consent to Patients with a positive faecal occult blood test result between participate screening and baseline Women of childbearing potential were required to have used Patients with clinically significant orthostatic changes in blood effective contraceptive measures for 4 weeks prior to the study pressure or heart rate between screening and baseline and throughout the study Patients with a history of hypersensitivity to PDE4 inhibitors Patients who had received an investigational drug within 30 days of entry into the study, or within 5 drug half-lives of the investigational drug (whichever was longer) or who had previously participated in cilomilast study Patients with a history (or suspected history) of alcohol misuse or any other recreational substance abuse Patients who required treatment with inhaled cromolyn sodium or nedocromil, inhaled long-acting β2-agonists, oral β2-agonists, nebulized β2-agonists, nebulized anticholinergics, xanthines, leukotriene modifiers or oral/inhaled corticosteroids beyond visit 1. All COPD medications except anticholinergic medication or salbutamol via MDI were withdrawn prior to or at visit 1 Patients receiving treatment with long-term oxygen therapy, patients who required supplemental oxygen more often than on an occasional basis, or patients who required nocturnal positive pressure for sleep apnoea Patients who had participated in a pulmonary rehabilitation programme within 4 weeks prior to visit 1 or who planned to enter a pulmonary rehabilitation programme during the study Patients unable to comply with study procedures (including completion of the health status questionnaires) a No upper age limit for study 657; no lower limit for percent of predicted normal for study 657.

ATS = American Thoracic Society; ERS = European Respiratory Society; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; MDI = metered dose inhaler; PDE4 = phosphodiesterase 4.

3.2.4 Statistical Analysis change over 24 weeks with additional comparisons The co-primary endpoints (change from baseline made at individual timepoints. Effects for treatment, in trough FEV1 and SGRQ) were analysed using a time and centre were included in the model. The repeated measures model to compare the average difference between treatment groups was evaluated

through a t-test on the least squares means. 95% The study was designed to detect a 50mL difference confidence intervals were calculated on the least in FEV1 and a 4-unit difference in SGRQ total score squares means of the two groups and on their differ- with 90% joint power. Based on previous studies, ence. Continuous secondary variables were analysed the powering of the study assumed a 160 mL similarly to the co-primaries. To account for co- standard deviation for FEV1, and a 10.5-unit primary endpoints, the Hochberg method was used standard deviation for SGRQ total score. to adjust the significance level in the test for treat- Details for study 039 have been previously pub- ment effect. If both p-values were <0.05, both pri- lished.[2] mary endpoints were declared significant. If the larger p-value was >0.05, the smaller p-value was compared against a significance level of 0.025. The 3.3 Results exacerbation-free survival rate at 24 weeks along with 95% confidence intervals was estimated for 3.3.1 Patient Disposition each treatment group using the Kaplan-Meier product limit. Analyses were performed for the intent-to- A summary of the number of patients exposed to treat (ITT) population, composed of all patients who cilomilast and placebo in the pivotal studies is pre- received at least one dose of double-blind med- sented in table X. Cilomilast was compared with ication and had a baseline and at least one on- placebo in populations ranging from 613 to 825 therapy efficacy assessment. patients per study. The number of patients withdrawn prior to randomization was in the range of 3.2.5 Sample Sizes 27–34% except for study 657, where this increased For studies 042 and 091, the planned sample size to 69% owing to the more difficult study entry was 645 patients to obtain 450 evaluable patients. criteria. In each study, the primary reason for with- This gave at least 90% power to detect a 4-unit drawal of patients prior to randomization was failure difference in total SGRQ score (adjusted signifi- to meet inclusion/exclusion criteria. This ranged cance level of 0.025 assuming a standard deviation from 11% of withdrawn patients in study 156 to of 12 units). For FEV1, there was at least 90% power 61% in study 657. The percentage of patients in each to detect a difference of 120 mL assuming a group that withdrew from the double-blind phase of standard deviation of 270 mL. For study 156, the the study was higher in the cilomilast treatment planned sample size was 830 patients to obtain 550 group (ranging from 26% to 35%) compared with completed patients. The study had 90% power to the placebo group (ranging from 23% to 26%). The detect a 50 mL difference in FEV1 (assuming a visit main reason for withdrawal after randomization in standard deviation of 210 mL with between-visit each study was an adverse event (see section 3.4). correlation of 0.68) and a 4-unit difference in the The percentage of patients withdrawn from all the SGRQ (assuming a standard deviation of 12) at a studies for reasons other than adverse experience significance level of 0.05. For study 657, the was comparable between the cilomilast and placebo planned sample size was 600 randomized patients. treatment groups.

Table X. Patient accountability in the pivotal efficacy studies Patient disposition Treatment Study 039[2] Study 156[35] Study 042[38] Study 091[37] Study 657[36] (n = 647) (n = 825) (n = 700) (n = 711) (n = 613) Randomized (no.) Placebo 216 407 226 242 317 Cilomilast 431 418 474 469 296 Withdrawn [no. (%)] Placebo 52 (24) 96 (24) 51 (23) 63 (26) 77 (24) Cilomilast 137 (32) 143 (34) 122 (26) 121 (26) 105 (35) Completed [no. (%)] Placebo 164 (76) 311 (76) 175 (77) 179 (74) 240 (76) Cilomilast 294 (68) 275 (66) 352 (74) 348 (74) 191 (65)

Table XI. Baseline demographics of patients (pts) entered into the five pivotal studies Study/treatment No. of Sex: Race: Age (y) Years since COPD Smoking status: Smoking history: pack- group pts M/F (%) Caucasian (%) [mean (SD)] diagnosis [mean (SD)] current/ex (%) years [mean (SD)] 039[2] Placebo 216 68/32 97 64.9 (8.4) 6.8 (6.6) 47/53 56.1 (29.3) Cilomilast 431 59/41 91 65.4 (8.6) 7.3 (7.3) 44/56 59.9 (32.7) 156[35] Placebo 407 62/38 93 64.4 (8.7) 5.8 (6.6) 46/54 61.8 (34.4) Cilomilast 418 56/44 94 64.5 (8.2) 6.4 (7.4) 47/53 58.9 (31.1) 042[38] Placebo 226 80/20 99 64.7 (8.5) 8.5 (9.0) 38/62 45.7 (22.6) Cilomilast 474 81/19 99 64.5 (8.1) 7.8 (7.7) 45/55 45.8 (23.3) 091[37] Placebo 242 86/14 98 62.6 (9.4) 9.2 (8.1) 38/62 40.3 (21.3) Cilomilast 469 86/14 98 62.9 (9.2) 10.6 (8.8) 38/62 41.3 (21.9) 657[36] Placebo 317 47/53 94 63.2 (9.7) 6.8 (6.3) 52/48 57.2 (28.8) Cilomilast 296 46/54 95 63.1 (9.6) 6.8 (5.4) 52/48 55.0 (26.7) F = female; M = male.

3.3.2 Baseline Characteristics treatment groups and ranged from 81% to 100% in The two treatment groups in the randomized pa- the cilomilast treatment group and 79% to 100% in tient population were well matched for demographic the placebo group. A similar number of patients characteristics and for baseline characteristics of continued with a stable dose of ipratropium bromide COPD including lung function (table XI and table during the study (33% to 57% in the cilomilast XII). The use of salbutamol was similar between the group and 31% to 55% in the placebo groups) and

Table XII. Pulmonary function characteristics and medication use of patients (pts) in the five pivotal studies at screening

Study/treatment No. of FEV1 (L) % predicted % reversibility FEV1/FVC Concomitant Prior ICS use: group pts [mean (SD)] FEV1 [mean (SD)] [mean (SD)] IAC use: use/no use (%) [mean (SD)] use/no use (%) 039[2] Placebo 216 1.48 (0.55) 50.5 (12.2) 6.7 (7.6) 0.51 (0.11) 44/56 34/66 Cilomilast 431 1.37 (0.49) 49.3 (12.6) 7.7 (7.1) 0.51 (0.11) 39/61 27/73 156[35] Placebo 407 1.45 (0.53) 50.0 (12.1) 8.6 (6.4) 0.53 (0.10) 31/69 31/69 Cilomilast 418 1.40 (0.48) 50.3 (11.6) 8.6 (6.4) 0.53 (0.10) 33/67 30/70 042[38] Placebo 226 1.45 (0.43) 48.9 (10.6) 4.9 (8.6) 0.53 (0.10) 44/56 43/57 Cilomilast 474 1.44 (0.42) 49.1 (11.1) 5.2 (9.0) 0.54 (0.10) 42/58 41/59 091[37] Placebo 242 1.53 (0.46) 50.5 (11.8) 5.4 (8.8) 0.54 (0.10) 29/71 43/57 Cilomilast 469 1.53 (0.48) 50.2 (11.9) 4.9 (8.2) 0.55 (0.10) 25/75 50/50 657[36] Placebo 317 1.22 (0.48) 45.8 (14.0) 7.8 (9.0) 0.48 (0.11) 23/77 21/79 Cilomilast 296 1.22 (0.49) 45.9 (14.6) 8.9 (8.5) 0.49 (0.12) 23/77 22/78 FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; IAC = ipratropium bromide; ICS = inhaled corticosteroid.

Table XIII. Mean change from baseline in trough forced expiratory volume in 1 second averaged over 24 weeks Study Treatment group n Baseline 24-wk change Mean difference p-Value [mean (SE)] [mean (SE)] 039[2] Placebo 207 1.42 (0.04) –0.03 (0.01) Cilomilast 378 1.34 (0.03) 0.01 (0.01) 0.040 0.002 156[35] Placebo 377 1.38 (0.03) –0.02 (0.01) Cilomilast 364 1.36 (0.03) 0.01 (0.01) 0.024 0.024 042[38] Placebo 219 1.36 (0.03) 0.00 (0.02) Cilomilast 440 1.38 (0.03) 0.03 (0.01) 0.030 0.044a 091[37] Placebo 230 1.44 (0.04) –0.03 (0.02) Cilomilast 435 1.45 (0.04) 0.00 (0.02) 0.029 0.055 657[36] Placebo 303 1.19 (0.03) 0.01 (0.01) Cilomilast 268 1.21 (0.03) 0.05 (0.01) 0.044 <0.001 a Not significantly different from placebo after Hochberg adjustment for multiple comparisons. similar percentages of patients in both treatment In general, the magnitude of the response at end- groups had previously used inhaled corticosteroids point was larger than that observed when averaged (ICS). 93 to 98% of placebo-treated patients and 87 over 24 weeks. Studies 657 and 156 demonstrated to 95% of cilomilast-treated patients were at least an improvement relative to placebo in mean change 80% compliant with their study medication during from baseline in FEV1 at endpoint of 38 mL the double-blind treatment period. (p = 0.018) and 40 mL (p = 0.013), respectively. In study 039, the difference was 80 mL (p < 0.001) and 3.3.3 Primary Efficacy Endpoints in studies 042 and 091, the differences in FEV1 at Trough Forced Expiratory Volume in 1 endpoint between the cilomilast and placebo treat- Second (FEV1) ment groups were 40 mL (p = 0.050) and 30 mL When averaged over 24 weeks, the mean change (p = 0.146), respectively. from baseline in FEV1 in the cilomilast group show- Health Status ed improvement compared with placebo in all studies (table XIII). The mean change from baseline in The mean total score of the SGRQ at baseline in the placebo- and cilomilast-treated patients in the FEV1 over time is presented graphically in figure 5. In studies 657 and 156, there was a statistically five pivotal studies ranged from 41.5 to 52.5 units. When averaged over 24 weeks, there were improve- significant difference in FEV1 between the cilomilast and placebo treatment groups (44 mL, p < 0.001 ments from baseline in the total score of the SGRQ for study 657; 24 mL, p = 0.024 for study 156). In in both the cilomilast and placebo treatment groups study 039 there was also a statistically significant in all pivotal studies, with the exception of the placebo group in study 039. difference in FEV1 between the cilomilast and placebo treatment groups of 40 mL (p = 0.002) [data Two studies (039 and 156) demonstrated a signif- previously published].[2] In studies 042 and 091, icant improvement in the total score of the SGRQ of when averaged over 24 weeks, the improvements in the cilomilast group compared with placebo when averaged over 24 weeks, whereas there were no FEV1 in the cilomilast treatment group relative to placebo were 30 and 29 mL, respectively, but these notable differences in studies 657, 042 and 091 were not statistically significant. In study 042, the (table XIV, figure 6). difference from placebo of 30 mL had a p-value 3.3.4 Secondary Endpoints <0.05 (p = 0.044); however, this difference was not statistically significant owing to adjustment of the Trough FVC significance level to 0.025 using the Hochberg The mean FVC at baseline in both treatment method to account for co-primary endpoints. groups in the five pivotal studies ranged from 2.48

a b 100 Cilomilast 100 75 Placebo 75 50 50 (mL) (mL) 1 1 25 25 0 0 –25 –25 –50 –50 trough FEV trough FEV Mean change from BL, Mean change from BL, –75 –75 –100 –100 BL 2 4 8 12 16 20 24 EP Avg24 BL 2 4 8 12 16 20 24 EP Avg24 Week Week

c d 100 100 75 75 50 50 (mL) (mL) 1 25 1 25 0 0 –25 –25 –50 –50 trough FEV trough FEV Mean change from BL, –75 Mean change from BL, –75 –100 –100 BL 2 4 8 12 16 20 24 EP Avg24 BL 2 4 8 12 16 20 24 EP Avg24 Week Week e 100 75 50 (mL)

1 25 0 –25 –50 trough FEV

Mean change from BL, –75 –100 BL 2 4 8 12 16 20 24 EP Avg24 Week

Fig. 5. Mean (SEM) change from baseline (BL) in trough forced expiratory volume in 1 second (FEV1). (a) Study 039[2] (reproduced from Rennard et al.,[2] with permission); (b) study 156;[35] (c) study 657;[36] (d) study 091;[37] (e) study 042.[38] Avg24 = average over 24 weeks; EP = endpoint. to 2.90 L. Across the pivotal studies, the mean im- cilomilast and placebo were 27 mL (p = 0.355), provement in FVC was 27–110 mL greater in the 50 mL (p = 0.129) and 60 mL (p = 0.073). cilomilast treatment group than in the placebo group (table XV). The largest increases were seen in stud- COPD Exacerbations ies 039 and 156, with improvements in FVC in the Across the five pivotal studies, the percentages of cilomilast treatment group relative to placebo at patients who were exacerbation-free at 24 weeks endpoint of 110 mL (p = 0.001) for study 039 and ranged from 64% to 80% in the placebo treatment 60 mL (p = 0.022) for study 156. In studies 657, 042 group and 66% to 82% in the cilomilast treatment and 091, the differences in FVC at endpoint between group (table XV). In two studies (039 and 091) there

Table XIV. Mean change from baseline in St George’s Respiratory Questionnaire total score averaged over 24 weeks Study Treatment group n Baseline 24-wk change Mean difference p-Value [mean (SE)] [mean (SE)] 039[2] Placebo 196 44.6 (1.2) 0.4 (0.8) Cilomilast 340 45.0 (0.9) –3.7 (0.7) –4.1 <0.001 156[35] Placebo 369 43.5 (0.9) –1.3 (0.6) Cilomilast 359 43.8 (0.9) –3.2 (0.6) –1.9 0.017 042[38] Placebo 202 46.0 (1.4) –4.9 (1.0) Cilomilast 406 43.9 (1.1) –4.2 (0.8) 0.7 0.473 091[37] Placebo 230 41.5 (1.6) –2.3 (1.2) Cilomilast 435 42.1 (1.4) –2.7 (1.1) –0.4 0.711 657[36] Placebo 310 52.1 (0.9) –1.8 (0.6) Cilomilast 292 52.5 (0.9) –1.8 (0.6) 0.0 0.951 were higher percentages of patients who were exac- compared with placebo in all studies, but these erbation-free at 24 weeks in the cilomilast treatment improvements were not statistically or clinically group compared with the placebo group. In significant. study 042, the percentages of patients who were exacerbation-free at 24 weeks were comparable be- 3.4 Safety and Tolerability tween the groups and in studies 156 and 657; the percentage of patients who were exacerbation-free A similar percentage of patients in each group at 24 weeks was higher in the placebo group than in experienced at least one adverse event during the the cilomilast group (table XV). 24-week period (cilomilast 78%; placebo 76%). The most commonly reported adverse events are shown Dyspnoea in table XVI. Adverse events associated with the GI The mean baseline post-exercise dyspnoea score body system such as nausea, diarrhoea, abdominal for the cilomilast- and placebo-treated patients pain, dyspepsia and vomiting were reported more ranged from 3.22 to 3.80 points (modified Borg frequently in the cilomilast treatment group com- Dyspnoea scale) across the four studies in which it pared with the placebo group. The time of initial was measured. When averaged over 24 weeks, there onset for the majority of GI adverse events in pa- were small improvements in the post-exercise tients who received cilomilast was in the first dyspnoea score in the cilomilast treatment group 2 weeks of therapy. Overall, the percentage of patients experiencing Study an adverse event on therapy which led to withdrawal 039 156 657 091 042 was higher in the cilomilast group (17%) than in the 1 placebo group (10%). The most common adverse 0 events leading to withdrawal are shown in table –1 XVII. The most frequent withdrawal adverse events for cilomilast-treated patients were nausea (5%), –2 abdominal pain (4%) and diarrhoea (4%). In com- –3 parison, the most frequent withdrawal event for –4 placebo-treated patients was COPD (3%). Eleven patients had fatal adverse events in the –5 pivotal trials either during treatment or during the Cilomilast –6 post-study follow-up period. Of these, four were

Change from baseline, SGRQ total score Placebo Fig. 6. Mean (SEM) change from baseline in the total score of the treated with placebo and seven with cilomilast. In St George’s Respiratory Questionnaire (SGRQ). addition, there were nine deaths reported during the

run-in periods. All of the on-therapy fatal events were due to cardiovascular or pulmonary disease and were attributed to adverse events judged not related or unlikely to be related to study medication by the investigator. No clinically relevant differences were observed 0.01 0.02 – – between treatment groups during cardiovascular

0.12/ 0.04/0.02 0.02/0.03 0.07/ 0.00/0.02 monitoring of ECG assessments, sitting, or orthosta- – – – – – tic vital signs. The mean changes from baseline in 12-lead ECG parameters performed at trough plasma levels were small, not clinically significant and similar between groups; 24-hour Holter monitoring in a subset of patients did not reveal any concerns regarding the cardiac safety of cilomilast. The mean changes from baseline in clinical laboratory para-

0.00 0.03 meters were small and were comparable between the – – change (mL) at endpoint FVC change (mL) at endpoint 1 treatment groups. The percentage of patients with 0.07/0.01 0.04/ 0.00/0.04 0.06/ – – – – laboratory values of potential clinical concern was low and there were no clinically relevant differences between groups. There were no clinically significant

= relative risk. differences in the rates of positive faecal occult RR bloods between cilomilast- and placebo-treated patients. Overall, a total of 2.1% of placebo-treated patients and 2.8% of cilomilast-treated patients who had negative faecal occult blood results at baseline shifted to positive during double-blind treatment in free (%) these five studies.

= forced vital capacity; Laboratory observations during the phase III piv-

FVC otal trials suggested no systematic effect of treatment with cilomilast on haematology values, serum measures of liver or kidney function, glucose meta- bolism and electrolytes.

3.5 Summary • In three studies (039,[2] 156, 657), there were statistically significant improvements in FEV1 in cilomilast-treated patients relative to placebo when averaged over 24 weeks. Although the

= forced expiratory volume in 1 second; other two studies demonstrated similar improve- 1 ments in FEV1, neither achieved statistical sig- FEV Comparison; p-valueComparison; p-valueComparison; p-valueComparison; p-value RR = 0.60; p 0.004Comparison; p-value RR = 1.22; p 0.212 Diff = 0.080; p < 0.001 RR = 0.96; p 0.791 Diff = 0.040; p 0.013 Diff = 0.110, p 0.001 RR = 0.68; p 0.009 Diff = 0.040; p 0.050 Diff = 0.060, p 0.022 RR = 1.03; p 0.707 Diff = 0.030; p 0.146 Diff = 0.050, p 0.129 Diff = 0.038; p 0.018 Diff = 0.060, p 0.073 Diff = 0.027, p 0.355 Placebo/cilomilastPlacebo/cilomilast 216/431Placebo/cilomilast 407/418Placebo/cilomilast 70/82 226/474Placebo/cilomilast 80/76 242/469 71/71 316/296nificance. 64/76 69/66 0.00/0.04 [2] Treatment difference between cilomilast and placebo in secondary endpoints the individual studies • Only one study (039) demonstrated a clinically significant effect following treatment with [2] [2] [35] [38] [37] [36] = difference; cilomilast on the total score of the SGRQ. In 156 042 091 657 Table XV. Study039 Treatment group n Level 2/level 3 exacerbation- FEV Diff the other studies, the placebo groups also im-

proved to a similar extent to the cilomilast 4.2 Materials and Methods groups. [2] • Two studies (039, 091) demonstrated statisti- 4.2.1 Study Design cally significant reductions in the risk of exper- Studies 040 and 041 were phase III, multicentre, iencing at least one level 2 or 3 COPD exacerba- open-label, extension studies. Patients who complet- tion in cilomilast-treated patients relative to pla- ed the phase III pivotal studies 042[38] or 091[37] cebo. could participate in study 040 and those who com- • All studies demonstrated cilomilast-induced im- pleted the phase III pivotal study 039[2] could par- provements in FVC but only two were statistical- ticipate in study 041. Patients were assessed for ly significant. eligibility to enter the studies at their final scheduled visit of the previous trial and enrolled directly into Except for GI adverse events, cilomilast was • the extension study to receive cilomilast 15 mg relatively well tolerated. twice daily. The study blind from the previous stud- • No clinically relevant differences were observed ies was not broken. Study 040 was conducted from between treatment groups during cardiovascular June 1999 to September 2002 at 130 centres in 10 monitoring of ECG assessments, sitting, or ortho- countries (Australia, South Africa, Belgium, Fin- static vital signs and no systematic effect of treat- land, France, Germany, the Netherlands, Norway, ment with cilomilast on haematology values and Spain and the UK) and study 041 was conducted serum measures of liver or kidney function. In from June 1999 to June 2002 at 78 centres in the US, addition, there were no clinically significant dif- Mexico and Canada. ferences in the rates of positive faecal occult Details of the inclusion and exclusion criteria for bloods between cilomilast- and placebo-treated the original phase III studies have been reported patients. above (see section 3). Patients attended the clinic after 1, 2 and 4 weeks and then at 4-week intervals, which transitioned to 12-week intervals from week 4. Long-Term Tolerability and Safety of 48 until the final visit in study 040 and remained at Cilomilast in Patients with COPD 4-week intervals in study 041. Patients attended a follow-up visit 1 week after treatment was completed (up to week 156). 4.1 Study Objectives Study 157[42] was a randomized, double-blind, placebo-controlled, parallel-group study, conducted Three studies were conducted. The primary ob- from November 2001 to January 2004 at 137 centres jective of two of these was to evaluate the long-term in 18 countries. Previous data from two phase III safety and tolerability of cilomilast in patients with studies (studies 039 and 091) had demonstrated that COPD, with secondary objectives to further evalu- cilomilast significantly reduced exacerbation rates ate the efficacy of cilomilast in terms of pulmonary over 24 weeks of treatment. Study 157 was designed function and quality of life (study numbers to confirm and extend the results observed in these SB207499/040[40] and SB207499/041[41]). The pri- studies over a longer time frame and was powered mary objective of the third study was to assess the for exacerbations. clinical efficacy of cilomilast over a 52-week treat- Patients were assessed for eligibility at the ment period in patients with COPD who were poorly screening visit and were required to meet the eligi- reversible to bronchodilators by assessment of the bility criteria as stated in the pivotal study section risk of the occurrence of exacerbations of COPD (section 3). The main difference was that in study and assessment of FEV1 at trough drug concentra- 157, reversibility was defined by increases in FEV1 tions (study number SB207499/157[42]). after the administration of salbutamol 400 µg of

≤10% of the predicted normal or ≤200 mL (or both). over 52 weeks and the incidence rate of level 2 After a 4-week, single-blind, placebo run-in period, (moderate) and level 3 (severe) COPD exacerba- eligible patients were randomized in a 1 : 1 ratio to tions during treatment. COPD exacerbations, de- receive twice-daily oral treatment with either fined as a worsening of COPD symptoms requiring cilomilast 15 mg or placebo during a 52-week doub- changes to normal treatment, including anti- le-blind phase. Assignment to study drug was strati- microbial therapy, short courses of oral steroids and fied according to smoking status (current smokers, other bronchodilator therapy, were recorded former smokers). Patients attended the clinic every 2 throughout the study. COPD exacerbations were weeks from the screening visit up to week 4 of categorized as level 1, 2 or 3, based on the treatment treatment, and then at 4-weekly intervals until the received by the patient for the exacerbation. Level 1 end of 3 months. Thereafter, patients attended the (mild) was defined as an acute worsening of COPD clinic at 8-weekly intervals from weeks 12 to 52 (a that was self-managed by the patient at home by total of 13 visits). A final follow-up visit occurred at increasing usual COPD medications, level 2 (mod- week 53. erate) for those that required additional treatment The local ethics committee or institutional review (e.g. a short course of oral steroids or antibiotics board approved the study protocols at each centre prescribed by the physician) and level 3 (severe) as and all patients gave written informed consent to requiring hospitalization. participate. Secondary efficacy endpoints included health 4.2.2 Assessments status determined using the SGRQ. Safety was mea- In studies 040 and 041, safety measurements sured by the assessment of adverse events, vital included the recording of adverse events, vital signs, signs, clinical laboratory tests including faecal oc- ECGs and collection of blood and urine specimens cult bloods and ECGs. for routine haematology and biochemistry and urin- Patients were asked to refrain from taking any alysis during the study at each visit. Faecal occult respiratory medication for at least 4 hours and re- blood, orthostatic blood pressure and heart rate were frain from smoking for at least 2 hours before each measured at 24 and 48 weeks and then every 48–52 clinic visit. Pulmonary function tests were per- weeks thereafter. formed before and 30 minutes after administration As a secondary objective of these studies, effi- of salbutamol 400 µg using the same type of spirom- cacy was assessed by measuring clinic trough pul- eter at all centres. COPD exacerbations were record- monary function parameters, and health status was ed throughout the study and the SGRQ was adminis- measured using the SGRQ. Patients were asked to tered at baseline and weeks 28 and 52. refrain from taking any respiratory medication or smoking for at least 2 hours before each clinic visit. Adverse events and vital signs were recorded at Trough (predose) lung function was performed us- each visit. Blood and urine specimens were taken for ing standardized spirometry equipment supplied by routine haematology and biochemistry and urinaly- GSK at all centres. The SGRQ was administered at sis during the study at each visit except for week 2 of weeks 0, 12 and 24 and every 24 weeks thereafter, the treatment period. A 12-lead ECG was performed prior to all other scheduled procedures. Patients at baseline and at weeks 12, 28 and 52 and at the continued to use β-agonists on an as-needed basis safety follow-up visit. Faecal occult blood tests were and all other COPD medications (with the exception performed between visits 1 and 3, immediately of theophylline and aminophylline) were permitted before or after visit 11 (for those who consented for without restriction at a stable dose if possible. an additional test) and also after the final dose of In study 157, the co-primary endpoints were the double-blind medication either at visit 12 or at the change from baseline in pre-bronchodilator FEV1 early withdrawal visit. For all studies, at all visits, measured at trough drug concentrations averaged patients were assessed for compliance with the med-

Table XVI. Number (%) of patients with the most frequently report- squares means. The rate of moderate or severe (level ed adverse events (≥5% patients in either treatment group) 2 or 3) COPD exacerbations occurring during the Adverse experience Treatment group treatment period was analysed using a maximum (preferred term) placebo cilomilast (n = 1408) (n = 2088) likelihood-based analysis, assuming a Poisson dis- Total 1071 (76) 1638 (78) tribution, with total duration on treatment as an Exacerbation of COPD 399 (28) 552 (26) offset variable. Nausea 67 (5) 344 (16) The total score of SGRQ was analysed using an Diarrhoea 106 (8) 308 (15) ANOVA model with fixed effects of treatment and Abdominal pain 93 (7) 232 (11) country at each double-blind visit as well as at Upper respiratory tract infection 161 (11) 209 (10) endpoint. Headache 110 (8) 194 (9) Analyses were performed for the ITT population, Vomiting 26 (2) 138 (7) composed of all patients who received at least one Dyspepsia 32 (2) 136 (7) Injury 55 (4) 96 (5) dose of double-blind medication and had a baseline Sinusitis 64 (5) 83 (4) and at least one on-therapy efficacy assessment. Coughing 70 (5) 75 (4) COPD = chronic obstructive pulmonary disease. 4.3 Results ication by counting the number of tablets returned as 4.3.1 Baseline Characteristics; Studies 040 and 041 well as for use of concomitant medications. A total of 723 and 355 patients were enrolled into studies 040 and 041, of whom 480 had been pre- 4.2.3 Statistical Analysis viously treated with cilomilast and 243 with placebo In studies 040 and 041, the safety population in study 040, and 215 with cilomilast and 140 with included all patients who received at least one dose of cilomilast. No formal power calculations or sta- Table XVII. On-therapy adverse events leading to withdrawal in ≥5 tistical hypothesis testing were performed. Clinical patients in either treatment group laboratory parameters, vital signs, ECGs of interest Adverse experience Treatment group [no. (%)] and efficacy endpoints were evaluated with descrip- (preferred term) placebo cilomilast (n = 1408) (n = 2088) tive statistics. Total 143 (10) 359 (17) In study 157, the planned sample size was 800 Nausea 6 (<1) 110 (5) patients to obtain 550 completed patients, which Abdominal pain 8 (<1) 82 (4) was estimated to have a >90% power to detect a Diarrhoea 7 (<1) 75 (4) difference of 50 mL in FEV1 assuming a standard Exacerbation of COPD 42 (3) 43 (2) deviation of 210 mL in the change from baseline, Vomiting 4 (<1) 34 (2) and a 30% reduction in exacerbation rate, assuming Dyspepsia 1 (<1) 18 (<1) an incidence of 0.8 exacerbations per patient per Headache 1 (<1) 17 (<1) year for the placebo group. Dizziness 4 (<1) 16 (<1) The primary assessment of treatment differences Anorexia 0 11 (<1) Flatulence 1 (<1) 9 (<1) for mean change from baseline in FEV1 (pre- Melena 1 (<1) 7 (<1) bronchodilator) averaged over 52 weeks was based Asthenia 2 (<1) 6 (<1) on a repeated measures model with fixed effects of Fatigue 0 5 (<1) treatment, time and country. A compound symmet- Malaise 1 (<1) 5 (<1) ric correlation structure was used. Least squares Myocardial infarction 4 (<1) 5 (<1) means along with 95% confidence intervals were Dyspnoea 5 (<1) 5 (<1) calculated for each treatment group and for the Pneumonia 5 (<1) 4 (<1) treatment difference. Differences between treatment Cardiac failure 6 (<1) 2 (<1) groups were assessed using t-tests on the least COPD = chronic obstructive pulmonary disease.

placebo in study 041 (table XVIII). During the study period, mean compliance with study medication was 95% and 89% in study 040 and 041, respectively.

4.3.2 Baseline Characteristics; Study 157 A total of 907 patients were randomized to receive either cilomilast (n = 455) or placebo (n = 452). Overall, the patients were representative of a moderate to severe COPD population (table XIX). More patients receiving cilomilast than placebo withdrew from the double-blind phase of the study (167 [37%] vs 121 [27%]), the main reason for withdrawal being an adverse event (80 [18%] cilomilast; 46 [10%] placebo). The use of [41] salbutamol was similar in both treatment groups

(97% for both groups) and a similar number of Study 041 patients (51% for placebo and 46% for cilomilast) continued with a stable dose of ipratropium bromide during the study. ICS (including fluticasone pro-

pionate and budesonide) stopped at study entry was = forced vital capacity, taken by 34% and 41%, respectively, of placebo and FVC cilomilast patients; 96% of placebo-treated patients and 94% of cilomilast-treated patients were at least 80% compliant with their study medication during the double-blind treatment period.

4.4 Safety and Tolerability Measurements

4.4.1 Adverse Events

In study 040, 62% of patients received treatment [40] for at least 108 weeks and 20% for at least 136 = forced expiratory volume in 1 second;

weeks. For study 041, 49% received treatment for at 1 prior placebo(n = 243) prior cilomilast total (n = 480) (n = 723) prior placebo (n = 140) prior cilomilast total (n = 215) (n = 355) least 108 weeks and 17% for at least 136 weeks. FEV Adverse events were reported by 677 patients (94%) in study 040 and by 333 (94%) in study 041. The most frequently reported adverse event during both studies was an exacerbation of COPD (table XX). GI adverse events occurred at a higher percentage in patients who had previously taken placebo, as this was the first time they had received cilomilast.

In study 157, a similar number of patients in each [mean (SD)] 49.4 (11.2) 50.1 (11.3) 49.8 (11.3) 50.9 (12.4) 48.0 (12.8) 49.2 (12.7) b 1 [mean (SD)] 0.54 (0.10) 0.55 (0.10) 0.55 (0.10) 0.51 (0.11) 0.51 (0.11) 0.51 (0.11) group experienced at least one adverse event during a the 24-week period (cilomilast 77%; placebo 76%). Baseline characteristics and demographics of the long-term safety studies (studies 040 041) The most commonly reported adverse events are = chronic obstructive pulmonary disease; (L) [mean (SD)] 1.50 (0.44) 1.53 (0.45) 1.52 (0.44) 1.53 (0.59) 1.35 (0.46) 1.42 (0.53) a /FVC ratio (L) [mean (SD)] 2.88 (0.80) 2.87 (0.78) 2.87 (0.78) 3.10 (1.06) 2.75 (0.76) 2.89 (0.90) a shown in table XXI. Adverse events associated with 1 1 Reversibility (%) [mean (SD)]FEV 4.9 (8.6) 4.8 (8.7) 4.8 (8.7) 7.3 (6.9) 7.5 (6.9) 7.4 (6.9) % Predicted FEV FVC the GI body system were reported more frequently Table XVIII. CharacteristicSex, male [no. (%)]Age (y) [mean (SD)]Race, Caucasian [no. (%)]Smoking history (pack-years) [mean (SD)]Current smoker [no. (%)]Years since COPD diagnosis [mean (SD)] 43.7 (22.2)FEV 8.5 (8.4) Study 040 44.8 (23.0) 205 (84) 238 (98) 63.3 (9.1)a 8.7 (8.4) 44.4 (22.7) 100 (41) Pre-salbutamol inhalation. b 404 (84) 474 (99) Post-salbutamol inhalation. 62.6 (8.9)COPD 56.6 (29.8) 8.7 (8.4) 214 (45) 609 (84) 712 (98) 62.9 (9.0) 62.5 (33.9) 7.1 (7.0) 314 (43) 65.3 (8.2) 100 (71) 136 (97) 60.2 (32.4) 7.3 (6.8) 69 (49) 65.3 (8.9) 130 (60) 196 (91) 7.2 (6.9) 65.3 (8.6) 95 (44) 230 (65) 332 (94) 164 (46)

Table XIX. Baseline characteristics and demographics of the 52-week maintenance study (study 157)[42] Characteristic Placebo (n = 452) Cilomilast (n = 455) Sex, male [no. (%)] 330 (73) 357 (78) Age (y) [mean (SD)] 63.3 (8.9) 64.6 (8.7) Race, Caucasian [no. (%)] 433 (96) 436 (96) Smoking history (pack-years) [mean (SD)] 43.8 (27.3) 44.8 (26.0) Current smoker [no. (%)] 188 (42) 196 (43) Years since COPD diagnosis [mean (SD)] 7.8 (7.4) 7.9 (7.4)

FEV1a (L) [mean (SD)] 1.42 (0.4) 1.36 (0.4) % Predicted FEV1b [mean (SD)] 52.7 (11.1) 50.4 (12.2) Reversibility (%) [mean (SD)] 5.6 (8.0) 5.6 (8.2)

FEV1/FVC ratioa [mean (SD)] 0.50 (0.1) 0.49 (0.1) FVCa (L) [mean (SD)] 2.86 (0.8) 2.78 (0.8) a Pre-salbutamol inhalation. b Post-salbutamol inhalation.

COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity. in the cilomilast treatment group (28%) than in the considered by the investigator to be related to study placebo group (15%). The time of initial onset for medication. the majority of GI adverse events in patients who In study 157 there were 12 deaths after received cilomilast was in the first 2 weeks of ther- randomization, eight in the placebo group and four apy. in the cilomilast group, all of which were assessed as unlikely to be related to or unrelated to study med- 4.4.2 Deaths ication. A total of 24 patients died during study 040. Fifteen deaths occurred while the patients were re- 4.4.3 Withdrawals ceiving study medication and nine occurred in the In study 040 and 041, 196 patients (18%) were post-treatment period. A total of seven patients died withdrawn because of on-therapy adverse events during study 041; five of the deaths occurred while (table XXII). As this was the first exposure to on study medication and two during the post-treat- cilomilast for the prior placebo group, withdrawals ment period. None of the deaths in either study was due to adverse events of the GI system were more

Table XX. Number (%) of patients with the most frequently reported adverse events (≥10% patients in any group) in long-term safety studies 040[40] and 041[41] Adverse event Studies 040 and 041 prior placebo (n = 383) prior cilomilast (n = 695) total (n = 1078) Total 359 (94) 651 (94) 1010 (94) Exacerbation of COPD 212 (55) 457 (66) 669 (62) Upper respiratory tract infection 60 (16) 133 (19) 193 (18) Diarrhoea 89 (23) 95 (14) 184 (17) Abdominal pain 79 (21) 100 (14) 179 (17) Injury 46 (12) 106 (15) 152 (14) Nausea 71 (19) 69 (10) 140 (13) Back pain 35 (9) 87 (13) 122 (11) Headache 55 (14) 67 (10) 122 (11) Rhinitis 45 (12) 76 (11) 121 (11) Dyspepsia 52 (14) 65 (9) 117 (11) COPD = chronic obstructive pulmonary disease.

Table XXI. Most frequently reported on-therapy adverse experi- Mean changes from baseline in ECG parameters ences in ≥5% of patients in either treatment group in study 157[42] were small. Transitions to high or low values for Adverse event Placebo Cilomilast (n = 452) (n = 455) ECG parameters at any one point during studies [no. (%)] [no. (%)] were not uncommon owing to the length of the Totala 343 (76) 351 (77) studies, and overall, intensive 12-lead ECG moni- Exacerbation of COPD 209 (46) 191 (42) toring did not raise any concerns about the cardiac Nausea 14 (3) 44 (10) safety of cilomilast. Nasopharyngitis 54 (12) 43 (9) In study 157, there were no clinically relevant Headache 22 (5) 35 (8) differences observed between treatment groups Diarrhoea 13 (3) 33 (7) during cardiovascular monitoring of ECG assess- Vomiting 8 (2) 21 (5) a Total number of patients who experienced at least one ments, sitting, or orthostatic vital signs. adverse event. COPD = chronic obstructive pulmonary disease. 4.5 Efficacy Evaluations frequent in the prior placebo group (13%) compared 4.5.1 COPD Exacerbations with the prior cilomilast group (4%). In study 157, there was no significant difference between the treatment groups over 52 weeks of In study 157, overall, the percentage of patients treatment in the rate of level 2/level 3 COPD exacer- experiencing an adverse event on therapy which led bations. The rate per patient-year in the placebo to withdrawal was higher in the cilomilast group group was 0.448 compared with 0.483 in the cilomi- (17%) than the placebo group (9%). The most com- last group (p = 0.580). At the end of 52 weeks, the mon adverse events leading to withdrawal for percentage of patients who were level 2/level 3 cilomilast-treated patients were nausea (4%), exac- exacerbation free was comparable, with 68% of erbation of COPD (3%) and diarrhoea (2%). In cilomilast-treated patients and 70% of placebo-treat- comparison, the most frequent adverse event leading ed patients exacerbation free (p = 0.637). This was to withdrawal for placebo-treated patients was an similar for all levels of exacerbations, with 51% exacerbation of COPD (4%) [table XXIII].

Table XXII. On-therapy adverse events leading to withdrawal of ≥4 4.4.4 Laboratory Safety and Vital Signs patients in studies 040[40] and 041[41] In studies 040 and 041 the mean change from Adverse event Studies 040 and 041 [no. (%)] baseline in clinical laboratory parameters was small prior prior total placebo cilomilast (n = 1078) and was comparable between the treatment groups. (n = 383) (n = 695) No trend for a treatment-related effect on any para- Totala 95 (25) 101 (15) 196 (18) meter was seen. Only small changes from baseline Abdominal pain 23 (6) 13 (2) 36 (3) were seen in vital signs throughout the studies. At Nausea 21 (5) 4 (<1) 25 (2) endpoint in study 040, the mean change from base- Diarrhoea 16 (4) 6 (<1) 22 (2) line in systolic and diastolic blood pressure for prior Exacerbation of COPD 7 (2) 14 (2) 21 (2) cilomilast patients was –2.3 ± 17.0 and –2.2 ± Pulmonary carcinoma 2 (<1) 10 (1) 12 (1) 10.2 mmHg, respectively, compared with –1.1 ± Vomiting 9 (2) 2 (<1) 11 (1) Pneumonia 3 (<1) 4 (<1) 7 (<1) 15.6 and –0.9 ± 9.6 mmHg for prior placebo pa- Myocardial infarction 3 (<1) 3 (<1) 6 (<1) tients. In study 041, the mean change from baseline Headache 3 (<1) 2 (<1) 5 (<1) in systolic blood pressure in the prior placebo group Cardiac failure 2 (<1) 2 (<1) 4 (<1) was –0.7 ± 18.4 mmHg compared with –2.2 ± Dyspepsia 3 (<1) 1 (<1) 4 (<1) 16.7 mmHg in the prior cilomilast group and for a Total number of patients who experienced at least one diastolic blood pressure was –1.3 ± 10.3 and –2.7 ± adverse event. 10.8 mmHg, respectively. COPD = chronic obstructive pulmonary disease.

Table XXIII. On-therapy adverse events leading to withdrawal of ≥3 Health Status [42] patients in either treatment group in study 157 When averaged over 52 weeks, there was an Adverse event Placebo Cilomilast improvement of 1.3 units in the mean total score of (n = 452) (n = 455) [no. (%)] [no. (%)] the SGRQ in patients receiving cilomilast compared Total 40 (9) 75 (17) with an improvement of 1.5 units in the placebo Exacerbation of COPD 17 (4) 12 (3) group (p = 0.835) in study 157. Nausea 1 (<1) 16 (3) In study 040, at endpoint there were decreases Diarrhoea 2 (<1) 11 (2) (improvement) in the SGRQ total score of –6.6 units Vomiting 0 7 (1) for the prior placebo group and –6.2 units for the Abdominal pain 0 5 (1) prior cilomilast group from baseline (start of feeder Dyspepsia 0 5 (1) study) [figure 9]. In study 041, at endpoint there Upper abdominal pain 0 4 (<1) were decreases in the SGRQ total score of –1.4 units Dizziness 0 4 (<1) – Headache 1 (<1) 3 (<1) for the prior placebo group and 4.0 units for the Anorexia 0 3 (<1) prior cilomilast group from baseline (figure 9). Exacerbation of dyspnoea 0 3 (<1) COPD = chronic obstructive pulmonary disease. 4.6 Summary remaining exacerbation free in both treatment • Long-term treatment with cilomilast 15 mg twice groups (p = 0.952). daily was well tolerated with no new safety issues being identified. There was no evidence of any 4.5.2 Lung Function adverse effects of long-term drug administration on vital signs, ECG or laboratory variables in all Trough FEV1 studies. In study 157, when averaged over 52 weeks, the • In study 157, treatment with cilomilast 15 mg mean change from baseline in trough pre- twice daily provided improvement in a range of bronchodilator FEV1 in patients receiving cilomilast spirometric parameters. Change from placebo in showed improvement compared with placebo with a FEV1 both before and after bronchodilator (at mean difference between the groups of 41 mL trough plasma levels) reached levels of statistical (p < 0.001). The mean change from baseline in significance when averaged over 52 weeks. FEV1 over time is presented graphically in figure 7. • In study 157, no significant difference was seen At endpoint, there was a statistically significant between cilomilast and placebo in any of the difference in the change from baseline of 46 mL parameters used to measure exacerbations. between the cilomilast and placebo groups (p = 0.002). 100 Cilomilast 75 Placebo In studies 040 and 041, patients who switched 50 (mL) from placebo to cilomilast at the start of both studies 1 25 showed initial improvements in lung function. How- 0 ever, at endpoint, FEV1 had decreased by a mean of –25 –50 90 mL in the prior placebo group and by 80 mL in trough FEV the prior cilomilast group compared with baseline Mean change from BL, –75 values of the feeder studies in study 040 (figure 8). –100 In study 041, a mean decrease of 110 mL from BL 4 8 12 20 28 36 44 52 EP Avg52 Week baseline was seen in the prior placebo group com- Fig. 7. Mean change from baseline (BL) in trough forced expiratory pared with 40 mL in the prior cilomilast group (fig- volume in 1 second (FEV1), study 157.[42] Avg52 = average over 52 ure 8). weeks; EP = endpoint.

a 5.2 Methods 1.6 Cilomilast/cilomilast Placebo/cilomilast 5.2.1 Patients

(L) 1.5 1 Study SB207499/168 (168)[43] was a 12-week study in which patients (aged 40–80 years) were 1.4 recruited from 42 centres in the US from July 2001 to August 2002. To be eligible for enrolment pa- 1.3 tients had to meet the following criteria: a clinical Mean trough FEV diagnosis of COPD, a pre-salbutamol FEV1 to FVC 1.2 ratio of ≤0.7 and a post-salbutamol FEV1 between BL 8 16 24 48 72 96 120 144 EP ≥30% and ≤70% of predicted normal, and ≥10 pack- Week year history of smoking. The study excluded pa- b tients with a primary diagnosis of asthma, poorly 1.6 controlled COPD, α1-antitrypsin deficiency, active

(L) pulmonary disease (other than COPD), lung volume

1 1.5 reduction surgery within the previous 12 months, clinically significant GI conditions and uncontrolled 1.4 disorders of major body systems. This study was the

1.3 a Mean trough FEV 50 Cilomilast/cilomilast 1.2 Placebo/cilomilast BL 8 16 24 48 72 96 120 144 EP 45 Week

Fig. 8. Trough forced expiratory volume in 1 second (FEV1) in study 40 040[40] (a) and study 041[41] (b). (a) BL = baseline from feeder studies (091[37] or 042[38]); EP = last observation from study 040. (b) [2] BL = baseline from feeder study (039); EP = last observation from 35 study 041. SGRQ total score

30 5. Cardiovascular Safety and Tolerability BL 8 16 24 48 72 96 120 144 EP of Cilomilast Week b 5.1 Study Objective 50

Two studies were conducted to primarily exam- 45 ine the cardiac safety of cilomilast versus placebo through the assessment of 24-hour Holter ECG 40 monitoring and standard ECGs. Other objectives were to further define the clinical safety and tolera-

SGRQ total score 35 bility of cilomilast versus placebo through the assessment of adverse events, vital signs and clinical 30 laboratory tests and to evaluate the efficacy of BL 8 16 24 48 72 96 120 144 EP cilomilast. Week Fig. 9. St George’s Respiratory Questionnaire (SGRQ total score, study 040[40] (a) and study 041[41] (b). (a) BL = baseline from feeder studies (091[37] or 042[38]); EP = last observation from study 040. (b) BL = baseline from feeder study (039);[2] EP = last observation from study 041.

first study to evaluate the efficacy of cilomilast The primary objective of the study was to evalu- without regard to bronchodilator response. Prior ate the cardiac safety of cilomilast via 24-hour studies with cilomilast excluded patients who dem- Holter monitoring which was measured at baseline onstrated a bronchodilator response to salbutamol and at day 6 and week 12 of treatment. Additional (i.e. change in FEV1 ≥15% and ≥200 mL). safety variables evaluated included adverse events, Study SB207499/125 (125)[44] was a 12-week vital signs, standard ECGs and clinical laboratory study designed to assess the safety of cilomilast in tests including faecal occult blood tests. Trough combination with salmeterol/fluticasone propionate FEV1 was measured at all visits except day 6. combination 50/250 µg (SFC). Patients (aged Study 125 was a multicentre, randomized, doub- ≥40 years) were recruited from 41 centres in the US le-blind, placebo-controlled study. Patients were from December 2002 to January 2004. The entry treated as outpatients with a minimum of 6 visits criteria were the same as for study 168 except that a (i.e. screening, treatment day 1, treatment weeks 2, 6 smoking history of least 20 pack-years (ex-smokers and 12 and 1 week post-treatment) over a period of were required to have quit smoking at least 6 months approximately 17 weeks. There was a 4-week open- prior to screening) was required. label run-in period during which all patients re- µ The protocols were approved by an institutional ceived SFC 50/250 g twice daily. At the end of the review board at all sites and all patients provided 4-week open-label run-in phase, patients were ran- µ written informed consent prior to any study proce- domized to receive SFC 50/250 g twice daily plus dures. cilomilast or placebo for 12 weeks. During the first 2 weeks of treatment, cilomilast 15 mg or placebo were administered once daily after which dosing 5.2.2 Study Design switched to twice daily. Study 168 was a multicentre, randomized, double-blind, placebo-controlled, parallel-group study Holter monitoring was measured at baseline and consisting of a 4-week single-blind placebo run-in week 12 of treatment. Adverse events and vital signs period and 12 weeks of active treatment with a were measured at all clinic visits. Spirometry and 1-week safety follow-up visit. Patients were re- plethysmography were measured at baseline, at quired to attend the clinic ten times over the week 6 and week 12. Additional safety variables 17-week study period with visits at day 6, day 7, evaluated included laboratory tests, including faecal week 4, week 8 and week 12 during treatment and a occult bloods. A 12-lead ECG was measured at follow-up visit 1 week after completion. A visit was screening and predose at week 12. also scheduled 1 day prior to week 12 for Holter assessment (day 83). At the end of the 4-week run-in 5.2.3 Statistical Methods phase patients were randomized in a ratio of 2 : 1 to For study 168, descriptive statistics for Holter receive cilomilast 15 mg twice daily or placebo for monitoring parameters during the first 6 and 12 weeks. Assignment to study drug was stratified 24 hours of monitoring were provided for visit 2 by reversibility to salbutamol at baseline. Reversible (baseline), visit 3 (day 7) and visit 6 (week 12). patients had an absolute volume increase in FEV1 of Cardiac events captured on Holter monitoring were >200 mL and >15% increase in FEV1 after adminis- classified into one of the following categories: atrio- tration of salbutamol 180 µg via metered dose inhal- ventricular block, supraventricular arrhythmia, or er with a spacer compared with their pre-salbutamol ventricular arrhythmia. The incidence of these baseline. All COPD medications except salbutamol events for each treatment arm was tabulated over the or ipratropium via metered dose inhaler and duration of the 12-week double-blind period. Evalu- mucolytics were withdrawn prior to or at the screen- ation of safety data was included for all randomized ing visit and were not allowed during the treatment patients. Differences between groups in the change period. from baseline to endpoint for FEV1 were evaluated

using an ANOVA model with effects for centre and treatment. For study 125, the proposed sample size was to provide 90% power to demonstrate equivalence between SFC/cilomilast and SFC/placebo using a 95% confidence interval and equivalence bounds of ±5 bpm, assuming that the true difference was no larger than ±2 bpm. Mean 24-hour heart rate and maximum and minimum heart rates were summarized and analysed using ANCOVA with covariates [44] of baseline heart rate, gender, age, investigator and treatment. Treatment difference in the change from baseline trough FEV1 was analysed using Study 125 ANCOVA, adjusted for baseline, investigator, gender, age and treatment. Both studies were, however, safety studies and not powered on FEV1.

5.3 Results

5.3.1 Study Population In study 168, a total of 428 patients were enrolled of which 282 (66%) were randomized to receive placebo (n = 94) or cilomilast (n = 188). A protocol- defined stopping point was identified for this study, [43] after which an additional 24 patients completed. The

additional data did not identify any new safety con- placebo (n = 94) cilomilast (n = 188) placebo/SFC (n =164) cilomilast/SFC (n = 162) cerns. At baseline, the two treatment groups were well matched for demographic and baseline characteristics of COPD and represented a moderate COPD population (table XXIV). Baseline characteristics between reversible and non-reversible patients were also similar between treatment groups. More patients receiving cilomilast than placebo withdrew from the double-blind phase of the study (30%, n = 57 vs 14%, n = 13). In study 125, 396 patients entered the open-label phase of the trial and 326 were randomized (162 to

the SFC/cilomilast group and 164 to the SFC/place- [mean (SD)] 52.8 (11.3) 51.7 (12.6) 47.5 (12.3) 48.0 (11.8) b bo group). Patient demographics were similar be- 1 tween treatment groups and are summarized in table Summary of demographic characteristics at screening (all randomized patients) [mean (SD)] 1.44 (0.48) 1.45 (0.50) 1.38 (0.44) 1.41 (0.51) XXIV. More patients receiving cilomilast/SFC (42 a (L)

[26%]) than placebo/SFC (20 [12%]) withdrew 1 Baseline reversibility (%) [mean (SD)] 15.9 (14.0) 16.3 (14.8) 14.5 (16.6) 14.5 (15.1) % Predicted FEV from the double-blind phase of the study. Table XXIV. CharacteristicSex, male [no. (%)]Race, Caucasian [no. (%)]Age (y) [mean (SD)]Current smoker [no. (%)]Smoking history (pack-years) [mean (SD)]Years since COPD diagnosis [mean (SD)]FEV a 50.3 (28.2) 86 (91) Pre-salbutamol inhalation. Study 168 59 (63)b 5.4 (5.2) Post-salbutamol inhalation. 64.9 (9.4) 36 (38) 58.8 (28.9) 177 (94) 5.4 (6.4) 133 (71) 63.7 (8.5) 96 (51) 55.5 (27.7) 140 (85) 7.8 (7.4) 87 (53) 63.9 (9.0) 56.7 (24.9) 71 (43) 135 (83) 8.0 (7.1) 87 (54) 62.6 (9.4) 85 (52)

Table XXV. Incidence of on-therapy new-onset cardiac events in Holter monitor (0–24 hours) parameters Cardiac event Treatment Treatment group (168[43]) Treatment group (125[44]) not present at new onset not present at new onset baseline (no.)a [no. (%)]b baseline (no.)a [no. (%)]b Atrial fibrillation Placebo 88 0 139 0 Cilomilast 168 1 (<1) 118 1 (<1) First-degree AV block Placebo 84 4 (5) 136 1 (<1) Cilomilast 165 4 (2) 116 1 (<1) Mobitz type I Placebo 88 0 Not measured Cilomilast 167 1 (<1) Second-degree AV block Placebo 88 2 (2) 139 2 (1) Cilomilast 167 1 (<1) 114 1 (<1) Mobitz type II Placebo 88 2 (2) Not measured Cilomilast 170 1 (<1) Sinus bradycardia Placebo 62 8 (13) 108 12 (11) Cilomilast 123 20 (16) 103 14 (14) Sinus pause Placebo 86 5 (6) 138 0 Cilomilast 162 1 (<1) 114 4 (4) Supraventricular tachycardia Placebo 41 20 (49) 139 0 Cilomilast 88 36 (41) 118 0 Nonsustained ventricular tachycardiac Placebo 84 8 (10) 136 1 (<1) Cilomilast 162 14 (9) 115 5 (4) a The total number of patients with a baseline measurement and at least one on-therapy measurement. b The total number of patients with no event at baseline and an event at week 6. c No new onset of sustained ventricular tachycardia occurred in either study. AV = atrioventricular.

5.3.2 Holter Monitoring tients had a mean of 80.9 bpm (SE 0.8 bpm). The Holter monitoring confirmed there were no clini- change from baseline at week 6 was 0.8 bpm for cally important differences between treatment cilomilast and 0.1 bpm for placebo. Clinical equiva- groups. In study 168, the most common new-onset lence was demonstrated, as the 95% confidence cardiac event was supraventricular tachycardia interval for the difference in mean 24-hour Holter (49% of placebo-treated vs 41% of cilomilast-treat- heart rate was (–1.1 bpm, 2.5 bpm), which fell with- ed patients) and in study 125 was sinus bradycardia in the prespecified equivalence bounds of ±5 bpm. (11% placebo/SFC vs 14% cilomilast/SFC) [table No clinically relevant differences between treatment XXV]. Week 12 Holter results were similar to week groups for minimum, maximum or mean heart rate, 1 results. In study 168, no clinically important dif- cardiac events or event-based ECG parameters were ferences between placebo-treated and cilomilast- observed in study 125. treated patients were seen in change from baseline to Holter data were also measured in other studies week 12 for minimum, maximum or average heart including three pivotal studies (039, 042 and 091) rate. Seven placebo-treated patients and nine cilomi- [see section 3 for relevant study information]. Data last-treated patients had episodes of non-sustained from these studies have been integrated with study ventricular tachycardia (≥3 beats and <30 seconds 168 and are found in table XXVII. with rate ≥100 bpm) at week 12 (table XXVI). In study 125, the primary safety endpoint was 5.3.3 Electrocardiograms mean 24-hour Holter monitoring heart rate. At base- There were small changes in trough and maxi- line, cilomilast-treated patients had a mean of mum concentration (Cmax) ECGs from baseline in 82.2 bpm (SE 0.8 bpm) and the placebo-treated pa- both treatment groups, and no clinically relevant

differences in trough ECGs were noted between treatments in both studies. Overall, the percentages of patients with specific new-onset ECG abnormalities were comparable between treatment groups. No safety concerns for cilomilast were noted with regard to QT interval and no differences were noted between Cmax ECGs at day 1 and week 12. Data from study 168 for corrected QT (QTc) values are shown in table XXVIII.

[43] 5.4 Other Safety Results

The percentages of patients who reported at least one adverse event were comparable between the two treatment groups, with overall incidences of 72% in the placebo and 68% in the cilomilast treatment group in study 168 and 66% in the placebo/SFC group versus 67% in the cilomilast/SFC group in study 125. The most commonly occurring events are shown in table XXIX. GI adverse events were reported more frequently in cilomilast-treated patients (35% vs 22% for placebo), which were primarily mild to moderate in intensity and occurred predominantly early in treatment. A total of 7 (7%) placebo-treated patients and 32 (17%) cilomilast-treated patients were withdrawn from study 168 because of an on-therapy adverse event (table XXX). The most frequent reasons for withdrawal for cilomilast-treated patients were diarrhoea (6%), nausea (4%) and abdominal pain (4%). In study 125, 3 (2%) placebo/SFC treated patients placebon mean (SD) n cilomilast mean (SD) n placebo mean (SD)and n 31 (19%) cilomilast mean (SD) cilomilast/SFC-treated patients were withdrawn because of an on-therapy adverse event. The most frequent reasons for withdrawal for cilomilast/SFC-treated patients were nausea (10%) and abdominal pain (3%) [table XXX]. In study 125, one patient receiving cilomilast/ SFC died during treatment because of a pneumotho- rax which was considered by the investigator as unrelated to study medication. No deaths occurred in study 168. Summary statistics for Holter monitor (0–24 hours) parameters post-study medication; intent-to-treat patients, study 168 No differences between treatment groups were observed in vital signs, orthostatic vital signs, laboratory values or other clinical assessments in either

Table XXVI. ParameterEpisodes of ventricular tachycardiaMaximum heart rate during ventricular tachycardia 5Maximum heart rate during supraventriculartachycardia 150.2 (28.6)Ventricular ectopics per 1000 beats 5 51Supraventricular ectopics per 1000 beats 1.2 (0.5) 8.9 (22.4) 10Episodes of sinus pause Baseline 132.9 (17.3)Episodes of sinus bradycardia 93 93Episodes of atrial fibrillation 90 10 5.2 (14.7) 8.9 (28.7)Episodes of atrial flutter 7 17.0 (106.0) 1.9 (2.2)study. 149.7 (16.7) 188 188 28 42 2 7.8 (29.7) 6.1 (24.2) 9 7 104.8 (226.8) 144.3 (25.7) 2.5 (2.1) 0 139.0 (39.6) 1.9 (1.9) 0 51 54 81 0 81 107.6 (164.0) 141.8 (26.6) 9 5.6 (14.8) 9.5 (22.3) 0 9 62.4 (121.6) Week 12 22 3.4 (5.0) 132 132 2 84.5 (123.4) 7.1 (32.1) 5.8 (18.1) 5 1.0 (0.0) 2 35 2.8 (2.5) 1.0 (0.0) 70 (150.8) 0 1 0 0 18.0 (0) 0 1 1.0 1 1.0

Table XXVII. Incidence of treatment-emergent new-onset cardiac events based on 24-hour Holter monitoring in studies 168,[43] 039,[2] 042[38] and 091[37] Event Onset Not present New onset Odds 95% CI pre-therapy no. %b ratioc (no.)a AIVR/IVR Placebo 141 3 2.1 Cilomilast 269 9 3.3 1.592 0.424, 5.978 Atrial fibrillation Placebo 142 0 0 Cilomilast 280 2 0.7 Atrial flutter Placebo 143 0 0 Cilomilast 281 1 0.4 First-degree AV block Placebo 139 5 3.6 Cilomilast 275 6 2.2 0.598 0.179, 1.994 Mobitz type I second-degree AV block Placebo 142 0 0 Cilomilast 279 2 0.7 Mobitz type II second-degree AV block Placebo 143 2 1.4 Cilomilast 283 1 0.4 0.250 0.022, 2.781 Sinus bradycardia Placebo 98 12 12.2 Cilomilast 192 29 15.1 1.319 0.643, 2.706 Sinus pause Placebo 140 6 4.3 Cilomilast 273 4 1.5 0.332 0.092, 1.197 Supraventricular tachycardia Placebo 62 29 46.8 Cilomilast 143 65 45.5 0.950 0.518, 1.741 Ventricular tachycardia Placebo 132 11 8.3 Cilomilast 263 23 8.7 1.054 0.497, 2.234 a Total number of patients with at least one on-therapy Holter monitor. b Percentages for each finding are based on the number of patients with specific finding absent pre-therapy. c Odds ratio is based on cilomilast divided by placebo. AIVR = accelerated idioventricular rhythm; AV = atrioventricular; IVR = idioventricular rhythm.

In both studies, the majority of patients had nega- 130 mL improvement in FEV1 compared with pla- tive faecal occult blood tests at all visits. In study cebo (n = 39), and non-reversible cilomilast patients 168, 1 of 74 patients who received placebo and 2 of (n = 105) demonstrated a 30 mL difference in FEV1 136 patients who received cilomilast had negative compared with placebo (n = 51) [figure 10]. baseline faecal occult blood tests and a positive test In study 125, there was no statistically significant during double-blind treatment. In study 125, a total difference between treatment groups in the mean of five patients treated with SFC/placebo and six change from baseline in predose FEV1 at week 12 patients treated with SFC/cilomilast had positive (0 mL for cilomilast/SFC vs –30 mL for SFC/place- faecal occult bloods during the study. bo; p = 0.196). For reversible patients, there was no difference between cilomilast (n = 41) and placebo 5.5 Efficacy Results patients (n = 49), and a 50 mL difference between treatment groups among non-reversible patients In study 168, there was a difference of 60 mL in (p = 0.183). the change from baseline at endpoint in trough FEV1 between the treatment groups (cilomilast 30 mL; 5.6 Summary placebo –30 mL; p = 0.072). Reversible patients treated with cilomilast had greater improvements in • The safety of cilomilast was extensively assessed FEV1 than non-reversible patients. Reversible in these two studies and no clinically relevant cilomilast-treated patients (n = 69) demonstrated a differences were identified in Holter monitoring,

Table XXVIII. Summary of mean change in 12-lead corrected QT (QTc) values at trough and peak (Cmax) concentrations (day 1 and week 12) in study 168[43] Parameter Placebo Cilomilast no. of patients mean (SD) no. of patients mean (SD) Trough

QTc (msec)a Baselineb 93 419.7 (17.8) 187 420.2 (19.9) Week 12 73 421.2 (17.4) 126 419.3 (19.7) Changec 73 1.7 (15.2) 126 0.7 (16.9)

Cmax: day 1 QTc (msec)a Baselineb 93 419.7 (17.8) 187 420.2 (19.9)

Cmax, day 1 88 423.0 (18.9) 172 422.2 (22.6) Change from baselinec 88 2.5 (13.5) 172 2.6 (16.5)

Cmax: Week 12 QTc (msec)a Baselineb 93 419.7 (17.8) 187 420.2 (19.9)

Cmax, week 12 71 423.7 (19.3) 120 421.3 (19.6) Change from baselinec 71 4.2 (16.5) 120 2.5 (17.6) a QT corrected by Bazett’s formula. b Includes all patients evaluated at baseline. c Change is reported for patients with both baseline and Cmax assessments.

vital signs or laboratory results including faecal • The patients included in these studies were not occult bloods. In addition, extensive cardiac screened specifically for cardiac disease, except monitoring confirmed the absence of cardio- that patients with uncontrolled disease of any vascular safety concerns with the addition of major organ system were excluded. The safety cilomilast to SFC. profile of cilomilast in patients with significant

Table XXIX. Summary of most frequently reported (≥5% of patients in any treatment group) on-therapy adverse events Adverse event (preferred term) Study 168[43] [no. (%)] Study 125[44] [no. (%)] placebo (n = 94) cilomilast (n = 188) placebo/SFC (n =164) cilomilast/SFC (n = 162) Total 68 (72) 128 (68) 109 (66) 109 (67) Exacerbation of COPD 17 (18) 28 (15) 1 (<1) 1 (<1) Diarrhoea 7 (7) 26 (14) 10 (6) 12 (7) Nausea 2 (2) 25 (13) 7 (4) 32 (20) Abdominal pain 6 (6) 18 (10) 2 (1) 5 (3) Upper respiratory tract infection 17 (18) 18 (10) 4 (2) 2 (1) Dyspepsia 6 (6) 15 (8) 3 (2) 7 (4) Vomiting 1 (1) 9 (5) 3 (2) 7 (4) Headache 4 (4) 8 (4) 26 (16) 29 (18) Rhinitis 5 (5) 5 (3) 1 (<1) 3 (2) Injury 7 (7) 3 (2) 0 0 Nasopharyngitis 3 (3) 3 (2) 13 (8) 8 (5) Back pain 3 (3) 2 (1) 10 (6) 7 (4) Pharyngolaryngeal pain 0 0 13 (8) 6 (4) Constipation 3 (3) 4 (2) 9 (5) 6 (4) COPD = chronic obstructive pulmonary disease; SFC = salmeterol/fluticasone propionate.

Table XXX. On-therapy adverse events leading to withdrawal of ≥2 patients in either treatment group of studies 168[43] and 125[44] Adverse event (preferred term) Study 168 [no. (%)] Study 125 [no. (%)] placebo (n = 94) cilomilast (n = 188) placebo/SFC (n =164) cilomilast/SFC (n = 162) Totala 7 (7) 32 (17) 3 (2) 31 (19) Diarrhoea 0 11 (6) 1 (<1) 2 (1) Nausea 1 (1) 8 (4) 0 16 (10) Abdominal pain 0 8 (4) 1 (<1) 5 (3) Vomiting 0 5 (3) 0 2 (1) Exacerbation of COPD 1 (1) 3 (2) 0 0 Dyspepsia 1 (1) 3 (2) 0 1 (<1) Dizziness 0 3 (2) 0 2 (1) Melena 0 3 (2) 0 0 Insomnia 0 2 (1) 0 1 (<1) Anorexia 0 1 (<1) 0 3 (2) Tremor 0 0 0 3 (2) Headache 0 0 0 2 (1) Faecal occult blood positive 0 0 0 2 (1) a Represents total number of patients who experienced at least one adverse event. COPD = chronic obstructive pulmonary disease; SFC = salmeterol/fluticasone propionate.

cardiac disease and, in particular, with unstable 6. Effect of Cilomilast on Hyperinflation cardiac disease is not addressed by these studies. • Gastrointestinal adverse events occurred more 6.1 Study Objectives frequently in patients treated with cilomilast, but the results did not identify any serious, drug- Two studies were conducted to assess the effect related effects of treatment with cilomilast on the of cilomilast on hyperinflation. The primary objec- GI tract. tive of study SB207499/111[45] was to examine the effect of cilomilast on gas trapping (change from Overall, treatment with cilomilast (with or with- • baseline to endpoint in volume of trapped gas). out SFC) was well tolerated, with no new safety Trapped gas volume represents the volume of poorly issues being identified. ventilated areas of the lung. Secondary objectives 1.5 Non-reversible Reversible were to evaluate the efficacy of cilomilast versus placebo on clinical endpoints which result from 1.4 hyperinflation and gas trapping and to further evaluate the safety profile of cilomilast in patients with 1.3 (L)

1 COPD. The primary objective of study SB207499/180[46] FEV 1.2 was to assess the effect of cilomilast on resting 1.1 hyperinflation measured by a reduction in resting functional residual capacity (FRC). Secondary 1.0 objectives were to evaluate the efficacy of cilomilast EP BL EP BL EP BL EP BL versus placebo on endurance time for constant-load Placebo Cilomilast Placebo Cilomilast exercise at 75% of the peak work load, on reductions Fig. 10. Trough forced expiratory volume in 1 second (FEV1) [L] for intent-to-treat, non-reversible and reversible patients in study 168. in exertional dyspnoea (modified Borg Dyspnoea BL = baseline; EP = endpoint. scale) and in dynamic hyperinflation.

6.2 Methods 1-week safety follow-up visit. Patients were required to attend the clinic for at least 10 visits over 6.2.1 Patients the 18-week period with visits at week 2, 4, 8 and 12 For study 111, patients (aged 40–80 years) en- during treatment and a follow-up visit 1 week after tered the study in 32 centres in the US, Canada and completion. At the end of the 4-week run-in phase Australia during a study period from September patients were randomized in a ratio of 1 : 1 to re- 1999 to August 2000. To be eligible for enrolment, ceive cilomilast 15 mg twice daily or placebo for 12 patients had to meet the following criteria: a clinical weeks. All COPD medications except salbutamol or diagnosis of COPD, a pre-salbutamol FEV1 to FVC ipratropium and mucolytics were withdrawn prior to ratio of ≤0.7 and a post-salbutamol FEV1 between or at the screening visit and were not allowed during ≥30% and ≤70% of predicted normal, fixed airway the treatment period. ≤ ≤ obstruction defined by 15% or 200 mL (or both) The key efficacy variable was change from base- increase in FEV1 after administration of salbutamol line to endpoint in volume of trapped gas. Total lung compared with baseline pre-salbutamol FEV1, evi- capacity (TLC) was evaluated using both body dence of hyperinflation, as assessed by residual vol- plethysmography and single-breath helium dilution ≥ ume (RV, from plethysmography) 120% of pre- (TLC ) techniques. Gas trapping was defined as ≥ He dicted RV and 10 pack-year history of smoking. the difference between plethysmographic and sin- The study excluded patients with a primary diag- gle-breath helium dilution TLCs. These tests were nosis of asthma, poorly controlled COPD, active conducted prior to treatment with salbutamol, with pulmonary disease (other than COPD), those receiv- the exception of visit 3 (baseline) and visit 7 ing treatment with long-term oxygen therapy, and (week 12) where assessments were conducted with clinically significant GI conditions and uncon- before and after administration of salbutamol. Se- trolled disorders of major body systems. condary measures of efficacy included additional ≥ For study 180, patients (aged 40 years) entered lung volume measurements including slow vital ca- the study in 34 centres in the US, Canada, Chile and pacity (SVC) and RV (RVBox and RVHe), dynamic Argentina during a study period from January 2003 pulmonary function measurements including inspir- to April 2005. The study criteria was similar to study atory capacity (IC), FEV , FVC, forced expiratory 111 except that patients did not have to demonstrate 1 flow at 25–75% vital capacity (FEF ), forced a ≤15% or ≤200 mL (or both) increase in FEV after 25–75 1 expiratory flow at 75% vital capacity (FEF ) administration of salbutamol, hyperinflated was de- 75 PEFR, specific conductance (calculated from air- fined as ≥140% predicted FRC, the pre-salbutamol ways resistance via plethysmographic measure- FEV was <70% predicted, patients had exercise 1 ment), carbon monoxide diffusing capacity limitation defined as peak symptom-limited oxygen (DLCO), exercise performance (6-minute walk uptake (VO˙ 2) < 75% and moderate/severe dyspnoea test), overall and exertional dyspnoea (as rated by defined as a baseline dyspnoea index score of 7 or lower. the modified Borg Dyspnoea scale), measure of respiratory muscle performance (as evaluated by The protocols were approved by an institutional maximal inspiratory and expiratory pressures [MIPs review board at all sites and all patients provided written informed consent prior to any study proce- and MEPs]) and exertional arterial oxygen concen- dures. tration (SaO2; measured immediately after exercise testing). Pulmonary function tests were performed at 6.2.2 Study Design trough (predose) plasma concentrations of study Study 111 was a multicentre, randomized, doub- medication and were assessed >4 hours after the last le-blind, placebo-controlled, parallel-group study dose of salbutamol and >6 hours after the last dose consisting of a 4-week single-blind placebo run-in of ipratropium. Lung volumes were measured with a period and 12 weeks of active treatment with a pressure body plethysmograph according to the cur-

rent clinical practice guidelines from the American Lung volumes were measured with a pressure Association for Respiratory Care.[47] Calibration of body plethysmograph (body box). The most com- the body plethysmograph occurred daily. mon measurements made using the body plethysmo- Study 180 was a multicentre, randomized, doub- graph were thoracic gas volume (VTG), the volume le-blind, placebo-controlled, parallel-group study of gas in the lung when the mouth shutter is closed. consisting of a 2-week single-blind placebo run-in In plethysmographic studies, VTG is commonly period and 18 weeks of active treatment with a used to represent the FRC. FRC at rest was measured predose at day 1 and postdose at weeks 6, 12 1-week safety follow-up visit. Patients were re- [39] quired to attend the clinic for at least 8 visits over the and 18. The modified Borg Dyspnoea scale was 21-week period with visits at day 1, weeks 6, 12 and used to assess breathlessness during cycle exercise 18 during treatment and a follow-up visit 1 week testing. Patients were asked to rate the intensity of dyspnoea using the modified Borg Dyspnoea scale after completion. At the end of the 2-week run-in before the start of loadless pedalling, every 2 min- phase, patients were randomized in a ratio of 1 : 1 to utes during exercise and at the end of exercise. receive cilomilast 15 mg twice daily or placebo for 18 weeks. Patients were stratified at each site by ICS Safety was assessed by examining adverse use and non-ICS use. COPD medications including events, resting and exercise ECGs, routine labora- ICS, ipratropium and salbutamol were allowed tory tests including faecal occult blood tests and vital signs in both studies. throughout the treatment period. The primary endpoint was the mean change from 6.2.3 Statistical Methods baseline trough at endpoint in 2-hour post-dose For study 111, the assessment of treatment differ- FRC. The key secondary efficacy endpoint analyses ences was based on an ANOVA model with factors were the mean change from baseline IC during of centre and treatment group. 110 evaluable pa- exercise, the mean change from baseline dyspnoea tients would provide at least 90% power to detect a Borg scale score and the mean change from baseline significant difference in trapped gas volume assum- in exercise endurance. Cycle exercise testing was ing a treatment difference of 500 mL, a standard performed using methodology described by O’Don- deviation of 700 mL and a significance level of 0.05. nell et al.[48,49] Cycle exercise testing was initiated For study 180, ANCOVA models used to com- after completion of plethysmography/spirometry pare treatment groups included terms for baseline, procedures. At visit 1, an incremental cycle exercise investigator, ICS use and treatment. Tests for treat- test was performed to a symptom-limited maximum ment effect were two-sided tests at the 0.05 signifi- (maximum work capacity). In subsequent exercise cance level. It was estimated that the standard devia- challenge visits, endurance cycle exercise tests were tion for change from baseline at endpoint in FRC performed in a similar manner with a constant-load was approximately 700 mL so 88 patients per group protocol at a work rate equivalent to 75% of the were planned to provide approximately 80% power maximum work rate achieved during visit 1. The to detect a difference of 300 mL in the change from patient exercised until limited by symptoms, or was baseline at endpoint in FRC. Analyses were per- unable to maintain a pedalling frequency of at least formed for the ITT population, consisting of all 40 rpm or was unable to continue safely. At the end randomized patients receiving at least one dose of of exercise (dropping of the load), the time of exer- study drug. cise was recorded. The resting IC manoeuvres were performed while the patient was seated comfortably 6.3 Results on the cycle ergometer and exercise IC manoeuvres were carried out at 2-minute intervals during exer- 6.3.1 Study Population cise. Peak IC was defined as that at the end of loaded In study 111, a total of 156 patients were random- pedalling. ized to receive placebo (n = 77) or cilomilast

(n = 79). A similar number of patients in each treatment group withdrew from the double-blind phase of the study (18% placebo; 19% cilomilast). In study 180, a total of 199 patients were randomized to receive placebo (n = 102) or cilomilast (n = 97). More patients receiving cilomilast withdrew during double-blind treatment (25%) com- ) pared with placebo-treated patients (13%), primarily [46] because of adverse events. At baseline, the treatment groups in both studies were well matched for demographic and baseline characteristics of COPD (table XXXI).

6.3.2 Primary Efficacy Measures of Hyperinflation In study 111, the difference in the mean volume of trapped gas between the cilomilast group and placebo groups was –0.14 L in favour of cilomilast. This difference was not statistically significant (p = 0.494) [figure 11]. At week 12, there was a decrease in the mean post-salbutamol volume of trapped gas in the cilomilast group (–0.11 L) and an increase in the placebo group (0.20 L). The differ- – ) Treatment group (180 ence between the groups of 0.31 L was not statisti- [45] cally significant (p = 0.129). In study 180, at endpoint, the cilomilast group demonstrated a decrease in postdose FRC from baseline compared with placebo with a mean difference of 128 mL. This difference was not statistically significant (p = 0.234) [figure 12]. placebo (n = 77) cilomilast (n = 79) placebo (n =102) cilomilast (n = 97)

6.3.3 Secondary Efficacy Endpoints In study 111, at endpoint there was a statistically = forced expiratory volume in 1 second significant decrease in the body plethysmography 1

RV in the cilomilast group compared with placebo FEV (–0.39 L; p = 0.005). Post-salbutamol RV decreased in the cilomilast group compared with the placebo group from baseline to week 12 (–0.28 L) and this difference was statistically significant (p = 0.029). At week 12, there was a statistically significant difference between the cilomilast and placebo groups in post-salbutamol FEF75 (0.07 L/sec;

p = 0.001) and at endpoint in mean pre-salbutamol [mean (SD)] 46.8 (13.1) 48.5 (13.0) 36.1 (12.1) 35.0 (13.2) b PEFR (–14.0 L/min; p = 0.047). There were no 1 statistically significant differences between the Summary of demographic characteristics at screening (all randomized patients)

cilomilast and placebo groups in mean change from = chronic obstructive pulmonary disease; (L) [mean (SD)] 1.34 (0.49) 1.35 (0.50) 1.12 (0.38) 1.07 (0.45) a baseline for SVC, RV (by helium dilution), TLC 1 Baseline reversibility (%) [mean (SD)] 8.8 (7.3) 9.0 (7.9) 23.4 (17.2) 22.0 (16.2) % Predicted FEV (helium), DLCO, trough FVC, trough FEF25–75, Table XXXI. CharacteristicSex, male [no. (%)]Race, Caucasian [no. (%)]Age (y) [mean (SD)]Current smoker [no. (%)]Smoking history (pack-years) [mean (SD)]Years since COPD diagnosis [mean (SD)]FEV a 57.9 (29.7) Pre-salbutamol inhalation. b 71 (92) Treatment group (111 7.2 (10.2) Post-salbutamol inhalation. 51 (66)COPD 34 (44) 64.2 (8.9) 60.1 (28.5) 5.1 (4.7) 75 (95) 51 (65) 65.0 (8.3) 34 (43) 59.1 (26.0) 9.1 (8.1) 85 (83) 78 (76) 64.7 (8.1) 59.3 (25.6) 45 (44) 8.2 (6.5) 82 (85) 67 (69) 63.7 (8.1) 44 (45)

400 Cilomilast assessment at endpoint, the placebo treatment group Placebo 300 had a 30.8-second reduction in exercise time and the 200 cilomilast group had a 108.0-second reduction. The 100 difference of 77.2 seconds between the treatment

0 groups was statistically significant (p = 0.045).

–100 6.4 Safety Results trapped gas (mL) –200 Mean change from BL, –300 6.4.1 Adverse Events

–400 In study 111, the overall incidence of adverse BL 2 4 8 12 EP events was lower in the placebo treatment group Week (64%) than in the cilomilast treatment group (80%). Fig. 11. Mean (SEM) change from baseline (BL) in pre-salbutamol The most common adverse event was COPD exacer- volume of trapped gas (L) in study 111.[45] EP = endpoint. bation, which occurred in 15 patients in each group. There was a higher incidence of GI body system trough FEF75, post-salbutamol PEFR, specific con- adverse events in the cilomilast group (34 patients ductance, exercise tolerance, overall breathlessness, [43%]) than in the placebo group (14 patients exertional breathlessness, MIP, MEP, exertional [18%]) [table XXXII]. A total of 8 (10%) placebo- SaO2 and IC. treated patients and 13 (17%) cilomilast-treated pa- In study 180, neither the cilomilast nor placebo tients were withdrawn from the double-blind treat- groups demonstrated an improvement in peak exer- ment because of an on-therapy adverse event. The cise IC. The cilomilast group had a 60 mL mean most common adverse events leading to withdrawal decrease in peak IC from baseline compared with are shown in table XXXIII. One patient in the place- 80 mL decrease in the placebo group. The difference bo group had a positive faecal occult blood test between the groups of 20 mL was not significant during the double-blind treatment compared with (p = 0.675). In addition, the difference between the none in the cilomilast group. cilomilast and placebo groups in the mean Borg Three patients died during the study; one of these dyspnoea scale score at peak was not significantly died during single-blind placebo treatment. In the different between the groups with a 0.2-unit differ- cilomilast treatment group, one patient died during ence in favour of cilomilast (p = 0.612). Neither the the double-blind treatment period and one died after cilomilast nor placebo groups demonstrated an im- therapy. None of the adverse events that resulted in provement in exercise endurance time. For postdose death were considered by the investigator to be related to study medication. 300 Cilomilast In study 180, the same percentage of patients in Placebo 200 each group experienced at least one adverse event during the 24-week period (67%). The most com- 100 monly reported adverse events are shown in table 0 XXXII. Adverse events associated with the GI body system such as nausea, diarrhoea, abdominal pain, –100 dyspepsia and vomiting were reported more fre- –200 quently in the cilomilast group than in the placebo group. The time of initial onset for the majority of –300

Mean change from BL, FRC (mL) GI adverse events in patients who received cilomi- BL 6 12 18 EP Week last was in the first 2 weeks of therapy. A total of six Fig. 12. Mean change from baseline (BL) at endpoint in functional (6%) placebo-treated patients and nine (9%) cilomi- residual capacity (FRC) in study 180.[46] EP = endpoint. last-treated patients were withdrawn from the doub-

Table XXXII. Number (%) of patients with the most frequently reported adverse events (≥5% patients in either treatment group in either study) Adverse event Study 111[45] Study 180[46] placebo (n = 77) cilomilast (n = 79) placebo (n = 102) cilomilast (n = 97) Totala 49 (64) 63 (80) 68 (67) 65 (67) Exacerbation of COPD 15 (19) 15 (19) 6 (6) 3 (3) Diarrhoea 3 (4) 14 (18) 3 (3) 9 (9) Nausea 4 (5) 13 (16) 2 (2) 11 (11) Headache 1 (1) 3 (4) 14 (14) 16 (16) Dyspepsia 2 (3) 10 (13) 1 (<1) 4 (4) Infection viral 3 (4) 8 (10) 1 (<1) 1 (1) Upper respiratory tract infection 5 (6) 8 (10) 6 (6) 2 (2) Nasopharyngitis 0 0 8 (8) 7 (7) Abdominal pain 0 6 (7) 0 2 (2) Rhinitis 4 (5) 5 (6) 0 2 (2) Gastro-oesophageal reflux 0 4 (5) 0 0 Myalgia 1 (1) 4 (5) 1 (<1) 1 (1) Sinusitis 3 (4) 4 (5) 3 (3) 2 (2) a Represents total number of patients reporting at least one adverse event. COPD = chronic obstructive pulmonary disease. le-blind treatment because of an on-therapy adverse 6.5 Summary event. The most common adverse events leading to withdrawal are shown in table XXXIII. Two pa- • While cilomilast demonstrated a reduction in gas tients treated with cilomilast and six treated with trapping and FRC compared with placebo, the placebo had positive faecal occult blood tests during differences were not statistically significant. the study. There were no deaths during the study. • Multiple secondary efficacy measures were evaluated. While cilomilast demonstrated numerical 6.4.2 Other Safety Assessments improvements over placebo for some of these Overall in both studies, mean changes from base- endpoints, none of these improvements were line in clinical laboratory parameters and vital signs clinically significant. were small and comparable between the treatment groups. There were small changes in ECG para- • The extensive GI monitoring performed in these meters from baseline to endpoint in both treatment studies did not identify any serious, potentially groups. However, no clinically relevant differences drug-related effects of treatment with cilomilast were noted within or between groups. on the GI tract.

Table XXXIII. Incidence of adverse events leading to withdrawal of ≥1 patient in either treatment group in either study Adverse event Study 111[45] [no. (%)] Study 180[46] [no. (%)] placebo (n = 77) cilomilast (n = 79) placebo (n = 102) cilomilast (n = 97) Totala 8 (10) 13 (16) 6 (6) 9 (9) Exacerbation of COPD 4 (5) 2 (3) 2 (2) 0 Diarrhoea 0 2 (3) 0 2 (2) Nausea 0 2 (3) 0 3 (3) Vomiting 0 0 0 2 (2) a Represents total number of patients withdrawn during the on-therapy period because of an adverse event. COPD = chronic obstructive pulmonary disease.

• There were no clinically relevant safety issues in ment and the laboratory technician. Calibration of laboratory values, vital signs or ECGs revealed in mouth pressure and box pressure transducers was this study. performed at least once each day prior to testing subjects. Safety was measured by the assessment of 7. Efficacy and Safety of Cilomilast in adverse events, vital signs, clinical laboratory tests, Chinese Patients with COPD faecal occult blood tests and ECGs.

7.1 Study Objective 7.2.2 Patients Male and female patients aged 40–75 years with The primary objective of the study was to demon- a clinical diagnosis of COPD, as defined by the strate the clinical efficacy of cilomilast versus place- American Thoracic Society, were eligible to partici- bo in Chinese patients with COPD by measuring the pate in the study. Patients had to be current or ex- change from baseline to endpoint in FEV1 at trough smokers with a cigarette smoking history of ≥10 drug concentrations. This study was conducted for pack-years. Lung function criteria requirements for Chinese local product registration. entry included a post-bronchodilator FEV1 between ≥25% and ≤70% of the predicted normal value and a 7.2 Materials and Methods ratio of the pre-bronchodilator FEV1 to FVC of <70%. Patients also had to have fixed airways dis- 7.2.1 Study Design ease (i.e. an increase in FEV1 of ≤10% from baseline This was a randomized, double-blind, placebo- or ≤200 mL 30 minutes after the administration of controlled, parallel-group study, conducted from salbutamol 200 µg). Patients were also required to January 2003 to November 2004 at 22 centres in have a history of COPD exacerbations in the 3 years China (study number SB207499/121).[50] The local prior to the study. At the sites performing plethys- ethics committee or institutional review board ap- mography, patients had to have a predicted FRC of proved the study protocol at each centre and all >120%. Patients with active tuberculosis, lung can- patients gave written informed consent to partici- cer or clinically overt bronchiectasis were excluded. pate. Additionally, patients with clinically significant Patients were assessed for eligibility at the cardiovascular, neurological, renal, endocrine, GI, screening visit. After a 4-week, single-blind, place- hepatic, or haematological abnormalities that were bo run-in period, eligible patients were randomized uncontrolled with permitted therapy were not eligi- in a 2 : 1 ratio to receive twice-daily oral treatment ble for inclusion in the study. with either cilomilast 15 mg, or placebo during a 24-week double-blind phase. Patients attended the Patients with poorly controlled COPD, defined as clinic every 2 weeks from the screening visit up to the occurrence of an acute worsening of COPD that randomization and then at week 1 and week 4 of was managed by the patient at home by self-treat- treatment, and thereafter at 4-weekly intervals. A ment with corticosteroids or antibiotics, that re- final visit occurred 1 week after completing the quired treatment prescribed by a physician, or for study. The primary endpoint in this study was the which the patient was hospitalized in the 2 weeks prior to screening were excluded. Patients receiving change from baseline in trough FEV1 measured at study endpoint. Secondary efficacy endpoints in- treatment with long-term oxygen therapy or who cluded the incidence of COPD exacerbations, health required supplemental oxygen more often than on an status measured by SGRQ and clinic visit trough occasional basis were also excluded. FVC measurements. In addition, at ten selected cen- Randomization criteria included stability of pul- tres, body box measurements of hyperinflation, RV monary function, which was defined as variability in and FRC were measured. These sites were selected FEV1 between the first and last run-in visit of not after evaluation of the laboratory, body box equip- more than 20% of the absolute trough pre-

salbutamol administration measurement and med- Baseline was also included in the model as a ication compliance of between 80% and 120%. covariate. Least squares means along with 95% con- Patients were provided with salbutamol metered fidence intervals were calculated for each treatment dose inhalers for use on an as-needed basis and were group and for the treatment difference. The differ- permitted to continue inhaled short-acting anticho- ences between treatment groups were assessed using linergics and mucolytics at a stable dose throughout t-tests on the least squares means. Continuous se- the study. No other COPD medications, including condary efficacy variables were analysed similarly traditional Chinese medication, were allowed except to the primary. for the short-term treatment of exacerbations. Differences between groups in time to first level 7.2.3 Study Procedures 2/level 3 COPD exacerbation was assessed using the Patients were asked to refrain from taking any log-rank test. The exacerbation-free survival rate at 24 weeks and the associated 95% confidence inter- respiratory medication for at least 6 hours and refrain from smoking for at least 2 hours before each vals were estimated for each treatment group using the Kaplan-Meier product limit method. clinic visit. Trough (predose) FEV1 was performed using the same type of spirometer at all centres. At The planned sample size was 900 randomized the screening visit, pulmonary function was as- patients to obtain data on 840 patients with both sessed before and after a standard dose of baseline and at least one post-baseline FEV1 evalua- salbutamol, whereas at subsequent visits assess- tion. The study was designed to detect a 50 mL ments were made at trough levels of study drug. difference in FEV1 with 90% power. Based on pre- Body box plethysmography was performed at ten vious studies, the powering of the study assumed a sites at baseline and weeks 6 and 12 of treatment. 210 mL standard deviation for FEV1 and a signifi- The SGRQ, a disease-specific health status tool, cance level of 0.05. was administered at weeks 0, 12 and 24. COPD exacerbations were recorded throughout 7.3 Results the study. They were categorized as level 1, 2 or 3, based on the treatment received by the patient for the 7.3.1 Patient Disposition exacerbation. Level 1 (mild) was defined as an acute A total of 1219 patients were screened for the worsening of COPD that was self-managed by the study, but of these, 201 (16%) were withdrawn prior patient at home by increasing usual COPD medica- to randomization. A total of 1018 patients were tions, level 2 (moderate) for those that required randomized to receive either cilomilast (n = 678) or additional treatment (e.g. ≥14 days of inhaled or oral placebo (n = 340). The primary reason for withdraw- steroids or antibiotics prescribed by a physician) and al of patients from the study prior to randomization level 3 (severe) as requiring hospitalization. was that the patients did not return (67 patients, 33% Adverse experiences, vital signs, ECGs, faecal of non-randomized patients). More patients receiv- occult blood tests and blood and urine specimens ing cilomilast than placebo withdrew from the doub- were taken for routine haematology and biochemis- le-blind phase of the study (18% [124] vs 10% [35]). try and urinalysis during the study at each visit. At The main reason for withdrawal after randomization all visits during the double-blind study period, pa- was an adverse event (7% of patients who received tients were assessed for compliance with the med- cilomilast; 2% of placebo-treated patients). ication as well as for use of concomitant medications. 7.3.2 Baseline Characteristics 7.2.4 Statistical Analysis The two treatment groups in the randomized pa- The primary endpoint (change from baseline in tient population were well matched for demographic trough FEV1) was analysed using an ANOVA characteristics and for baseline characteristics of model with fixed effects for treatment and centre. COPD (table XXXIV). The treatment groups had

Table XXXIV. Demographics and screening characteristics Characteristic Placebo (n = 340) Cilomilast (n = 678) Sex, male [no. (%)] 311 (91) 631 (93) Age (y) [mean (SD)] 63.9 (7.5) 64.6 (7.8) Smoking history (pack-years) [mean (SD)] 32.8 (17.4) 37.3 (19.9) Current smoker [no. (%)] 77 (23) 160 (24) Years since COPD diagnosis [mean (SD)] 12.1 (9.2) 11.4 (8.9)

FEV1a (L) [mean (SD)] 1.17 (0.44) 1.19 (0.43) % Predicted FEV1b [mean (SD)] 42.1 (12.6) 42.8 (12.2) Reversibility (%) [mean (SD)] 4.3 (4.6) 4.3 (5.0) FVCa (L) [mean (SD)] 2.69 (0.76) 2.74 (0.75) Prior inhaled corticosteroid use [no. (%)] 280 (82) 538 (79) a Pre-salbutamol inhalation. b Post-salbutamol inhalation.

COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second. similar lung function and, overall, the patients were smokers at baseline it was –0.012 L in the placebo representative of a moderate COPD population. group and 0.012 L in the cilomilast group. A signif- The use of salbutamol was similar in both treat- icant effect of smoking status on change from base- ment groups (78% for placebo and 74% for cilomi- line in FEV1 at endpoint was observed (p ≤ 0.004). last) and a similar number of patients were receiving ICS prior to the study (82% in the placebo group vs 7.3.4 Secondary Endpoints 79% for cilomilast). During the double-blind treatment period 97% of placebo- and 94% of cilomilast- COPD Exacerbations treated patients were at least 80% compliant with There was no significant difference between their study medication. There were no notable dif- treatments in the time to first level 2 or level 3 ferences between centres in baseline plethys- COPD exacerbation (p = 0.598). At week 24, 77% mographic parameters. of the placebo group and 76% of the cilomilast group had not experienced a level 2 or level 3

7.3.3 Primary Efficacy Endpoint; Trough FEV1 exacerbation. Proportional hazards regression ana- At study endpoint, there was no significant dif- lysis of time to first level 2 or level 3 exacerbation ference between treatments for the primary end- 100 Cilomilast point, with a small increase of 14 mL in FEV1 at Placebo (mL) endpoint in the cilomilast group compared with a 1 75 small decrease of –6 mL in the placebo group (treat- 50 ment difference of 21 mL; p = 0.093). Analysis of 25 the average change from baseline in FEV1 over 24 weeks showed a significant difference in favour of 0 cilomilast compared with placebo (treatment differ- –25 ence 25 mL; p = 0.008). Differences between the –50 treatments were in favour of cilomilast at each visit –75 and significant differences were seen over the first 16 weeks of the study (figure 13). Mean change from BL, trough FEV –100 BL 4 8 12 16 20 24 EP Avg24 The mean change from baseline in FEV1 at end- Week point for patients who were smokers at baseline was Fig. 13. Mean (SEM) change from baseline (BL) in trough forced 0.019 L in the placebo group and 0.027 L in the expiratory volume in 1 second (FEV1). Avg24 = average over 24 cilomilast group and for subjects who were non- weeks; EP = endpoint.

showed no significant effect of treatment (relative was higher in the cilomilast group (5%) than the risk for cilomilast to placebo 1.09; p = 0.534). placebo group (2%). The most common adverse event leading to withdrawal in both treatment Plethysmography groups was an exacerbation of COPD (table There were 121 patients in the placebo group and XXXVI). 250 patients in the cilomilast group who had plethysmography measured during the study. Base- There were three deaths during the double-blind line values for placebo and cilomilast were 5.21 L study phase, two in the placebo group and one in the and 5.14 L, respectively, for FRC and 4.11 L for RV cilomilast group. All of the on-therapy fatal events for both groups. There was no significant difference were due to cardiovascular disease or cancer and between treatments at endpoint for RV (mean differ- were attributed to adverse events judged not related ence 0.058 L; p = 0.497) or FRC (mean difference or unlikely to be related to study medication by the 0.082 L; p = 0.234). investigator. Nonfatal serious adverse events were

Trough FVC reported in 10 patients (3%) treated with placebo The baseline FVC was 2.70 L for cilomilast and and 38 patients (6%) treated with cilomilast; the 2.67 L for placebo. At endpoint, the cilomilast group most frequent was a COPD exacerbation, which had an FVC increase of 18 mL, and the placebo occurred in 4 patients (1%) receiving placebo and 21 group had a decrease of 23 mL. There was no signif- patients (3%) receiving cilomilast. icant difference between treatments (treatment dif- No clinically relevant differences were observed ference 41 mL; p = 0.129). between treatment groups during cardiovascular monitoring of ECG assessments, sitting, or orthosta- Health Status The baseline SGRQ total score was 45.0 units for tic vital signs. The mean changes from baseline in the cilomilast group and 44.7 units for the placebo clinical laboratory parameters were small and were group. At study endpoint, there was a clinically comparable between the treatment groups. Overall, significant improvement in the mean change from 13 patients (4%) in the placebo group and 28 pa- baseline for the total score of the SGRQ in both tients (5%) in the cilomilast group had positive treatment groups. Patients receiving cilomilast had a faecal occult bloods during double-blind treatment. mean improvement of –9.0 units compared with an improvement of –8.7 units in the placebo group Table XXXV. Most frequently reported on-therapy adverse experiences in ≥3% of patients in either treatment group (–0.3-unit difference; p = 0.790). Adverse event Placebo Cilomilast (n = 340) (n = 678) 7.4 Safety and Tolerability [no. (%)] [no. (%)] Totala 245 (72) 518 (76) A majority of patients in each group experienced Exacerbation of COPD 178 (52) 297 (44) at least one adverse event during the 24-week period Nasopharyngitis 63 (19) 129 (19) (cilomilast 76%; placebo 72%). The most common- Diarrhoea 20 (6) 94 (14) ly reported adverse events are shown in table Dyspepsia 4 (1) 40 (6) XXXV. Adverse events associated with the GI body Nausea 3 (<1) 39 (6) system were reported more frequently in the cilomi- Abdominal pain 10 (3) 36 (5) Anorexia 2 (<1) 29 (4) last treatment group (38%) compared with the place- Flatulence 8 (2) 27 (4) bo group (17%). The time of initial onset for the Abdominal discomfort 2 (<1) 26 (4) majority of GI adverse events in patients who re- Abdominal distension 0 21 (3) ceived cilomilast was in the first week of therapy. a Total number of patients who experienced at least one Overall, the percentage of patients experiencing adverse event. an adverse event on therapy which led to withdrawal COPD = chronic obstructive pulmonary disease.

Table XXXVI. On-therapy adverse events leading to withdrawal in III studies failed to definitively confirm the earlier ≥2 patients in either treatment group programme results, which led to the programme’s Adverse event Placebo Cilomilast (n = 340) (n = 678) termination. [no. (%)] [no. (%)] Totala 6 (2) 36 (5) 8.1 Anti-Inflammatory Effects of Cilomilast Exacerbation of COPD 3 (1) 7 (1) Anorexia 0 3 (<1) The pathogenesis of COPD is complex, and stud- Diarrhoea 0 3 (<1) ies have demonstrated that airway inflammation [51-53] Dyspepsia 0 3 (<1) plays an important role. Many haematopoietic Gastro-oesophageal reflux 0 3 (<1) and parenchymal cells participate in the inflamma- Abdominal pain 0 2 (<1) tory response in the lung. The neutrophil is a prima- Insomnia 0 2 (<1) ry mediator of inflammation in COPD and the lung Nausea 0 2 (<1) is clearly a primary target for neutrophil recruitment Palpitations 0 2 (<1) and activation.[54] Few currently available therapeu- Vasculitis 0 2 (<1) tic agents, including corticosteroids, effectively Vomiting 0 2 (<1) downregulate neutrophil pro-inflammatory activity. a Total number of patients who experienced at least one on- therapy adverse event leading to withdrawal. This emphasizes the need for novel pharmacological COPD = chronic obstructive pulmonary disease. strategies to control the potentially harmful proinflammatory activities of these cells. 7.5 Summary Cilomilast demonstrated significant anti-inflammatory activity in various animal models in • Although improvements in lung function were preclinical studies.[30] In the phase II study 076 observed with cilomilast, significant differences (previously published),[1] a small improvement was compared with placebo were not seen for primary seen in subepithelial neutrophils in the cilomilast or secondary endpoints and the clinical efficacy treatment group relative to placebo, along with a of cilomilast compared with placebo was not reduction in subepithelial macrophages (CD68+) demonstrated in Chinese patients with COPD. and subepithelial CD8+ lymphocytes. However, in • As in previous studies, treatment with cilomilast two further studies (110[33] and 181[34]), the anti- was generally well tolerated, although a higher inflammatory activity of cilomilast was not con- proportion of patients reported GI adverse events firmed. Data from the three studies did not provide compared with those receiving placebo. conclusive evidence of an anti-inflammatory action • In this study, there was a notably large improve- of cilomilast. The studies, all of which were de- ment (>8 units) in the SGRQ in both treatment signed to assess anti-inflammatory action of cilomi- groups that did not differ significantly. last in COPD patients as a whole, were not suffi- ciently large to permit meaningful subset analyses. 8. Discussion As a whole, however, the data provided by these studies do not support a role for cilomilast in reduc- During the cilomilast development programme a ing any measure of inflammation in the lung. Thus, number of different endpoints were investigated to it is not possible to determine if cilomilast might be characterize the efficacy and safety of this second- an effective anti-inflammatory in a subset of COPD generation PDE4 inhibitor. Safety assessments patients. throughout the late-phase programme did not reveal any evidence of serious safety concerns with the use 8.2 FEV1 of cilomilast. Initial studies in phase II and early phase III showed improvements in efficacy end- Five pivotal well controlled, 24-week studies points and some evidence of an anti-inflammatory were conducted to compare cilomilast with placebo mechanism of action. However, subsequent phase on the change from baseline in FEV1 measured at

trough drug concentrations in poorly reversible tion.[55] They also have a relatively rapid rate of COPD patients (study numbers 039,[2] 156,[35] decline in FEV1 with associated trends for increased 042,[38] 091[37] and 657;[36] see section 3). In three of morbidity and mortality.[56] Although the improve- the five pivotal studies (039, 156, 657) over 24 ments in FEV1 experienced by cilomilast-treated weeks of treatment, there was a statistically signif- patients in this population were modest (up to icant difference in FEV1 between the cilomilast and 50 mL), this is comparable to that observed in placebo treatment groups. Treatment differences COPD patients who quit smoking compared with ranged from 24 to 44 mL, and in the absence of continued smokers over a duration of 1 year.[51] improvements in other clinical parameters, this Study 168 was a cardiovascular safety study modest improvement was not considered to be clini- which included 115 patients who were reversible cally meaningful. and 167 poorly reversible patients. FEV1 was evalu- Considering the potential for anti-inflammatory ated as an exploratory endpoint. Both reversible and effects of a PDE4 inhibitor, a greater benefit with poorly reversible patients treated with cilomilast extended duration of treatment would be predicted. demonstrated improvements in FEV1 at study end- However, in study 157, the treatment difference point compared with placebo, and the improvement was much greater in the reversible population (130 over 52 weeks (41 mL) was comparable to the treat- vs 30 mL in the poorly reversible population), which ment differences found in the pivotal trials over 24 may suggest that the treatment effect for cilomilast weeks. However, an anti-inflammatory agent might may be larger in a more general COPD population. improve airflow in COPD both by relatively acute Whether such a population would also show differ- effects, e.g. by reducing oedema and tissue infiltra- ences in long-term effects or other outcomes, such tion with inflammatory cells, and by slowing the as health status or exacerbations, can not be ascer- progression of airflow limitation, which is believed tained from the studies performed. to be a consequence of chronic inflammation. COPD progresses at a rate of FEV1 loss of 40–60 8.3 Forced Vital Capacity mL/year. A reduction in this rate by 20 mL/year has been suggested as a therapeutic target in several Since small airways disease is an important com- large studies. A meaningful difference in FEV1 be- ponent of COPD and FEV1 is not very sensitive to tween 24 and 52 weeks therefore might be in the changes in small airway calibre,[3] other measures order of 10 mL, which may not have been observa- such as FVC may more accurately reflect small ble with the number of patients studied. Neverthe- airway function. Some patients with irreversible less, the available data do not suggest a progressive COPD experience subjective benefit from treatment increase in the difference between patients treated without change in FEV1. However, across the five with cilomilast and those treated with placebo. pivotal studies, the mean improvements in FVC at endpoint were 27 to 110 mL greater in the cilomilast When reviewing the FEV1 response to treatment with cilomilast, the fact that poorly reversible pa- treatment group relative to placebo and were similar tients were included in these studies should be con- to the improvements observed for FEV1. sidered. The cilomilast clinical programme was pre- 8.4 Hyperinflation dominantly restricted to patients who had a poor reversibility to bronchodilator (<15% or 200 mL The impact of lung hyperinflation on symptoms improvement over baseline in FEV1). This was and impairment at rest and during exertion is also done, in large part, to help evaluate benefits from increasingly recognized in COPD.[57] Expiratory air- non-bronchodilator effects of cilomilast. Patients flow limitation in COPD leads to air trapping who are poorly reversible are known to have a (hyperinflation) when there is insufficient time for decreased magnitude of FEV1 response in response adequate lung emptying. Dynamic hyperinflation is to therapy compared with a more reversible popula- a primary mechanism for the exertional dyspnoea

and reduced exercise capacity associated with groups, which were not significantly different, dem- COPD.[58,59] Functional residual capacity and onstrated improvement by >8 units. This marked residual volume determine the initial positioning of improvement may have been consequent to partici- tidal breathing during exercise and are resting mea- pation in the clinical trial, with the resulting in- sures of hyperinflation that correlate with exercise creased medical attention, the so-called Hawthorne performance and exertional dyspnoea.[57-59] Effect.[62] This effect may have masked, to some Although a statistically significant difference be- degree, any potential benefit of the study med- tween cilomilast and placebo was shown for mean ication. change from baseline FRC in study 111 (290 mL), a Although a trend towards an improvement in significant difference was not seen in study 180 health status measured by the SGRQ was observed (128 mL). This was also true for residual volume following treatment with cilomilast, these improve- and total lung capacity. No other secondary end- ments were not consistent across the studies. points reached statistical significance in either study, suggesting that there was little overall effect 8.6 Exacerbations of cilomilast on hyperinflation. Many COPD patients experience periodic wors- 8.5 Health Status ening of their symptoms reflecting an acute deterioration in lung mechanics[63] and airway inflamma- Assessment of health status, often termed ‘quali- tion secondary to viral and/or bacterial infec- ty of life’, is recognized as an important additional tion.[64,65] These exacerbations contribute to measurement in patients with chronic respiratory impaired health status,[66,67] increased hospitaliza- disease and is a better predictor of admission to tion costs[68] and predict mortality.[69] The effect of hospital and death within 12 months than FEV1.[60] cilomilast on exacerbations was therefore measured The quality of life in patients with COPD decreases as a key secondary endpoint in the pivotal studies. significantly with disease progression, and because Data from two of the pivotal studies (studies patients often modify their lifestyles to compensate 039[2]and 091[37]) demonstrated that cilomilast sig- for dyspnoea and activity limitation, it is important nificantly reduced exacerbation rates over 24 weeks that therapeutic interventions also result in improve- of treatment. Although these studies were not pow- ments in the patient’s quality of life. Health status ered for exacerbations, cilomilast significantly re- outcomes such as these are regarded as important in duced the risk of having an exacerbation relative to all aspects of COPD because they are felt to re- placebo. An additional study was therefore designed present changes that are clinically most relevant to based on these results to assess the efficacy and patients and that may not be measurable by other safety of cilomilast versus placebo on exacerbations more conventional parameters. The SGRQ has been over a longer timeframe of 52 weeks (study 157). designed to measure and quantify the impact of The study was powered for exacerbations and in- chronic respiratory disease on a patient’s health- tended to confirm and extend the results observed in related quality of life.[61] Health status measured by other phase III studies. However, no difference be- the SGRQ was therefore used as a co-primary end- tween the treatment groups in the rate of level 2/3 point in the pivotal phase III studies. COPD exacerbations (exacerbations requiring phy- In two of the five pivotal studies (039,[2] 156[35]) sician-prescribed treatment or a hospital visit) was there was a statistically significant difference in observed. SGRQ between the cilomilast and placebo treatment Despite cilomilast reducing exacerbations in a groups, with only one study (039) reaching the couple of the early phase III pivotal studies, this was clinically relevant difference of –4.0 units.[2] These not observed in the later pivotal trials and specifical- results contrasted with the study performed in Chi- ly in study 157, which was designed to investigate na, where both the placebo and cilomilast treatment the effect of cilomilast on exacerbations.

8.7 Dyspnoea sistently reported at a lower incidence in patients treated with cilomilast than in placebo-treated pa- The modest improvements in lung function seen tients. There was also no difference between cilomi- in the pivotal studies were accompanied by some last- and placebo-treated patients on routine faecal relief of dyspnoea as measured by the Borg occult bloods. The increase in nausea observed in [39] Dyspnoea Scale. Consistent trends for improve- cilomilast-treated patients is consistent with a cen- ments in post-exercise breathlessness scores at end- tral nervous system effect that is well described for point were observed in the cilomilast-treated pa- PDE4 inhibitors. In contrast, there were no diagno- tients compared with placebo-treated patients across ses of mesenteric vasculitis, an effect of PDE4 in- all pivotal studies in which it was measured. Small hibitors in rats that has caused serious concern. The decreases in FEV1 associated with episodes of results from this clinical programme, therefore, are dyspnoea have previously been reported in a similar consistent with other studies that suggest this com- [70] poorly reversible population. plication of PDE4 inhibitors is species specific, as there is no evidence that it occurs in humans. 8.8 Safety 8.8.2 Adverse Events Leading to Withdrawal The cilomilast clinical development programme In all phase III studies, higher percentages of evaluated the safety of cilomilast in more than 6000 cilomilast-treated patients were withdrawn than pla- patients with COPD by tabulation of adverse events, cebo-treated patients with a higher percentage with- examination of laboratory parameters, testing for drawn due to an adverse event. Adverse events faecal occult blood, serial ECGs and 24-hour Holter leading to withdrawal were reported by a relatively monitor studies. Monitoring of GI adverse events small proportion of patients across the treatment was undertaken throughout the clinical programme groups in the five pivotal studies (5–16% in the owing to the pharmacology of PDE4 inhibitors. placebo groups; 15–22% in the cilomilast treatment 8.8.1 Adverse Events groups) with adverse events related to the GI system As expected for a study population of older pa- predominating. The most common adverse event tients with chronic disease receiving a variety of leading to withdrawal in the cilomilast group was medications, most patients with COPD reported one nausea, and in the placebo group it was an exacerba- or more adverse events while on treatment with tion of COPD. cilomilast or placebo. Adverse events, irrespective 8.8.3 Deaths of relationship to study medication, were reported in Eleven patients died during double-blind treat- comparable percentages of patients treated with ment in the five pivotal studies or during the post- cilomilast. The most frequently reported events therapy follow-up period; of these, four received were exacerbations of COPD, nausea, diarrhoea, placebo. All of the on-therapy fatal adverse events abdominal pain, upper respiratory tract infection, were due to cardiac failure, aneurysm, cancer, brain headache, dyspepsia and vomiting. Overall, the inci- haemorrhage or pulmonary disease. The investiga- dence of adverse events related to the GI system was tors judged all the fatal adverse events as not related higher among COPD patients treated with cilomilast to study medication and there appeared to be no than among those treated with placebo. The most relationship between the occurrence of fatal adverse common GI events reported in the cilomilast group events and study participation. compared with the placebo group were nausea, diarrhoea, abdominal pain, dyspepsia and vomiting. By 8.8.4 Laboratory Data and Vital Signs approximately 3 weeks, patients were equally likely Laboratory observations during the phase III to start having GI events when treated with cilomi- trials demonstrated no systemic effect of treatment last as compared with placebo. Dyspnoea, chronic with cilomilast on haematology values, serum mea- obstructive airways disease and coughing were con- sures of liver or kidney function, glucose metabol-

ism, electrolytes or other biochemistry parameters. monitoring, and overall, treatment with SFC and Overall, there were small, clinically insignificant cilomilast was well tolerated with no new safety mean changes in blood pressure and heart rate from issues being identified. baseline to on-therapy in both cilomilast and place- 8.8.6 Summary bo treatment groups. The proportion of patients with Observations from the clinical development pro- diastolic blood pressure or heart rate changes was gramme suggest that except for episodes of GI ad- similar across the placebo and cilomilast groups in verse events, cilomilast was relatively well tolerated all studies. Small changes in mean orthostatic vital in the clinical studies of patients with COPD. GI signs were recorded at baseline and at endpoint of intolerance related to adverse events such as nausea, comparable magnitude between placebo and cilomi- diarrhoea, abdominal pain, dyspepsia and vomiting last patients in the phase III studies. Overall, the were consistently reported at a higher incidence in differences and changes in vital signs are unlikely to patients treated with cilomilast than in patients treat- be clinically important. ed with placebo. Extensive monitoring including faecal occult blood testing, assessment of orthostatic 8.8.5 Cardiovascular Findings changes in vital signs and laboratory assessments Extensive cardiovascular monitoring during the showed no evidence of more significant GI patho- development programme included frequent ECGs in logy associated with these GI adverse events. the phase III controlled trials and in the long-term Patients who experienced GI adverse effects trials plus additional 24-hour Holter monitor exami- from cilomilast were most likely to do so within the nations in several studies. More than 72 000 ECGs first few weeks of exposure but most of the events were obtained across studies, including long-term were mild or moderate in intensity. studies. There were small changes in trough ECG values from baseline to study endpoint in both treat- 9. Conclusion ment groups, which is not unexpected in a cohort of older patients with chronic lung disease with a PDE4 inhibitors, including cilomilast, have smoking history. No meaningful trends were seen in shown limited effects on inflammation and lung transitions from normal to concern values at trough function compared with corticosteroids and bron- between treatment groups for atrial and ventricular chodilators, respectively. While PDE4 inhibitors are rates, QRS interval, uncorrected QT interval, QTc currently limited by their dose-dependent adverse change, PR interval or QRS axis. There were no effects, in the future this limitation may be less major differences in the emergence of specific ECG likely to occur when they are administered by the abnormalities between treatment groups at trough or inhaled route, or with newer inhibitors with im- at Cmax. These data demonstrate that there is no proved subtype or tissue selectivity. excess cardiovascular risk associated with cilomilast therapy. The clinical trials with cilomilast, however, Acknowledgements excluded patients with unstable cardiac disease. The The authors acknowledge technical support from Diana effects of cilomilast in this potentially vulnerable Jones, a professional medical writer, who was compensated population, therefore, can not be assessed from the by GlaxoSmithKline (GSK), in the preparation of this manu- script. results of this clinical programme. SR has had or currently has a number of relationships with An additional study was conducted to evaluate companies who provide products and/or services relevant to the safety and additional efficacy of cilomilast when outpatient management of chronic obstructive pulmonary dis- given concurrently with salmeterol/fluticasone pro- ease. These relationships include serving as a consultant, pionate 250/50 µg twice daily (SFC) [study 125]. It advising regarding clinical trials, speaking at continuing medical education programmes and performing funded re- was shown that there was no difference between search both at basic and clinical levels. He does not own stock SFC + cilomilast versus SFC alone in the primary in any pharmaceutical companies. In the last 3 years, SR has safety measure of mean 24-hour heart rate by Holter received laboratory and industry grants from Almirall, Al-

tana, Astellas, Centocor, GSK, Nabi, Novartis and Pfizer; has 11. Jeffery PK. Investigation and assessment of airway and lung served on consultancy and advisory boards for Adams, Al- inflammation: we now have the tools, what are the questions? mirall, Altana, AstraZeneca, Bend, Biolipox, Centocor, Criti- Eur Respir J 1998; 11: 524-8 12. Daffern PJ, Jagels MA, Hugli TF. Multiple epithelial cell- cal Therapeutics, Dey, GSK, ICOS, Johnson & Johnson, derived factors enhance neutrophil survival. Regulation by Novartis, Ono Pharma, Parengenix, Pfizer, Roche, Sankyo, glucocorticoids and tumour necrosis factor-alpha. Am J Respir Sanofi, Schering-Plough and Talecris; and has received Cell Mol Biol 1999; 21: 259-67 speakers fees from AstraZeneca, Boehringer Ingelheim, 13. Cox G. Glucocorticoid treatment inhibits apoptosis in human GSK, Osuka and Pfizer. AM is an employee of GSK (clinical) neutrophils. J Immunol 1995; 154: 4719-25 and owns stock and stock options in GSK. FB is an employee 14. Kroegel C, Foerster M. Phosphodiesterase-4 inhibitors as a of GSK (clinical) and holds stock options with GSK. KR has novel approach for the treatment of respiratory disease: cilomilast. Expert Opin Investig Drugs 2007; 16 (1): 109-24 been consulting, participated in Advisory Board meetings and 15. Torphy TJ, Undem BJ. Phosphodiesterase inhibitors: new op- received lecture fees from AstraZenica, Boehringer, Chiesi portunities for the treatment of asthma. Thorax 1991; 46: Pharmaceuticals, Pfizer, Novartis, AltanaPharma, MSD and 512-23 GSK. The Department of Pulmonology, and thereby Profes- 16. Sutherland EW, Rall TW. Fractionation and characterization of sor Rabe as head of the department, has received grants from a cyclic adenine ribonucleotide formed by tissue particles. J Novartis, AstraZeneca, Boehrigner Ingelheim, Roche and Biol Chem 1958; 232: 1077-91 GSK between 2005 and 2008 and has a grant pending from 17. Essayan DM. Cyclic nucleotide phosphodiesterases. J Allergy Polen. 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