Drugs

, Volume 68, Supplement 2, pp 3–57

The Efficacy and Safety of Cilomilast in COPD

Authors

    • Pulmonary and Critical Care MedicineUniversity of Nebraska Medical Center
  • Katharine Knobil
    • GlaxoSmithKline
  • Klaus F. Rabe
    • Leiden University Medical Centre
  • Andrea Morris
    • GlaxoSmithKline
  • Neil Schachter
    • Mount Sinai School of Medicine
  • Nicholas Locantore
    • GlaxoSmithKline
  • Walter G. Canonica
    • Medical University of Genoa
  • Yuanjue Zhu
    • Peking Union Medical CollegeChinese Academy of Medical Sciences
  • Frank Barnhart
    • GlaxoSmithKline
Review Article

DOI: 10.2165/0003495-200868002-00002

Cite this article as:
Rennard, S., Knobil, K., Rabe, K.F. et al. Drugs (2008) 68: 3. doi:10.2165/0003495-200868002-00002

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

The aim of this review is to ensure that the clinical data for the efficacy and safety of cilomilast in chronic obstructive pulmonary disease (COPD) are available in the public domain. To accomplish this, data from 18 trials that evaluated cilomilast are summarized. These trials include two studies, results from which have been published.[1,2]

1.1 Chronic Obstructive Pulmonary Disease (COPD)

COPD is a common disease which is usually characterized by partially reversible airflow limitation, progressive loss of lung function and an abnormal inflammatory response in the lung to noxious substances, the most common of which is cigarette smoke.[3] The disease is associated with increased frequency of exacerbations and deterioration of health status, as well as the development of non-pulmonary complications.[3] The pathogenesis of COPD remains unclear but chronic inflammation throughout airways, parenchyma and pulmonary vasculature is believed to have a central role.[3,4]

1.2 Potential Shortcomings of Pharmacotherapy in COPD

Inflammatory processes have been implicated in both the bronchiolar and alveolar damage seen in COPD and are thought to underlie the accelerated yearly decline in forced expiratory volume in 1 second (FEV1) that is characteristic of COPD.[5] The inflammation seen in COPD is clearly different from that seen in asthma with a predominantly neutrophilic rather than eosinophilic bronchitis.[6,7] The prevalent T cells in COPD are the CD8+ cells, which are found in increased numbers in the airway epithelium.[7] There is also an increase in alveolar macrophages, neutrophils, B cells and CD8+ T lymphocytes in various parts of the lung, which is usually associated with a decline in lung function.[810] Airway wall inflammation is present even in the early stages of COPD.[11]

There is a need for a novel anti-inflammatory treatment, as experimental data indicate that the inflammatory process in COPD, particularly those that are neutrophil mediated, may be resistant to the anti-inflammatory effects of corticosteroids.[12,13] Novel anti-inflammatory therapies are therefore being developed as potential therapeutic agents, including selective phosphodiesterase (PDE) inhibitors.[14]

1.3 Phosphodiesterase Inhibitors

Phosphodiesterase 4 (PDE4) inhibitors act by inhibiting the degradation of the intracellular second messenger, cyclic adenosine monophosphate (cAMP).[14] cAMP mediates a broad suppression of immune and inflammatory cell activity[15] and mediates the relaxation of airway smooth muscle through the activation of protein kinase A.[15] It is degraded by the PDE enzymes, which are widely distributed in a variety of tissues.[16] Currently, there are at least 11 distinct families of PDE isoenzymes identified.[1618] Of these, PDE4 is the predominant PDE isoenzyme in nearly all immune and inflammatory cells and is a major regulator of cAMP content in airway smooth muscle.[15,19] Inactivation of cAMP by PDE4 increases the level of cAMP, which in turn leads to inhibition of proinflammatory mediator release, augmentation of the release of anti-inflammatory mediators and bronchodilation.[20]

PDE4 inhibitors have a high therapeutic potential as nonsteroidal disease controllers in inflammatory airway diseases such as asthma, COPD and rhinitis.[15,19,20] PDE4 inhibition leads to the suppression of two very important cytokines, tumour necrosis factor (TNF)-α and granulocyte-macrophage colony-stimulating factor (GM-CSF), which may play a role in COPD.[21,22]

In airway diseases, control of inflammation by specific PDE4 inhibition is expected to decrease the adverse effects observed with the initial nonselective PDE inhibitors such as theophylline.[23] The first-generation PDE4 inhibitors such as rolipram were shown to have efficacy but, unfortunately, their beneficial actions were significantly offset by their potent adverse effects including nausea and vomiting, which resulted from central nervous stimulation and increased gastric acid secretion due to gastric parietal cell stimulation.[24,25] Newer PDE4 inhibitors such as cilomilast have been developed in recent years as an attempt to improve the therapeutic index of the first generation of PDE4 inhibitors. Cilomilast (Ariflo®, GlaxoSmithKline [GSK]) is an orally active second-generation PDE4 inhibitor with a half-life of 7 hours and a better side-effect profile than the first-generation PDE4 inhibitors.[20]

Cilomilast is a potent and selective PDE4 inhibitor which modulates pathophysiological processes of direct relevance to COPD. In preclinical studies, cilomilast relaxed airway smooth muscle, inhibited immune and inflammatory cell activation and inhibited cellular infiltration and mediator release.[2628] The effect of cilomilast on airway cells was evaluated using bronchial epithelial cells and induced-sputum cells (squamous and immune cells) from COPD patients, normal controls and smokers.[29] Cilomilast significantly reduced TNFα release by bronchial epithelial and sputum cells, and GM-CSF release by sputum cells.[29] Supernatants of sputum and bronchial epithelial cells treated with cilomilast also demonstrated significantly reduced neutrophil chemotaxis.[29] Furthermore, cilomilast attenuated the inhaled lipopolysaccharide-induced pulmonary neutrophilia and oedema with equivalent effectiveness to that of high-dose, orally administered prednisolone in an animal model.[30] This suggested a possible beneficial role for cilomilast on the neutrophilic inflammation in COPD.

The anti-inflammatory effects of cilomilast demonstrated in both in vitro and in vivo preclinical studies have also been observed in patients with COPD. In a study designed to evaluate the effects of cilomilast on inflammation in patients with COPD, although 12 weeks’ treatment with cilomilast did not significantly reduce neutrophils in induced sputum, which was the primary endpoint, cilomilast significantly reduced subepithelial CD68+ macrophages and CD8+ lymphocytes in biopsies when compared with placebo.[1] At the time, this was the first demonstration of a reduction of airway tissue inflammatory cells in COPD by any therapy and it was suggested that the clinical benefits of cilomilast may be due primarily to anti-inflammatory effects.

1.4 Clinical Studies with Cilomilast

Cilomilast was studied in an extensive clinical programme, with over 6000 patients exposed to cilomilast. Two phase II clinical trials were conducted in outpatients with moderate COPD to evaluate the safety, tolerability and efficacy of orally administered cilomilast. In one of these studies (study 032), patients were randomized to receive either cilomilast (5, 10 or 15 mg twice daily) or placebo for 6 weeks.[31] At the highest dose, cilomilast produced a progressive and statistically significant increase in trough (predose) FEV1, and at the end of week 6 cilomilast had improved trough FEV1 by 11% compared with placebo.[31] Similar improvements at week 6, relative to placebo, were observed for the 15 mg twice-daily dose in forced vital capacity (FVC), peak expiratory flow rate (PEFR), exertional dyspnoea and rescue bronchodilator use. Lower doses of cilomilast produced negligible improvements in lung function, which was confirmed in a similar multicentre 4-week study (study 038).[32] Quality-of-life assessments using the St George’s Respiratory Questionnaire (SGRQ) were also recorded before and after therapy with cilomilast (15 mg twice daily) or placebo.[31] Consistent improvements approaching that defined as clinically meaningful in the total and composite scores of the SGRQ were recorded for patients who received cilomilast 15 mg when compared with the placebo group, although this did not reach statistical significance.[32]

The improvement in lung function and health status demonstrated in the phase II trial resulted in a commitment to a comprehensive phase III development programme evaluating the efficacy, safety and mechanism of action of cilomilast at the maximum tolerated dose of 15 mg twice daily.

During the preclinical development of cilomilast, gastrointestinal (GI) effects were noted as a potential safety concern. Extensive monitoring of GI adverse events was therefore undertaken throughout the clinical programme including testing for faecal occult blood. The cilomilast clinical development programme also evaluated the safety of patients by examination of laboratory parameters, vital signs, serial electrocardiograms and 24-hour Holter monitoring.

Five pivotal, randomized, double-blind, placebo-controlled, multicentre, parallel-group studies of similar design were conducted evaluating the effect of cilomilast (15 mg twice daily) for 24 weeks in patients with COPD. Additional phase III and long-term safety studies were conducted to provide supporting data (table I). Data from these studies are found in the subsequent sections of this review. An overall discussion and conclusion of all data is found in section 8.
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Table I

Phase II and III studies in the cilomilast development programmea,b

Despite early promise from the phase II studies and some of the early pivotal phase III studies, data from the other phase III studies were disappointing. A lack of consistency of results was observed which did not support the use of cilomilast in COPD and therefore the clinical programme was terminated.

2. Evidence of Anti-Inflammatory Activity of Cilomilast in Induced Sputum and Bronchial Biopsies from COPD Patients

2.1 Study Objectives

Three studies were conducted to assess the anti-inflammatory properties of cilomilast.

In study SB207499/076 (076)[1] and study SB207499/110 (110),[33] the primary objectives were to examine the effects of cilomilast and placebo on the inflammatory cell profile and inflammatory mediator concentrations in induced sputum and, in addition, to further evaluate the clinical efficacy of cilomilast in terms of pulmonary function. In study 076 a further objective was to examine the effects on tissue histology and morphology in patients with COPD by using bronchoscopic bronchial biopsy. Study 076 has been previously published.[1]

In study SB207499/181 (181)[34] the primary objective was to compare the numbers of inflammatory cells of distinct immuno and ultrastructural phenotypes after treatment with cilomilast and placebo in patients with COPD, using bronchial biopsy. The secondary objective was to compare the relative numbers (i.e. percentage) of distinct inflammatory cells after treatment in induced sputum.

2.2 Methods

2.2.1 Patients

For study 076, patients (aged 40–80 years) entered the study in seven centres in the UK, Germany, Italy, Spain and the Netherlands during a study period from September 1999 to September 2000.[1] To be eligible for enrolment patients had to meet the following criteria: a clinical diagnosis of COPD, a cigarette-smoking history of ≥10 pack-years, a pre-salbutamol FEV1 to FVC ratio ≤0.7, post-salbutamol reversibility ≤15% or ≤200 mL and post-salbutamol FEV1 ≥1.2 L and ≥30% and ≤70% (FEV1 ≥40% and ≤70% for one centre) of predicted normal. In selected centres, an additional inclusion criterion was patients without hypoxaemia. The study excluded patients with a primary diagnosis of asthma, poorly controlled COPD, active pulmonary disease (other than COPD), those receiving treatment with long-term oxygen therapy, and with clinically significant GI conditions and uncontrolled disorders of major body systems.[1]

For study 110,[33] patients entered the study in ten 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 post-salbutamol FEV1 was ≥1.0 L and there was no requirement for hypoxaemia.

For study 181,[34] patients entered the study in 27 centres in 12 countries during a study period from March 2003 to April 2004. The entry criteria were the same as for study 076 except that all patients were required to have an FEV1 ≥40% and ≤70% of predicted normal and a poor reversibility after administration of salbutamol 400 μg (i.e. ≤10% of predicted normal FEV1 or ≤200 mL increase).

The protocols were approved by an institutional review board at all sites and all patients provided written informed consent prior to any study procedures.

2.2.2 Study Design

Studies 076[1] and 110[33] were multicentre, randomized, 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 least 8 visits over the 16-week period with visits at weeks 1, 2, 4, 8 and 12 during treatment. At the end 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 induced sputum sample was taken at screening, baseline and after 2, 4, 8 and 12 weeks of treatment. 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, bronchial biopsies were performed at week —2 (baseline sample) and week 10.

Study 181[34] was a multicentre, randomized, double-blind, placebo-controlled, parallel-group 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+ (macrophages) and subepithelial CD8+ (cytotoxic T lymphocytes) in biopsy tissue with secondary endpoints of inflammatory cells measured in induced sputum. Bronchial biopsies were performed prior to randomization and after 12 weeks of treatment. Six biopsies of adequate size (2 mm) were performed on the right side beginning at the subcarinae in the right lower lobe (2 biopsies), then the right middle lobe (2 biopsies) and finally the right upper lobe (2 biopsies).

Prior to biopsy, patients were required to have a pre-salbutamol FEV1 40–80% predicted normal value, no history of bleeding diathesis and a normal platelet count. Sputum induction was carried out at baseline and after 13 weeks of treatment.

In all studies, safety assessments included evaluation of adverse events (including additional monitoring for GI adverse events), vital signs, electrocardiograms (studies 076 and 110) and clinical laboratory tests including faecal occult blood tests.

2.2.3 Statistical Methods

Studies 076 and 110 intended to have at least 90% power to detect a significant difference in sputum neutrophils assuming a 20% treatment difference, a standard deviation (SD) of 15% and a significance level of 0.05. It was therefore estimated that 30 patients per group be evaluable (i.e. without protocol violations) at endpoint.

Study 181 had 90% power to detect an approximate difference of 175 cells/mm2 (assumed SD of 230 cells/mm2) in CD8+ cells and a difference of 80 cells/mm2 (assumed SD 75 cells/mm2) in CD68+ between cilomilast and placebo at significance level of 2.5%.

The primary population of interest in these studies was the per protocol population excluding patients with protocol violations. Descriptive assessment of treatment differences for the efficacy variables were based on an analysis of variance model with effects for centre and treatment group. Least squares means along with associated 95% confidence intervals were calculated for each treatment group. Treatment differences were assessed using t-tests on the least squares means.

2.3 Results

2.3.1 Study Population

In study 076, 59 patients were randomized to receive placebo (n = 30) or cilomilast (n = 29) and in study 110, 65 patients were randomized to receive placebo (n = 34) or cilomilast (n = 31). In study 181, 127 patients were randomized to receive placebo (n = 62) or cilomilast (n = 65). In general, there were no marked differences in the baseline characteristics of the two treatment groups in any study and the demographic and baseline characteristics of COPD for all studies are shown in table II.
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Table II

Summary of demographic characteristics at screening (all randomized patients)

2.3.2 Primary Efficacy Measures

In study 076, there was no evidence for a difference in sputum neutrophils as a percentage of the total cells between cilomilast and placebo at any timepoint (figure 1). At endpoint, the mean difference was 2.1% (p = 0.697).[1]
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Fig. 1

Mean (SEM) change from baseline (BL) in sputum neutrophil counts by week in study 076.[1] EP = endpoint.

In study 110, there were changes in percentage sputum neutrophils that favoured cilomilast (figure 2). When compared with placebo, cilomilast decreased the mean percentage of sputum neutrophils at endpoint (−14.9%), although this difference was not statistically significant (p = 0.065). It should be noted that samples from a number of patients resulted in inadequate sputum slides (e.g. due to the presence of too few cells, squamous contamination being too high or cell degradation) in both treatment groups.
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Fig. 2

Mean (SEM) change from baseline (BL) in sputum neutrophil counts by week in study 110.[33] EP = endpoint.

In study 181, at endpoint there was a smaller reduction from baseline in CD68+ cells in the cilomilast group than in the placebo group (20.8 vs 50.0 cells/mm2) which was not statistically significant (p = 0.093). This represented a 35% and 17% decrease from baseline levels of CD68+ cells in the placebo and cilomilast groups, respectively. Reductions from baseline at endpoint in CD8+ cells were similar in both groups (75.3 cells/mm2 in the cilomilast group and 69.8 cells/mm2 in the placebo group) which was not statistically significant (p = 0.690). The reductions from baseline in the level of CD8+ T lymphocytes were 37% and 33% in the cilomilast and placebo treatment groups, respectively (figure 3).
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Fig. 3

Mean (SEM) change from baseline (BL) in (a) CD68+ macrophages and (b) CD8+ lymphocytes in study 181.[34] EP = endpoint.

2.3.3 Secondary Efficacy Endpoints

In study 076, a statistically significant mean decrease from baseline in subepithelial macrophages CD68+ per area tissue at endpoint was shown (−42.8 cells/mm2 for cilomilast, 33.2 cells/mm2 for placebo; p = 0.005). The mean change from baseline in subepithelial CD8+ lymphocytes per area tissue showed some improvement (cilomilast group −132.4 compared with 24.4 for placebo group), but did not reach statistical significance (p = 0.055).[1] There was no difference between cilomilast and placebo for the other endpoints (table III).
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Table III

Mean change from baseline to endpoint in secondary efficacy endpoints in study 076[1]

In study 110, there were no statistically significant differences between the cilomilast and placebo groups for sputum macrophages, sputum total cell counts, sputum eosinophils or sputum lymphocytes (table IV).
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Table IV

Change from baseline to endpoint in secondary efficacy endpoints in study 110[33]

In study 181, there were reductions in the total cell count in both groups (cilomilast 5.3 × 106/mL; placebo 8.0 × 106/mL), but the difference was not statistically significant (p = 0.439). Other results were generally similar in both groups and there were no statistically significant differences between treatments (table V). For biopsy endpoints, there was a reduction from baseline in the number of subepithelial neutrophils per unit area of biopsy tissue at endpoint in the cilomilast and placebo groups (2.2 and 21.6 cells/mm2, respectively). The reduction was significantly larger in the placebo group (p = 0.019). Reduction in cell numbers per area of biopsy tissue were seen for CD4+ lymphocytes, interleukin-8 mRNA positive cells, TNFα mRNA positive cells and CD45 positive cells in both treatment groups. There were no statistically significant differences between the treatments, although in most cases the reductions in cell numbers were smaller in the cilomilast group (table VI).
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Table V

Change from baseline to endpoint in sputum secondary efficacy endpoints in study 181[34]

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Table VI

Change from baseline to endpoint in biopsy secondary efficacy endpoints in study 181[34]

2.4 Safety Results

2.4.1 Adverse Events

In study 076, during the double-blind phase, 20 patients (67%) in the placebo group had adverse events, compared with 22 patients (76%) in the cilomilast group. There was a higher incidence of adverse events relating to the GI and central/peripheral nervous system body systems in the cilomilast group compared with placebo (GI 52% cilomilast, 27% placebo; CNS/peripheral 24% cilomilast, 7% placebo) [table VII]. Most of the events in the central/peripheral nervous system body system were headaches. In study 110, the overall incidence of adverse events was lower in the placebo group (59%) than in the cilomilast group (77%). The most common adverse events in the cilomilast group were back pain, diarrhoea, dyspepsia, viral infection and nausea (all 13%) and in the placebo group a COPD exacerbation (15%) [table VII]. In study 181, the overall incidence of adverse events was similar in both treatment groups and the most frequently reported events in both groups were headache and nasopharyngitis. There was a higher incidence of adverse events relating to the GI body system in the cilomilast group compared with placebo (31% vs 16%) with events such as nausea, diarrhoea and vomiting occurring more frequently in the cilomilast group (table VII).
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Table VII

Patients with the most frequently reported adverse events (≥10% patients in any group in any study)

2.4.2 Adverse Events Leading to Withdrawal

In study 076, adverse events leading to withdrawal occurred in four patients in the cilomilast group and no patients in the placebo group. The adverse events leading to withdrawal that had a suspected or probable relationship to study medication were abdominal pain, dyspepsia and nausea. No patient was withdrawn because of an adverse event in study 110, and in study 181 five patients were withdrawn owing to adverse events, four (6%) in the cilomilast group and one (2%) in the placebo group. The events leading to withdrawal were atrial flutter, gastritis, gastro-oesophageal reflux disease, nausea and enteritis (cilomilast) and an exacerbation of COPD (placebo). No deaths occurred in any of the three studies.

2.4.3 Other Safety Assessments

Overall, in all studies the mean changes from baseline in clinical laboratory parameters and vital signs were small and comparable between the treatment groups. There were small changes in ECG parameters in studies 076 and 110 from baseline to endpoint in both treatment groups, with no clinically relevant differences noted within or between groups.

In study 076, 4% of patients receiving placebo (1 of 25) and 16% receiving cilomilast (4 of 25, one of whom had a positive test at baseline) had positive faecal occult blood results. In study 110, overall, 3.4% (1 of 29) of patients who received placebo and 3.7% (1 of 27) who received cilomilast had a positive faecal occult blood result during double-blind treatment. In study 181, 7.3% of patients receiving cilomilast (3 of 41, one of whom had a positive test at baseline) and 12.5% receiving placebo (5 of 40, two of whom had a positive test at baseline) had positive faecal occult blood results.

2.5 Summary

  • Study 076 was the first study to demonstrate a reduction of airway tissue inflammatory cells in COPD by any therapy.[1] Although no significant change was found in the primary endpoint, sputum neutrophil count, a substantial reduction in tissue CD8+ T lymphocytes and CD68+ macrophages was demonstrated.

  • Study 110 did not provide definitive evidence of activity of cilomilast on the cellular and biochemical indices of inflammation in patients with COPD.

  • Study 181 did not provide any definitive evidence of activity of cilomilast on the cellular and biochemical indices of inflammation in patients with COPD.

  • No clinically relevant safety issues in laboratory values including faecal occult bloods, vital signs or ECGs were revealed in these studies.

3. Efficacy and Safety of Cilomilast in the Pivotal Phase III Studies

3.1 Study Objectives

The primary objective of the pivotal studies was to assess the clinical efficacy of oral cilomilast 15 mg twice daily by assessment of trough FEV1 and total score of the SGRQ over 24 weeks in patients with COPD. Secondary objectives included assessment of the efficacy of cilomilast on COPD exacerbation rates, FVC, and post-exercise breathlessness.

3.2 Materials and Methods

3.2.1 Study Design

Five pivotal, multicentre, randomized, double-blind, placebo-controlled, parallel-group studies of similar design were conducted evaluating the effect of cilomilast (15 mg twice daily) for 24 weeks in patients with COPD. Three studies were conducted in North America (studies SB207499/039,[2] SB207499/156[35] and CIL103657;[36] NCT00103922) and two studies were conducted in Europe and the rest of the world (studies SB207499/091[37] and SB207499/042[38]) [table VIII]. Study 039 was the first pivotal phase III study completed and has been previously published.[2] The studies had the same study design with a 4-week, single-blind, placebo run-in period followed by 24 weeks of double-blind treatment (figure 4). One tablet of cilomilast 15 mg or matched placebo was taken immediately after breakfast and after the evening meal, in order to improve GI tolerability. The treatment period was followed by a 1-week safety follow-up period for patients who did not enter an optional open-label extension (see section 4) or who withdrew prior to the end of the study.
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Table VIII

Study details

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Fig. 4

Study schematic of a 24-week phase III pivotal study. * No visit (V) 2 in study 657. bid = twice daily.

The local ethics committee or institutional review board approved the study protocol at each centre and all patients gave written informed consent to participate.

Patients were assessed for eligibility at the screening visit. After the 4-week run-in period, eligible patients were randomized in a 2 : 1 ratio (studies 039, 042 and 091) or 1 : 1 ratio (studies 156 and 657) to receive twice-daily oral treatment with either cilomilast 15 mg or placebo during a 24-week double-blind phase.

Patients attended the clinic weekly up to week 2, every 2 weeks up to week 4 of treatment and then at 4-weekly intervals. A final follow-up visit occurred 1 week after treatment completion (figure 4). The co-primary endpoints in these studies were the change from baseline in FEV1 measured at trough drug concentrations, and health status measured using the SGRQ. Secondary efficacy endpoints included FVC, incidence of COPD exacerbations and post-exercise dyspnoea assessed by the modified Borg Dyspnoea scale.[39] Immediately after exercise, patients were asked to rate their breathlessness on a scale from 0 (nothing at all) to 10 (maximal) in all studies except study 657.[36] Safety was measured by the assessment of adverse events, vital signs, clinical laboratory tests including faecal occult blood tests, ECGs and 24-hour Holter readings (in a subset of patients in studies 091, 039 and 042).

3.2.2 Patients

The studies generally had the same patient selection criteria (table IX). The cilomilast pivotal development programme was restricted to patients with poor reversibility to bronchodilator (<15% or 200 mL improvement over baseline in FEV1).
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Table IX

Main inclusion and exclusion criteria used in the pivotal phase III studies

To be eligible for participation, patients had to be diagnosed with COPD (by American Thoracic Society or European Respiratory Society definition), be aged 40–80 years, have a pre-bronchodilator FEV1 to FVC ratio of ≤0.7, a post-bronchodilator FEV1 between ≥30% and ≤70% of predicted normal (except study 657, which had no lower limit) and have a cigarette smoking history of ≥10 pack-years. Randomization criteria required a total symptom score (cough, sputum production and breathlessness) of ≥3 on at least 5 of 10 days prior to baseline for studies 039, 091 and 042. There were no symptom score requirements for study 156.

Study 657 was designed to achieve a more symptomatic population to optimize the potential of cilomilast to show an improvement in SGRQ and exacerbations. The criteria were therefore amended to include at least one exacerbation requiring either antibiotics or oral corticosteroids or hospitalization in the year prior to screening, a symptom score of ≥4 on at least 5 of 10 days prior to randomization and removal of the lower end FEV1 requirement (previous studies had 30–70% predicted requirement).

Patients were provided with salbutamol metered dose inhalers for use on an as-needed basis and were permitted to continue inhaled short-acting anticholinergics and mucolytics at a stable dose throughout the study. No other COPD medications were allowed except for the short-term treatment of exacerbations.

3.2.3 Study Procedures

Patients were asked to refrain from taking any respiratory medication for at least 2 hours and refrain from smoking for at least 2 hours before each clinic visit. Trough (predose) FEV1 was performed using standardized spirometry equipment supplied by GSK at all centres within each study.

Overall and post-exercise (6-minute walk) dyspnoea were assessed using the modified Borg Dyspnoea scale at baseline and at each visit after randomization (except study 657). The SGRQ, a disease-specific health status tool, was administered at weeks 0, 12 and 24. COPD exacerbations, defined as a worsening of COPD symptoms requiring changes to normal treatment, including antimicrobial therapy, short courses of oral steroids and other bronchodilator therapy, were recorded throughout the study. COPD exacerbations were categorized as level 1, 2 or 3, based on the treatment received by the patient for the exacerbation. Level 1 (mild) was defined as an acute worsening of COPD that was self-managed by the patient at home by increasing usual COPD medications, level 2 (moderate) for those who required additional treatment (e.g. a short course of oral steroids or antibiotics prescribed by the physician) and level 3 (severe) as requiring hospitalization.

At all visits during the double-blind study period, patients were assessed for compliance with the medication as well as for use of concomitant medications.

3.2.4 Statistical Analysis

The co-primary endpoints (change from baseline in trough FEV1 and SGRQ) were analysed using a repeated measures model to compare the average change over 24 weeks with additional comparisons made at individual timepoints. Effects for treatment, time and centre were included in the model. The difference between treatment groups was evaluated through a t-test on the least squares means. 95% confidence intervals were calculated on the least squares means of the two groups and on their difference. Continuous secondary variables were analysed similarly to the co-primaries. To account for co-primary endpoints, the Hochberg method was used to adjust the significance level in the test for treatment effect. If both p-values were <0.05, both primary 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 exacerbation-free survival rate at 24 weeks along with 95% confidence intervals was estimated for each treatment group using the Kaplan-Meier product limit. Analyses were performed for the intent-to-treat (ITT) population, composed of all patients who received at least one dose of double-blind medication and had a baseline and at least one on-therapy efficacy assessment.

3.2.5 Sample Sizes

For studies 042 and 091, the planned sample size was 645 patients to obtain 450 evaluable patients. This gave at least 90% power to detect a 4-unit difference in total SGRQ score (adjusted significance level of 0.025 assuming a standard deviation of 12 units). For FEV1, there was at least 90% power to detect a difference of 120 mL assuming a standard deviation of 270 mL. For study 156, the planned sample size was 830 patients to obtain 550 completed patients. The study had 90% power to detect a 50 mL difference in FEV1 (assuming a visit standard deviation of 210 mL with between-visit correlation of 0.68) and a 4-unit difference in the SGRQ (assuming a standard deviation of 12) at a significance level of 0.05. For study 657, the planned sample size was 600 randomized patients. The study was designed to detect a 50 mL difference in FEV1 and a 4-unit difference in SGRQ total score with 90% joint power. Based on previous studies, the powering of the study assumed a 160 mL standard deviation for FEV1, and a 10.5-unit standard deviation for SGRQ total score.

Details for study 039 have been previously published.[2]

3.3 Results

3.3.1 Patient Disposition

A summary of the number of patients exposed to cilomilast and placebo in the pivotal studies is presented in table X. Cilomilast was compared with placebo in populations ranging from 613 to 825 patients per study. The number of patients withdrawn prior to randomization was in the range of 27–34% except for study 657, where this increased to 69% owing to the more difficult study entry criteria. In each study, the primary reason for withdrawal of patients prior to randomization was failure to meet inclusion/exclusion criteria. This ranged from 11% of withdrawn patients in study 156 to 61% in study 657. The percentage of patients in each group that withdrew from the double-blind phase of the study was higher in the cilomilast treatment group (ranging from 26% to 35%) compared with the placebo group (ranging from 23% to 26%). The main reason for withdrawal after randomization in each study was an adverse event (see section 3.4). The percentage of patients withdrawn from all the studies for reasons other than adverse experience was comparable between the cilomilast and placebo treatment groups.
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Table X

Patient accountability in the pivotal efficacy studies

3.3.2 Baseline Characteristics

The two treatment groups in the randomized patient population were well matched for demographic characteristics and for baseline characteristics of COPD including lung function (table XI and table XII). The use of salbutamol was similar between the treatment groups and ranged from 81% to 100% in the cilomilast treatment group and 79% to 100% in the placebo group. A similar number of patients continued with a stable dose of ipratropium bromide during the study (33% to 57% in the cilomilast group and 31% to 55% in the placebo groups) and similar percentages of patients in both treatment groups had previously used inhaled corticosteroids (ICS). 93 to 98% of placebo-treated patients and 87 to 95% of cilomilast-treated patients were at least 80% compliant with their study medication during the double-blind treatment period.
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Table XI

Baseline demographics of patients (pts) entered into the five pivotal studies

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Table XII

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

3.3.3 Primary Efficacy Endpoints

Trough Forced Expiratory Volume in 1 Second (FEV1)
When averaged over 24 weeks, the mean change from baseline in FEV1 in the cilomilast group showed improvement compared with placebo in all studies (table XIII). The mean change from baseline in FEV1 over time is presented graphically in figure 5. In studies 657 and 156, there was a statistically significant difference in FEV1 between the cilomilast and placebo treatment groups (44 mL, p < 0.001 for study 657; 24 mL, p = 0.024 for study 156). In study 039 there was also a statistically significant difference in FEV1 between the cilomilast and placebo treatment groups of 40 mL (p = 0.002) [data previously published].[2] In studies 042 and 091, when averaged over 24 weeks, the improvements in FEV1 in the cilomilast treatment group relative to placebo were 30 and 29 mL, respectively, but these were not statistically significant. In study 042, the difference from placebo of 30 mL had a p-value <0.05 (p = 0.044); however, this difference was not statistically significant owing to adjustment of the significance level to 0.025 using the Hochberg method to account for co-primary endpoints.
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Table XIII

Mean change from baseline in trough forced expiratory volume in 1 second averaged over 24 weeks

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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.

In general, the magnitude of the response at endpoint was larger than that observed when averaged over 24 weeks. Studies 657 and 156 demonstrated an improvement relative to placebo in mean change from baseline in FEV1 at endpoint of 38 mL (p = 0.018) and 40 mL (p = 0.013), respectively. In study 039, the difference was 80 mL (p < 0.001) and in studies 042 and 091, the differences in FEV1 at endpoint between the cilomilast and placebo treatment groups were 40 mL (p = 0.050) and 30 mL (p = 0.146), respectively.

Health Status

The mean total score of the SGRQ at baseline in the placebo- and cilomilast-treated patients in the five pivotal studies ranged from 41.5 to 52.5 units. When averaged over 24 weeks, there were improvements from baseline in the total score of the SGRQ in both the cilomilast and placebo treatment groups in all pivotal studies, with the exception of the placebo group in study 039.

Two studies (039 and 156) demonstrated a significant improvement in the total score of the SGRQ of the cilomilast group compared with placebo when averaged over 24 weeks, whereas there were no notable differences in studies 657, 042 and 091 (table XIV, figure 6).
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Table XIV

Mean change from baseline in St George’s Respiratory Questionnaire total score averaged over 24 weeks

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Fig. 6

Mean (SEM) change from baseline in the total score of the St George’s Respiratory Questionnaire (SGRQ).

3.3.4 Secondary Endpoints

Trough FVC
The mean FVC at baseline in both treatment groups in the five pivotal studies ranged from 2.48 to 2.90 L. Across the pivotal studies, the mean improvement in FVC was 27–110 mL greater in the cilomilast treatment group than in the placebo group (table XV). The largest increases were seen in studies 039 and 156, with improvements in FVC in the cilomilast treatment group relative to placebo at endpoint of 110 mL (p = 0.001) for study 039 and 60 mL (p = 0.022) for study 156. In studies 657, 042 and 091, the differences in FVC at endpoint between cilomilast and placebo were 27 mL (p = 0.355), 50 mL (p = 0.129) and 60 mL (p = 0.073).
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Table XV

Treatment difference between cilomilast and placebo in secondary endpoints in the individual studies

COPD Exacerbations

Across the five pivotal studies, the percentages of patients who were exacerbation-free at 24 weeks ranged from 64% to 80% in the placebo treatment group and 66% to 82% in the cilomilast treatment group (table XV). In two studies (039 and 091) there were higher percentages of patients who were exacerbation-free at 24 weeks in the cilomilast treatment group compared with the placebo group. In study 042, the percentages of patients who were exacerbation-free at 24 weeks were comparable between the groups and in studies 156 and 657; the percentage of patients who were exacerbation-free at 24 weeks was higher in the placebo group than in the cilomilast group (table XV).

Dyspnoea

The mean baseline post-exercise dyspnoea score for the cilomilast- and placebo-treated patients ranged from 3.22 to 3.80 points (modified Borg Dyspnoea scale) across the four studies in which it was measured. When averaged over 24 weeks, there were small improvements in the post-exercise dyspnoea score in the cilomilast treatment group compared with placebo in all studies, but these improvements were not statistically or clinically significant.

3.4 Safety and Tolerability

A similar percentage of patients in each group experienced at least one adverse event during the 24-week period (cilomilast 78%; placebo 76%). The most commonly reported adverse events are shown in table XVI. Adverse events associated with the GI body system such as nausea, diarrhoea, abdominal pain, dyspepsia and vomiting were reported more frequently in the cilomilast treatment group compared with the placebo group. The time of initial onset for the majority of GI adverse events in patients who received cilomilast was in the first 2 weeks of therapy.
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Table XVI

Number (%) of patients with the most frequently reported adverse events (≥5% patients in either treatment group)

Overall, the percentage of patients experiencing an adverse event on therapy which led to withdrawal was higher in the cilomilast group (17%) than in the placebo group (10%). The most common adverse events leading to withdrawal are shown in table XVII. The most frequent withdrawal adverse events for cilomilast-treated patients were nausea (5%), abdominal pain (4%) and diarrhoea (4%). In comparison, the most frequent withdrawal event for placebo-treated patients was COPD (3%).
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Table XVII

On-therapy adverse events leading to withdrawal in ≥5 patients in either treatment group

Eleven patients had fatal adverse events in the pivotal trials either during treatment or during the post-study follow-up period. Of these, four were treated with placebo and seven with cilomilast. In 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 between treatment groups during cardiovascular monitoring of ECG assessments, sitting, or orthostatic 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 parameters were small and were comparable between the treatment groups. The percentage of patients with laboratory values of potential clinical concern was low and there were no clinically relevant differences between groups. There were no clinically significant differences in the rates of positive faecal occult 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 these five studies.

Laboratory observations during the phase III pivotal trials suggested no systematic effect of treatment with cilomilast on haematology values, serum measures of liver or kidney function, glucose metabolism 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 other two studies demonstrated similar improvements in FEV1, neither achieved statistical significance.

  • Only one study (039)[2] demonstrated a clinically significant effect following treatment with cilomilast on the total score of the SGRQ.[2] In the other studies, the placebo groups also improved to a similar extent to the cilomilast groups.

  • Two studies (039,[2] 091) demonstrated statistically significant reductions in the risk of experiencing at least one level 2 or 3 COPD exacerbation in cilomilast-treated patients relative to placebo.

  • All studies demonstrated cilomilast-induced improvements in FVC but only two were statistically significant.

  • Except for GI adverse events, cilomilast was relatively well tolerated.

  • No clinically relevant differences were observed between treatment groups during cardiovascular monitoring of ECG assessments, sitting, or orthostatic vital signs and no systematic effect of treatment with cilomilast on haematology values and serum measures of liver or kidney function. In addition, there were no clinically significant differences in the rates of positive faecal occult bloods between cilomilast- and placebo-treated patients.

4. Long-Term Tolerability and Safety of Cilomilast in Patients with COPD

4.1 Study Objectives

Three studies were conducted. The primary objective of two of these was to evaluate the long-term safety and tolerability of cilomilast in patients with COPD, with secondary objectives to further evaluate the efficacy of cilomilast in terms of pulmonary function and quality of life (study numbers SB207499/040[40] and SB207499/041[41]). The primary objective of the third study was to assess the clinical efficacy of cilomilast over a 52-week treatment period in patients with COPD who were poorly reversible to bronchodilators by assessment of the risk of the occurrence of exacerbations of COPD and assessment of FEV1 at trough drug concentrations (study number SB207499/157[42]).

4.2 Materials and Methods

4.2.1 Study Design

Studies 040 and 041 were phase III, multicentre, open-label, extension studies. Patients who completed the phase III pivotal studies 042[38] or 091[37] could participate in study 040 and those who completed the phase III pivotal study 039[2] could participate in study 041. Patients were assessed for eligibility to enter the studies at their final scheduled visit of the previous trial and enrolled directly into the extension study to receive cilomilast 15 mg twice daily. The study blind from the previous studies was not broken. Study 040 was conducted from June 1999 to September 2002 at 130 centres in 10 countries (Australia, South Africa, Belgium, Finland, France, Germany, the Netherlands, Norway, Spain and the UK) and study 041 was conducted from June 1999 to June 2002 at 78 centres in the US, Mexico and Canada.

Details of the inclusion and exclusion criteria for the original phase III studies have been reported 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 48 until the final visit in study 040 and remained at 4-week intervals in study 041. Patients attended a follow-up visit 1 week after treatment was completed (up to week 156).

Study 157[42] was a randomized, double-blind, placebo-controlled, parallel-group study, conducted from November 2001 to January 2004 at 137 centres in 18 countries. Previous data from two phase III studies (studies 039 and 091) had demonstrated that cilomilast significantly reduced exacerbation rates over 24 weeks of treatment. Study 157 was designed to confirm and extend the results observed in these studies over a longer time frame and was powered for exacerbations.

Patients were assessed for eligibility at the screening visit and were required to meet the eligibility criteria as stated in the pivotal study section (section 3). The main difference was that in study 157, reversibility was defined by increases in FEV1 after the administration of salbutamol 400 μg of ≤10% of the predicted normal or ≤200 mL (or both). After a 4-week, single-blind, placebo run-in period, eligible patients were randomized in a 1 : 1 ratio to receive twice-daily oral treatment with either cilomilast 15 mg or placebo during a 52-week double-blind phase. Assignment to study drug was stratified according to smoking status (current smokers, former smokers). Patients attended the clinic every 2 weeks from the screening visit up to week 4 of treatment, and then at 4-weekly intervals until the end of 3 months. Thereafter, patients attended the clinic at 8-weekly intervals from weeks 12 to 52 (a total of 13 visits). A final follow-up visit occurred at week 53.

The local ethics committee or institutional review board approved the study protocols at each centre and all patients gave written informed consent to participate.

4.2.2 Assessments

In studies 040 and 041, safety measurements included the recording of adverse events, vital signs, ECGs and collection of blood and urine specimens for routine haematology and biochemistry and urinalysis during the study at each visit. Faecal occult blood, orthostatic blood pressure and heart rate were measured at 24 and 48 weeks and then every 48–52 weeks thereafter.

As a secondary objective of these studies, efficacy was assessed by measuring clinic trough pulmonary function parameters, and health status was measured using the SGRQ. Patients were asked to refrain from taking any respiratory medication or smoking for at least 2 hours before each clinic visit. Trough (predose) lung function was performed using standardized spirometry equipment supplied by GSK at all centres. The SGRQ was administered at weeks 0, 12 and 24 and every 24 weeks thereafter, prior to all other scheduled procedures. Patients continued to use β-agonists on an as-needed basis and all other COPD medications (with the exception of theophylline and aminophylline) were permitted without restriction at a stable dose if possible.

In study 157, the co-primary endpoints were the change from baseline in pre-bronchodilator FEV1 measured at trough drug concentrations averaged over 52 weeks and the incidence rate of level 2 (moderate) and level 3 (severe) COPD exacerbations during treatment. COPD exacerbations, defined as a worsening of COPD symptoms requiring changes to normal treatment, including antimicrobial therapy, short courses of oral steroids and other bronchodilator therapy, were recorded throughout the study. COPD exacerbations were categorized as level 1, 2 or 3, based on the treatment received by the patient for the exacerbation. Level 1 (mild) was defined as an acute worsening of COPD that was self-managed by the patient at home by increasing usual COPD medications, level 2 (moderate) for those that required additional treatment (e.g. a short course of oral steroids or antibiotics prescribed by the physician) and level 3 (severe) as requiring hospitalization.

Secondary efficacy endpoints included health status determined using the SGRQ. Safety was measured by the assessment of adverse events, vital signs, clinical laboratory tests including faecal occult bloods and ECGs.

Patients were asked to refrain from taking any respiratory medication for at least 4 hours and refrain from smoking for at least 2 hours before each clinic visit. Pulmonary function tests were performed before and 30 minutes after administration of salbutamol 400 μg using the same type of spirometer at all centres. COPD exacerbations were recorded throughout the study and the SGRQ was administered at baseline and weeks 28 and 52.

Adverse events and vital signs were recorded at each visit. Blood and urine specimens were taken for routine haematology and biochemistry and urinalysis during the study at each visit except for week 2 of the treatment period. A 12-lead ECG was performed at baseline and at weeks 12, 28 and 52 and at the safety follow-up visit. Faecal occult blood tests were performed between visits 1 and 3, immediately before or after visit 11 (for those who consented for an additional test) and also after the final dose of double-blind medication either at visit 12 or at the early withdrawal visit. For all studies, at all visits, patients were assessed for compliance with the medication by counting the number of tablets returned as well as for use of concomitant medications.

4.2.3 Statistical Analysis

In studies 040 and 041, the safety population included all patients who received at least one dose of cilomilast. No formal power calculations or statistical hypothesis testing were performed. Clinical laboratory parameters, vital signs, ECGs of interest and efficacy endpoints were evaluated with descriptive statistics.

In study 157, the planned sample size was 800 patients to obtain 550 completed patients, which was estimated to have a >90% power to detect a difference of 50 mL in FEV1 assuming a standard deviation of 210 mL in the change from baseline, and a 30% reduction in exacerbation rate, assuming an incidence of 0.8 exacerbations per patient per year for the placebo group.

The primary assessment of treatment differences for mean change from baseline in FEV1 (pre-bronchodilator) averaged over 52 weeks was based on a repeated measures model with fixed effects of treatment, time and country. A compound symmetric correlation structure was used. Least squares means along with 95% confidence intervals were calculated for each treatment group and for the treatment difference. Differences between treatment groups were assessed using t-tests on the least squares means. The rate of moderate or severe (level 2 or 3) COPD exacerbations occurring during the treatment period was analysed using a maximum likelihood-based analysis, assuming a Poisson distribution, with total duration on treatment as an offset variable.

The total score of SGRQ was analysed using an ANOVA model with fixed effects of treatment and country at each double-blind visit as well as at endpoint.

Analyses were performed for the ITT population, composed of all patients who received at least one dose of double-blind medication and had a baseline and at least one on-therapy efficacy assessment.

4.3 Results

4.3.1 Baseline Characteristics; Studies 040 and 041

A total of 723 and 355 patients were enrolled into studies 040 and 041, of whom 480 had been previously treated with cilomilast and 243 with placebo in study 040, and 215 with cilomilast and 140 with 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.
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Table XVIII

Baseline characteristics and demographics of the long-term safety studies (studies 040 and 041)

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 salbutamol was similar in both treatment groups (97% for both groups) and a similar number of patients (51% for placebo and 46% for cilomilast) continued with a stable dose of ipratropium bromide during the study. ICS (including fluticasone propionate and budesonide) stopped at study entry was taken by 34% and 41%, respectively, of placebo and 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.
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Table XIX

Baseline characteristics and demographics of the 52-week maintenance study (study 157)[42]

4.4 Safety and Tolerability Measurements

4.4.1 Adverse Events

In study 040, 62% of patients received treatment for at least 108 weeks and 20% for at least 136 weeks. For study 041, 49% received treatment for at least 108 weeks and 17% for at least 136 weeks.

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.
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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]

In study 157, a similar number of patients in each group experienced at least one adverse event during the 24-week period (cilomilast 77%; placebo 76%). The most commonly reported adverse events are shown in table XXI. Adverse events associated with the GI body system were reported more frequently in the cilomilast treatment group (28%) than in the placebo group (15%). The time of initial onset for the majority of GI adverse events in patients who received cilomilast was in the first 2 weeks of therapy.
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Table XXI

Most frequently reported on-therapy adverse experiences in ≥5% of patients in either treatment group in study 157[42]

4.4.2 Deaths

A total of 24 patients died during study 040. Fifteen deaths occurred while the patients were receiving study medication and nine occurred in the post-treatment period. A total of seven patients died during study 041; five of the deaths occurred while on study medication and two during the post-treatment period. None of the deaths in either study was considered by the investigator to be related to study medication.

In study 157 there were 12 deaths after randomization, eight in the placebo group and four in the cilomilast group, all of which were assessed as unlikely to be related to or unrelated to study medication.

4.4.3 Withdrawals

In study 040 and 041, 196 patients (18%) were withdrawn because of on-therapy adverse events (table XXII). As this was the first exposure to cilomilast for the prior placebo group, withdrawals due to adverse events of the GI system were more frequent in the prior placebo group (13%) compared with the prior cilomilast group (4%).
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Table XXII

On-therapy adverse events leading to withdrawal of ≥4 patients in studies 040[40] and 041[41]

In study 157, overall, the percentage of patients experiencing an adverse event on therapy which led to withdrawal was higher in the cilomilast group (17%) than the placebo group (9%). The most common adverse events leading to withdrawal for cilomilast-treated patients were nausea (4%), exacerbation of COPD (3%) and diarrhoea (2%). In comparison, the most frequent adverse event leading to withdrawal for placebo-treated patients was an exacerbation of COPD (4%) [table XXIII].
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Table XXIII

On-therapy adverse events leading to withdrawal of ≥3 patients in either treatment group in study 157[42]

4.4.4 Laboratory Safety and Vital Signs

In studies 040 and 041 the mean change from baseline in clinical laboratory parameters was small and was comparable between the treatment groups. No trend for a treatment-related effect on any parameter was seen. Only small changes from baseline were seen in vital signs throughout the studies. At endpoint in study 040, the mean change from baseline in systolic and diastolic blood pressure for prior cilomilast patients was −2.3 ± 17.0 and −2.2 ± 10.2 mmHg, respectively, compared with −1.1 ± 15.6 and −0.9 ± 9.6 mmHg for prior placebo patients. In study 041, the mean change from baseline in systolic blood pressure in the prior placebo group was −0.7 ± 18.4 mmHg compared with −2.2 ± 16.7 mmHg in the prior cilomilast group and for diastolic blood pressure was −1.3 ± 10.3 and −2.7 ± 10.8 mmHg, respectively.

Mean changes from baseline in ECG parameters were small. Transitions to high or low values for ECG parameters at any one point during studies were not uncommon owing to the length of the studies, and overall, intensive 12-lead ECG monitoring did not raise any concerns about the cardiac safety of cilomilast.

In study 157, there were no clinically relevant differences observed between treatment groups during cardiovascular monitoring of ECG assessments, sitting, or orthostatic vital signs.

4.5 Efficacy Evaluations

4.5.1 COPD Exacerbations

In study 157, there was no significant difference between the treatment groups over 52 weeks of treatment in the rate of level 2/level 3 COPD exacerbations. The rate per patient-year in the placebo group was 0.448 compared with 0.483 in the cilomilast group (p = 0.580). At the end of 52 weeks, the percentage of patients who were level 2/level 3 exacerbation free was comparable, with 68% of cilomilast-treated patients and 70% of placebo-treated patients exacerbation free (p = 0.637). This was similar for all levels of exacerbations, with 51% remaining exacerbation free in both treatment groups (p = 0.952).

4.5.2 Lung Function

Trough FEV1
In study 157, when averaged over 52 weeks, the mean change from baseline in trough pre-bronchodilator FEV1 in patients receiving cilomilast showed improvement compared with placebo with a mean difference between the groups of 41 mL (p < 0.001). The mean change from baseline in FEV1 over time is presented graphically in figure 7. At endpoint, there was a statistically significant difference in the change from baseline of 46 mL between the cilomilast and placebo groups (p = 0.002).
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Fig. 7

Mean change from baseline (BL) in trough forced expiratory volume in 1 second (FEV1), study 157.[42] Avg52 = average over 52 weeks; EP = endpoint.

In studies 040 and 041, patients who switched from placebo to cilomilast at the start of both studies showed initial improvements in lung function. However, at endpoint, FEV1 had decreased by a mean of 90 mL in the prior placebo group and by 80 mL in the prior cilomilast group compared with baseline values of the feeder studies in study 040 (figure 8). In study 041, a mean decrease of 110 mL from baseline was seen in the prior placebo group compared with 40 mL in the prior cilomilast group (figure 8).
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Fig. 8

Trough forced expiratory volume in 1 second (FEV1) in 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.

Health Status

When averaged over 52 weeks, there was an improvement of 1.3 units in the mean total score of the SGRQ in patients receiving cilomilast compared with an improvement of 1.5 units in the placebo group (p = 0.835) in study 157.

In study 040, at endpoint there were decreases (improvement) in the SGRQ total score of −6.6 units for the prior placebo group and −6.2 units for the prior cilomilast group from baseline (start of feeder study) [figure 9]. In study 041, at endpoint there were decreases in the SGRQ total score of −1.4 units for the prior placebo group and −4.0 units for the prior cilomilast group from baseline (figure 9).
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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.

4.6 Summary

  • Long-term treatment with cilomilast 15 mg twice daily was well tolerated with no new safety issues being identified. There was no evidence of any adverse effects of long-term drug administration on vital signs, ECG or laboratory variables in all studies.

  • In study 157, treatment with cilomilast 15 mg twice daily provided improvement in a range of spirometric parameters. Change from placebo in FEV1 both before and after bronchodilator (at trough plasma levels) reached levels of statistical significance when averaged over 52 weeks.

  • In study 157, no significant difference was seen between cilomilast and placebo in any of the parameters used to measure exacerbations.

5. Cardiovascular Safety and Tolerability of Cilomilast

5.1 Study Objective

Two studies were conducted to primarily examine the cardiac safety of cilomilast versus placebo through the assessment of 24-hour Holter ECG monitoring and standard ECGs. Other objectives were to further define the clinical safety and tolerability of cilomilast versus placebo through the assessment of adverse events, vital signs and clinical laboratory tests and to evaluate the efficacy of cilomilast.

5.2 Methods

5.2.1 Patients

Study SB207499/168 (168)[43] was a 12-week study in which patients (aged 40–80 years) were recruited from 42 centres in the US from July 2001 to August 2002. To be eligible for enrolment patients had to meet the following criteria: a clinical diagnosis of COPD, a pre-salbutamol FEV1 to FVC ratio of ≤0.7 and a post-salbutamol FEV1 between ≥30% and ≤70% of predicted normal, and ≥10 pack-year history of smoking. The study excluded patients with a primary diagnosis of asthma, poorly controlled COPD, α1-antitrypsin deficiency, active pulmonary disease (other than COPD), lung volume reduction surgery within the previous 12 months, clinically significant GI conditions and uncontrolled disorders of major body systems. This study was the first study to evaluate the efficacy of cilomilast without regard to bronchodilator response. Prior studies with cilomilast excluded patients who demonstrated a bronchodilator response to salbutamol (i.e. change in FEV1 ≥15% and ≥200 mL).

Study SB207499/125 (125)[44] was a 12-week study designed to assess the safety of cilomilast in combination with salmeterol/fluticasone propionate combination 50/250 μg (SFC). Patients (aged ≥40 years) were recruited from 41 centres in the US from December 2002 to January 2004. The entry criteria were the same as for study 168 except that a smoking history of least 20 pack-years (ex-smokers were required to have quit smoking at least 6 months prior to screening) was required.

The protocols were approved by an institutional review board at all sites and all patients provided written informed consent prior to any study procedures.

5.2.2 Study Design

Study 168 was a multicentre, randomized, double-blind, placebo-controlled, parallel-group study 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. Patients were required to attend the clinic ten times over the 17-week study period with visits at day 6, day 7, week 4, week 8 and week 12 during treatment and a follow-up visit 1 week after completion. A visit was also scheduled 1 day prior to week 12 for Holter assessment (day 83). At the end of the 4-week run-in phase patients were randomized in a ratio of 2 : 1 to receive cilomilast 15 mg twice daily or placebo for 12 weeks. Assignment to study drug was stratified by reversibility to salbutamol at baseline. Reversible patients had an absolute volume increase in FEV1 of >200 mL and >15% increase in FEV1 after administration of salbutamol 180 μg via metered dose inhaler with a spacer compared with their pre-salbutamol baseline. All COPD medications except salbutamol or ipratropium via metered dose inhaler and mucolytics were withdrawn prior to or at the screening visit and were not allowed during the treatment period.

The primary objective of the study was to evaluate the cardiac safety of cilomilast via 24-hour Holter monitoring which was measured at baseline and at day 6 and week 12 of treatment. Additional safety variables evaluated included adverse events, vital signs, standard ECGs and clinical laboratory tests including faecal occult blood tests. Trough FEV1 was measured at all visits except day 6.

Study 125 was a multicentre, randomized, double-blind, placebo-controlled study. Patients were treated as outpatients with a minimum of 6 visits (i.e. screening, treatment day 1, treatment weeks 2, 6 and 12 and 1 week post-treatment) over a period of approximately 17 weeks. There was a 4-week open-label run-in period during which all patients received SFC 50/250 μg twice daily. At the end of the 4-week open-label run-in phase, patients were randomized to receive SFC 50/250 μg twice daily plus 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 switched to twice daily.

Holter monitoring was measured at baseline and week 12 of treatment. Adverse events and vital signs were measured at all clinic visits. Spirometry and plethysmography were measured at baseline, at week 6 and week 12. Additional safety variables evaluated included laboratory tests, including faecal occult bloods. A 12-lead ECG was measured at screening and predose at week 12.

5.2.3 Statistical Methods

For study 168, descriptive statistics for Holter monitoring parameters during the first 6 and 24 hours of monitoring were provided for visit 2 (baseline), visit 3 (day 7) and visit 6 (week 12). Cardiac events captured on Holter monitoring were classified into one of the following categories: atrioventricular block, supraventricular arrhythmia, or ventricular arrhythmia. The incidence of these events for each treatment arm was tabulated over the duration of the 12-week double-blind period. Evaluation of safety data was included for all randomized patients. Differences between groups in the change 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 of baseline heart rate, gender, age, investigator and treatment. Treatment difference in the change from baseline trough FEV1 was analysed using 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, after which an additional 24 patients completed. The additional data did not identify any new safety concerns. 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).
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Table XXIV

Summary of demographic characteristics at screening (all randomized patients)

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/placebo group). Patient demographics were similar between treatment groups and are summarized in table XXIV. More patients receiving cilomilast/SFC (42 [26%]) than placebo/SFC (20 [12%]) withdrew from the double-blind phase of the study.

5.3.2 Holter Monitoring

Holter monitoring confirmed there were no clinically important differences between treatment groups. In study 168, the most common new-onset cardiac event was supraventricular tachycardia (49% of placebo-treated vs 41% of cilomilast-treated patients) and in study 125 was sinus bradycardia (11% placebo/SFC vs 14% cilomilast/SFC) [table XXV]. Week 12 Holter results were similar to week 1 results. In study 168, no clinically important differences between placebo-treated and cilomilast-treated patients were seen in change from baseline to week 12 for minimum, maximum or average heart rate. Seven placebo-treated patients and nine cilomilast-treated patients had episodes of non-sustained ventricular tachycardia (≥3 beats and <30 seconds with rate ≥100 bpm) at week 12 (table XXVI).
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Table XXV

Incidence of on-therapy new-onset cardiac events in Holter monitor (0–24 hours) parameters

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Table XXVI

Summary statistics for Holter monitor (0–24 hours) parameters post-study medication; intent-to-treat patients, study 168[43]

In study 125, the primary safety endpoint was mean 24-hour Holter monitoring heart rate. At baseline, cilomilast-treated patients had a mean of 82.2 bpm (SE 0.8 bpm) and the placebo-treated patients had a mean of 80.9 bpm (SE 0.8 bpm). The change from baseline at week 6 was 0.8 bpm for cilomilast and 0.1 bpm for placebo. Clinical equivalence was demonstrated, as the 95% confidence interval for the difference in mean 24-hour Holter heart rate was (−1.1 bpm, 2.5 bpm), which fell within the prespecified equivalence bounds of ±5 bpm. No clinically relevant differences between treatment groups for minimum, maximum or mean heart rate, cardiac events or event-based ECG parameters were observed in study 125.

Holter data were also measured in other studies including three pivotal studies (039, 042 and 091) [see section 3 for relevant study information]. Data from these studies have been integrated with study 168 and are found in table XXVII.
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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]

5.3.3 Electrocardiograms

There were small changes in trough and maximum concentration (Cmax) ECGs from baseline in 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.
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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]

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.
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Table XXIX

Summary of most frequently reported (≥5% of patients in any treatment group) on-therapy adverse events

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 and 31 (19%) 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].
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Table XXX

On-therapy adverse events leading to withdrawal of ≥2 patients in either treatment group of studies 168[43] and 125[44]

In study 125, one patient receiving cilomilast/SFC died during treatment because of a pneumothorax which was considered by the investigator as unrelated to study medication. No deaths occurred in study 168.

No differences between treatment groups were observed in vital signs, orthostatic vital signs, laboratory values or other clinical assessments in either study.

In both studies, the majority of patients had negative faecal occult blood tests at all visits. In study 168, 1 of 74 patients who received placebo and 2 of 136 patients who received cilomilast had negative baseline faecal occult blood tests and a positive test during double-blind treatment. In study 125, a total of five patients treated with SFC/placebo and six patients treated with SFC/cilomilast had positive faecal occult bloods during the study.

5.5 Efficacy Results

In study 168, there was a difference of 60 mL in the change from baseline at endpoint in trough FEV1 between the treatment groups (cilomilast 30 mL; placebo −30 mL; p = 0.072). Reversible patients treated with cilomilast had greater improvements in FEV1 than non-reversible patients. Reversible cilomilast-treated patients (n = 69) demonstrated a 130 mL improvement in FEV1 compared with placebo (n = 39), and non-reversible cilomilast patients (n = 105) demonstrated a 30 mL difference in FEV1 compared with placebo (n = 51) [figure 10].
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Fig. 10

Trough forced expiratory volume in 1 second (FEV1) [L] for intent-to-treat, non-reversible and reversible patients in study 168. BL = baseline; EP = endpoint.

In study 125, there was no statistically significant difference between treatment groups in the mean change from baseline in predose FEV1 at week 12 (0 mL for cilomilast/SFC vs −30 mL for SFC/placebo; p = 0.196). For reversible patients, there was no difference between cilomilast (n = 41) and placebo patients (n = 49), and a 50 mL difference between treatment groups among non-reversible patients (p = 0.183).

5.6 Summary

  • The safety of cilomilast was extensively assessed in these two studies and no clinically relevant differences were identified in Holter monitoring, vital signs or laboratory results including faecal occult bloods. In addition, extensive cardiac monitoring confirmed the absence of cardiovascular safety concerns with the addition of cilomilast to SFC.

  • The patients included in these studies were not screened specifically for cardiac disease, except that patients with uncontrolled disease of any major organ system were excluded. The safety profile of cilomilast in patients with significant cardiac disease and, in particular, with unstable cardiac disease is not addressed by these studies.

  • Gastrointestinal adverse events occurred more frequently in patients treated with cilomilast, but the results did not identify any serious, drug-related effects of treatment with cilomilast on the GI tract.

  • Overall, treatment with cilomilast (with or without SFC) was well tolerated, with no new safety issues being identified.

6. Effect of Cilomilast on Hyperinflation

6.1 Study Objectives

Two studies were conducted to assess the effect of cilomilast on hyperinflation. The primary objective of study SB207499/111[45] was to examine the effect of cilomilast on gas trapping (change from baseline to endpoint in volume of trapped gas). Trapped gas volume represents the volume of poorly ventilated areas of the lung. Secondary objectives were to evaluate the efficacy of cilomilast versus placebo on clinical endpoints which result from hyperinflation and gas trapping and to further evaluate the safety profile of cilomilast in patients with COPD.

The primary objective of study SB207499/180[46] was to assess the effect of cilomilast on resting hyperinflation measured by a reduction in resting functional residual capacity (FRC). Secondary objectives were to evaluate the efficacy of cilomilast versus placebo on endurance time for constant-load exercise at 75% of the peak work load, on reductions in exertional dyspnoea (modified Borg Dyspnoea scale) and in dynamic hyperinflation.

6.2 Methods

6.2.1 Patients

For study 111, patients (aged 40–80 years) entered the study in 32 centres in the US, Canada and Australia during a study period from September 1999 to August 2000. To be eligible for enrolment, patients had to meet the following criteria: a clinical diagnosis of COPD, a pre-salbutamol FEV1 to FVC ratio of ≤0.7 and a post-salbutamol FEV1 between ≥30% and ≤70% of predicted normal, fixed airway obstruction defined by ≤15% or ≤200 mL (or both) increase in FEV1 after administration of salbutamol compared with baseline pre-salbutamol FEV1, evidence of hyperinflation, as assessed by residual volume (RV, from plethysmography) ≥120% of predicted RV and ≥10 pack-year history of smoking. The study excluded patients with a primary diagnosis of asthma, poorly controlled COPD, active pulmonary disease (other than COPD), those receiving treatment with long-term oxygen therapy, and with clinically significant GI conditions and uncontrolled disorders of major body systems.

For study 180, patients (aged ≥40 years) entered the study in 34 centres in the US, Canada, Chile and Argentina during a study period from January 2003 to April 2005. The study criteria was similar to study 111 except that patients did not have to demonstrate a ≤15% or ≤200 mL (or both) increase in FEV1 after administration of salbutamol, hyperinflated was defined as ≥140% predicted FRC, the pre-salbutamol FEV1 was <70% predicted, patients had exercise limitation defined as peak symptom-limited oxygen uptake (V-dotO2) < 75% and moderate/severe dyspnoea defined as a baseline dyspnoea index score of 7 or lower.

The protocols were approved by an institutional review board at all sites and all patients provided written informed consent prior to any study procedures.

6.2.2 Study Design

Study 111 was a multicentre, randomized, double-blind, placebo-controlled, parallel-group study 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. Patients were required to attend the clinic for at least 10 visits over the 18-week period with visits at week 2, 4, 8 and 12 during treatment and a follow-up visit 1 week after completion. At the end 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 withdrawn prior to or at the screening visit and were not allowed during the treatment period.

The key efficacy variable was change from baseline to endpoint in volume of trapped gas. Total lung capacity (TLC) was evaluated using both body plethysmography and single-breath helium dilution (TLCHe) techniques. Gas trapping was defined as the difference between plethysmographic and single-breath helium dilution TLCs. These tests were conducted prior to treatment with salbutamol, with the exception of visit 3 (baseline) and visit 7 (week 12) where assessments were conducted before and after administration of salbutamol. Secondary measures of efficacy included additional lung volume measurements including slow vital capacity (SVC) and RV (RVBox and RVHe), dynamic pulmonary function measurements including inspiratory capacity (IC), FEV1, FVC, forced expiratory flow at 25–75% vital capacity (FEF25–75), forced expiratory flow at 75% vital capacity (FEF75) PEFR, specific conductance (calculated from airways resistance via plethysmographic measurement), carbon monoxide diffusing capacity (DLCO), exercise performance (6-minute walk test), overall and exertional dyspnoea (as rated by the modified Borg Dyspnoea scale), measure of respiratory muscle performance (as evaluated by maximal inspiratory and expiratory pressures [MIPs and MEPs]) and exertional arterial oxygen concentration (SaO2; measured immediately after exercise testing). Pulmonary function tests were performed at trough (predose) plasma concentrations of study medication and were assessed >4 hours after the last dose of salbutamol and >6 hours after the last dose of ipratropium. Lung volumes were measured with a pressure body plethysmograph according to the current clinical practice guidelines from the American Association for Respiratory Care.[47] Calibration of the body plethysmograph occurred daily.

Study 180 was a multicentre, randomized, double-blind, placebo-controlled, parallel-group study consisting of a 2-week single-blind placebo run-in period and 18 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 21-week period with visits at day 1, weeks 6, 12 and 18 during treatment and a follow-up visit 1 week after completion. At the end of the 2-week run-in phase, patients were randomized in a ratio of 1 : 1 to receive cilomilast 15 mg twice daily or placebo for 18 weeks. Patients were stratified at each site by ICS use and non-ICS use. COPD medications including ICS, ipratropium and salbutamol were allowed throughout the treatment period.

The primary endpoint was the mean change from baseline trough at endpoint in 2-hour post-dose FRC. The key secondary efficacy endpoint analyses were the mean change from baseline IC during exercise, the mean change from baseline dyspnoea Borg scale score and the mean change from baseline in exercise endurance. Cycle exercise testing was performed using methodology described by O’Donnell et al.[48,49] Cycle exercise testing was initiated after completion of plethysmography/spirometry procedures. At visit 1, an incremental cycle exercise test was performed to a symptom-limited maximum (maximum work capacity). In subsequent exercise challenge visits, endurance cycle exercise tests were performed in a similar manner with a constant-load protocol at a work rate equivalent to 75% of the maximum work rate achieved during visit 1. The patient exercised until limited by symptoms, or was unable to maintain a pedalling frequency of at least 40 rpm or was unable to continue safely. At the end of exercise (dropping of the load), the time of exercise was recorded. The resting IC manoeuvres were performed while the patient was seated comfortably on the cycle ergometer and exercise IC manoeuvres were carried out at 2-minute intervals during exercise. Peak IC was defined as that at the end of loaded pedalling.

Lung volumes were measured with a pressure body plethysmograph (body box). The most common measurements made using the body plethysmograph were thoracic gas volume (VTG), the volume of gas in the lung when the mouth shutter is closed. In plethysmographic studies, VTG is commonly used to represent the FRC. FRC at rest was measured predose at day 1 and postdose at weeks 6, 12 and 18. The modified Borg Dyspnoea scale[39] was used to assess breathlessness during cycle exercise testing. Patients were asked to rate the intensity of dyspnoea using the modified Borg Dyspnoea scale before the start of loadless pedalling, every 2 minutes during exercise and at the end of exercise.

Safety was assessed by examining adverse events, resting and exercise ECGs, routine laboratory tests including faecal occult blood tests and vital signs in both studies.

6.2.3 Statistical Methods

For study 111, the assessment of treatment differences was based on an ANOVA model with factors of centre and treatment group. 110 evaluable patients would provide at least 90% power to detect a significant difference in trapped gas volume assuming a treatment difference of 500 mL, a standard deviation of 700 mL and a significance level of 0.05.

For study 180, ANCOVA models used to compare treatment groups included terms for baseline, investigator, ICS use and treatment. Tests for treatment effect were two-sided tests at the 0.05 significance level. It was estimated that the standard deviation for change from baseline at endpoint in FRC was approximately 700 mL so 88 patients per group were planned to provide approximately 80% power to detect a difference of 300 mL in the change from baseline at endpoint in FRC. Analyses were performed for the ITT population, consisting of all randomized patients receiving at least one dose of study drug.

6.3 Results

6.3.1 Study Population

In study 111, a total of 156 patients were randomized 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%) compared with placebo-treated patients (13%), primarily because of adverse events.

At baseline, the treatment groups in both studies were well matched for demographic and baseline characteristics of COPD (table XXXI).
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Table XXXI

Summary of demographic characteristics at screening (all randomized patients)

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 difference between the groups of −0.31 L was not statistically significant (p = 0.129).
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Fig. 11

Mean (SEM) change from baseline (BL) in pre-salbutamol volume of trapped gas (L) in study 111.[45] EP = endpoint.

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].
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Fig. 12

Mean change from baseline (BL) at endpoint in functional residual capacity (FRC) in study 180.[46] EP = endpoint.

6.3.3 Secondary Efficacy Endpoints

In study 111, at endpoint there was a statistically significant decrease in the body plethysmography RV in the cilomilast group compared with placebo (−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 PEFR (−14.0 L/min; p = 0.047). There were no statistically significant differences between the cilomilast and placebo groups in mean change from baseline for SVC, RV (by helium dilution), TLC (helium), DLCO, trough FVC, trough FEF25–75, trough FEF75, post-salbutamol PEFR, specific conductance, exercise tolerance, overall breathlessness, exertional breathlessness, MIP, MEP, exertional SaO2 and IC.

In study 180, neither the cilomilast nor placebo groups demonstrated an improvement in peak exercise IC. The cilomilast group had a 60 mL mean decrease in peak IC from baseline compared with 80 mL decrease in the placebo group. The difference between the groups of 20 mL was not significant (p = 0.675). In addition, the difference between the cilomilast and placebo groups in the mean Borg dyspnoea scale score at peak was not significantly different between the groups with a 0.2-unit difference in favour of cilomilast (p = 0.612). Neither the cilomilast nor placebo groups demonstrated an improvement in exercise endurance time. For postdose assessment at endpoint, the placebo treatment group had a 30.8-second reduction in exercise time and the cilomilast group had a 108.0-second reduction. The difference of 77.2 seconds between the treatment groups was statistically significant (p = 0.045).

6.4 Safety Results

6.4.1 Adverse Events

In study 111, the overall incidence of adverse events was lower in the placebo treatment group (64%) than in the cilomilast treatment group (80%). The most common adverse event was COPD exacerbation, which occurred in 15 patients in each group. There was a higher incidence of GI body system adverse events in the cilomilast group (34 patients [43%]) than in the placebo group (14 patients [18%]) [table XXXII]. A total of 8 (10%) placebo-treated patients and 13 (17%) cilomilast-treated patients were withdrawn from the double-blind treatment because of an on-therapy adverse event. The most common adverse events leading to withdrawal are shown in table XXXIII. One patient in the placebo group had a positive faecal occult blood test during the double-blind treatment compared with none in the cilomilast group.
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Table XXXII

Number (%) of patients with the most frequently reported adverse events (≥5% patients in either treatment group in either study)

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Table XXXIII

Incidence of adverse events leading to withdrawal of ≥1 patient in either treatment group in either study

Three patients died during the study; one of these died during single-blind placebo treatment. In the cilomilast treatment group, one patient died during the double-blind treatment period and one died after therapy. None of the adverse events that resulted in death were considered by the investigator to be related to study medication.

In study 180, the same percentage of patients in each group experienced at least one adverse event during the 24-week period (67%). The most commonly reported adverse events are shown in table XXXII. Adverse events associated with the GI body system such as nausea, diarrhoea, abdominal pain, dyspepsia and vomiting were reported more frequently in the cilomilast group than in the placebo group. The time of initial onset for the majority of GI adverse events in patients who received cilomilast was in the first 2 weeks of therapy. A total of six (6%) placebo-treated patients and nine (9%) cilomilast-treated patients were withdrawn from the double-blind treatment because of an on-therapy adverse event. The most common adverse events leading to withdrawal are shown in table XXXIII. Two patients treated with cilomilast and six treated with placebo had positive faecal occult blood tests during the study. There were no deaths during the study.

6.4.2 Other Safety Assessments

Overall in both studies, mean changes from baseline in clinical laboratory parameters and vital signs were small and comparable between the treatment groups. There were small changes in ECG parameters from baseline to endpoint in both treatment groups. However, no clinically relevant differences were noted within or between groups.

6.5 Summary

  • While cilomilast demonstrated a reduction in gas trapping and FRC compared with placebo, the differences were not statistically significant.

  • Multiple secondary efficacy measures were evaluated. While cilomilast demonstrated numerical improvements over placebo for some of these endpoints, none of these improvements were clinically significant.

  • The extensive GI monitoring performed in these studies did not identify any serious, potentially drug-related effects of treatment with cilomilast on the GI tract.

  • There were no clinically relevant safety issues in laboratory values, vital signs or ECGs revealed in this study.

7. Efficacy and Safety of Cilomilast in Chinese Patients with COPD

7.1 Study Objective

The primary objective of the study was to demonstrate the clinical efficacy of cilomilast versus placebo in Chinese patients with COPD by measuring the change from baseline to endpoint in FEV1 at trough drug concentrations. This study was conducted for Chinese local product registration.

7.2 Materials and Methods

7.2.1 Study Design

This was a randomized, double-blind, placebo-controlled, parallel-group study, conducted from January 2003 to November 2004 at 22 centres in China (study number SB207499/121).[50] The local ethics committee or institutional review board approved the study protocol at each centre and all patients gave written informed consent to participate.

Patients were assessed for eligibility at the screening visit. After a 4-week, single-blind, placebo run-in period, eligible patients were randomized in a 2 : 1 ratio to receive twice-daily oral treatment with either cilomilast 15 mg, or placebo during a 24-week double-blind phase. Patients attended the clinic every 2 weeks from the screening visit up to randomization and then at week 1 and week 4 of treatment, and thereafter at 4-weekly intervals. A final visit occurred 1 week after completing the study. The primary endpoint in this study was the change from baseline in trough FEV1 measured at study endpoint. Secondary efficacy endpoints included the incidence of COPD exacerbations, health status measured by SGRQ and clinic visit trough FVC measurements. In addition, at ten selected centres, body box measurements of hyperinflation, RV and FRC were measured. These sites were selected after evaluation of the laboratory, body box equipment and the laboratory technician. Calibration of mouth pressure and box pressure transducers was performed at least once each day prior to testing subjects. Safety was measured by the assessment of adverse events, vital signs, clinical laboratory tests, faecal occult blood tests and ECGs.

7.2.2 Patients

Male and female patients aged 40–75 years with a clinical diagnosis of COPD, as defined by the American Thoracic Society, were eligible to participate in the study. Patients had to be current or ex-smokers with a cigarette smoking history of ≥10 pack-years. Lung function criteria requirements for entry included a post-bronchodilator FEV1 between ≥25% and ≤70% of the predicted normal value and a ratio of the pre-bronchodilator FEV1 to FVC of <70%. Patients also had to have fixed airways disease (i.e. an increase in FEV1 of ≤10% from baseline or ≤200 mL 30 minutes after the administration of salbutamol 200 μg). Patients were also required to have a history of COPD exacerbations in the 3 years prior to the study. At the sites performing plethysmography, patients had to have a predicted FRC of >120%. Patients with active tuberculosis, lung cancer or clinically overt bronchiectasis were excluded. Additionally, patients with clinically significant cardiovascular, neurological, renal, endocrine, GI, hepatic, or haematological abnormalities that were uncontrolled with permitted therapy were not eligible for inclusion in the study.

Patients with poorly controlled COPD, defined as the occurrence of an acute worsening of COPD that was 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 in the 2 weeks prior to screening were excluded. Patients receiving treatment with long-term oxygen therapy or who required supplemental oxygen more often than on an occasional basis were also excluded.

Randomization criteria included stability of pulmonary function, which was defined as variability in FEV1 between the first and last run-in visit of not more than 20% of the absolute trough pre-salbutamol administration measurement and medication compliance of between 80% and 120%.

Patients were provided with salbutamol metered dose inhalers for use on an as-needed basis and were permitted to continue inhaled short-acting anticholinergics and mucolytics at a stable dose throughout the study. No other COPD medications, including traditional Chinese medication, were allowed except for the short-term treatment of exacerbations.

7.2.3 Study Procedures

Patients were asked to refrain from taking any respiratory medication for at least 6 hours and refrain from smoking for at least 2 hours before each clinic visit. Trough (predose) FEV1 was performed using the same type of spirometer at all centres. At the screening visit, pulmonary function was assessed before and after a standard dose of salbutamol, whereas at subsequent visits assessments were made at trough levels of study drug. Body box plethysmography was performed at ten sites at baseline and weeks 6 and 12 of treatment.

The SGRQ, a disease-specific health status tool, was administered at weeks 0, 12 and 24.

COPD exacerbations were recorded throughout the study. They were categorized as level 1, 2 or 3, based on the treatment received by the patient for the exacerbation. Level 1 (mild) was defined as an acute worsening of COPD that was self-managed by the patient at home by increasing usual COPD medications, level 2 (moderate) for those that required additional treatment (e.g. ≥14 days of inhaled or oral steroids or antibiotics prescribed by a physician) and level 3 (severe) as requiring hospitalization.

Adverse experiences, vital signs, ECGs, faecal occult blood tests and blood and urine specimens were taken for routine haematology and biochemistry and urinalysis during the study at each visit. At all visits during the double-blind study period, patients were assessed for compliance with the medication as well as for use of concomitant medications.

7.2.4 Statistical Analysis

The primary endpoint (change from baseline in trough FEV1) was analysed using an ANOVA model with fixed effects for treatment and centre. Baseline was also included in the model as a covariate. Least squares means along with 95% confidence intervals were calculated for each treatment group and for the treatment difference. The differences between treatment groups were assessed using t-tests on the least squares means. Continuous secondary efficacy variables were analysed similarly to the primary.

Differences between groups in time to first level 2/level 3 COPD exacerbation was assessed using the log-rank test. The exacerbation-free survival rate at 24 weeks and the associated 95% confidence intervals were estimated for each treatment group using the Kaplan-Meier product limit method.

The planned sample size was 900 randomized patients to obtain data on 840 patients with both baseline and at least one post-baseline FEV1 evaluation. The study was designed to detect a 50 mL difference in FEV1 with 90% power. Based on previous studies, the powering of the study assumed a 210 mL standard deviation for FEV1 and a significance level of 0.05.

7.3 Results

7.3.1 Patient Disposition

A total of 1219 patients were screened for the study, but of these, 201 (16%) were withdrawn prior to randomization. A total of 1018 patients were randomized to receive either cilomilast (n = 678) or placebo (n = 340). The primary reason for withdrawal of patients from the study prior to randomization was that the patients did not return (67 patients, 33% of non-randomized patients). More patients receiving cilomilast than placebo withdrew from the double-blind phase of the study (18% [124] vs 10% [35]). The main reason for withdrawal after randomization was an adverse event (7% of patients who received cilomilast; 2% of placebo-treated patients).

7.3.2 Baseline Characteristics

The two treatment groups in the randomized patient population were well matched for demographic characteristics and for baseline characteristics of COPD (table XXXIV). The treatment groups had similar lung function and, overall, the patients were representative of a moderate COPD population.
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Table XXXIV

Demographics and screening characteristics

The use of salbutamol was similar in both treatment groups (78% for placebo and 74% for cilomilast) and a similar number of patients were receiving ICS prior to the study (82% in the placebo group vs 79% for cilomilast). During the double-blind treatment period 97% of placebo- and 94% of cilomilast-treated patients were at least 80% compliant with their study medication. There were no notable differences between centres in baseline plethysmographic parameters.

7.3.3 Primary Efficacy Endpoint; Trough FEV1

At study endpoint, there was no significant difference between treatments for the primary endpoint, with a small increase of 14 mL in FEV1 at endpoint in the cilomilast group compared with a small decrease of −6 mL in the placebo group (treatment difference of 21 mL; p = 0.093). Analysis of the average change from baseline in FEV1 over 24 weeks showed a significant difference in favour of cilomilast compared with placebo (treatment difference 25 mL; p = 0.008). Differences between the treatments were in favour of cilomilast at each visit and significant differences were seen over the first 16 weeks of the study (figure 13).
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Fig. 13

Mean (SEM) change from baseline (BL) in trough forced expiratory volume in 1 second (FEV1). Avg24 = average over 24 weeks; EP = endpoint.

The mean change from baseline in FEV1 at endpoint for patients who were smokers at baseline was 0.019 L in the placebo group and 0.027 L in the cilomilast group and for subjects who were non-smokers at baseline it was −0.012 L in the placebo group and 0.012 L in the cilomilast group. A significant effect of smoking status on change from baseline in FEV1 at endpoint was observed (p ≤ 0.004).

7.3.4 Secondary Endpoints

COPD Exacerbations

There was no significant difference between treatments in the time to first level 2 or level 3 COPD exacerbation (p = 0.598). At week 24, 77% of the placebo group and 76% of the cilomilast group had not experienced a level 2 or level 3 exacerbation. Proportional hazards regression analysis of time to first level 2 or level 3 exacerbation showed no significant effect of treatment (relative risk for cilomilast to placebo 1.09; p = 0.534).

Plethysmography

There were 121 patients in the placebo group and 250 patients in the cilomilast group who had plethysmography measured during the study. Baseline values for placebo and cilomilast were 5.21 L and 5.14 L, respectively, for FRC and 4.11 L for RV for both groups. There was no significant difference between treatments at endpoint for RV (mean difference 0.058 L; p = 0.497) or FRC (mean difference 0.082 L; p = 0.234).

Trough FVC

The baseline FVC was 2.70 L for cilomilast and 2.67 L for placebo. At endpoint, the cilomilast group had an FVC increase of 18 mL, and the placebo group had a decrease of 23 mL. There was no significant difference between treatments (treatment difference 41 mL; p = 0.129).

Health Status

The baseline SGRQ total score was 45.0 units for the cilomilast group and 44.7 units for the placebo group. At study endpoint, there was a clinically significant improvement in the mean change from baseline for the total score of the SGRQ in both treatment groups. Patients receiving cilomilast had a mean improvement of −9.0 units compared with an improvement of −8.7 units in the placebo group (−0.3-unit difference; p = 0.790).

7.4 Safety and Tolerability

A majority of patients in each group experienced at least one adverse event during the 24-week period (cilomilast 76%; placebo 72%). The most commonly reported adverse events are shown in table XXXV. Adverse events associated with the GI body system were reported more frequently in the cilomilast treatment group (38%) compared with the placebo group (17%). The time of initial onset for the majority of GI adverse events in patients who received cilomilast was in the first week of therapy.
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Table XXXV

Most frequently reported on-therapy adverse experiences in ≥3% of patients in either treatment group

Overall, the percentage of patients experiencing an adverse event on therapy which led to withdrawal was higher in the cilomilast group (5%) than the placebo group (2%). The most common adverse event leading to withdrawal in both treatment groups was an exacerbation of COPD (table XXXVI).
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Table XXXVI

On-therapy adverse events leading to withdrawal in ≥2 patients in either treatment group

There were three deaths during the double-blind study phase, two in the placebo group and one in the cilomilast group. All of the on-therapy fatal events were due to cardiovascular disease or cancer and were attributed to adverse events judged not related or unlikely to be related to study medication by the investigator. Nonfatal serious adverse events were reported in 10 patients (3%) treated with placebo and 38 patients (6%) treated with cilomilast; the most frequent was a COPD exacerbation, which occurred in 4 patients (1%) receiving placebo and 21 patients (3%) receiving cilomilast.

No clinically relevant differences were observed between treatment groups during cardiovascular monitoring of ECG assessments, sitting, or orthostatic vital signs. The mean changes from baseline in clinical laboratory parameters were small and were comparable between the treatment groups. Overall, 13 patients (4%) in the placebo group and 28 patients (5%) in the cilomilast group had positive faecal occult bloods during double-blind treatment.

7.5 Summary

  • Although improvements in lung function were observed with cilomilast, significant differences compared with placebo were not seen for primary or secondary endpoints and the clinical efficacy of cilomilast compared with placebo was not demonstrated in Chinese patients with COPD.

  • As in previous studies, treatment with cilomilast was generally well tolerated, although a higher proportion of patients reported GI adverse events compared with those receiving placebo.

  • In this study, there was a notably large improvement (>8 units) in the SGRQ in both treatment groups that did not differ significantly.

8. Discussion

During the cilomilast development programme a number of different endpoints were investigated to characterize the efficacy and safety of this second-generation PDE4 inhibitor. Safety assessments throughout the late-phase programme did not reveal any evidence of serious safety concerns with the use of cilomilast. Initial studies in phase II and early phase III showed 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 the programme’s termination.

8.1 Anti-Inflammatory Effects of Cilomilast

The pathogenesis of COPD is complex, and studies have demonstrated that airway inflammation plays an important role.[5153] Many haematopoietic and parenchymal cells participate in the inflammatory response in the lung. The neutrophil is a primary mediator of inflammation in COPD and the lung is clearly a primary target for neutrophil recruitment and activation.[54] Few currently available therapeutic agents, including corticosteroids, effectively downregulate neutrophil pro-inflammatory activity. This emphasizes the need for novel pharmacological strategies to control the potentially harmful pro-inflammatory activities of these cells.

Cilomilast demonstrated significant anti-inflammatory activity in various animal models in preclinical studies.[30] In the phase II study 076 (previously published),[1] a small improvement was seen in subepithelial neutrophils in the cilomilast treatment group relative to placebo, along with a reduction in subepithelial macrophages (CD68+) and subepithelial CD8+ lymphocytes. However, in two further studies (110[33] and 181[34]), the anti-inflammatory activity of cilomilast was not confirmed. Data from the three studies did not provide conclusive evidence of an anti-inflammatory action of cilomilast. The studies, all of which were designed to assess anti-inflammatory action of cilomilast in COPD patients as a whole, were not sufficiently large to permit meaningful subset analyses. As a whole, however, the data provided by these studies do not support a role for cilomilast in reducing any measure of inflammation in the lung. Thus, it is not possible to determine if cilomilast might be an effective anti-inflammatory in a subset of COPD patients.

8.2 FEV1

Five pivotal well controlled, 24-week studies were conducted to compare cilomilast with placebo on the change from baseline in FEV1 measured at trough drug concentrations in poorly reversible COPD patients (study numbers 039,[2] 156,[35] 042,[38] 091[37] and 657;[36] see section 3). In three of the five pivotal studies (039, 156, 657) over 24 weeks of treatment, there was a statistically significant difference in FEV1 between the cilomilast and placebo treatment groups. Treatment differences ranged from 24 to 44 mL, and in the absence of improvements in other clinical parameters, this modest improvement was not considered to be clinically meaningful.

Considering the potential for anti-inflammatory effects of a PDE4 inhibitor, a greater benefit with extended duration of treatment would be predicted. However, in study 157, the treatment difference over 52 weeks (41 mL) was comparable to the treatment differences found in the pivotal trials over 24 weeks. However, an anti-inflammatory agent might improve airflow in COPD both by relatively acute effects, e.g. by reducing oedema and tissue infiltration with inflammatory cells, and by slowing the progression of airflow limitation, which is believed to be a consequence of chronic inflammation. COPD progresses at a rate of FEV1 loss of 40–60 mL/year. A reduction in this rate by 20 mL/year has been suggested as a therapeutic target in several large studies. A meaningful difference in FEV1 between 24 and 52 weeks therefore might be in the order of 10 mL, which may not have been observable with the number of patients studied. Nevertheless, the available data do not suggest a progressive increase in the difference between patients treated with cilomilast and those treated with placebo.

When reviewing the FEV1 response to treatment with cilomilast, the fact that poorly reversible patients were included in these studies should be considered. The cilomilast clinical programme was predominantly restricted to patients who had a poor reversibility to bronchodilator (<15% or 200 mL improvement over baseline in FEV1). This was done, in large part, to help evaluate benefits from non-bronchodilator effects of cilomilast. Patients who are poorly reversible are known to have a decreased magnitude of FEV1 response in response to therapy compared with a more reversible population.[55] They also have a relatively rapid rate of decline in FEV1 with associated trends for increased morbidity and mortality.[56] Although the improvements in FEV1 experienced by cilomilast-treated patients in this population were modest (up to 50 mL), this is comparable to that observed in COPD patients who quit smoking compared with continued smokers over a duration of 1 year.[51]

Study 168 was a cardiovascular safety study which included 115 patients who were reversible and 167 poorly reversible patients. FEV1 was evaluated as an exploratory endpoint. Both reversible and poorly reversible patients treated with cilomilast demonstrated improvements in FEV1 at study endpoint compared with placebo, and the improvement was much greater in the reversible population (130 vs 30 mL in the poorly reversible population), which may suggest that the treatment effect for cilomilast may be larger in a more general COPD population. Whether such a population would also show differences in long-term effects or other outcomes, such as health status or exacerbations, can not be ascertained from the studies performed.

8.3 Forced Vital Capacity

Since small airways disease is an important component of COPD and FEV1 is not very sensitive to changes in small airway calibre,[3] other measures such as FVC may more accurately reflect small airway function. Some patients with irreversible COPD experience subjective benefit from treatment without change in FEV1. However, across the five pivotal studies, the mean improvements in FVC at endpoint were 27 to 110 mL greater in the cilomilast treatment group relative to placebo and were similar to the improvements observed for FEV1.

8.4 Hyperinflation

The impact of lung hyperinflation on symptoms and impairment at rest and during exertion is also increasingly recognized in COPD.[57] Expiratory airflow limitation in COPD leads to air trapping (hyperinflation) when there is insufficient time for adequate lung emptying. Dynamic hyperinflation is a primary mechanism for the exertional dyspnoea and reduced exercise capacity associated with COPD.[58,59] Functional residual capacity and residual volume determine the initial positioning of tidal breathing during exercise and are resting measures of hyperinflation that correlate with exercise performance and exertional dyspnoea.[5759]

Although a statistically significant difference between cilomilast and placebo was shown for mean change from baseline FRC in study 111 (290 mL), a significant difference was not seen in study 180 (128 mL). This was also true for residual volume and total lung capacity. No other secondary endpoints reached statistical significance in either study, suggesting that there was little overall effect of cilomilast on hyperinflation.

8.5 Health Status

Assessment of health status, often termed ‘quality of life’, is recognized as an important additional measurement in patients with chronic respiratory disease and is a better predictor of admission to hospital and death within 12 months than FEV1.[60] The quality of life in patients with COPD decreases significantly with disease progression, and because patients often modify their lifestyles to compensate for dyspnoea and activity limitation, it is important that therapeutic interventions also result in improvements in the patient’s quality of life. Health status outcomes such as these are regarded as important in all aspects of COPD because they are felt to represent changes that are clinically most relevant to patients and that may not be measurable by other more conventional parameters. The SGRQ has been designed to measure and quantify the impact of chronic respiratory disease on a patient’s health-related quality of life.[61] Health status measured by the SGRQ was therefore used as a co-primary endpoint in the pivotal phase III studies.

In two of the five pivotal studies (039,[2] 156[35]) there was a statistically significant difference in SGRQ between the cilomilast and placebo treatment groups, with only one study (039) reaching the clinically relevant difference of −4.0 units.[2] These results contrasted with the study performed in China, where both the placebo and cilomilast treatment groups, which were not significantly different, demonstrated improvement by >8 units. This marked improvement may have been consequent to participation in the clinical trial, with the resulting increased medical attention, the so-called Hawthorne Effect.[62] This effect may have masked, to some degree, any potential benefit of the study medication.

Although a trend towards an improvement in health status measured by the SGRQ was observed following treatment with cilomilast, these improvements were not consistent across the studies.

8.6 Exacerbations

Many COPD patients experience periodic worsening of their symptoms reflecting an acute deterioration in lung mechanics[63] and airway inflammation secondary to viral and/or bacterial infection.[64,65] These exacerbations contribute to impaired health status,[66,67] increased hospitalization costs[68] and predict mortality.[69] The effect of cilomilast on exacerbations was therefore measured as a key secondary endpoint in the pivotal studies.

Data from two of the pivotal studies (studies 039[2] and 091[37]) demonstrated that cilomilast significantly reduced exacerbation rates over 24 weeks of treatment. Although these studies were not powered for exacerbations, cilomilast significantly reduced the risk of having an exacerbation relative to placebo. An additional study was therefore designed based on these results to assess the efficacy and safety of cilomilast versus placebo on exacerbations over a longer timeframe of 52 weeks (study 157). The study was powered for exacerbations and intended to confirm and extend the results observed in other phase III studies. However, no difference between the treatment groups in the rate of level 2/3 COPD exacerbations (exacerbations requiring physician-prescribed treatment or a hospital visit) was observed.

Despite cilomilast reducing exacerbations in a couple of the early phase III pivotal studies, this was not observed in the later pivotal trials and specifically in study 157, which was designed to investigate the effect of cilomilast on exacerbations.

8.7 Dyspnoea

The modest improvements in lung function seen in the pivotal studies were accompanied by some relief of dyspnoea as measured by the Borg Dyspnoea Scale.[39] Consistent trends for improvements in post-exercise breathlessness scores at endpoint were observed in the cilomilast-treated patients compared with placebo-treated patients across all pivotal studies in which it was measured. Small decreases in FEV1 associated with episodes of dyspnoea have previously been reported in a similar poorly reversible population.[70]

8.8 Safety

The cilomilast clinical development programme evaluated the safety of cilomilast in more than 6000 patients with COPD by tabulation of adverse events, examination of laboratory parameters, testing for faecal occult blood, serial ECGs and 24-hour Holter monitor studies. Monitoring of GI adverse events was undertaken throughout the clinical programme owing to the pharmacology of PDE4 inhibitors.

8.8.1 Adverse Events

As expected for a study population of older patients with chronic disease receiving a variety of medications, most patients with COPD reported one or more adverse events while on treatment with cilomilast or placebo. Adverse events, irrespective of relationship to study medication, were reported in comparable percentages of patients treated with cilomilast. The most frequently reported events were exacerbations of COPD, nausea, diarrhoea, abdominal pain, upper respiratory tract infection, headache, dyspepsia and vomiting. Overall, the incidence of adverse events related to the GI system was higher among COPD patients treated with cilomilast than among those treated with placebo. The most common GI events reported in the cilomilast group compared with the placebo group were nausea, diarrhoea, abdominal pain, dyspepsia and vomiting. By approximately 3 weeks, patients were equally likely to start having GI events when treated with cilomilast as compared with placebo. Dyspnoea, chronic obstructive airways disease and coughing were consistently reported at a lower incidence in patients treated with cilomilast than in placebo-treated patients. There was also no difference between cilomilast- and placebo-treated patients on routine faecal occult bloods. The increase in nausea observed in cilomilast-treated patients is consistent with a central nervous system effect that is well described for PDE4 inhibitors. In contrast, there were no diagnoses of mesenteric vasculitis, an effect of PDE4 inhibitors in rats that has caused serious concern. The results from this clinical programme, therefore, are consistent with other studies that suggest this complication of PDE4 inhibitors is species specific, as there is no evidence that it occurs in humans.

8.8.2 Adverse Events Leading to Withdrawal

In all phase III studies, higher percentages of cilomilast-treated patients were withdrawn than placebo-treated patients with a higher percentage withdrawn due to an adverse event. Adverse events leading to withdrawal were reported by a relatively small proportion of patients across the treatment groups in the five pivotal studies (5–16% in the placebo groups; 15–22% in the cilomilast treatment groups) with adverse events related to the GI system predominating. The most common adverse event leading to withdrawal in the cilomilast group was nausea, and in the placebo group it was an exacerbation of COPD.

8.8.3 Deaths

Eleven patients died during double-blind treatment in the five pivotal studies or during the post-therapy follow-up period; of these, four received placebo. All of the on-therapy fatal adverse events were due to cardiac failure, aneurysm, cancer, brain haemorrhage or pulmonary disease. The investigators judged all the fatal adverse events as not related to study medication and there appeared to be no relationship between the occurrence of fatal adverse events and study participation.

8.8.4 Laboratory Data and Vital Signs

Laboratory observations during the phase III trials demonstrated no systemic effect of treatment with cilomilast on haematology values, serum measures of liver or kidney function, glucose metabolism, electrolytes or other biochemistry parameters. Overall, there were small, clinically insignificant mean changes in blood pressure and heart rate from baseline to on-therapy in both cilomilast and placebo treatment groups. The proportion of patients with diastolic blood pressure or heart rate changes was similar across the placebo and cilomilast groups in all studies. Small changes in mean orthostatic vital signs were recorded at baseline and at endpoint of comparable magnitude between placebo and cilomilast patients in the phase III studies. Overall, the differences and changes in vital signs are unlikely to be clinically important.

8.8.5 Cardiovascular Findings

Extensive cardiovascular monitoring during the development programme included frequent ECGs in the phase III controlled trials and in the long-term trials plus additional 24-hour Holter monitor examinations in several studies. More than 72 000 ECGs were obtained across studies, including long-term studies. There were small changes in trough ECG values from baseline to study endpoint in both treatment groups, which is not unexpected in a cohort of older patients with chronic lung disease with a smoking history. No meaningful trends were seen in transitions from normal to concern values at trough between treatment groups for atrial and ventricular rates, QRS interval, uncorrected QT interval, QTc change, PR interval or QRS axis. There were no major differences in the emergence of specific ECG abnormalities between treatment groups at trough or at Cmax. These data demonstrate that there is no excess cardiovascular risk associated with cilomilast therapy. The clinical trials with cilomilast, however, excluded patients with unstable cardiac disease. The effects of cilomilast in this potentially vulnerable population, therefore, can not be assessed from the results of this clinical programme.

An additional study was conducted to evaluate the safety and additional efficacy of cilomilast when given concurrently with salmeterol/fluticasone propionate 250/50 μg twice daily (SFC) [study 125]. It was shown that there was no difference between SFC + cilomilast versus SFC alone in the primary safety measure of mean 24-hour heart rate by Holter monitoring, and overall, treatment with SFC and cilomilast was well tolerated with no new safety issues being identified.

8.8.6 Summary

Observations from the clinical development programme suggest that except for episodes of GI adverse events, cilomilast was relatively well tolerated in the clinical studies of patients with COPD. GI intolerance related to adverse events such as nausea, diarrhoea, abdominal pain, dyspepsia and vomiting were consistently reported at a higher incidence in patients treated with cilomilast than in patients treated with placebo. Extensive monitoring including faecal occult blood testing, assessment of orthostatic changes in vital signs and laboratory assessments showed no evidence of more significant GI pathology associated with these GI adverse events.

Patients who experienced GI adverse effects from cilomilast were most likely to do so within the first few weeks of exposure but most of the events were mild or moderate in intensity.

9. Conclusion

PDE4 inhibitors, including cilomilast, have shown limited effects on inflammation and lung function compared with corticosteroids and bronchodilators, respectively. While PDE4 inhibitors are currently limited by their dose-dependent adverse effects, in the future this limitation may be less likely to occur when they are administered by the inhaled route, or with newer inhibitors with improved subtype or tissue selectivity.

Acknowledgements

The authors acknowledge technical support from Diana Jones, a professional medical writer, who was compensated by GlaxoSmithKline (GSK), in the preparation of this manuscript.

SR has had or currently has a number of relationships with companies who provide products and/or services relevant to outpatient management of chronic obstructive pulmonary disease. These relationships include serving as a consultant, advising regarding clinical trials, speaking at continuing medical education programmes and performing funded research both at basic and clinical levels. He does not own stock in any pharmaceutical companies. In the last 3 years, SR has received laboratory and industry grants from Almirall, Altana, Astellas, Centocor, GSK, Nabi, Novartis and Pfizer; has served on consultancy and advisory boards for Adams, Almirall, Altana, AstraZeneca, Bend, Biolipox, Centocor, Critical Therapeutics, Dey, GSK, ICOS, Johnson & Johnson, Novartis, Ono Pharma, Parengenix, Pfizer, Roche, Sankyo, Sanofi, Schering-Plough and Talecris; and has received speakers fees from AstraZeneca, Boehringer Ingelheim, GSK, Osuka and Pfizer. AM is an employee of GSK (clinical) and owns stock and stock options in GSK. FB is an employee of GSK (clinical) and holds stock options with GSK. KR has been consulting, participated in Advisory Board meetings and received lecture fees from AstraZenica, Boehringer, Chiesi Pharmaceuticals, Pfizer, Novartis, AltanaPharma, MSD and GSK. The Department of Pulmonology, and thereby Professor Rabe as head of the department, has received grants from Novartis, AstraZeneca, Boehrigner Ingelheim, Roche and GSK between 2005 and 2008 and has a grant pending from Polen. NL has been an employee of GSK (statistician) since 2003. KK is an employee of GSK (clinical) and holds stock options in GSK. NS, WGC and YZ have no conflicts of interest.

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