Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2) agonist is more protective than a once-daily longacting β(2) agonist alone against exacerbations of ...chronic obstructive pulmonary disease (COPD) is unknown. We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone.
We did two replicate double-blind parallel-group 1 year trials. Both studies began on Sept 25, 2009. Study 1 ended on Oct 31, 2011, and study 2 on Oct 17, 2011. Eligible patients were aged 40 years or older, had a history of COPD, a smoking history of 10 or more pack-years, a ratio of forced expiratory volume in 1 s (FEV(1)) to forced vital capacity of 0·70 or less after bronchodilators (and an FEV(1) of 70% or less of predicted), and a documented history of one or more moderate or severe disease exacerbations in the year before screening. Patients were randomly assigned (1:1:1:1) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg, 100 μg, or 200 μg fluticasone furoate once daily. Our primary endpoint was the yearly rate of moderate and severe exacerbations. The trials were analysed separately and a pooled analysis was also done. These trials are registered with ClinicalTrials.gov (NCT01009463 and NCT01017952).
1622 patients in study 1 and 1633 patients in study 2 were randomly assigned. In study 1, no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group (mean 0·90 events vs 1·05 events per year; ratio 0·9 95% CI 0·7-1·0). Because of the statistical hierarchy used, we could not infer significance for the 50 μg and 100 μg groups. In study 2, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (p=0·0398 for the 50 μg group, 0·0244 for the 100 μg group, and 0·0004 for the 200 μg group). In the pooled analysis, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (0·0141 for the 50 μg group, <0·0001 for the 100 μg group, and 0·0003 for the 200 μg group). Nasopharyngitis was the most frequently reported adverse event in both studies. Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone. Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group.
Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk.
GlaxoSmithKline.
The frequency of COPD exacerbations during treatment with a triple inhaler — delivering a long-acting beta-agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled glucocorticoid — ...was compared with that with a LABA–LAMA or LABA–inhaled glucocorticoid.
Vilanterol (GW642444M) (VI) is a novel, inhaled, long-acting β(2) agonist with inherent 24-h activity under development as a once-daily combination therapy with an inhaled corticosteroid for COPD and ...asthma. This study assessed the dose response, efficacy, and safety of VI at doses of 3 to 50 μg in patients with moderate to severe COPD.
Six hundred two patients (intent-to-treat) were randomized (double-blind) to VI 3, 6.25, 12.5, 25, or 50 μg or placebo once daily for 28 days. The primary end point was change from baseline in trough FEV1 at the end of the 28-day treatment period. Secondary end points included 0- to 24-h weighted mean FEV(1) on days 1 and 28 and time to increases of ≥ 100 mL or ≥ 12% from baseline FEV(1) on day 1. Safety assessments included adverse events, vital signs, ECG assessment, and clinical laboratory tests.
VI once daily for 28 days significantly improved trough FEV(1) in a dose-dependent manner vs placebo. Clinically relevant treatment differences of ≥ 130 mL in trough and 0- to 24-h weighted mean FEV(1) were observed with VI 25- and 50-μg doses vs placebo. All doses of VI were associated with a low incidence of treatment-related adverse events/serious adverse events, with no suggestion of effects on BP, pulse rate, QT intervals corrected for heart rate calculated by Fridericia formula, or blood glucose and potassium levels.
VI 25 and 50 μg once daily provided both statistically and clinically relevant 24-h improvements in lung function in patients with COPD compared with placebo. All doses of VI had a safety and tolerability profile similar to placebo.
Radiographically confirmed pneumonia risk with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD) has not been assessed to date.
To determine the incidence of pneumonia, risk ...factors, and clinical attributes with inhaled fluticasone furoate (FF) in patients with COPD with an exacerbation history.
Two replicate, 1-year, double-blind clinical trials enrolled subjects with COPD with moderate to very severe airflow limitation and at least one exacerbation within the prior year. Subjects were randomized 1:1:1:1 to receive inhaled once-daily vilanterol (VI) 25 μg or VI 25 μg combined with 50, 100, or 200 μg FF. Subjects were required to have a chest radiograph at screening and within 48 hours of any suspected pneumonia or exacerbation.
Among 3,255 randomized subjects, 205 pneumonia events occurred in 181 subjects. Chest imaging was available for 195 (95%) of these events. Chest radiographs were also obtained for 1,793 (70%) of the 2,545 moderate and severe exacerbations. For VI alone and the combination with 50, 100, or 200 μg FF, reported pneumonia incidence was 3, 6, 6, and 7%, respectively. However, for events with compatible parenchymal infiltrates, the respective incidences were 2, 4, 4, and 5%. Factors associated with at least a twofold increase in the risk of pneumonia with FF/VI treatment were being a current smoker, having prior pneumonia, body mass index <25 kg/m(2), and severe airflow limitation.
Radiographically confirmed pneumonia risk is increased with inhaled FF/VI, although at less than investigator-defined rates. Modifiable pneumonia risk factors should be considered when attempting to optimize COPD management. Clinical trial registered with www.clinicaltrials.gov (NCT01009463 HZC102871; NCT01017952 HZC102970).
The Efficacy and Safety of Cilomilast in COPD Rennard, Stephen; Knobil, Katharine; Rabe, Klaus F. ...
Drugs (New York, N.Y.),
2008/12, Letnik:
68, Številka:
Suppl 2
Journal Article
Recenzirano
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 (FEV
1
) 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) FEV
1
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 FEV
1
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.
Background Vilanterol (GW642444M) (VI) is a novel, inhaled, long-acting β2 agonist with inherent 24-h activity under development as a once-daily combination therapy with an inhaled corticosteroid for ...COPD and asthma. This study assessed the dose response, efficacy, and safety of VI at doses of 3 to 50 μg in patients with moderate to severe COPD. Methods Six hundred two patients (intent-to-treat) were randomized (double-blind) to VI 3, 6.25, 12.5, 25, or 50 μg or placebo once daily for 28 days. The primary end point was change from baseline in trough FEV1 at the end of the 28-day treatment period. Secondary end points included 0- to 24-h weighted mean FEV1 on days 1 and 28 and time to increases of ≥ 100 mL or ≥ 12% from baseline FEV1 on day 1. Safety assessments included adverse events, vital signs, ECG assessment, and clinical laboratory tests. Results VI once daily for 28 days significantly improved trough FEV1 in a dose-dependent manner vs placebo. Clinically relevant treatment differences of ≥ 130 mL in trough and 0- to 24-h weighted mean FEV1 were observed with VI 25- and 50-μg doses vs placebo. All doses of VI were associated with a low incidence of treatment-related adverse events/serious adverse events, with no suggestion of effects on BP, pulse rate, QT intervals corrected for heart rate calculated by Fridericia formula, or blood glucose and potassium levels. Conclusions VI 25 and 50 μg once daily provided both statistically and clinically relevant 24-h improvements in lung function in patients with COPD compared with placebo. All doses of VI had a safety and tolerability profile similar to placebo. Trial registry ClinicalTrials.gov ; No.: NCT00606684 ; URL: www.clinicaltrials.gov
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