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Bronchodilatory Effect of the PPAR-γ Agonist Rosiglitazone in Smokers With Asthma
M Spears1, I Donnelly2, L Jolly2, M Brannigan1, K Ito3, C McSharry2, J Lafferty1, R Chaudhuri1,
G Braganza1, P Bareille4, L Sweeney4, IM Adcock3, PJ Barnes3, S Wood5 and NC Thomson1
Smokers with asthma show a reduced response to inhaled subtypes in vitro and reduce inflammation in animal models of
corticosteroids. We hypothesized that a peroxisome asthma and neutrophilic airways disease.12 On the basis of this
proliferator–activated receptor-γ (PPAR-γ) agonist would be evidence, we hypothesized that the PPAR-γ agonist rosiglitazone
superior for the clinical treatment of these asthma patients. would have anti-inflammatory activity that would be of benefit
Forty-six smokers with asthma were randomized to inhaled in smokers with asthma. Therefore, we undertook an exploratory
beclometasone dipropionate (200 µg per day) or rosiglitazone clinical trial to examine the effect of rosiglitazone on lung
(8 mg per day) for 4 weeks. Rosiglitazone produced function, Asthma Control Questionnaire (ACQ) score, and
improvements in lung function (forced expiratory volume in inflammatory end points in a group of smokers with asthma.
1 s (FEV1) = 183 ml, P = 0.051; forced expiratory flow between
25 and 75% of the forced vital capacity (FEF25–75) = 0.24 l/s, Results
P = 0.030) as compared with inhaled beclometasone A total of 3,895 subjects with asthma were invited to participate
dipropionate. Further trials using PPAR-γ agonists in steroid-
in the study between August 2005 and May 2007, of whom resistant airway disease are indicated.
294 gave positive responses. Following screening through telephone calls, visits were arranged for 187 subjects. After a Inhaled corticosteroids are recommended as the first line run-in period involving weaning from inhaled corticosteroids of treatment in patients with chronic persistent asthma.1 and assessment of bronchodilator reversibility, 91 subjects Smokers with asthma, however, exhibit an impaired response met the criteria for randomization (see Methods for further to both inhaled and oral corticosteroids,2–5 possibly because of details). The trial contained four treatment arms, and subjects noneosinophilic airway inflammation, impaired glucocorticoid were randomly allocated to the various treatments. Forty- receptor function, and/or reduced histone deacetylase activity.6 five subjects were randomized to other treatments, which Cigarette smoking in asthma patients is also associated with an are not discussed in this article.13 The other 46 subjects were accelerated decline in lung function,7 increase in the number randomized equal y to rosiglitazone and inhaled beclometasone of emergency department visits for asthma (with associated dipropionate. The demographic, clinical (including previous costs)7,8 and increase in severity of symptoms, as compared with inhaled corticosteroid and long-acting β2-agonist use), and nonsmoking asthmatic patients.9 The prevalence of smoking inflammatory baseline characteristics of the recruited subjects in subjects with asthma reflects the prevalence in the general in each group were well matched. All the end points population, and therefore smokers with asthma constitute a presented are the changes relative to the response in the group large group of patients with poorly control ed disease.10 Smoking assigned to inhaled corticosteroids.
cessation is an effective therapy in this group,11 but because sustained quitting rates are low, additional or alternative therapies lung function
are needed for individuals with asthma who continue to smoke.
At 2 weeks, rosiglitazone demonstrated a borderline The glucocorticoid receptor is a member of the nuclear improvement in prebronchodilator forced expiratory volume hormone receptor family, which includes the peroxisome in 1 s (FEV1) (164 ml, 95% confidence interval (CI), −1 to 329, proliferator–activated receptor-γ (PPAR-γ). PPAR-γ agonists P = 0.051) nda significant improvement exert anti-inflammatory effects on multiple inflammatory cell in prebronchodilator peak expiratory flow (32.7 l/min, 95% CI 1Department of Respiratory Medicine, Faculty of Medicine, University of Glasgow, Glasgow, UK; 2Department of Immunology, Faculty of Medicine, University of Glasgow, Glasgow, UK; 3Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK; 4Discovery Medicine, GlaxoSmithKline, London, UK; 5Department of General Practice, Faculty of Medicine, University of Glasgow, Glasgow, UK. Correspondence: NC T Received 24 January 2009; accepted 2 March 2009; advance online publication 8 April 2009. CliniCal pharmaCology & TherapeuTiCs
table 1 Baseline demographics and induced sputum results
Characteristic
beclometasone
rosiglitazone
Figure 1 Comparison of treatment responses at 14 and 28 days. (a) Change
in forced expiratory volume in 1 s (FEV1) (ml) at 14 and 28 days. (b) Change
in forced expiratory volume in 1 s (FEF25–75) (l/s) at 14 and 28 days. The changes presented are mean group changes from randomization to 14 and 28 days of treatment (paired t-test; error bars represent 95% confidence intervals). P values were derived by comparing the relative changes in the two treatment arms, using analysis of covariance. ICS, inhaled corticosteroid (beclometasone dipropionate); Rosi, rosiglitazone.
ACQ score
When changes in ACQ scores were compared , there was no difference between the rosiglitazone group and the one on inhaled beclometasone dipropionate.
(absolute count (104 cells))Bronchial epithelial cells (%) sputum samples
Induced sputum cytology. No relative differences in sputum cell
proportions were observed between the two treatment arms Data presented as median (interquartile range) unless stated otherwise.
95% CI; 95% confidence interval; ACQ, Asthma Control Questionnaire score (range, 0–6, with higher scores indicating worse asthma control); BMI, body mass index; FEV1, forced expiratory volume in 1 s; FEF25–75, forced expiratory flow between 25 and Sputum supernatant. A borderline reduction in sputum inter-
75% of the forced vital capacity; IgE, immunoglobulin E; IU, international units; LABA, long-acting β leukin-8 was observed in the group treated with rosiglitazone 2-agonist; PEF, peak expiratory flow; pre-BD, prebronchodilator.
(−534.1 pg/ml, 95% CI, −1,844.4 to 36.5, P = 0.068) relative to the group on inhaled beclometasone dipropionat 5.7–59.7, P = 0.018), and significant improvement in both forced expiratory flow between 25 and 75% of the forced vital capacity Compliance
(FEF25–75) (0.36 l/s, 95% CI, 0.09–0.63, P = Eighty-five percent of the subjects who completed the study and FEF75 (0.24 l/s, 95% CI, 0.09–0.39, P = 0.002). After 4 weeks, achieved >80% compliance with therapy.
the group treated with rosiglitazone again demonstrated a bor- derline improvement in prebronchodilator FEV1 (183 ml 95% Adverse events
CI −1.0 to 367.0, P = andand a sig- No serious adverse events occurred in subjects in either of the nificant improvement in FEF25–75 (0.24 l/s, 95% CI, 0.03–0.46, treatment arms during the trial. There were two withdrawals P = andWith respect to other meas- due to adverse events. One occurred in the rosiglitazone group urements of lung function, there was no difference between the (allergic reaction, periorbital edema) and one in the inhaled beclometasone dipropionate group (diarrhea and vomiting). www.nature.com/cpt
table 2 Predefined and exploratory end point changes
This improvement is much larger than the effect seen end point
Change by 14 days
Change by 28 days
in previous trials that examined the effect of inhaled corticosteroids in smokers with asthma2,3 and was associated with improvements in our predefined secondary lung function end points, suggesting that the FEV1 improvement is real. The failure to produce a conclusive improvement may be due to an Δ Pre-BD FEF25–75 (l/s (95% CI)) 0.36* (0.09, 0.63) The improvement in lung function produced by rosiglitazone was not associated with a reduction in asthma symptoms (as detected by the ACQ score), sputum profile, or supernatant at 28 days. What can explain this? The subjects had relatively mild asthma and did not display sputum eosinophilia or neutrophilia at baseline, and therefore we would not have been able to detect substantial changes in these cells or sputum cytokines. The lack of change in ACQ score is possibly an example of dissociation between change in lung function and ACQ score, as has What is the mechanism by which rosiglitazone produces the improvements that we have detected in lung function? The reason for the poor response to corticosteroids in smokers with asthma is currently unknown. However, one possible reason is that cigarette smoking may induce an oxidative stress–mediated change in the glucocorticoid receptor, resulting in a change in its behavior and efficacy.18 Recent research has demonstrated that rosiglitazone is able to bind to the glucocorticoid receptor ligand-binding domain and thereby alter gene transcription.19 Therefore, our results may be a demonstration of an alternative mode of glucocorticoid-receptor activation leading to the detected improvements in lung function. An alternative explanation emerges from the fact that PPAR-γ has been Changes in lung function, Asthma Control Questionnaire (ACQ) score, and induced shown to modulate a distinct but partially overlapping set of sputum results following treatment with rosiglitazone (compared to response inflammatory genes relative to corticosteroids.20 Further studies to treatment with inhaled beclometasone alone). Lung function data and ACQ score differences are difference of adjusted means with adjustment for baseline examining the relative effects of rosiglitazone on corticosteroid measurement (analysis of covariance).
and PPAR-γ-specific functional outputs are indicated in smokers Δ, change; 95% CI, 95% confidence interval; FEV1, forced expiratory volume in 1 s; with asthma and other conditions that are associated with FEF25–75, forced expiratory flow between 25 and 75% of the forced vital capacity; FVC, forced vital capacity; IL-8, interleukin-8; MPO, myeloperoxidase; PEF, peak relative corticosteroid insensitivity.
expiratory flow; pre-BD, prebronchodilator.
The improvement seen in FEF75 at 14 days and FEF25–75 at *P < 0.05, †P = 0.05.
both 14 and 28 days is of interest, given that there are currently few therapies available for the treatment of small-airway The frequency of occurrence of headaches was similar in the obstruction. Smal -airway obstruction, seen in many pulmonary two the groups (five in the beclometasone dipropionate group conditions,21–23 is associated with dynamic hyperinflation, and four in the rosiglitazone group). Three subjects in the reduced tolerance to exercise, and increased dyspnea. Given beclometasone dipropionate group reported pharyngitis.
the improvement seen in our patients, consideration should be given to studying PPAR-γ agonists in subjects with small- DisCussion
There exists a subpopulation of asthma patients who fail to In conclusion, this trial—to our knowledge, the first to respond adequately to current therapies.14 As a result, this group examine the efficacy of a PPAR-γ agonist in subjects with has poorer asthma control and consumes a disproportionate asthma—has demonstrated modest improvements in lung share of health-care budgets. Smokers with asthma are part of function measurements in a group of smokers with mild this large, difficult-to-treat group. This randomized, controlled, to moderate asthma. Our conclusions are tempered by the exploratory clinical trial examined the impact of a novel alterna- exploratory nature of this work, reflected in the short duration tive approach using the PPAR-γ agonist rosiglitazone in a group of treatment and the small number of subjects involved. Given of smokers with mild to moderate asthma.
that we have detected an effect in a treatment-resistant group, Treatment with rosiglitazone produced a trend toward further trials should be undertaken to examine PPAR-γ agonists improvement in prebronchodilator FEV1 relative to low- in asthma and other obstructive airway conditions. Issues that dose inhaled corticosteroids, at both 14 days and 28 days. should be addressed in future trials include dose response, CliniCal pharmaCology & TherapeuTiCs
interaction with corticosteroids,19,24 PPAR-γ polymorphisms,25 from a previous clinical trial with oral corticosteroids in smokers with and PPAR-γ endobronchial expression response to treatment.26 asthma.5 This led us to estimate that we needed to recruit 22 subjects per PPAR-γ agonists may represent a new therapeutic class for group to detect a 230 ml difference in FEV1 between the treatment arms, al owing for a 10% dropout rate. There was a slightly higher dropout rate (13%) in the trial, resulting in a short time extension to allow a larger number of subjects to be randomized to treatment.
The primary end point was the difference in prebronchodilator FEV1 subjects. Patients with mild to moderate1 stable asthma, aged 18–60
between the group on rosiglitazone and the one on beclometasone years, and on ≤1,000 µg of beclometasone dipropionate (or equiva- dipropionate at 28 days. The secondary end points were changes in lent) per day and smokers of 5 or more cigarettes per day with at least 5 pre- and postbronchodilator peak expiratory flow, forced vital capacity, pack-years of smoking history were eligible for enrollment. All subjects FEF25–75, FEF75, and ACQ. Exploratory end points were changes in demonstrated reversible airflow obstruction.27 Exclusion criteria sputum differential, sputum supernatant, and serum cytokines. The included diabetes, recent myocardial infarction, and other active randomization schedule was generated in blocks using a validated pulmonary diseases (full criteria available at http://www. clinicaltrials.
system (RandAll). Lung function changes were examined with analysis gov; NCT00119496). Patients were recruited from general practice, of covariance (incorporating the Kenward–Rogers method) using SAS hospital clinics, and research databases. The West Glasgow Research v8.2 (SAS Institute, Cary, NC). All data obtained after day 1 of treatment Ethics Committee approved the study, and all patients gave written were used for analysis. The remaining statistical analysis was performed using Minitab 15 (Minitab, State College, PA). The level of statistical significance was set at <0.05. Parametric data were examined using paired study design. The study was a randomized, prospective, double-blind,
t-testing, two-sided t-testing, or analysis of variance, and nonparametric double-dummy, active comparator, parallel-group design. Subjects data were analyzed with Mann–Whitney or Kruskal–Wallis testing, as were monitored for asthma stability for up to 6 weeks and underwent a appropriate. Given the exploratory nature of the trial, the secondary and corticosteroid weaning and monitoring phase that lasted 1 month within exploratory analyses were not corrected for type 1 errors due to multiple this period. All the subjects were treated with inhaled β 2 weeks and were excluded from randomization if they experienced an exacerbation of asthma at any point during this run-in phase.
ACknowleDgMents
If subjects were stable and met entry criteria at the end of the 2-week This study is dedicated to the memory of S.W., who died shortly after the corticosteroid-free period (including bronchodilator reversibility), commencement of recruitment. The study was a collaborative project they attended a randomization visit that entailed spirometry and peak between the University of Glasgow, Imperial College, and GlaxoSmithKline’s expiratory flow recordings, completion of an ACQ,28 induced sputum (GSK) discovery arm. Sponsorship was provided by GSK. M.S. was a expectoration for differential cell count and supernatant mediators, beneficiary of research training fellowships from Chest, Heart & Stroke and routine blood tests for safety (full blood count and renal and Scotland and the Chief Scientist’s Office (Scotland) during the course of liver function tests) and characterization (levels of total and specific the study. An employee of GSK, blinded to the group allocations of the immunoglobulin E; total, low-density lipoprotein, and high-density individual patients, performed the lung function statistical analysis. We lipoprotein cholesterol; and triglycerides).
specifically express our gratitude to Brian Rae, Greater Glasgow and Clyde The subjects were then randomized with equal bias to one of four Primary Care R&D, for his help and support with this project. We also thank groups. Two of the treatment arms and their corresponding results the participants and the participating general practices from the Greater are not discussed in this article.13 The subjects discussed in this article Glasgow and Lanarkshire region; without their help this study would not received either 4 mg twice a day of oral rosiglitazone maleate ( Avandia; GlaxoSmithKline, Greenford, UK) or 100 µg twice a day of inhaled ConFliCt oF inteRest
hydrofluoroalkane beclometasone dipropionate (Qvar; IVAX, Runcorn, P.B. and L.S. are employees of and own shares in GlaxoSmithKline. The other UK) (equivalent to ~400 µg per day chlorofluorocarbon beclometasone authors declared no conflict of interest.
dipropionate).29 The subjects returned for prebronchodilator lung function tests at 2 weeks and repeated the assessments carried out at 2009 American Society for Clinical Pharmacology and Therapeutics 1. Global Initiative for Asthma. Global Strategy for Asthma Management and Measurements. Lung function assessments conformed to consensus
Prevention (2008). <http:/www.ginasthma.com/>.
guidelines.27 Sputum induction, differential count, and supernatant 2. Chalmers, G.W., Macleod, K.J., Little, S.A., Thomson, L.J., McSharry, C.P. & analysis were performed as previously described.11,30 Sputum Thomson, N.C. Influence of cigarette smoking on inhaled corticosteroid supernatants were collected for determination of interleukin-8 and treatment in mild asthma. Thorax 57, 226–230 (2002).
myeloperoxidase (interleukin-8; R&D Systems, Abingdon, UK; 3. Tomlinson, J.E., McMahon, A.D., Chaudhuri, R., Thompson, J.M., Wood, S.F. myeloperoxidase; Immundiagnostik, Oxford Biosystems, Oxford, UK). & Thomson, N.C. Efficacy of low and high dose inhaled corticosteroid in Local hospital laboratories performed the full blood counts, urea and smokers versus non-smokers with mild asthma. Thorax 60, 282–287 (2005).
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