Control of moderate-to-severe asthma with randomized ciclesonide doses of 160, 320 and 640 μg/day

Abstract

Background

The inhaled corticoteroid (ICS) ciclesonide (Cic), controls asthma symptoms in the majority of patients at the recommended dose of 160 µg/day. However, the relationship between the level of asthma control and increasing doses of Cic is unknown. This study investigated whether long-term treatment with higher doses of Cic would further improve asthma symptoms in patients with uncontrolled asthma despite ICS use.

Patients and methods

In a double-blind, randomized, parallel-group study, 367 patients were allocated to one of three treatment arms (Cic 160, 320 and 640 µg/day). After a single-blind, 3-week baseline period with Cic 160 µg/day, eligible patients were randomized to receive 52 weeks of treatment with Cic 160, 320 or 640 µg/day (double-blind period) during which forced expiratory volume in 1 second (FEV₁), exacerbations and Asthma Control Questionnaire (ACQ) scores were measured.

Results

Treatment with all the three doses was associated with significant improvements in ACQ scores, FEV₁ and asthma symptoms (P<0.01). There were no statistically significant differences between the three doses. The results of the primary end point analysis showed a numerical improvement in the ACQ score with Cic 640 µg/day compared with Cic 160 µg/day (least square [LS] mean: −0.122; two-sided P-value: 0.30). Post hoc subgroup analyses showed that the improvement in the ACQ score with Cic 640 µg/day compared with Cic 160 µg/day was statistically significant in subjects who experience at least one exacerbation per year (LS mean: −0.586; 95% confidence interval: −1.110, −0.062, P=0.0285). Adverse events were low and consistent with the known safety profile of Cic.

Conclusion

In patients with persistent, uncontrolled asthma, increasing the Cic dose from 160 to 640 µg/day provided no clear additional effect. Patients who experience more than one exacerbation per year may benefit from higher doses; however, further studies are necessary to confirm this. All Cic doses were well tolerated.

Keywords:

• dose-response
• asthma control

Supplementary materials

Statistical methods

• All the data were summarized using descriptive statistics. Statistical tests were two sided and conducted at the 5% significance level unless otherwise specified. Intention-to-treat (ITT) and per-protocol analyses were performed for the primary end point based on the full and valid case analysis sets, respectively. All other efficacy analyses were performed using an ITT analysis only.

• The primary end point change from baseline to last visit in Asthma Control Questionnaire (ACQ) was analyzed using an analysis of covariance (ANCOVA) model including baseline ACQ and age as covariates, and treatment center, sex and pre-study inhaled corticosteroid (ICS) dose as factors.

• To adjust for critical factors, a nonparametric ANCOVA was performed using the same factors and covariates as the ANCOVA model for the primary end point. Similar descriptive and graphical analyses were performed for the ACQ cutoff points 0.5, 0.75, 1.0, 1.25 and 1.5.

• The number of weeks with well-controlled asthma was defined as the number of weeks that the patient had an ACQ score of 0.75 or lower over the course of the study. Treatment comparisons were carried out using an exact Wilcoxon–Mann–Whitney test for the percentage of weeks with well-controlled asthma.

• The prevalence of patients with well-controlled asthma at the end of the study and the prevalence of patients with an ACQ improvement by at least 0.5 at the end of the study were analyzed using Fisher’s exact test.

• To account for differences in the time to the first of these events, a log-rank test was used for the analysis of the time to the first measurement of well-controlled asthma and the time to the first ACQ improvement.

• A Cox proportional hazards regression was computed using the same factors and covariates as the ANCOVA model for the primary end point.

• Asthma exacerbation rates were analyzed using a Poisson regression model with the same factors and covariates as the ANCOVA model for the primary variable.

• Confirmatory statistical testing was performed using a hierarchical approach to address multiplicity. All statistical analyses were performed using SAS Version 9.1.3 or later (SAS Institute Inc., Cary, NA, USA).

• It was calculated that a sample size of 120 in each group would provide almost 90% power to detect a difference in mean values of 0.5, assuming that the common standard deviation is 1.2 using a two-group t-test with a 0.05 two-sided significance level.

Demographics

Additional demographic and baseline characteristics are summarized Table S1.

Concomitant medication

Exclusion criteria

Patients treated with an ICS at a stable dose between 200 and 1000 µg fluticasone propionate/day or equivalent for a minimum of 12 weeks could enter the study. The use of systemic glucocorticosteroids was not allowed for the entire duration of the study. If the administration of systemic glucocorticosteroids became necessary, the patient was withdrawn. Patients treated with one of the following nonsteroidal controllers (used either concurrently or in fixed combination with the ICS) in the 2 weeks prior to the first visit during the baseline period were not allowed to enter the study:

• Chromones (eg, inhaled disodium cromoglycate and inhaled nedocromil)

• Xanthines (eg, sustained-release theophylline and aminophylline)

• Leukotriene antagonists (eg, montelukast and zafirlukast)

• Lipoxygenase inhibitors (eg, zileuton)

• Inhaled long-acting beta-agonists (LABAs; eg, formoterol and salmeterol)

• Oral beta 2-agonists (eg, oral preparations of bambuterol, terbutaline, albuterol and salbutamol).

Subgroup analyses

Subgroup analyses to assess the impact of key demographic variables on the primary end point were performed (Table S3); data are presented for subgroups by ACQ score at baseline, pre-study ICS dose, body mass index, smoking status, completers/withdrawals and baseline forced expiratory volume in 1 second (FEV₁).

Adverse events

Adverse events occurring in at least 5% of patients in any treatment group are shown in Table S4.

Table S1 Additional baseline demographics in the ITT population

Table S2 Concomitant use of short-acting beta 2-agonists in the ITT population

Table S3 Subgroup analyses of change from baseline to last visit in ACQ score of between-treatment differences with Cic 640 μg/day and Cic 160 μg/day (ITT)

Table S4 AEs occurring in at least 5% of patients in any treatment group

Acknowledgments

We thank Renate Engelstaetter for the full support of setting up the study designs and protocol. We also thank her for her substantial contribution to the development of the protocol of this study and all the investigators who recruited and treated patients at the 37 centers involved in the CONTRAST study. Editorial support was provided by Caroline Loder and Rebecca Birch of Synergy Vision London and funded by Takeda Pharmaceuticals International AG and AstraZeneca.

Author contributions

Dirkje S Postma and Søren E Pedersen contributed to the study design and protocol. All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

Dr Søren E Pedersen reports personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Sandoz. Dirkje S Postma reports grants for research (for the University of Groningen) from AstraZeneca, Chiesi, Genentech, GSK and Roche. Fees for consultancies were given to the University of Groningen by AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. Niyati Prasad, Udo-Michael Goehring and Henrik Andersson were employees of Takeda Pharmaceuticals International GmbH during the time the study was conducted. The authors report no other conflicts of interest in this work.