Comparison of the efficacy of ciclesonide 160 μg QDand budesonide 200 μg BID in adults with persistent asthma: A phase III, randomized, double-dummy, open-label study

doi:10.1016/j.clinthera.2005.11.005

Clinical Therapeutics

Volume 27, Issue 11, November 2005, Pages 1752-1763

https://doi.org/10.1016/j.clinthera.2005.11.005 Get rights and content

Abstract

Objective:

The efficacy of ciclesonide 160 μg QD (given either in the morning or evening) was compared with budesonide 200 μg BID in adults with stable asthma that was pretreated with inhaled corticosteroids.

Methods:

This was a randomized, 3-arm, parallel-groupstudy comparing ciclesonide (given in a double-blind, double-dummy regimen) with open-label budesonide. After 2 to 2.5 weeks, during which patients were treated with budesonide 200 μg BID, patients (n = 405) were randomly assigned to receive ciclesonide 160 μg QD AM or 160 μg QD pm, or budesonide 200 μg BID (all administered by metered-dose inhaler) for 12 weeks. All patients received 2 puffs of medication (or placebo) in the morning and evening. The primary efficacy variable was the difference in spirometric forced expiratory volume in 1 second (FEV₁ in liters) from randomization to study end. Secondary efficacy end points were forced vital capacity, peak expiratory flow by spirometry, and diary assessments of peak expiratory flow, asthma symptoms, and rescue medication use. Adverse events were assessed by patient report, investigator observation, physical examination, and laboratory testing; events were classified as mild, moderate, or severe.

Results:

Baseline demographic characteristics with regard to sex, age, weight, smoking status, baseline medication use, and FEV₁ were balanced among the treatment groups. Over the course of treatment, both ciclesonide and budesonide maintained FEV₁ compared with baseline. Both ciclesonide regimens were as effective as budesonide 200 μg BID in maintaining FEV₁ during the treatment period versus baseline (ciclesonide 160 μg QD am: 95% CI, −0.120 to 0.045 vs budesonide; P = NS; ciclesonide 160 μg QD pm: 95% CI, −0.061 to 0.105 vs budesonide; P = NS). Ciclesonide 160 μg QD (morning or evening) was comparable with budesonide 200 μg BID for maintaining pulmonary function, asthma symptom scores, and rescue medication use. The incidence of adverse events was not significantly different among the treatment groups, and most adverse events were not related to study medication.

Conclusions:

In this study, ciclesonide 160 μg QDwas as effective as budesonide 200 μg BID (400 μg total daily dose) in these adults with persistent asthma. Both treatments were well tolerated.

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Direct drug administration to the esophagus faces several obstacles, including continuous salivary dilution and removal of the dosage form from the tissue surface due to esophageal peristalsis. These actions often result in short exposure times and reduced concentrations of drug at the esophageal surface, providing limited opportunities for drug absorption into or across the esophageal mucosa. A variety of bioadhesive polymers were investigated for their ability to resist removal by salivary washings using an ex vivo porcine esophageal tissue model. Hydroxypropylmethylcellulose and carboxymethylcellulose both have reported bioadhesive properties, but neither was able to withstand repeated exposure to saliva, and the gels formulated with these polymers were quickly removed from the esophageal surface. Two polyacrylic polymers, carbomer and polycarbophil, also showed limited esophageal surface retention when exposed to salivary washing, likely due to the ionic composition of saliva affecting the inter-polymer interactions necessary for these polymers to maintain their increased viscosities. In situ gel forming polysaccharide gels (ion-triggered), including xanthan gum, gellan gum, and sodium alginate, showed superior tissue surface retention, and formulations containing these bioadhesive polymers along with ciclesonide, an anti-inflammatory soft prodrug, were investigated as potential, locally-acting esophageal delivery systems. Exposure of a segment of esophagus to the ciclesonide-containing gels resulted in therapeutic concentrations of des-ciclesonide, the active drug metabolite, in the tissues within 30 min. Increasing des-CIC concentrations were also observed over a 3-hour exposure interval suggesting continued release and absorption of ciclesonide into the esophageal tissues. These results demonstrate the ability to achieve therapeutic drug concentrations in the esophageal tissues using in situ gel-forming bioadhesive polymer delivery systems, and these systems provide promising opportunities for the local treatment of esophageal disease.
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Ciclesonide: A Pro-Soft Drug Approach for Mitigation of Side Effects of Inhaled Corticosteroids
2016, Journal of Pharmaceutical Sciences
Citation Excerpt :
Ciclesonide is a novel pro-soft drug ICS, which gets activated to its active drug, called desisobutyryl-ciclesonide (des-CIC) by pulmonary esterases in the lungs, exert its therapeutic actions in the lungs and gets inactivated in a controlled metabolism.4,14 It possesses several PK and PD properties which leads to an advantageous safety profile and fewer oropharyngeal and systemic side effects in comparison to existing ICSs such as beclomethasone dipropionate and fluticasone propionate.27,28 The unique PK and PD properties of ciclesonide due to its design as a soft drug are explained in the following sections.
Inhaled corticosteroids are used as one of the first-line drug therapy in patients with asthma. However, their long-term use is associated with various oropharyngeal and systemic side and adverse effects. Design of pro-soft drug is one of the strategies, which was adopted in the design of ciclesonide for mitigation of side effects usually observed with the use of inhaled corticosteroids. Ciclesonide, a pro-soft drug, is converted to an active metabolite desisobutyryl-ciclesonide in the lungs. The anti-inflammatory effect of desisobutyryl-ciclesonide is much higher than ciclesonide, and therefore, the local effect of the metabolite is higher with lower systemic side effects. Ciclesonide has favorable pharmacokinetic and pharmacodynamic properties as inhaled corticosteroid including low oral bioavailability, high plasma protein binding and rapid systemic clearance, high pulmonary deposition and distribution and long pulmonary residence duration. These advantageous properties make ciclesonide a very effective treatment option with low side effects. Various clinical studies support safety and efficacy of ciclesonide use in mild, moderate, and severe asthma patients.
Asthma outcomes: Exacerbations
2012, Journal of Allergy and Clinical Immunology
The goals of asthma treatment include preventing recurrent exacerbations. Yet there is no consensus about the terminology for describing or defining “exacerbation” or about how to characterize an episode’s severity.
National Institutes of Health institutes and other federal agencies convened an expert group to propose how asthma exacerbation should be assessed as a standardized asthma outcome in future asthma clinical research studies.
We used comprehensive literature reviews and expert opinion to compile a list of asthma exacerbation outcomes and classified them as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at a National Institutes of Health–organized workshop in March 2010 and finalized in September 2011.
No dominant definition of “exacerbation” was found. The most widely used definitions included 3 components, all related to treatment, rather than symptoms: (1) systemic use of corticosteroids, (2) asthma-specific emergency department visits or hospitalizations, and (3) use of short-acting β-agonists as quick-relief (sometimes referred to as “rescue” or “reliever”) medications.
The working group participants propose that the definition of “asthma exacerbation” be “a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome.” As core outcomes, they propose inclusion and separate reporting of several essential variables of an exacerbation. Furthermore, they propose the development of a standardized, component-based definition of “exacerbation” with clear thresholds of severity for each component.
Comparison of the effect of low-dose ciclesonide and fixed-dose fluticasone propionate and salmeterol combination on long-term asthma control
2011, Chest
Citation Excerpt :
It seems unlikely that the once-daily dosage of ICS in the present study would have caused the difference seen in the time to first asthma exacerbation because several studies have shown clinical benefits, including reduced exacerbation rates in patients with mild to moderate asthma, with ciclesonide once daily.4,5,7,10 Moreover, once-daily ciclesonide has shown consistent and comparable clinical efficacy with other ICSs, including budesonide24,25 and fluticasone propionate,5,10,26 in improving pulmonary function, controlling asthma symptoms, and reducing rescue medication use and exacerbations. We acknowledge that mild symptoms may not equate mild pathophysiology.
Patients with mild persistent asthma constitute about 70% of the asthma population; thus, it is important to know which first-line treatment is best for the management of mild asthma. We compared benefits of first-line treatment with ciclesonide and a combination of fluticasone and salmeterol in patients with mild asthma.
Patients aged 12 to 75 years with mild persistent asthma were enrolled in a randomized, double-blind, placebo-controlled study. After run-in, patients were randomized to ciclesonide 160 μg once daily (CIC160), fluticasone propionate/salmeterol 100/50 μg bid (FP200/S100), or placebo for 52 weeks. The primary variable was time to first severe asthma exacerbation; the coprimary variable was the percentage of poorly controlled asthma days. Patients recorded asthma symptoms and salbutamol use in electronic diaries and completed a standardized version of the Asthma Quality of Life Questionnaire.
Compared with placebo, the time to first severe asthma exacerbation was prolonged, and lung function was improved with FP200/S100 treatment (P = .0002) but not with CIC160. Both CIC160 and FP200/S100 provided significantly fewer poorly controlled asthma days than placebo (P ≤ .0016 for both active treatments). Moreover, both active treatments provided significantly more asthma symptom-free days (P ≤ .0001), rescue medication-free days (P = .0005, one-sided), and days with asthma control (P ≤ .0033). Overall Asthma Quality of Life Questionnaire scores were significantly higher in both active treatment groups than placebo (P ≤ .0017).
In mild asthma, FP200/S100 prolonged time to first severe asthma exacerbation, and CIC160 and FP200/S100 were clinically equieffective for most measures of asthma control.
ClinicalTrials.gov; No.: NCT00163358; URL: www.clinicaltrials.gov
Efficacy and safety of ciclesonide in the treatment of 24,037 asthmatic patients in routine medical care
2011, Respiratory Medicine
Citation Excerpt :
A placebo-controlled study by Langdon et al. also noted significant improvements in FEV1 (significant increases of +0.13 l with 80 μg and +0.19 l with 320 μg ciclesonide versus placebo after 3 months) and PEF in patients treated with 80 μg or 320 μg daily ciclesonide for 3 months compared to placebo.12 Other 3-month, randomized, double-blind, active controlled studies also demonstrated a significant increase in FEV1 from baseline to study end with non-inferiority to budesonide and fluticasone.37–39 Similarly, the mean PEF increased in the course of the treatment with 160 μg ciclesonide by 14% which is comparable to the previously reported clinical trials with 22.4 l/min with half the dose.12
The efficacy and safety profile of ciclesonide (CIC) in the treatment of asthma was evaluated in a large patient population in a real-life setting in Germany.
24,037 patients with persistent mild/moderate bronchial asthma were enrolled into three observational studies with identical design. Data were pooled and analyzed. Patients received ciclesonide (160 μg/day) and were observed for 3 months. FEV₁, PEF, NO, asthma episodes, use of rescue medication and adverse drug reactions (ADR) were recorded.
Mean (95% CI) FEV₁ significantly increased from 80.7 [80.5; 80.9]% of predicted at baseline to 90.1 [89.9; 90.2]% after 3 months (n = 20,297), mean PEF significantly increased from 338 [335; 340] l/min to 392 [390; 395] l/min (n = 8100). NO was significantly reduced from 53.6 [51.8; 55.4] ppb to 26.2 [25.2; 27.1] ppb (n = 971). The percentage of patients with daily symptoms declined from 24.3% to 1.9%, night-time symptoms from 13.3% to 1.3%, and β₂-agonists use from 26.9% to 8.8%. ADRs were reported by 51 patients (0.2%). Most frequent ADRs were: dysphonia (n = 11), cough (n = 10), dyspnoea, throat irritation, and oral candidiasis (n = 5 each). 46 patients terminated the study prematurely, 41 due to ADR and 5 due to unknown/missing reason. One patient died due to cardiac failure (no causal relation).
These observational studies under real-life conditions support findings from controlled clinical studies regarding efficacy and tolerability of ciclesonide in patients with mild to moderate bronchial asthma. No unexpected ADRs were detected.

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Original researchComparison of the efficacy of ciclesonide 160 μg QDand budesonide 200 μg BID in adults with persistent asthma: A phase III, randomized, double-dummy, open-label study

Abstract

Objective:

Methods:

Results:

Conclusions:

J Allergy Clin Immunol

J Allergy Clin Immunol

Respir Med

J Allergy Clin Immunol

Primary Care Respir J

J Allergy Clin Immunol

Pulm Pharmacol Ther

Respir Med

Global strategy for asthma management and prevention

NIH publication 02-3659

Systemic effect comparisons of six inhaled corticosteroid preparations

Am J Respir Crit Care Med

Once-daily inhaled corticosteroids for the treatment of asthma

Curr Opin Pulm Med

PK/PD of inhaled corticosteroids: The risk/benefit of inhaled ciclesonide

J Allergy Clin Immunol

High lung deposition of 99mTc-labelled ciclesonide administered via HFA-MDI to asthma patients

Eur Respir J

Esterases involved in the hydrolysis of ciclesonide in human tissues

Eur Respir J

Original research
Comparison of the efficacy of ciclesonide 160 μg QDand budesonide 200 μg BID in adults with persistent asthma: A phase III, randomized, double-dummy, open-label study