Ciclesonide for chronic asthma in adults and children
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objectives are as follows: 1). to determine the effectiveness of ciclesonide in clinical studies and 2). the comparative efficacy of ciclesonide when compared to other inhaled corticosteroids, as well as 3) the safety of the once daily inhaled corticosteroid Ciclesonide in adults (aged 18 years and older) and children (less than 18 years) who have persistent asthma of any severity compared with either placebo therapy or another inhaled corticosteroid therapy.
Background
On a worldwide basis asthma is a common chronic disease in clinical practice affecting over 300 million people. It is responsible for one in 250 deaths per year and 15 million disability adjusted life years (DALYs) lost worldwide (GBA 2004). It is a condition which develops in early childhood and generally persists into adulthood (Gerritsen 1989; Martin 1982; Williams 1969). Asthma is a chronic inflammatory disease of the airways involving a complex interaction between airway structural cells and specific allergic inflammatory cells including mast cells, eosinophils and T‐lymphocytes, and the release of specific cytokines and mediators of inflammation. This inflammatory response is associated with airway narrowing, especially in smaller airways, which cause patients to complain of symptoms such as cough and wheeze (Tattersfield 2002; GINA 1998). The anti‐inflammatory corticosteroids have been an effective therapy for asthma for over 30 years and are now the main therapy for asthma control currently for those with persistent asthma (Adams 2000; Adams 2005; Powell 2003; BGAM 1997; BTS/SIGN 2003; Consensus 1999; Consensus 2005; GINA 1998).
Corticosteroids deal effectively with the asthma inflammatory process through interaction with the glucocorticoid receptor, thus leading to the amelioration in asthma symptoms and control of the disease. The main advantage of the inhaled route is to bring the therapy directly to the disease location and at a reduced dose and hence less systemic side‐effects compared to higher dose oral steroid therapy (Mash 2001). There are different types of inhaled corticosteroids available on the market given either by multi‐dose dry powder or aerosol inhaler devices (e.g. beclomethasone, fluticasone, budesonide, and mometasone). Inhaled corticosteroids significantly reduce the hospitalisation rate for asthma (and hence reduce cost associated with the disease) and the mortality from the condition (Suissa 2000; Suissa 2002) when taken on a regular basis. Non‐compliance is a significant problem with inhaled corticosteroid therapy due to a number of factors including increased dosing frequency and may occur due to recurrent local and also systemic side effects (Buston 2000). However, while inhaled steroids may be more effective when used four times per day, reducing dosing to twice daily or even once daily dosing can give effective control (Malo 1989; Toogood 1982). However, compliance with increased dosing frequency of inhaled steroids in asthmatics especially four times daily can be poor (Coutts 1992; Eisen 1990). The novel inhaled corticosteroid Ciclesonide has recently been approved in Europe. Research from clinical trials has shown the drug to be an effective therapy in persistent asthma in improving lung function, and in reducing asthma symptoms. This therapy has novel release and distribution properties, reported to result in better targeting of the anti‐inflammatory effects in the airways especially to the small airways. It is inhaled as a pro‐drug, which is converted to an active metabolite (des CIC) in the airways reportedly with reduced systemic and local (e.g. oropharyngeal) side effects. In addition, Ciclesonide is given as a once daily therapy, and may lead to better compliance with inhaled corticosteroids.
It has been decided to address the efficacy verus placebo and relative efficacy versus other inhaled steroid comparators for this review. However, into the future it may be necessary to split them into two reviews.
Objectives
The objectives are as follows: 1). to determine the effectiveness of ciclesonide in clinical studies and 2). the comparative efficacy of ciclesonide when compared to other inhaled corticosteroids, as well as 3) the safety of the once daily inhaled corticosteroid Ciclesonide in adults (aged 18 years and older) and children (less than 18 years) who have persistent asthma of any severity compared with either placebo therapy or another inhaled corticosteroid therapy.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCT) comparing the inhaled corticosteroid Ciclesonide with placebo or another inhaled corticosteroid will be considered for inclusion. Trials that use parallel group designs or cross‐over design with a wash out period of two weeks or more will be eligible. Studies published in abstract form will be included. Unpublished data, if available, will be considered.
Types of participants
Adults (aged 18 years and older) and children (less than 18 years) will be eligible for inclusion. All study subjects must have a diagnosis of chronic asthma, including those with intermittent and chronic symptoms. Studies that base the diagnosis of asthma on physician opinion or on objective criteria related to symptoms, airway reversibility to an inhaled short‐acting 2‐agonist or airway hyper‐responsiveness in keeping with international asthma guidelines such as GINA 1998 (Global Initiative On Asthma) / National Institutes of Health (NIH) or BTS/SIGN 2003) or evidenced based guidelines will be included. Studies that deliver interventions to patients in the community/family practice setting or hospital‐based settings will be included. Studies with subjects with pulmonary diagnosis other than asthma (e.g. COPD) will be excluded.
Types of interventions
Studies that include inhaled Ciclesonide at any dose versus placebo and/or another inhaled corticosteroid, such as budesonide, beclomethasone, fluticasone, triamcinolone, flunisolide will be considered. Comparisons between placebo and other steroids will be considered separately within the review. Therapy should be for at least 4 weeks. Concomitant therapies for asthma, such as short‐acting 2‐agonists (rescue therapy), theophyllines, long‐acting 2‐agonists (Serevent or formoterol), inhaled anti‐cholinergics will be allowed provided that patient's asthma is stable. Studies involving anti‐leukotrienes (singular or Accolate), the combined inhalers (fluticasone‐serevent and pulmicort‐formoterol) or other airway anti‐inflammatory asthma therapy (e.g. chromones) will be excluded.
Types of outcome measures
The primary outcomes will be:
1. Asthma exacerbations requiring use of systemic steroids.
2. Measures of lung function, forced expired volume in one second (FEV1) and or peak expiratory flow rates (PEF).
3. FEV1 or PEF rates variability.
4. Rescue 2‐agonists use
5. Mild asthma exacerbations not requiring systemic steroids, or severe exacerbations requiring hospital admissions.
6. Asthma control: a composite measure of outcomes 1 to 5.
7. Measures of adverse effects including oropharyngeal (candidiasis, sore throat, hoarseness), and systemic (osteopenia, adrenal suppression, growth rate) side‐effects and withdrawal rate due to side‐effects will be included.
The secondary outcomes will include:
1.Measures of healthcare utilisation: doctor visits, emergency visits and or hospital admissions for asthma.
2.Measures of morbidity: days of school absences, days of restricted activities, nights disturbed by asthma symptoms, health‐related quality of life, asthma severity, asthma‐free days,
3.Measures of compliance. As a surrogate to include study withdrawal or patient preference in crossover studies.
We will give a narrative overview of the following metrics, creating an additional table and re‐expressing their effects as standardised mean differences:
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am PEF
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FEV1
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Symptoms
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Rescue medication usage
Search methods for identification of studies
Electronic Searches
Trials will be identified using the Cochrane Airways Group Specialised Register of trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, and handsearching of respiratory journals and meeting abstracts. All records in the Specialised Register coded as 'asthma' will be searched using the following terms:
ciclesonide* or Alveso* or pregnenedione* or CIC
Other sources
Reference lists of all primary studies and review articles will be reviewed for additional references. Authors of identified trials will be contacted and asked to identify other published and unpublished studies. Pharmaceutical manufacturers (Altana) will also be contacted for information on any unpublished trials.
Data collection and analysis
Study assessment
The title and abstract of each citation identified using the search strategy identified will be screened by a study investigator for eligibility. Articles that appear to fulfil the inclusion criteria will be retrieved in full text. From the full text of the articles, two reviewers will independently establish whether each study meets the inclusion criteria as a RCT with the above interventions. Translation into English will be performed where necessary. Data on at least one of the primary outcome measures must be included in the study. Disagreement will be settled by consensus.
Data from included trials will be extracted independently and entered into RevMan 4.2. We will attempt to contact the author to identify additional papers, confirm data for correctness and completeness and if necessary to obtain missing data.
Data extraction
We will extract the following characteristics of each study:
Methods:design, randomisation method, blinding, follow‐up procedures and withdrawals.
Population:recruitment, sample size, age, gender, inclusion and exclusion criteria (including asthma therapy), asthma diagnosis and severity, pulmonary function, other medical diagnoses and therapies.
Intervention:Inhaled steroid, including Ciclesonide, dose, timing and duration of therapy, method of delivery, co‐intervention medications.
Outcomes:Reported outcomes
Numerical outcome data will be extracted independently by two reviewers.
Statistical considerations
Trial data will be combined using RevMan 4.2. Data will be pooled using a fixed effect model. Where heterogeneity is observed (I square >/=20%, Higgins 2003), a sensitivity analysis using a random effects model will be applied, to determine whether variation between the studies affects the pooled estimate. A WMD (weighted mean difference) and 95% CI will be calculated for continuous variables measured on identical metrics. SMD (standardised mean difference) will be used for the same continuous variables measured with different metrics. Generic inverse variance will be used to pool data derived from the same scale if they are only available as mean differences with 95% CIs or standard errors.
For dichotomous outcomes, a Risk Ratio (RR) will be calculated based upon the number of participants with an event versus the number of participants without an event. Fixed Effect modelling will be used to pool data for RRs unless heterogeneity is observed (I square >/=25%, Higgins 2003), in which case a Random Effects model will be used.
Study quality will be assessed using the Cochrane approach to assessment of allocation concealment. All trials will be scored and entered using the following principals.
Grade A: adequate concealment
Grade B: uncertain
Grade C: clearly inadequate concealment
Separate comparisons will be made for children and adults.
