Inhaled ciclesonide versus inhaled budesonide or inhaled beclomethasone or inhaled fluticasone for chronic asthma in adults: a systematic review

Inhaled corticosteroids (ICS) have a central role in the treatment of asthma. They are the most effective prophylactic agents available, particularly in patients with mild to moderate asthma and persistent symptoms[1] and are recommended for most adult patients with chronic asthma whose symptoms are not controlled by inhaled short acting β 2 agonists [2‐4]. Regular treatment with corticosteroids reduces exacerbations, improves control of symptoms and lung function, while reducing hospital admissions and deaths from asthma[1, 5]. However, prolonged use in persistent asthma and increased doses in severe cases may result in suppression of the hypothalamic pituitary adrenal (HPA) system with concern that this might cause growth impairment in children (including premature closure of the epiphyses of long bones), disturbed glucose tolerance, decreased mineralisation of bone (increasing the risk of fractures), ocular problems such as glaucoma and cataracts as well as thinning of the skin [6‐8]. Local adverse affects, even at low doses may include dysphonia, pharyngitis and oral candidiasis[2, 9].

The mainstay of ICS treatment has been with three agents: beclomethasone dipropionate (BDP), budesonide (BUD) and, more recently, fluticasone propionate (FP). All these agents are similar chemically and structurally but have different pharmacodynamic properties resulting in different clinical effects[10]. A Cochrane review of 48 studies comparing the three agents concluded that FP given at half the daily dose of BDP or BUD leads to small improvement in measures of airway calibre (peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1) while at the same daily dose FP appears to have a higher risk of side effects than BDP or BUD[10].

Ciclesonide (CIC) is a new ICS, manufactured by Altana Pharma Ltd. CIC is licensed only for the treatment of persistent asthma in adults (18 years older) and is delivered via a hydrofluoroalkane metered-dose inhaler (HFA MDI) in 40, 80 and 160 mcg formulations. The recommended starting dose is 160 mcg given in the evening, with reduction to 80 mcg for maintenance[11]. These doses are "ex-actuator", i.e. the dose expelled, as opposed to "ex-valve" i.e. the actual dose contained in the inhaler (for consistency, throughout this review ex-valve doses are used for all inhalers).

Ciclesonide has little anti-inflammatory activity itself and requires cleavage by endogenous carboxyl esterases in the lung, which creates the active metabolite desisobutryl-ciclesonide (des-CIC)[12]. This targets activity at the desired location. Des-Ciclesonide undergoes rapid hepatic metabolism into inactive metabolites on leaving the lung[13]. These factors, together with the fact that ciclesonide has very low oral bioavailability due to almost complete first pass metabolism[14] would seem to create conditions favouring the maximisation of therapeutic effect in the lung and minimisation of the risk of systemic adverse effects.

Given that ciclesonide is being actively marketed as an alternative to alternative to other inhaled corticosteroids, our objective in this study was to systematically review published randomised controlled trials of the effectiveness and safety of ciclesonide compared to alternative inhaled corticosteroids in people with asthma.

There are few data directly comparing CIC to other ICS and no published evidence directly comparing CIC to BDP specifically. None of the RCTs showed CIC to offer any benefit over BUD or FP for effectiveness i.e. none of the RCTs showed CIC to offer any benefit over BUD or FP for any patient based outcomes (asthma symptoms or QoL in these trials). Furthermore none of the trials demonstrated any benefit from CIC over BUD or FP for indirect outcomes of efficacy i.e. lung function, improving response to AMP or metacholine as provoking agents or for decreasing markers of inflammation.

All but one of the trials were sponsored by drug companies manufacturing CIC and seem to endeavour to demonstrate CIC to have equivalent efficacy to other ICS but with an improved safety profile. However, none of the studies report analyses which exclude superiority of one treatment over another (hence it is not possible to conclude that CIC was equivalent to FP or BUD for any efficacy outcomes) and the evidence regarding safety is not conclusive.

The conflicting evidence from the Lee, Fardon et al trial might indicate that CIC has less systemic adverse effects than FP. Challenges to this conclusion, however, are twofold. The first comes from the trial itself. This is the only published trial comparing HPA suppression between CIC and other ICS and the results were not unequivocal. There were also some methodological weaknesses in the trial. There was no evidence of concealment of allocation, an attrition rate of 30%, no evidence of blinding other than the participants and the choice of a comparator (i.e. FP) that is reported to have the highest risk of side effects[10] (there is no published evidence directly comparing HPA suppression after treatment with CIC to either BUD or BDP).

The second challenge relates to the correlation between the intermediate outcome of HPA suppression measured at four weeks after the start of treatment with ICS correlates and clinically adverse effects for patients. HPA suppression is a well reported outcome of both short and long term ICS use [22‐25]. However the clinical significance of such suppression is uncertain[6, 22, 25]. Current evidence suggests that ICS do not cause important systemic side effects in doses of up to 400 mcg/day in children and 800 mcg/day in adults,[26] and even in doses of more than 1 mg/day there is no conclusive evidence that patients are at any increased risk from side-effects[25, 23]. Hanania et al report HPA suppression and decreased bone density after regular use of conventional doses of ICS for asthma[24] but there is no conclusive evidence of a clinically adverse effect e.g. bone fractures.

Further long term studies are required to determine the long term risk of clinically significant adverse effects as a result of HPA suppression associated with ICS use in general and specifically with CIC. In the meantime it is not possible to conclude that CIC offers any benefit over other ICS in terms of systemic adverse effects.

With respect to local adverse effects there are similar challenges. Although, CIC might be expected to have fewer local adverse effects (due to the inhaled agent being its inactive metabolite des-CIC) there is no logical explanation why CIC should be deposited in the oropharynx in such smaller amounts than FP or BUD. In the Nave et al study the authors point out that the difference in deposition could be due to the different inhaler devices used. HFA MDIs have been shown to produce ICS with a smaller particle size than CFC MDIs[27] resulting in 17% of a 200 mcg dose of BUD being respirable[15] compared to 48% of a 200 mcg dose of CIC[8, 13]. However, in the Richer et al study both inhalers were HFA MDI and the authors make no mention of why deposition might be less given that both treatments are inhaled via the same device. Neither trial was blinded in any way, which could have been a source of bias, and the lack of a logical explanation for such vastly different deposition rates makes it difficult to draw any definite conclusion. Further studies (preferably parallel) with larger populations are required before concluding whether CIC offers any benefit in terms of local adverse effects

In addition to the RCTs outlined above there are number of abstracts that have not yet been published as full papers. These trials involved substantially larger numbers of participants and ran for longer duration but have not been included in the analysis since they contained insufficient detail for critical appraisal of methodological quality. The results reported in these abstracts do not alter the conclusions drawn from the full papers but are reported for interest in Appendix 1.

Irrespective of any clinical benefit or not CIC is more expensive compared to BEC, BUD and FP as shown in Table 5. Treatment with CIC would come at substantial financial cost since at high dose (1000 mcg daily) CIC is 5.13 as expensive as BDP, 2.27 times as expensive as BUD (800 mcg daily) and 1.39 times as expensive as FP.

Any advantage that CIC might have over existing, cheaper, ICS is predicated on assertions regarding the long term dangers of ICS use. "Steroid phobia" is recognised in other fields[28] and is likely to form the basis for effective direct to patient marketing of CIC, where such advertising is permitted. However, the evidence base on long term inhaled steroid use is far from certain and it is not clear whether the dangers are such that the precautionary principle is justified.

Although it is clear that the evidence base for ciclesonide will expand considerably with the publication of the larger studies excluded from this review, we believe it is important to highlight the limited nature of the evidence base that is currently available for scrutiny by clinicians and policy makers seeking to practice and support evidence based medicine.

There is very little evidence that has been published in full comparing CIC to other ICS. Current evidence is restricted to very small, phase II studies of low power. These demonstrate CIC has similar effectiveness and efficacy to FP and BUD (though equivalence is not certain) and findings regarding oral deposition and HPA suppression are inconclusive. There is no direct comparative evidence that CIC causes fewer side effects since none of the studies reported patient-based outcomes. Treatment with CIC would also come at substantial financial cost compared to other ICS.

No specific funding was received for the study.

MD's post in PenTAG was funded by the NHS Public Health Training Scheme (South West Region).

The search resulted in the retrieval of eight abstracts recorded in Table 6. The Hansel et al and Engelstatter et al abstracts had the same author group, trial characterists and results and were assumed to be from the same trial. Hence only one (Hansel et al) was included. The Fardon et al abstract appeared to be an abstract form of the Lee, Haggart et al full paper and hence the abstract was excluded. The Derom et al and Pauwels et al abstracts were identical in all ways other than that the former had 25 participants and the latter 26. This could have been a typographical error and they were assumed to be abstracts of the same trial and only the Derom et al abstract included. The Biberger et al and Ukena et al abstracts had exactly the same author group, the same number of trial participants, the same trial and comparator doses but a slight difference in the results i.e. FEV1 increase after CIC and FP was 411 ml and 319 ml respectively in Biberger et al and 416 ml and 321 ml respectively in Ukena et al with all other results the same. It was assumed that the data had been analysed differently in each case but that these results represented the same trial and only one (Ukena et al) was included. Table 7 shows details of the abstracts.