Difference Between Patient-Reported Side Effects of Ciclesonide Versus ﬂuticasone Propionate

View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector Respiratory Medicine (2010) 104, 1825e1833

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/rmed

Difference between patient-reported side effects of ciclesonide versus ﬂuticasone propionate

Thys van der Molen a, Juliet M. Foster a,b, Manfred Caeser c,e, Thomas Mu¨ller c, Dirkje S. Postma d,*

a Department of General Practice, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands b Woolcock Institute of Medical Research, 431 Glebe Point Rd, Glebe NSW 2037, Sydney, Australia c Nycomed GmbH, Byk-Gulden-Straße 2, 78467 Konstanz, Konstanz, Germany d Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands

Received 18 January 2010; accepted 26 May 2010 Available online 2 July 2010

KEYWORDS Summary Adverse events; Rationale: Patient-reported outcomes provide new insights into the dynamics of asthma Inhaled corticosteroid management. Further to asthma control and quality of life, self-reported side effects of treat- questionnaire; ment can be assessed with the validated Inhaled Corticosteroid Questionnaire (ICQ). ICQ; Objectives: To compare patient-reported side effects between the inhaled corticosteroids Patient-reported ciclesonide and fluticasone propionate. outcomes Methods: Patients with moderate or moderate-to-severe asthma, pre-treated with a constant dose and type of medication, were randomized in three separate studies: 1) once daily ciclesonide 320 mg(n Z 234) or twice daily fluticasone propionate 200 mg(n Z 240); 2) twice daily ciclesonide 320 mg(n Z 255) or twice daily fluticasone propionate 375 mg(n Z 273); and 3) twice daily ciclesonide 320 mg(n Z 259) or twice daily fluticasone propionate 500 mg (n Z 244). Patients rated the side effect questions of the 15 domain ICQ on a 7-point Likert scale (0 Z not at all, 6 Z a very great deal) during scheduled visits. Results: The majority of side effect scores remained similar with ciclesonide but worsened statistically significantly withfluticasonepropionatefrombaselinetotheendofthestudy in within-treatment analyses. In between-treatment analyses of studies 1 and 3 ciclesonide significantly improved total side effect scores (p < 0.025) and 14 out of 30 individual local and systemic domain scores (p < 0.025) compared with fluticasone propionate. In Study 2, although ciclesonide improved the majority of scores compared with fluticasone propionate only ‘oropharyngeal itching’ reached statistical significance (p < 0.025, one-sided).

* Corresponding author. Tel.: þ31 (0) 50 3613532; fax: þ31 (0) 50 3619320. E-mail address: [email protected] (D.S. Postma). e Dr Caeser was an employee of Nycomed GmbH at the time the studies were conducted and now works as a self-employed healthcare consultant.

Conclusion: Patient-perceived side effects differ depending on the type of inhaled corticosteroids used. Patients with moderate-to-severe asthma report less intense side effects assessed with ICQ with ciclesonide than with ﬂuticasone propionate. Clinical trial registration: The reported trials were completed before July 1 2005 and, therefore, are not registered. ª 2010 Elsevier Ltd. All rights reserved.

Introduction inhaling 200e400 mg salbutamol, prior to randomization. Appendix 1 contains further information on inclusion and Inhaled corticosteroids (ICS) are accepted worldwide as the exclusion criteria. recommended first-line treatment for persistent asthma of all severities in both adults and children.1,2 However, many Study design patients perceive relatively mild side effects even with 3 low-dose ICS. Although patients often do not mention All studies had a multicentre, randomized, parallel-group these mild side effects during consultation, the conse- design (Table 1). Prior to randomization and at each quences of side effects are not trivial as quality of life can scheduled visit correct inhaler technique was reviewed. No 4 be significantly affected and treatment compliance spacer device was used for study-drug administration. 5 reduced. The extent of patient-perceived side effects Patients were randomized as follows: study 1) ciclesonide related to ICS use is likely to be underestimated in daily (CIC) 320 mg once daily or fluticasone propionate (FP) 6,7 clinical practice. 200 mg twice daily; study 2) CIC 320 mg twice daily or FP Today, patient-reported outcomes are increasingly 375 mg twice daily; and study 3) CIC 320 mg twice daily or combined with traditional clinical data in order to form FP 500 mg twice daily. CIC was administered via metered- a comprehensive assessment of how asthma treatment and dose inhaler (MDI) in all studies. FP was administered via 8,9 management can be tailored to patient-focused care. dry powder inhaler (DPI) in Study 1 and via MDI in Studies 2 Patients’ perception of their quality of life and symptom and 3. Patients were blinded to medication in Study 3. control can yield important information unattainable from Salbutamol (100 mg/puff) was used as rescue medication routine clinical testing and may provide evidence of throughout all studies. Suspected fungal infections of the 9 a treatment benefit from a patient’s perspective. mouth or throat were confirmed in the laboratory. Patients Further to quality of life and asthma control ques- recorded treatment compliance in daily diaries. All studies 8,10e12 tionnaires, the Inhaled Corticosteroid Questionnaire were performed in compliance with the Guidelines for Good (ICQ) has been developed to measure the prevalence and Clinical Practice and the Declaration of Helsinki in its 3,13 intensity of patient-perceived side effects. The ICQ has revised form (Somerset West 1996). The protocols were been validated, and its reliability, reproducibility and approved by the relevant Independent Ethics Committee or responsiveness to increasing ICS dose have been repor- Institutional Review Board for each participating centre. 3,13,14 ted. Recent clinical studies of ICS safety have shown Before recruitment into the studies, all patients gave improved systemic and local safety profiles with ciclesonide written informed consent. For adolescents taking part in 15e20 versus fluticasone propionate. We hypothesise that the studies, their legal representative also gave written patient-based outcomes could reveal more precisely the informed consent. side effect profile of ciclesonide compared with fluticasone For more information regarding the methodologies of propionate from the perspective of the patient than these studies, we refer the reader to the respective 21 traditionally spontaneously reported side effects. Here publications.15,19,20 we present the findings from the first three clinical studies comparing the patient-reported side effects of ciclesonide Patient-reported side effect assessment with fluticasone propionate in patients with moderate or moderate-to-severe asthma, as measured by the ICQ. The ICQ consists of 57 side effect-related questions grouped into 15 domains covering both oropharyngeal and systemic Methods side effects (Appendix 2).13 Patients completed the ICQ at baseline, and after 4 and 12 weeks of treatment in Study 1; Patients at baseline and after 8, 16 and 24 weeks of treatment in Study 2; and during run-in, at baseline and after 4, 8, 12, In three separate studies, patients aged 12e75 years with 16, 20 and 24 weeks of treatment in Study 3. At all time a history of bronchial asthma, as defined by the American points, patients assessed their experiences with asthma Thoracic Society,22 for 6 months but otherwise in good medications over the previous 2 weeks. health were included if they had been pre-treated with Patients rated the questions on a 7-point Likert scale a constant dose and type of asthma medication (except from 0 (not at all) to 6 (a very great deal). The scoring rules rescue medication). All participants had reversible airway recommended by the ICQ authors were followed.23 The raw obstruction, i.e. an improvement in forced expiratory scores of the ICQ were transformed into 15 domain scores volume in 1 s (FEV1) 12% of initial and 200 mL after on a scale from 0 (none) to 100 (worst possible). All Patient-reported side effects of inhaled steroids 1827

Table 1 Summarized study details and selected baseline and patient characteristics of the intention-to-treat population in the three studies. Study 1 (N Z 474) Study 2 (N Z 528) Study 3 (N Z 503) Run-in period (weeks) 1e42 2 Run-in medication FP 250 mg, or equivalent FP 500e1000 mg, or equivalent BDP 1000 mg, or equivalent Asthma severity Moderate Moderate-to-severe Moderate-to-severe Treatment period 12 24 24 (weeks) Design of study Randomized, open-label, Randomized, open-label, Randomized, double-blind, double-dummy, parallel-group parallel-group parallel-group Study treatment CIC 320 mg FP 200 mg CIC 320 mg FP 375 mg CIC 320 mg twice daily FP 500 mg twice daily once daily twice daily twice daily twice daily Sex (n): Female 144 146 158 164 136 125 Male 89 93 97 109 123 119 Age, yearsa 38 (12e73) 40 (12e74) 43 (13e74) 44 (12e75) 46 (18e75) 47 (18e73)

FEV1% predicted 88.2 15.4 90.4 13.8 93.5 11.6 93.0 10.7 93.5 10.9 94.4 12.1 b at T0 Reversibility (%) 19.6 8.6 19.6 8.4 16.6 8.0 17.6 8.3 17.6 8.0 18.7 9.8 b at T0 Prior ICS dose 491 173 506 201 1125 378 1146 408 1376 556 1385 537 b,c (mg/day) at T0 CIC administered via MDI in all studies (CIC 320 mg ex-actuator equivalent to CIC 400 mg ex valve); FP administered via DPI in Study 1 (FP 200 mg twice daily is equivalent to a total nominal daily dose of FP 400 mg) and MDI in Studies 2 (FP 375 mg ex valve equivalent to FP 330 mg ex-actuator) and 3 (FP 500 mg ex valve equivalent to FP 440 mg ex-actuator). a Data are presented as median (range). b Data are presented as mean standard deviation. c Beclometasone dipropionate equivalent. CIC Z ciclesonide; FP Z ﬂuticasone propionate; BDP Z beclomethasone dipropionate;

MDI Z metered-dose inhaler; DPI Z dry powder inhaler; FEV1 Z forced expiratory volume in 1 s; T0 Z randomization-to-treatment visit. returned questionnaires were checked for missing Patients responses that were, where possible, completed by patients during their visit. Baseline and patient characteristics were similar between- treatment groups for each of the three studies (Table 1). Of Statistical analyses the 637 patients enrolled in Study 1, 474 were randomized to treatment and the ITT population for ICQ assessment Least squares means were calculated for each of the 15 consisted of 452 patients (CIC, n Z 224; FP, n Z 228). In domains in each study. In Studies 1 and 2, if non-inferiority Study 2, of 658 patients enrolled, 528 patients were (non-inferiority margin for ICQ: þ4, one-sided p < 0.025, randomized to treatment and 498 patients were evaluated per-protocol analysis) of CIC in comparison with FP was (CIC, n Z 244; FP, n Z 254). In Study 3, of 614 patients demonstrated, then superiority (one-sided p < 0.025, enrolled, 503 were randomized (CIC, n Z 259; FP, n Z 244) intention-to-treat [ITT] analysis) of CIC versus FP was and 487 patients were evaluated (CIC, n Z 250; FP, tested. In Study 3, superiority of CIC versus FP was tested. n Z 237). Median treatment compliance was 100% in both Comparison of total and domain scores with baseline scores treatment groups in all three studies. were performed with an analysis of covariance analogous to 24 that used by Ebbut and Frith. The overall level of signif- Patient-reported side effect assessment icance was 5%, two-sided (type _ error of a Z 0.05), which in case of a one-sided hypothesis corresponds to 2.5%. Results are presented sequentially by study. Within-treat- Therefore, within-treatment differences were significant if ment results reflect changes in patient-perceived side p < 0.05 and between-treatment differences if p < 0.025. effects from baseline over the treatment period, as pre- The ICQ questionnaire was not a primary outcome and no sented in Table 2 and Fig. 1. Between-treatment results prospective power analysis was performed. reflect differences in patient-perceived side effects associated with CIC versus FP over the treatment period, and Results are presented in Figs. 2 and 3. Key results are summarized in Table 3. Positive within- or between-treatment differ- In all three studies asthma control was maintained in both ences correspond to increases in patient-reported side the CIC and FP groups; for additional results we refer the effects. reader to the published clinical studies for the efficacy and Non-inferiority of CIC versus FP was demonstrated for investigator-recorded safety results.15,19,20 the total ICQ score and all domain scores in both Studies 1 1828 T. van der Molen et al.

Table 2 Within-treatment differences in total patient-reported side effect scores from baseline to the end of the study. n LS mean SE 95% CI p-Value(two-sided) Study 1 CIC 320 mg once daily 224 0.38 0.61 0.82, 1.58 0.54 FP 200 mg twice daily 228 2.90 0.60 1.72, 4.09 <0.0001 Study 2 CIC 320 mg twice daily 244 1.27 0.72 0.15, 2.69 0.08 FP 375 mg twice daily 254 2.77 0.71 1.38, 4.17 0.0001 Study 3 CIC 320 mg twice daily 250 1.06 0.56 2.16, 0.04 0.06 FP 500 mg twice daily 237 0.99 0.57 0.14, 2.12 0.08 p-Values are significant if p < 0.05 vs baseline. Intention-to-treat population. Positive within-treatment differences correspond to an increase in patient-reported side effects. LS Z least squares; SE Z standard error of the LS mean; CI Z confidence interval; CIC Z ciclesonide; FP Z fluticasone propionate.

and 2 and, therefore, superiority data are reported herein. (p < 0.05; Fig. 1b), with the exception of ‘mood problems’, In the first analysis of the confirmatory testing procedure of ‘dental deterioration’, ‘oropharynx problems’, ‘facial Study 3, superiority of CIC versus FP was not shown for the oedema’ and ‘tiredness’ scores. primary variable ‘proportion of patients with local oropharyngeal adverse events’. Therefore, superiority of Between-treatment results CIC over FP was tested in an exploratory manner in Study 3. With the exception of a significant improvement in ‘oropharyngeal itching’ in the CIC 320 mg twice daily group Study 1 (ciclesonide 320 mg once daily vs fluticasone compared with the FP 375 mg twice daily group (p < 0.025, propionate 200 mg twice daily; 12 weeks) one-sided), there was no significant difference between the Within-treatment results treatment groups for total (Fig. 2) or domain (Fig. 3) scores There was no significant change from baseline to the end of in Study 2. the study in the total score (Table 2) or the majority of domain scores within the CIC 320 mg once daily group, with Study 3 (ciclesonide 320 mg twice daily vs fluticasone the exception of a significant worsening for ‘perspiration’ propionate 500 mg twice daily; 24 weeks) and ‘skin hair nails’ (p < 0.05; Fig. 1a). FP 200 mg twice Within-treatment results daily resulted in a significant worsening from baseline in the There was no significant change from baseline to the end of total score (p < 0.0001; Table 2) and the majority of the study in total score in the CIC 320 mg twice daily group domain scores (p < 0.05; Fig. 1a). There was no significant (Table 2). The scores for ‘mood problems’, ‘oropharynx change in scores for ‘mood problems’, ‘dental deteriora- problems’, ‘oropharyngeal itching’ and ‘thirst’ all signifi- tion’ and ‘oropharyngeal itching’ in the FP 200 mg twice cantly improved in the CIC group (p < 0.05; Fig. 1c), and daily group. there was no significant change in the remainder of the domain scores. There was no significant change in total Between-treatment results score (Table 2) or the majority of the domain scores in the Compared with FP 200 mg twice daily treatment, the change FP 500 mg twice daily group, with the exception of in ICQ total score was significantly different with CIC 320 mg a significant worsening in the scores for ‘perspiration’, ‘eye once daily, resulting in a significant improvement, i.e. dryness’ and ‘tiredness’ (p < 0.05; Fig. 1c). a lower, total score (p Z 0.0011, one-sided; Fig. 2). For eight domains e ‘oral candidiasis’, ‘oropharynx problems’, Between-treatment results ‘taste disruption’, ‘unpleasant taste’, ‘vision deteriora- The change in total score was significantly different in the tion’, ‘voice problems’, ‘thirst’ and ‘tiredness’ e scores CIC 320 mg twice daily group compared with the FP 500 mg were significantly improved in the CIC 320 mg once daily twice daily group (p Z 0.0047, one-sided; Fig. 2), with the group compared with the FP 200 mg twice daily group CIC group showing an improvement compared with FP (p < 0.025, one-sided; Fig. 3). treatment. In addition, scores for ‘oropharyngeal itching’, ‘perspiration’, ‘eye dryness’, ‘voice problems’, ‘thirst’ and Study 2 (ciclesonide 320 mg twice daily vs fluticasone ‘tiredness’ were significantly improved with CIC compared propionate 375 mg twice daily; 24 weeks) with FP (p < 0.025, one-sided; Fig. 3). There was no Within-treatment results significant difference between the treatment groups for the There was no significant change in the total score (Table 2) remaining domain scores. or the domain scores in the CIC 320 mg twice daily group from baseline to the end of the study, with the exception of Discussion a significant worsening of the ‘perspiration’ and ‘voice problems’ scores (p < 0.01; Fig. 1b). In the FP 375 mg twice We used the validated ICQ3,13 to assess patient-reported daily group, there was a significant worsening in total score side effects in patients with moderate and moderate-to- (p Z 0.0001; Table 2) and the majority of domain scores severe asthma treated with CIC or FP in three randomized, Patient-reported side effects of inhaled steroids 1829

controlled clinical studies. Together, these studies showed very few significant overall changes in patient-perceived side effects during the study when CIC was used (four domains significantly improved and four significantly worsened). In contrast, these studies showed significant worsening with FP (no domains significantly improved and 12, 10 and three domains significantly worsened in Studies 1, 2 and 3, respectively). Comparing CIC and FP, CIC treatment provided significant improvements in the total score, as well as in individual systemic and local side effect domains, in two of the three studies (eight and six domains in Studies 1 and 3, respectively). In Study 2, only ‘oropharyngeal itching’ significantly improved with CIC compared with FP. These results are supported by studies demonstrating a lower systemic and local side effect profile of CIC compared with FP using the standard open question for spontaneous side effects reporting.15e20 This highlights the need for physicians to be aware of patient-perceived side effects when prescribing ICS or when considering switching between ICS treatments. Such patient-perceived side effects can result in reduced compliance with treatment5,25 and, subsequently, in suboptimal asthma control. The doses of ciclesonide and fluticasone investigated in the current studies were found to be equivalent for efficacy and are also in a similar range of estimated equipotent doses according to the GINA guidelines.15,19,20 We, therefore, believe it is reasonable to compare patient-perceived side effects across the current doses. Since systemic side effects are related to both the pharmacodynamic characteristics of the drug and drug deposition, it is difficult for physicians to choose the best possible combination of ICS and inhaler device when a patient reports systemic side effects. In all three studies reported here, there was a clear trend or a significant difference for at least one systemic domain in favour of CIC. Systemic side effects associated with long-term ICS use may include cataracts and glaucoma.26,27 Interestingly, ‘vision deterioration’ significantly worsened with FP treatment in Studies 1 (12 weeks) and 2 (24 weeks), and CIC was significantly superior to FP for this side effect in Study 1 (12 weeks). In addition, higher ICS doses have been related to increased psychological side effects.28,29 Therefore, it may be important from a patient’s perspective to switch from a dose of beclomethasone dipropionate 1000 mg/day or equivalent, as used by patients prior to study enrolment, to, for example, CIC 640 mg/day, as the ‘mood problems’ domain was significantly improved in the CIC treatment group in Study 3. Together with the ICQ data, the studies reported here also collected investigator-recorded spontaneous side effect data that have been published elsewhere.15,19,20 This Figure 1 Within-treatment differences in individual domains gave us the opportunity to investigate whether patient- of patient-perceived side effect scores from baseline to the reported and investigator-recorded side effects may differ. end of the study. *p < 0.05 versus baseline. Intention-to-treat In terms of local side effects, oral candidiasis did not occur population data: n Z 221e224 and 225e228 in Study 1, (0%) in the CIC group, whereas it was diagnosed in nine 240e244 and 251e254 in Study 2, and 248e250 and 231e237 in patients (3.8%) in the FP group of Study 1, with a significant Study 3 for CIC and FP, respectively. Positive within-treatment difference between the groups.15 This is reflected in the differences correspond to an increase in patient-reported side patient-reported side effect scores of Study 1 as assessed effects. CIC Z ciclesonide; FP Z fluticasone propionate; by the ICQ, since the score for the question related to oral LS Z least squares; SE Z standard error of the LS mean. candidiasis significantly worsened in the FP group from baseline, but did not in the CIC group, and there was a significant between-treatment difference. However, 1830 T. van der Molen et al.

Figure 2 Between-treatment differences in change of side effect perception (ciclesonideefluticasone propionate) in total Inhaled Corticosteroid Questionnaire scores during the three studies. Differences were significant if p < 0.025 (one-sided). Intention-to-treat population data: n Z 224 and 228 in Study 1, 244 and 254 in Study 2, and 250 and 237 in Study 3 for CIC and FP, respectively. Positive between-treatment differences correspond to an increase in patient-reported side effects. LS Z least squares; SE Z standard error of the LS mean; CIC Z ciclesonide; FP Z fluticasone propionate. despite significantly fewer local side effects being recorded A number of factors may have contributed to the wors- by the investigator with CIC compared with FP in Studies 2 ening in patient-reported side effects with FP treatment (dysphonia and candidiasis)20 and 3 (candidiasis),19 the from baseline to the end of the study. In Study 1, the dose improvement observed in patient-reported oral candidiasis of ICS was higher during the treatment period than during in the CIC group compared to FP group did not reach the run-in period in both the CIC and FP groups. In all three statistical significance in these studies. studies, a switch to a different type of device or ICS may

Figure 3 Between-treatment differences in change in individual domain Inhaled Corticosteroid Questionnaire scores during the study. *p < 0.025 CIC versus FP. Intention-to-treat population data: n Z 221e224 and 225e228 in Study 1, 240e244 and 251e254 in Study 2, and 248e250 and 231e237 in Study 3 for CIC and FP, respectively. Positive between-treatment differences correspond to an increase in patient-reported side effects. CIC Z ciclesonide; FP Z ﬂuticasone propionate; LS Z least squares; SE Z standard error of the LS mean. Patient-reported side effects of inhaled steroids 1831

Table 3 Summary of within- and between-treatment differences in patient-reported side effect scores across the three studies. Study 1 Study 2 Study 3 CIC 320 mg once daily CIC 320 mg twice daily CIC 320 mg twice daily vs FP 200 mg twice daily vs FP 375 mg twice daily vs FP 500 mg twice daily Within-CIC-group differencesa Total score worsened Not significant Not significant Not significant Total score improved Not significant Not significant Not significant Domain scores worsened (n) 2 2 None Domain scores improved (n) None None 4 Within-FP-group differencesa Total score worsened Significant Significant Not significant Total score improved Not significant Not significant Not significant Domain scores worsened (n)12103 Domain scores improved (n) None None None Between-treatment differencesb CIC total score superior to FP Significant Not significant Significant total score CIC domain scores superior to 816 FP domain scores (n) a Differences significant with p < 0.05 vs baseline. b Differences significant with p < 0.025 vs FP; Intention-to-treat population data: n Z 221e224 and 225e228 in Study 1; 240e244 and 251e254 in Study 2; and 248e250 and 231e237 in Study 3 for CIC and FP, respectively; CIC Z ciclesonide; FP Z fluticasone propionate.

have occurred and inhaler technique was reviewed at the include the probability that the side effects experienced by randomization-to-treatment visit and at each scheduled the patients included in the present studies are generally visit thereafter, which possibly resulted in higher lung mild, as patients have volunteered to participate and deposition as the studies progressed. There were no data continued to use their ICS regardless of their perceived side prior to study entry to determine any changes in compli- effects.3 This so-called survival bias implies that patients in ance, but compliance was high during the treatment period real life may experience even more side effects than those of all three studies, as is often the case in trial settings.30 reported here and may benefit from prescription strategies These factors are likely to have been similar in the FP that aim to avoid side effects. Moreover, a quick and reli- and CIC treatment groups; however, the majority of able patient-reported method for measuring side effects, patient-reported side effects did not significantly worsen such as the ICQ, may encourage patients to become more from baseline to the end of the study with CIC treatment. active in the management of their asthma; patient self- These studies, therefore, provide important information management has been shown to improve quality of life and from a patient’s perspective regarding the results of compliance.32,33 In addition, patients are more likely to switching between ICS treatments. report side effects when questioned specifically compared It is possible that different devices may account for with neutral questioning.34,35 differences in patient-reported side effects seen between- In summary, patients with moderate and moderate-to- treatments in Study 1, in which CIC was delivered via MDI severe asthma treated with CIC reported significantly less versus FP via DPI, but not in Study 2 or 3 where MDI was intense side effects compared with patients of similar used in both arms. However, a previous placebo-controlled severity treated with FP, as assessed by the ICQ.3,13 These study comparing both MDI and DPI devices of FP suggested results mimic the results of the individual clinical studies no differences between these devices in the investigator- demonstrating an improved side effect profile assessed by recorded side effects, dysphonia, oral candidiasis and spontaneous side effect reporting of CIC in comparison with throat irritation, which were similar across all FP treatment FP but the assessment with the ICQ provides more detail groups.31 In Study 3, the daily dose of FP was higher regarding the side effect profile.15e20 There is, therefore, (1000 mg ex valve) than the dose of CIC (640 mgex not only a need for physicians to be aware of patient- mouthpiece Z 880 mg ex valve), which may partly explain perceived side effects with respect to the dose and the the differences observed, although differences were still application method but also the choice of the inhaled observed in Study 1 and 2 where microgram doses were steroid prescribed. similar. Finally, it cannot be ruled out that the open-label design of Studies 1 and 2 may also have contributed to the differences in patient-reported side effects seen between- Competing interests treatments. The general limitations of all patient-reported ques- Thys van der Molen has received research grants from tionnaires include respondent fatigue and measurement Merck Sharp & Dohme, GlaxoSmithKline, AstraZeneca and bias. Limitations specific to the report of side effects Nycomed GmbH and honoraria for presentations and 1832 T. van der Molen et al. advisory boards from MSD, GlaxoSmithKline, Nycomed 9. Guidance for industry. patient-reported outcome measures: GmbH, and AstraZeneca. Juliet M Foster has received use in medical product development to support labeling lecture fees of <$10,000 from Nycomed GmbH and Astra- claims: draft guidance. Health Qual Life Outcomes 2006;4:79. Zeneca and an unrestricted research grant from AstraZe- 10. Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, neca of <$10,000. Manfred Caeser was a full-time Hiller TK. Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in employee of Nycomed GmbH at the time of study conduct. clinical trials. Thorax 1992;47:76e83. Thomas Mu¨ller is a full-time employee of Nycomed GmbH. 11. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Dirkje S Postma has served as a consultant and/or received Development and validation of a questionnaire to measure honoraria for lectures with AstraZeneca, Boehringer Ingel- asthma control. Eur Respir J 1999;14:902e7. heim, Chiesi, GlaxoSmithKline, Nycomed GmbH and Teeva. 12. Schatz M, Sorkness CA, Li JT, Marcus P, Murray JJ, Nathan RA, et al. Asthma control test: reliability, validity, and respon- Funding and role of sponsor siveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol 2006;117:549e56. 13. Foster JM, van Sonderen E, Lee AJ, Sanderman R, Nycomed GmbH funded the three studies from which the Dijkstra A, Postma DS, et al. A self-rating scale for patient- data were reported, supported the writing of the manu- perceived side effects of inhaled corticosteroids. Respir Res script and was involved in the discussion about the journal 2006;7:131. that was selected to publish the results. 14. Foster JM, van der Molen T, Caeser M, Hannaford P. The use of questionnaires for measuring patient-reported side effects of drugs: its importance and methodological challenges. Phar- Acknowledgements macoepidemiol Drug Saf 2007;16:1e19. 15. Boulet LP, Bateman ED, Voves R, Mu¨ller T, Wolf S, The authors would like to thank Medicus International for Engelsta¨tter R. A randomized study comparing ciclesonide and editorial assistance with the manuscript. Editorial support fluticasone propionate in patients with moderate persistent was funded by Nycomed GmbH. asthma. Respir Med 2007;101:1677e86. 16. Lipworth BJ, Kaliner MA, LaForce CF, Baker JW, Kaiser HB, Amin D, et al. Effect of ciclesonide and fluticasone on hypo- Supplementary data thalamic-pituitary-adrenal axis function in adults with mild-to- moderate persistent asthma. Ann Allergy Asthma Immunol 2005;94:465e72. Supplementary data associated with this article can be 17. Derom E, Van De Velde V, Marissens S, Engelstatter R, found, in the online version, at doi:10.1016/j.rmed. Vincken W, Pauwels R. Effects of inhaled ciclesonide and flu- 2010.05.021. ticasone propionate on cortisol secretion and airway responsiveness to adenosine 5’monophosphate in asthmatic patients. Pulm Pharmacol Ther 2005;18:328e36. 18. Engelstatter R, Escher A, Haefner D. Low incidence of oropharyngeal adverse events in asthma patients treated with References ciclesonide. Eur Respir J 2005;26(Suppl 49):255s. 19. Tamm M, Dusser D, Fernandez J, Hellwig M, Engelsta¨tter R. 1. Global Strategy for Asthma Management and Prevention. Efficacy and tolerability of ciclesonide compared with flutica- Global initiative for asthma (GINA). Available from: http:// sone propionate in patients with well-controlled moderate to www.ginasthma.org; 2007. severe persistent asthma. Allergy 2007;62:A381. 2. National Asthma Education and Prevention Programme. Expert 20. Bateman ED, Linnhof AE, Homik L, Freudensprung U, Smau L, panel report: guidelines for the diagnosis and management of Engelstatter R. Comparison of twice-daily inhaled ciclesonide asthma update on selected topics 2002. J Allergy Clin Immunol and fluticasone propionate in patients with moderate-to- 2002;110:S142e219. severe persistent asthma. Pulm Pharmacol Ther 2008;21: 3. Foster JM, Aucott L, van der Werf RH, van der Meijden MJ, Schraa G, 264e75. Postma DS, et al. Higher patient perceived side effects related to 21. Dyer MJ, Halpin DM, Stein K. Inhaled ciclesonide versus inhaled higher daily doses of inhaled corticosteroids in the community: budesonide or inhaled beclomethasone or inhaled fluticasone a cross-sectional analysis. Respir Med 2006;100:1318e36. for chronic asthma in adults: a systematic review. BMC Fam 4. Pont LG, van der Molen T, Denig P, van der Werf GT, Haaijer- Pract 2006;7:34. Ruskamp FM. Relationship between guideline treatment and 22. Standards for the diagnosis and care of patients with chronic health-related quality of life in asthma. Eur Respir J 2004;23: obstructive pulmonary disease (COPD) and asthma. This official 718e22. statement of the American thoracic society was adopted by 5. Canonica GW, Baena-Cagnani CE, Blaiss MS, Dahl R, Kaliner MA, the ATS board of directors, November 1986. Am Rev Respir Dis Valovirta EJ. Unmet needs in asthma: global asthma physician 1987;136:225e44. and patient (GAPP) survey: global adult findings. Allergy 2007; 23. The Inhaled Corticosteroid Questionnaire Website. Available 62:668e74. at: http://www.ICQscale.nl. 6. Boulet LP. Perception of the role and potential side effects of 24. Ebbutt AF, Frith L. Practical issues in equivalence trials. Stat inhaled corticosteroids among asthmatic patients. Chest 1998; Med 1998;17:1691e701. 113:587e92. 25. Ivanova JI, Birnbaum HG, Hsieh M, Yu AP, Seal B, van der 7. Storms WW, Theen C. Clinical adverse effects of inhaled Molen T, et al. Adherence to inhaled corticosteroid use and corticosteroids: results of a questionnaire survey of asthma local adverse events in persistent asthma. Am J Manag Care specialists. Ann Allergy Asthma Immunol 1998;80:391e4. 2008;14:801e9. 8. Baiardini I, Braido F, Brandi S, Canonica GW. Allergic diseases 26. Lipworth B. Systemic adverse effects of inhaled corticosteroid and their impact on quality of life. Ann Allergy Asthma therapy: a systematic review and meta-analysis. Arch Intern Immunol 2006;97:419e28. Med 1999;159:941e55. Patient-reported side effects of inhaled steroids 1833

27. Peters SP. Safety of inhaled corticosteroids in the treat- 32. Gallefoss F, Bakke PS. How does patient education and self- ment of persistent asthma. JNatlMedAssoc2006;98: management among asthmatics and patients with chronic 851e61. obstructive pulmonary disease affect medication? Am J Respir 28. Stuart FA, Segal TY, Keady S. Adverse psychological effects of Crit Care Med 1999;160:2000e5. corticosteroids in children and adolescents. Arch Dis Child 33. Thoonen BP, Schermer TR, Van Den Boom G, Molema J, 2005;90:500e6. Folgering H, Akkermans RP, et al. Self-management of asthma 29. Warrington TP, Bostwick JM. Psychiatric adverse effects of in general practice, asthma control and quality of life: corticosteroids. Mayo Clin Proc 2006;81:1361e7. a randomised controlled trial. Thorax 2003;58:30e6. 30. Rief W, Avorn J, Barsky AJ. Medication-attributed adverse 34. Sheftell FD, Feleppa M, Tepper SJ, Rapoport AM, Ciannella L, effects in placebo groups: implications for assessment of Bigal ME. Assessment of adverse events associated with trip- adverse effects. Arch Intern Med 2006;166:155e60. tans-methods of assessment inﬂuence the results. Headache 31. Langley SJ, Holden J, Derham A, Hedgeland P, Sharma RK, 2004;44:978e82. Woodcock A. Fluticasone propionate via the Diskhaler or 35. Wernicke JF, Faries D, Milton D, Weyrauch K. Detecting hydroﬂuoroalkane-134a metered-dose inhaler on methacho- treatment emergent adverse events in clinical trials: line-induced airway hyperresponsiveness. Chest 2002;122: a comparison of spontaneously reported and solicited collec- 806e11. tion methods. Drug Saf 2005;28:1057e63.