Intervention Review

You have free access to this content

Ciclesonide versus other inhaled corticosteroids for chronic asthma in children

  1. Sharon Kramer1,*,
  2. Bart L Rottier2,
  3. Rob JPM Scholten3,
  4. Nicole Boluyt4

Editorial Group: Cochrane Airways Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 7 NOV 2012

DOI: 10.1002/14651858.CD010352


How to Cite

Kramer S, Rottier BL, Scholten RJPM, Boluyt N. Ciclesonide versus other inhaled corticosteroids for chronic asthma in children. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD010352. DOI: 10.1002/14651858.CD010352.

Author Information

  1. 1

    Monash University, Australasian Cochrane Centre, School of Public Health and Preventive Medicine, Melbourne, Victoria, Australia

  2. 2

    Beatrix Childrens Hospital, University Medical Center Groningen, Pediatric Pulmonology and Allergology, Groningen, Netherlands

  3. 3

    Academic Medical Center, Dutch Cochrane Centre, Amsterdam, Netherlands

  4. 4

    Emma Children's Hospital, Department of Pediatrics, Amsterdam, Netherlands

*Sharon Kramer, Australasian Cochrane Centre, School of Public Health and Preventive Medicine, Monash University, The Alfred Centre, 99 Commercial Road, Melbourne, Victoria, 3004, Australia. sharon.kramer@monash.edu.

Publication History

  1. Publication Status: New
  2. Published Online: 28 FEB 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Hiremath 2006

MethodsDesign: randomised controlled trial following a baseline period of 2 to 4 weeks (rescue medication only) and an intervention period of 12 weeks

Location and number of centres: not reported


ParticipantsNumber screened: not reported

Number randomised: 512

Number completed: not reported

Age: children and adolescents (4 to 15 years) with predominantly moderate-to-severe asthma

Gender: not reported

Asthma severity: forced expiratory volume in 1 second (FEV1) 50-90% of predicted

Inclusion/exclusion criteria: not reported


InterventionsCiclesonide 160 μg (ex-actuator; N = 254) once daily in the evening

Fluticasone 88 μg twice daily (176 μg/day, ex-actuator; N = 258)

Delivery: both medications were administered via a metered-dose inhaler with spacer (AeroChamber Plus®)

Inhalation technique: not reported

Treatment period: 12 weeks (following 2 to 4 weeks' baseline period rescue medication only)

Allowed asthma medication: not reported


OutcomesFEV1 from baseline to the end of the treatment period, morning peak expiratory flow, median percentage of asthma symptom- and rescue medication-free days and incidence of adverse events


NotesIncomplete data since this study was only published as an abstract


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
Outcomes 1, 3, 4, 5
Unclear riskNot described

Blinding (performance bias and detection bias)
Other outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
Outcomes 1, 3, 4, 5
Unclear riskNot described

Incomplete outcome data (attrition bias)
Other outcomes
Unclear riskNot described

Selective reporting (reporting bias)Unclear riskNot enough information

Other biasUnclear riskNot enough information

Paunovic 2010

MethodsDesign: randomised, double-blind, 2 parallel-group study

Location and number of centres: not reported


ParticipantsNumber screened: not reported

Number randomised: 420

Number completed: not reported

Age: 7 to 12 years

Gender: not reported

Asthma severity: FEV1 50-90% of predicted

Inclusion/exclusion criteria: not described


Interventions1. Ciclesonide once daily (160 µg/day)

2. Fluticasone twice daily (176 µg/day)

Delivery: not reported

Inhalation technique: not reported

Treatment period: 12 weeks (following 2 to 4 weeks baseline period rescue medication only)

Allowed asthma medication: not reported


OutcomesForced expiratory volume in 1 second (FEV1) (mL), peak expiratory flow (PEF) (L/minute), asthma symptom scores, rescue medication use, asthma exacerbation


NotesIncomplete data since this study was only published as an abstract


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
Outcomes 1, 3, 4, 5
Unclear riskNot described

Blinding (performance bias and detection bias)
Other outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
Outcomes 1, 3, 4, 5
Unclear riskNot described

Incomplete outcome data (attrition bias)
Other outcomes
Unclear riskNot described

Selective reporting (reporting bias)Unclear riskNot enough information

Other biasUnclear riskNot enough information

Pedersen 2006

MethodsDesign: 12-week, randomised, multicentre, double-blind, double-dummy, 2-arm, parallel group study, with a 2- to 4-week baseline period

Location and number of centres: 51 centres in Europe, South Africa and Canada


ParticipantsNumber screened: 728 enrolled
Number randomised: 556 (baseline details given for per-protocol set. Ciclesonide: N = 277; fluticasone: N = 279)
Number completed: not reported.

Age: median 10 years

Gender: 331 boys; 180 girls
Baseline details: add-on therapy prior to baseline: ciclesonide N = 80, 64%; fluticasone N = 170, 66%; inhaled corticosteroid (ICS) therapy prior to baseline: ciclesonide N = 162, 31%; fluticasone N = 67, 27%; mean ICS dose: 390 μg/day overall; mean forced expiratory volume in 1 second (FEV1): 1.7 L overall; mean FEV1 % predicted: 80% overall; mean reversibility change in FEV1: 20%
Inclusion criteria: aged 6 to 15 years; persistent asthma for at least 6 months (American Thoracic Society criteria); clinically stable for 4 weeks prior to study entry; FEV1 predicted: 50-90% rescue medication only, 80-100% in patients treated with ICS only; symptom score > 1 on 6 of last 10 days of run-in; adequate metered dose inhaler (MDI) device technique without spacer
Exclusion criteria: history of life-threatening asthma; 2 or more inpatient hospitalisations in previous year; > 60 days of systemic corticosteroids in past year; > 400 budesonide or equivalent/day in 30 days prior to baseline; > 8 puffs short-acting beta2-agonist/day for 3 consecutive days during run-in


Interventions1. Ciclesonide 100 μg twice daily
2. Fluticasone 100 μg twice daily

Delivery: hydro-fluoroalkane metered dose inhaler

Inhalation technique: adequate inhalation technique no details described
Treatment period: 12 weeks (following 2- to 4-week baseline period with rescue medication (beta2 agonist only)
Allowed asthma medication: not reported


OutcomesFEV1, clinic peak expiratory flow (PEF), a.m. PEF, p.m. PEF, symptoms, rescue medication usage, adverse events


NotesAnalysis of co-variance included age and randomisation values as co-variates and sex, treatment, and region/country as fixed factors

Funding: Grant sponsor: ALTANA Pharma AG, Konstanz, Germany. This study was supported by ALTANA Pharma, Konstanz, Germany. The authors would like to thank Pro Ed Communications, Inc., Beachwood, also all Medicus International, London, UK for their editorial assistance. Editorial support was funded by ALTANA Pharma. Dr. Søren Pedersen has received remuneration for lectures from AstraZeneca and GlaxoSmithKline and served as a paid consultant for ALTANA Pharma and AstraZeneca. Ilse Theron is an employee of ALTANA Madaus Ltd, Woodmead, South Africa. Dr. Renate Engelstatter is an employee of ALTANA Pharma AG, Konstanz, Germany


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Randomization was based on a computer-generated list (Program RANDOM) provided to the study centres by ALTANA Pharma AG (Konstanz, Germany)"

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
Outcomes 1, 3, 4, 5
Low riskQuote: "Neither the investigator nor anyone at the study centre knew whether ciclesonide or fluticasone was administered"

Blinding (performance bias and detection bias)
Other outcomes
Low riskQuote: "Neither the investigator nor anyone at the study centre knew whether ciclesonide or fluticasone was administered"

Incomplete outcome data (attrition bias)
Outcomes 1, 3, 4, 5
Unclear riskNot described which values used in intention-to-treat (ITT) analysis

Incomplete outcome data (attrition bias)
Other outcomes
Unclear riskNot described which values used in ITT analysis

Selective reporting (reporting bias)Low riskThe results of all outcomes described in methods were reported

Other biasLow riskSmall differences in baseline characteristics

Pedersen 2009

MethodsDesign: 12-week, randomised, double-blind, double-dummy, 3-arm, parallel-group study, following a 2– to 4-week run-in period

Location and number of centres: 50 centres in Brazil, Germany, Hungary, Poland, Portugal and South Africa


ParticipantsNumber screened: 904 enrolled

Number randomised: 744 randomised and entered treatment period

Number completed: 33 patients terminated study, 711 completed (of the 744, 50 violated protocol leaving 694 in per protocol population)

Age: 6 to 11 years; median age in each group 9 years (range: 6 to 11).

Gender: 170 boys; 161 girls

Inclusion criteria: outpatients aged 6 to 11 years with a history of persistent bronchial asthma, for ≥ 6 months were eligible for participation. To be entered into the treatment period, patients were required to have a forced expiratory volume in 1 second (FEV1) 50–90% of predicted and a FEV1 reversibility of ≥ 12% after inhalation of salbutamol 200 to 400 mg at the end of the run-in period. In addition, patients had to present asthma symptoms on at least 6 of the last 10 consecutive days of the baseline period, or to use at least 8 puffs of rescue medication within the last 10 consecutive days of the baseline period. Furthermore, patients had to demonstrate a good inhalation technique when using a metered dose inhaler (MDI) without a spacer

Exclusion criteria: a history of near-fatal asthma that required intubation; a respiratory tract infection or asthma exacerbation within the last 30 days prior to study entry; more than 2 inpatient hospitalisations for asthma in the previous year; use of systemic corticosteroids during the study, within the last 30 days prior to study entry or for more than 60 days in the previous 2 years


Interventions1. Ciclesonide MDI (80 μg once daily) (N = 252)

2. Ciclesonide 160 MDI (160 μg once daily) (N = 242)

Both: in the evening (ex-actuator; equivalent to 100 and 200 μg ex-valve)

3. Fluticasone MDI (88 μg twice daily) (N = 250) - fluticasone 176 (ex-actuator; equivalent to 100 μg twice daily ex-valve) in the morning and evening without a spacer

Delivery: administered via HFA134-a MDIs

Inhalation technique: good inhalation technique, no details described

Treatment period: a run-in period (of at least 2 weeks and up to 4 weeks), in which eligible patients discontinued previous inhaled corticosteroids (ICS) and other controller medications followed by a 12-week treatment period

Allowed asthma medication: rescue medication salbutamol, patients were allowed to continue regular nasal corticosteroids at a constant dose


OutcomesChange in FEV1 (L), peak expiratory flow (PEF) (L/minute), PD20FEV1 to methacholine (bronchial provocation test with methacholine to assess the provocative dose producing a 20% fall of FEV1) was performed at a subgroup of sites, Pediatric Asthma Quality of Life Questionnaire (PAQLQ) and Pediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ), asthma symptom scores and use of rescue medication (salbutamol), safety was assessed by adverse effect reporting, physical examination, vital signs and laboratory investigations, including haematology, urinalysis and biochemistry


NotesAnalysis of co-variance included treatment, gender and centre pool as fixed factors and baseline value and age as co-variates

Funding: Professor S. Pedersen has received consultancy fees and lecture honoraria from Nycomed and GlaxoSmithKline, and has worked on research projects supported by Nycomed, GlaxoSmithKline and AstraZeneca. Dr R. Engelstatter and Dr S. Hirsch are employees of Nycomed. Dr H.-J. Weber was an employee of Nycomed at the time of writing of the manuscript. Professor A. Emeryk has received consultancy fees from Nycomed and lecture honoraria from Nycomed, GlaxoSmithKline and AstraZeneca, and has
worked on research projects supported by Nycomed, Thorax-Chisei and Pierre Fabre Medicament. Dr J. Vermeulen has worked on research projects supported by Nycomed. Professor L. Barkai and Dr H. Weber have nothing to disclose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote "…a 1:1:1 randomisation scheme by means of a computer generated randomisation list.…."

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
Outcomes 1, 3, 4, 5
Low riskDouble-blind and double-dummy design

Blinding (performance bias and detection bias)
Other outcomes
Low riskCiclesonide provided in the evening 1 or 2 puffs and fluticasone was administered in the morning and evening

Incomplete outcome data (attrition bias)
Outcomes 1, 3, 4, 5
Unclear riskNot described which values used in intention-to-treat (ITT) analysis

Incomplete outcome data (attrition bias)
Other outcomes
Unclear riskNot described which values used in ITT analysis

Selective reporting (reporting bias)Low riskThe results of all outcomes described in methods were reported

Other biasLow riskNo obvious baseline differences

Vermeulen 2007

MethodsDesign: 12-week, randomised, double-blind, double-dummy, parallel-group study, following

a 2-week run-in period

Location and number of centres: 31 centres in Europe and South Africa


ParticipantsNumber screened: 431
Number randomised: 403 (ciclesonide: 272; budesonide: 131)
Number completed: 384
Age: median 14 years

Gender: 272 boys; 131 girls
Astma severity: forced expiratory volume in 1 second (FEV1) 73% predicted
Inclusion criteria: 12 to 17 years old; FEV1 50-80% predicted; severe asthma (GINA 2003 definition); not well controlled after constant treatment with fixed-dose budesonide 400 mg/day (or equivalent) 4 weeks prior to study entry with FEV1 45-80% predicted; Alternatively constant treatment with fixed-dose budesonide 400 to 800 mg/day (or equivalent) 4 weeks prior to study entry, with FEV1 46-85% predicted; entry into treatment period at randomisation (baseline), FEV1 50-80% predicted, FEV1 reversibility > 15%
salbutamol.

Exclusion criteria: oral corticosteroids within 4 weeks of study entry; concomitant severe diseases; relevant lung diseases or clinically relevant abnormal laboratory values; > 10 cigarette pack-year smoking history; females of child-bearing potential without contraception


Interventions1. Ciclesonide 400 μg once daily
2. Budesonide 800 μg once daily

Delivery: HFA-MDI (ciclesonide); Turbohaler® dry powder inhaler (DPI) (budesonide)

Inhalation technique: not described
Treatment period: 12 weeks
Allowed asthma medication: not reported
% on inhaled corticosteroids (ICS): 100


OutcomesFEV1; peak expiratory flow (PEF); 24-hour urinary free cortisol concentrations


NotesAnalysis of co-variance included baseline value, treatment, age, sex and country pool as co-variates or factors (not specified)

Funding: this study (EudraCT No: 2004- 001233-41) was sponsored by ALTANA Pharma. ALTANA Pharma had a role in the study design, the collection, analysis and interpretation of the data and was involved in the writing of the report and the decision to submit the manuscript. The co-authors H. Rauerc and R. Engelstatter were both employees of ALTANA Pharma


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "the randomisation list was generated by the sponsor using a multiplicative congruential pseudo-random number generator with modulus 231-1 (Program RANDOM based on Fishman and Moore"

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
Outcomes 1, 3, 4, 5
Low riskDouble-blind and double-dummy design

Blinding (performance bias and detection bias)
Other outcomes
Low riskDouble-dummy but ciclesonide was administered in 2 puffs with metered dose inhaler (MDI) and budesonide with Turbohaler® device 4 inhalations

Incomplete outcome data (attrition bias)
Outcomes 1, 3, 4, 5
Unclear riskNot described which values used in intention-to-treat (ITT) analysis

Incomplete outcome data (attrition bias)
Other outcomes
Unclear riskNot described which values used in ITT analysis

Selective reporting (reporting bias)Low riskThe results of all outcomes described in methods were reported

Other biasLow riskNo obvious baseline differences

von Berg 2007

MethodsDesign: 12-week, randomised, double-blind, double-dummy, 2-arm, parallel-group study, following

a 2- to 4-week run-in period

Location and number of centres: 59 centres in Europe and South Africa


ParticipantsNumber screened: 774
Number randomised: 621 (ciclesonide: 416; budesonide: 205)
Number completed: 594
Age: mean 9 years

Gender: 395 boys; 226 girls
Astma severity: forced expiratory volume in 1 second (FEV1) 78% predicted; inhaled corticosteroid (ICS) treatment: 51%
Inclusion criteria: aged 6 to 11 years; diagnosis of persistent asthma for 6 months; FEV1 > 50-90% predicted if rescue medication only, > 50-100% predicted if using constant dose of controller medication other than corticosteroids for 1 month; FEV1 80%-105% predicted if using ≤ 400 μg/day beclomethasone dipropionate equivalent for 1 month before inclusion. Post-run-in: FEV1 50-90% predicted after withholding short-acting beta2-agonist (SABA) for at least 4 hours; reversibility of FEV1 > 12% of initial post-SABA; asthma symptom scores > 1 on at least 6 of previous 10 days or use of > 8 puffs of rescue medication during the previous 10 days

Exclusion criteria: history of life-threatening asthma, concomitant severe diseases; 2 or more hospitalisations for asthma within previous 12 months; asthma exacerbation during 4 weeks before baseline; systemic corticosteroids during 30 days before baseline; use of systemic corticosteroids for more than 60 days within the previous 2 years; participation in another study within 30 days before baseline. No other asthma medication permitted during study


Interventions1. Ciclesonide 200 μg once daily
2. Budesonide 400 μg once daily

Delivery: ciclesonide: hydro-fluoroalkane metered dose inhaler (HFA-MDI) (+ AeroChamber®); budesonide: Pulmicort Turbohaler®

Inhalation technique: not described
Treatment period: 12 weeks
Allowed co-medication: none
% on ICS: not reported


OutcomesFEV1, peak expiratory flow, asthma symptoms, rescue medication, bone growth, 24-hour urinary cortisol, adverse events


NotesAnalysis of co-variance included baseline value at randomisations visit and age as co-variates

Funding: this study was funded and sponsored by ALTANA Pharma. The authors would like to thank ProEd Communications, Inc., Beachwood Ohio and Medicus International, London, UK, for their editorial assistance. Editorial support was funded by ALTANA Pharma. The co-authors Renate Engelstatter Stefan Leichtl, Stefan Hellbardt and Thomas D. Bethke were employees of ALTANA Pharma


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Eligible patients were randomised at a ratio of 2:1…"

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
Outcomes 1, 3, 4, 5
Low riskDouble-blind and double-dummy design

Blinding (performance bias and detection bias)
Other outcomes
Low riskDouble-blind, double-dummy, not specified who was blinded

Ciclesonide and budesonide were administered in the evening via an HFA-MDI with an AeroChamber Plus® spacer and Pulmicort Turbohaler®, respectively

Incomplete outcome data (attrition bias)
Outcomes 1, 3, 4, 5
Unclear riskNot described which values used in intention-to-treat (ITT) analysis

Incomplete outcome data (attrition bias)
Other outcomes
Unclear riskNot described which values used in ITT analysis

Selective reporting (reporting bias)Low riskThe results of all outcomes described in methods were reported

Other biasLow riskNo obvious baseline differences

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Adachi 2006Children not analysed separately

Agertoft 2010Treatment < 4 weeks

Bateman 2008Children not analysed separately

Berger 2009Placebo controlled

BY9010/M1-207Children not analysed separately

Cohen 2011Placebo controlled

Dahl 2010Children not analysed separately

Derom 2009Included patients > 18 years of age

Dusser 2007Included patients > 18 years of age

Erin 2008Included patients > 18 years of age

Gelfand 2006Placebo controlled

Hoshino 2010Included patients > 18 years of age

Knox 2007Children not analysed separately

Kosztyla-Hojna 2007Included patients > 18 years of age

Malozowski 2008Not a randomised controlled trial

Matsunaga 2009Treatment < 4 weeks

Meltzer 2009Placebo controlled

Molen 2010Children not analysed separately

Pedersen 2010Placebo controlled

Postma 2011Children not analysed separately

Skoner 2006Placebo controlled

Stoica 2010Children not analysed separately

van den Berge 2009Included patients > 18 years of age

 
Characteristics of studies awaiting assessment [author-defined order]
BY9010/M1-205

MethodsRandomised controlled trial, double-blind, study duration consists of a baseline period (2 to 4 weeks) and a treatment period (12 weeks)

ParticipantsChildren aged 4 to 15 years

Main inclusion criteria: history of persistent bronchial asthma for at least 6 months, forced expiratory volume in one second (FEV1) 50-90% of predicted

Main exclusion criteria: concomitant severe diseases or diseases which are contraindications for the use of inhaled corticosteroids; chronic obstructive pulmonary disease (chronic bronchitis or emphysema), other relevant lung diseases causing alternating impairment in lung function, or a combination; respiratory tract infection or asthma exacerbation within the last 30 days prior to entry into the study; history of life-threatening asthma; premature birth; current smoking; smoking history with either ≥ 10 pack-years; pregnancy; intention to become pregnant during the course of the study; breast feeding; lack of safe contraception

InterventionsCiclesonide 200 μg/day

Fluticasone propionate 200 μg/day

OutcomesPrimary outcome measures: FEV1 absolute values

Secondary outcome measures: FEV1 as % of predicted, peak expiratory flow (PEF) from spirometry, diary-based morning and evening PEF, diary-based symptom score, diary-based salbutamol metered dose inhaler (MDI) use, diurnal PEF fluctuation, drop-out rate due to asthma exacerbations, time until asthma exacerbation, number of symptom-free and rescue medication-free days, number of days with asthma control, physical examination, vital signs, laboratory work-up, adverse events

Notes

 
Comparison 1. Ciclesonide versus budesonide (dose ratio 1:2)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Patients with exacerbations21024Risk Ratio (M-H, Fixed, 95% CI)2.20 [0.75, 6.43]

 2 Quality of life PAQLQ (S)21010Mean Difference (IV, Fixed, 95% CI)-0.00 [-0.09, 0.09]

 3 FEV1 least square means (L)21021Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.10, 0.05]

 
Comparison 2. Ciclesonide versus fluticasone

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Patients with exacerbations2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Dose ratio 1:1
21003Risk Ratio (M-H, Fixed, 95% CI)1.37 [0.58, 3.21]

    1.2 Dose ratio 1:2
1502Risk Ratio (M-H, Fixed, 95% CI)3.57 [1.35, 9.47]

 2 Adverse events: number of patients with adverse events1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Dose ratio 1:1
1492Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.72, 1.07]

    2.2 Dose ratio 1:2
1502Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.81, 1.17]

 3 Adverse events: 24-hour urine free cortisol adjusted for creatinine (nmol/mmol)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 Dose ratio 1:1
1492Mean Difference (IV, Fixed, 95% CI)0.54 [-5.92, 7.00]

    3.2 Dose ratio 1:2
1502Mean Difference (IV, Fixed, 95% CI)1.15 [0.07, 2.23]

 4 Generic FEV1 least square mean (L)2Mean Difference (Fixed, 95% CI)Subtotals only

    4.1 Dose ratio 1:1
21000Mean Difference (Fixed, 95% CI)-0.01 [-0.04, 0.02]

    4.2 Dose ratio 1:2
1499Mean Difference (Fixed, 95% CI)-0.05 [-0.11, 0.01]

 
Summary of findings for the main comparison. Ciclesonide versus budesonide (dose ratio 1:2) for chronic asthma in children

Ciclesonide versus budesonide (dose ratio 1:2) for chronic asthma in children

Patient or population: patients with chronic asthma in children
Settings: all settings
Intervention: ciclesonide
Comparison: budesonide (dose ratio 1:2)

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Budesonide (dose ratio 1:2)Ciclesonide

Asthma symptoms
Asthma symptom score (scale 0 to 4)
Follow-up: 12 weeks
See commentSee commentNot estimable1024
(2 studies)
⊕⊕⊝⊝
low1,2
Both studies used a 5-point scale, but insufficient data were reported to allow meta-analysis

Patients with exacerbations
Number of patients with exacerbations
Follow-up: 12 weeks
12 per 100026 per 1000
(9 to 77)
RR 2.2
(0.75 to 6.43)
1024
(2 studies)
⊕⊝⊝⊝
very low1,2,3,4

Adverse events
Number of patients with adverse events
Follow-up: 12 weeks
See commentSee commentNot estimable1024
(2 studies)
⊕⊕⊝⊝
low1,2,3
The data could not be meta-analysed because the definitions of adverse events were too diverse

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 In one study the dose of budesonide was much higher than what is commonly prescribed in clinical practice.
2 Both studies were sponsored by the manufacturer and at least one of the authors of each study was an employee of the manufacturer that sponsored the study.
3 The intervention period of 12 weeks was too short to expect any major changes in this outcome.
4 Confidence intervals of estimated effect include no effect and exceed a relative reduction or increase risk of 25%.
 
Summary of findings 2. Ciclesonide versus fluticasone (dose ratio 1:1) for chronic asthma in children

Ciclesonide versus fluticasone (dose ratio 1:1) for chronic asthma in children

Patient or population: patients with chronic asthma in children
Settings: all settings
Intervention: ciclesonide
Comparison: fluticasone (dose ratio 1:1)

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Fluticasone (dose ratio 1:1)Ciclesonide

Asthma symptoms
Asthma symptom score (scale 0 to 4)
Follow-up: 12 weeks
See commentSee commentNot estimable1468
(3 studies)
⊕⊕⊕⊝
moderate1
2 studies used a 5-point scale and 1 study did not provide details how asthma symptoms were measured. Data could not be pooled due to diversity in scales

Patients with exacerbations
Number of patients with exacerbations
Follow-up: 12 weeks
18 per 100024 per 1000
(10 to 57)
RR 1.37
(0.58 to 3.21)
1003
(2 studies)
⊕⊝⊝⊝
very low1,2,3

Adverse events
Number of patients with adverse events
Follow-up: 12 weeks
See commentSee commentNot estimable1560
(6 studies)
⊕⊕⊝⊝
low1,2
Adverse events were defined differently across studies therefore results could not be pooled

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Two fully published studies were sponsored by the manufacturer and at least one of the authors of each study was an employee of the manufacturer that sponsored the study.
2 The intervention period of 12 weeks is too short to expect any major changes in this outcome.
3 Confidence intervals of estimated effect include no effect and exceed a relative reduction or increase risk of 25%.
 
Summary of findings 3. Ciclesonide versus fluticasone (dose ratio 1:2) for chronic asthma in children

Ciclesonide versus fluticasone (dose ratio 1:2) for chronic asthma in children

Patient or population: patients with chronic asthma in children
Settings: all settings
Intervention: ciclesonide
Comparison: fluticasone (dose ratio 1:2)

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Fluticasone (dose ratio 1:2)Ciclesonide

Asthma symptom
Asthma symptom score (scale 0 to 4)
Follow-up: 12 weeks
The mean asthma symptom in the control groups was
1.33
The mean asthma symptom in the intervention groups was
0.07 higher
(0.14 to 0.29 higher)
482
(1 study)
⊕⊕⊝⊝
low1,2
Estimates are medians indicating data was skewed

Patients with exacerbations
Number of patients with exacerbations
Follow-up: 12 weeks
20 per 100070 per 1000
(27 to 174)
RR 3.48
(1.35 to 8.71)
502
(1 study)
⊕⊝⊝⊝
very low1,2,3

Adverse events
Number of patients with adverse events
Follow-up: 12 weeks
476 per 1000471 per 1000
(424 to 514)
RR 0.99 (0.89 to 1.08)502
(1 study)
⊕⊝⊝⊝
very low1,2,3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Based on one study that was underpowered for a non-inferiority trial.
2 The study was sponsored by the manufacturer and at least one author was an employee of the manufacturer that sponsored the study.
3 The intervention period of 12 weeks is too short to expect any major changes in this outcome.
 
Table 1. Characteristics of the interventions

Study IDCiclesonide doseComparator ICSApplicationInhalation techniqueTreatment period

Ciclesonide versus budesonide

von Berg 2007160 μg OD (ex-actuator; equivalent to 200 μg ex-valve) 2 x 80 μg puffs in the eveningBudesonide 400 μg OD 2 x 200 μg puffsCiclesonide: HFA-MDI with an AeroChamber®;

Budesonide: Turbohaler®
Not described12 weeks

Vermeulen 2007320 μg OD (ex-actuator; equivalent to 2 puffs of 200 μg ex-valve) 2 x 160 μg puffs administered in the eveningBudesonide 800 μg OD (4 inhalations of
200 μg from the Turbohaler® device), administered in the evening
Ciclesonide: HFA-MDI without spacer Budesonide: Turbohaler®Not described12 weeks

Ciclesonide versus fluticasone

Hiremath 2006160 μg ODFluticasone 88 μg BIDMDI with spacer, AeroChamber Plus®Not described12 weeks

Paunovic 2010160 μg ODFluticasone 88 μg BIDNo information providedNot described12 weeks

Pedersen 200680 μg BID (ex-actuator; equivalent to 100 μg BID ex-valve)Fluticasone 88 μg BID (ex-actuator dose, equivalent to 100 μg BID ex-valve)HFA-MDI without spacerAdequate inhalation technique no details described12 weeks

Pedersen 200980 or 160 μg OD (ex-actuator; equivalent to 100 and 200 μg ex-valve) administered in the eveningFluticasone 88 μg BID (176 ex-actuator; equivalent to 100 μg BID ex-valve) in the morning and eveningHFA 134-MDI without spacerGood inhalation technique, no details described12 weeks

 BID: twice daily; ex-actuator: drugs that leaves the inhaler; ex-valve: drugs that leaves the metering chamber valve; HFA-MDI: hydrofluoroalkane-propelled metered dose inhaler; ICS: inhaled corticosteroid; MDI: metered dose inhaler; OD: once daily.
 
Table 2. Effect of the intervention: ciclesonide versus budesonide

DoseCIC 160 μg OD versus BUD 400 μg ODCIC 320 μg OD versus BUD 800 μg OD

Dose ratio1:21:2

Studyvon Berg 2007Vermeulen 2007

Primary outcomes

Asthma symptoms: asthma symptom score (sum score)ITT: MD 0.01, 95% CI -0.14 to 0.16

PP: MD 0.03, 95% CI -0.20 to 0.25

Non-inferiority acceptance limit = 0.3
Median change from baseline (no CIs reported)

ITT: CIC: -0.07; BUD: -0.14

PP: CIC: -0.07; BUD: -0.14

Asthma symptoms: use of rescue medication (puff/day)ITT: MD 0.06 puffs/day, 95% CI -0.26 to 0.38Not assessed

Asthma symptoms: % of asthma symptom and rescue medication-free daysITT: CIC: mean 73%; BUD: mean 70%

No difference between groups
ITT and PP: CIC: median 84%; BUD: median 85%

Lower limit of the between difference was -1.4% and above non-inferiority limit of -8%

Exacerbations: patients with exacerbations*ITT: RR 2.71, 95% CI 0.61 to 12.11;  Analysis 1.1ITT: RR 1.69, 95% CI 0.36 to 8.00;  Analysis 1.1

Adverse events: patients with adverse eventsAdverse events were reported in 38% of patients in both groupsITT: RR** 1.44, 95% CI 0.96 to 2.18

Adverse events: change in body heightMean change from baseline (least square mean)

CIC: 1.18 cm; BUD: 0.70 cm
Not assessed

Adverse events: 24-hour urine cortisol adjusted for creatinineITT: 2.99 nmol/mmol creatinine; P < 0.0001, one-sided (decrease greater in the BUD group)ITT: significant difference between groups (lower level in BUD group)

Secondary outcomes

Quality of life: PAQLQ(S)ITT: MD -0.11, 95% CI -0.12 to 0.10, one-sided superiority;  Analysis 1.2

Non-inferiority acceptance limits = not provided

PP not reported
ITT: MD (least square mean) 0.01, 95% CI -0.14 to 0.16;  Analysis 1.2

Non-inferiority acceptance limit = -0.5%

PP results were similar

Quality of life: PACQLQITT: MD -0.08, 95% CI -0.27 to 0.11, one-sided superiority

Non-inferiority acceptance limit not provided

PP not reported
Not assessed

ComplianceNot assessed Not assessed

Lung function: FEV1 (L)ITT: MD (least square means) -0.019 L, 95% CI -0.059 to 0.022;  Analysis 1.3

PP: MD (least square means) -0.034 L, 95% CI -75 to 10

Non-inferiority acceptance limit = -100 mL
ITT: MD (least square means) -0.03 L, 95% -0.14 to 0.8;  Analysis 1.3

PP: MD (least square means) -0.02 L, 95% CI -0.13 to 0.1

Non-inferiority acceptance limit = -150 mL

Airway inflammation Not assessedNot assessed

 BUD: budesonide; CI: confidence interval; CIC: ciclesonide; ITT: intention to treat analysis; MD: mean difference; OD: once daily; PACQLQ: Pediatric Asthma Caregiver Quality of Life Questionnaire; PAQLQ: Pediatric Asthma Quality of Life Questionnaire; PP: per protocol; RR: risk ratio.
* Exacerbations were defined as an increasing asthma symptoms requiring change or addition of patient's medication other than increasing rescue medication.
** Adverse events that needed treatment, reported in over 2% of patients in CIC or BUD group of safety population (N = 403).
 
Table 3. Effects of the intervention: ciclesonide versus fluticasone

DoseCIC 80 μg BID vs. FP 88 μg BIDCIC 160 μg OD vs. FP 88 μg BIDCIC 80 μg BID vs. FP 88 μg BIDCIC 160 μg OD vs. FP 88 μg BIDCIC 80 μg OD vs. FP 88 μg BID

Dose ratio1:11:11:11:11:2

StudyPedersen 2006Pedersen 2009Hiremath 2006Paunovic 2010Pedersen 2009

Primary outcomes


Asthma symptoms: asthma symptom scoreMedian difference (Hodges Lehmann point estimate)

ITT and PP:

0.00, 95% CI -0.29 to 0.14
Median difference (Hodges Lehmann point estimate)

Unclear if ITT or PP *:

0.07, 95% CI -0.14 to 0.28

Non-inferiority acceptance limit = 0.30 sum score
Not assessedAsthma symptom score decreased and was similar in both groupsMedian difference (Hodges Lehmann point estimate)

Unclear if ITT or PP **:

0.07, 95% CI -0.14 to 0.28

Non-inferiority acceptance limit = 0.30 sum score

Asthma symptoms: use of rescue medicationMedian difference (Hodges Lehmann point estimate)

ITT and PP: 0.00, 95% CI -1.23 to 2.12
Median change from baseline (Hodges Lehmann point estimate)

ITT: CIC: -1.13; FP: -1.29

PP: CIC: -1.14; FP: -1.29

All P < 0.0001
Not assessedUse of rescue medication decreased and was similar in both groupsMedian change from baseline (Hodges Lehmann point estimate)

ITT: CIC: -1.20; FP: -1.29

PP: CIC: -1.21; FP: -1.29

All P < 0.0001

Asthma symptoms: a sthma symptom-free daysMedian difference (Hodges Lehmann point estimate)

ITT: -1.01, 95% CI -4.60 to 2.46

PP: -1.01, 95% CI -4.82 to 2.51
Not assessedNot assessedNot assessedNot assessed

Asthma symptoms: % of asthma symptom and rescue medication-free days combinedNot assessedMean percentage was high and did not differ significantly between the treatment groups (PP)Median

CIC: 91.5%; FP: 94%

P = 0.1320 (2-sided between treatments)
Not assessedPP: mean percentage was high and did not differ between the treatment groups

Exacerbations: number of patients with exacerbationsRR 1.26, 95% CI 0.34 to 4.66;  Analysis 2.1RR 1.45, 95% CI 0.47 to 4.49;  Analysis 2.1Not assessedCIC: 2.3%; FP: 2.2%RR 3.57, 95% CI 1.35 to 9.47;  Analysis 2.1

Adverse events: % of patients with adverse eventsA similar percentage of patients reported adverse eventsRR 0.88, 95% CI 0.72 to 1.07;  Analysis 2.2The incidence of adverse events was similar in both groupsNot assessedRR 0.98, 95% CI 0.81 to 1.17;  Analysis 2.2

Adverse events: cortisol 24-hour urine sample (nmol/mmol)ITT: difference between 2 groups was not statistically significant

ITT and restricted ITT

(which included only

those urine cortisol

measurements with a

corresponding urine

creatinine value within

the normal range)

A statistically significant

difference in favour of CIC was seen in the restricted ITT analysis

(P = 0.006). The findings were similar

for patients who were ICS-naive and patients who had received ICS prior to study entry

although the differences were numerically greater in previously ICS-naive patients
Safety analysis**: MD

0.54 nmol/mmol, 95% CI -5.92 to 7.00;  Analysis 2.3
Not assessedNot assessedSafety analysis**: MD 1.15 nmol/mmol, 95% CI 0.07 to 2.23;  Analysis 2.3

Secondary outcomes


Quality of life: PAQLQNot assessedITT and PP:

Non-inferiority was confirmed CIC 160 compared to FP (P < 0.0001, one-sided)

Non-inferiority limit = -0.5
Not assessedNot assessedITT and PP:

Non-inferiority was confirmed for CIC80 compared to FP (P < 0.0001, one-sided)

Non-inferiority limit = -0.5

Quality of life: PACQLQNot assessedITT and PP:

Non-inferiority was confirmed CIC 160 compared to FP (P < 0.0001, one-sided)

Non-inferiority limit = 15
Not assessedNot assessedITT and PP:

Non-inferiority was confirmed for CIC80 compared to FP (P < 0.0001, one-sided)

Non-inferiority limit = 15

ComplianceNot assessedNot assessedNot assessedNot assessedNot assessed

Change in lung function:

FEV1 (L)
ITT: MD (least square means) 0.0 L, 95% CI -0.042 to 0.042;  Analysis 2.4

PP: MD (least square means) 0.001, 95% -0.044 to 0.046
ITT: MD (least square means) -0.02 L, 95% CI -0.07 to 0.04;  Analysis 2.4

PP: MD (least square means) -0.026, 95% CI -0.086 to 0.34
Improvement similar between groups no point estimatesImprovement similar between groups no point estimatesITT: MD (least square means) -0.05 L, 95% CI -0.11 to 0.01;  Analysis 2.4

PP: MD (least square means) -0.056, 95% CI -0.12 to -0.004

Airway inflammationNot assessedNot assessedNot assessedNot assessedNot assessed

 BID: twice daily; CI: confidence interval; CIC: ciclesonide; FP: fluticasone; ICS: inhaled corticosteroid; ITT: intention to treat analysis; OD: once daily; PACQLQ: Pediatric Asthma Caregiver Quality of Life Questionnaire; PAQLQ: Pediatric Asthma Quality of Life Questionnaire; PP: per protocol analysis.
* = In this study analyses were based on PP population and analysis of ITT population was used to confirm results, description of the results are unclear but we assumed it to be based on analysis of PP population.
** = safety analysis excluded patients with concurrent nasal, ophthalmological or dermatological corticosteroid treatment.