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Jonas DE, Wines RCM, DelMonte M, et al. Drug Class Review: Controller Medications for Asthma: Final Update 1 Report [Internet]. Portland (OR): Oregon Health & Science University; 2011 Apr.

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Drug Class Review: Controller Medications for Asthma: Final Update 1 Report [Internet].

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Appendix JTolerability and overall adverse events of ICSs

Summary table of ICS adverse events and tolerability from head-to-head RCTs

StudyStudy design
N
Duration
Country
Population
Setting
Comparison (total daily dose in mcg)Equivalent dosingResultsQuality rating
Beclomethasone compared with budesonide
Molimard et al. 20051RCT, open- label

460

12 weeks
France

Age 18–60, moderate to severe persistent, not controlled on ICS, smoking status NR

Multicenter, subspecialty clinics
BDP MDI (800)
vs.
BUD DPI (1600)
vs.
FP DPI (1000)
Yes (all high)Overall AEs(%): 38 vs 35 vs 37, P = 0.791 between all

Withdrawals due to AEs (#):
1 vs 1 vs 2

Dysphonia (%): 13 vs 16 vs 20

Respiratory infection (%):
19 vs 14 vs 16

Central and peripheral nervous system disorders (%):
18 vs 19 vs 20
Fair
Tattersfield et al. 20012RCT, open label

377

24 months
Multinational (France, New Zealand, Spain, UK)

Age 20–60, mild, no ICS for previous 3 months

Multicenter (19)
BUD DPI (adjustable dosing; range 133–1729)
vs
BDP MDI with spacer (176–1906)
vs.
non-steriod treatment “placebo”
Yes (range low to high for both)Overall AEs(%): NR

Withdrawals due to AEs (%):
4.6 vs 2.7 vs 6.4

Oral candidiasis- thrush (%):
3 vs 2 vs 0

Dysphonia (%): 2 vs 1 vs 1

Upper respiratory tract infection (%): 20 vs 23 vs 12

Back pain (%): 7 vs 8 vs 2

Fractures (%): 1.1 vs 0 vs 0

Reduction in bone mineral density (%): did not differ among treatment groups over the 2 years

No difference in BMD/fractures between BDP, BUD, and placebo over 2 years
Fair
Worth et al. 20013RCT, open- label

209

8 weeks
Germany, France, Netherlands

Age 18–75, moderate to severe, on ICS, smoking status NR

Multicenter (39)
BDP MDI (800)
vs.
BUD DPI (1600)
Yes (high)Overall AEs (%): 24.3 vs. 26.5

Withdrawals due to AEs(%):
3 vs. 5

Dysphonia (%): 5.4 vs. 4.08

fungal infection (%): 2.7 vs. 4.08
Fair
Beclomethasone compared with ciclesonide
Chylack 20084RCT

1,568
Multinational (US, Poland, South Africa)

Age ≥ 18, moderate to severe, on ICS, excluded smokers

Multicenter
CIC HFA- MDI (640)
vs.
BDP HFA- MDI (640)
Yes (high)Overall AEs (%):incidence of treatment emergent AEs: 83.5 vs. 85.6

Withdrawals due to AEs(%): 3.7 vs. 2.8

Oral candidiasis- thrush (%): 1.4 vs. 6.3

Dysphonia (%): 2.2 vs. 1.5

Pharyngitis (%): 8.0 vs. 8.4
Fair
Beclomethasone compared with flunisolide
No systematic reviews or head-to-head trials found
Beclomethasone compared with fluticasone
Barnes et al. 19935RCT, DB

154

6 weeks
Multinational (7 countries worldwide)

Age ≥ 18, severe, 20% smokers

Multicenter (18 outpatient clinics)
FP MDI (1000)
vs.
BDP MDI (2000)
Yes (high)Overall AEs: 52% vs. 51%, P > 0.15

Withdrawals due to AEs(%):
2.4% vs. 4.2%

Oral candidiasis- thrush (%):
6% vs. 4%

Cough (%): 2% vs. 3%

Sore throat (%): 5% vs. 6%

Headache (%): 4% vs. 1%

Upper respiratory tract infection (%): 6% vs. 3%

Rhinitis (%): 7% vs. 3%

Additional adverse events and comments: no significant differences (P > 0.15) between treatments in the incidence or nature of AEs
Fair
Boe et al. 19946RCT, DB

134

12 weeks
Norway

Age ≥ 18, poorly controlled, 34% smokers

Multicenter
FP DPI (1600)
vs.
BDP DPI (2000)
Yes (high)Overall AEs: NR

Withdrawals due to AEs (%): 8 vs. 2

Oral candidiasis- thrush (%):
31 vs. 30

Sore throat (%): 28 vs. 14

Upper respiratory tract infection (%): 27 vs. 38

Respiratory infection (%): 14 vs. 10

Hoarseness (%): 14 vs. 5

GI disorders(%): 13 vs. 19

Muscoskeletal disorders(%): 13 vs. 25
Fair
de Benedictis et al. 20017RCT, DB

343

52 weeks
Multinational (7 countries: Holland, Hungary, Italy, Poland, Argentina, Chile, South Africa)

Age 4–11, prepubertal, severity and smoking status NR

Multicenter (32)
FP DPI (400)
vs.
BDP DPI (400)
Yes (medium)Overall AEs(%): 80 vs. 80.9

Withdrawals due to AEs: NR

Growth: Adjusted mean growth velocity greater in FP treated subjects (4.76 cm/year (0.28)) than BDP treated subjects (4.06 cm/year (0.29) (Difference 0.70 (95% CI: 0.13, 1.26 cm, P < 0.02))

Cough (%): 5.3 vs. 8.1

Upper respiratory tract infection (%): 13.5 vs. 14.5

Rhinitis (%): 25.3 vs. 11.6

Bronchitis (%): 14.1 vs. 11.6

Ear, nose, and throat infection (%): 14.1 vs. 9.2

Pharyngitis/throat infection(%): 12.4 vs. 14.5

Viral infection(%): 11.8 vs. 7.5

Viral respiratory infection(%): 9.4 vs. 10.4
Fair
Fabbri et al. 19938RCT, DB

274

12 months (daily symptom outcomes collected for initial 12 weeks)
Multinational (10 European)

Age 12–80, moderate to severe, not controlled on ICS, 11% smokers

Multicentre (25)
FP MDI (1500)
vs.
BDP MDI (1500)
Yes (high)Overall AEs(%):70% vs. 73% of pts

Withdrawals due to AEs (%):
8 vs. 8

Deaths (#): 2 deaths, not asthma related vs. 1 death, not asthma related

Oral candidiasis- thrush (%):
4 vs. 7

Sore throat (%):
5 vs. 2

Headache (%):
4 vs. 5

Upper respiratory tract infection (%): 6 vs. 5

Respiratory infection (%):
15 vs. 11

Hoarseness (%):
6 vs. 3

influenza (%):
4 vs. 5
Fair
Fairfax et al. 20019RCT, DB, DD

172

6 weeks
UK and Ireland

Age 18–65, mild to severe, symptomatic on ICS, 24% current smokers

Multicenter (30 general practice sites)
BDP MDI (extrafine HFA, 400)
vs.
FP MDI (CFC, 400)
Yes (medium)Overall AEs(%): 41 vs. 37

Withdrawals due to AEs: NR

Deaths: 0 vs. 0
Fair
Lorentzen et al. 199610RCT, DB

213

12 months
Multinational (7, Europe)

Age 18–77, severe, well controlled on high dose ICS, 19% smokers

Multicenter (20 outpatient clinics)
FP MDI (1000)
vs.
BDP MDI (2000)
Yes (high)Overall AEs(%): 72 vs. 72

Withdrawals due to AEs (%):
13 vs. 9

Oral candidiasis- thrush (%):
4 vs. 4

Cough (%): 7 vs. 2

Sore throat (%): 4 vs. 7

Headache (%): < 1 vs. 7, P = 0.03

Respiratory infection (%):
6 vs. 9

Rhinitis (%):
10 vs. 1

Hoarseness (%):
6 vs. 7

influenza (%):
5 vs. 13
Fair
Lundback et al. 199311RCT, DB

585

6 weeks (N = 48989 continued an additional 46 weeks)
Multinational (10)

Age 15–90, moderate, not controlled on ICS, smoking status NR

Multicenter (47)
FP MDI (500)
vs.
FP DPI (500)
vs.
BDP MDI (1000)
No, only for FP MDI vs. BDP MDI (high); FP DPI 500 is mediumOverall AEs: NR

Withdrawals due to AEs (%):
3.6 vs 4.0 vs 2.6

Oral candidiasis- thrush (%):
2 vs 2 vs 4

Sore throat (%): 5 vs 2 vs 1

Headache (%): 5 vs 7 vs 7

Upper respiratory tract infection (%): 6 vs 9 vs 7

Rhinitis (%): 2 vs 5 vs 2

Hoarseness (%): 2 vs 2 vs < 1
Fair
Malo et al. 199912RCT, DB, crossover

69

16 weeks
Canada

Age ≥ 18, severity NR, excluded current or former smokers

multicenter
FP MDI (400–1000)
vs.
BDP MDI (800–2000)
No (medium – high vs. medium - really high)Overall AEs: NR

Withdrawals due to AEs: NR

Skin bruising: was not significantly different in terms of the number of subjects affected; its severity and frequency, as well as the number of bruises on direct examination were significantly greater in subjects taking BDP (mean 1.64 lesions on BDP and 1.24 lesions on FP)
Fair
Medici et al. 200013RCT, DB

69

12 months
Switzerland

Age 20–55, mild to moderate, on ICS for 6 months, 5–23% current smokers

Multicenter (7 outpatient sites)
FP MDI (400)
vs.
FP MDI (750)
vs.
BDP MDI (800)
vs.
BDP MDI (1500)
Yes (medium vs high vs medium vs high)Overall AEs: NR

Adverse events caused withdrawal (%): 0 vs 0 vs 0 vs 7.7

Hoarseness/dysphonia (#):
1 vs 1 vs 1 vs 0

Oral candidiasis: 0 for all

Allergic skin reactions: 0 for all

Rash/skin eruptions: 0 for all

Reduction in bone mineral density (%):No difference in BMD between BDP- and FP- treated patients over 1 year
Fair
Molimard, M et al. 20051RCT, open- label

460

12 weeks
France

Age 18–60, moderate to severe persistent, not controlled on ICS, smoking status NR

Multicenter, subspecialty clinics (69 pulmonologists)
BDP MDI (800)
vs.
BUD DPI (1600)
vs.
FP DPI (1000)
Yes (all high)Overall AEs(%): 38 vs 35 vs 37, P = 0.791 between all

Withdrawals due to AEs (#):
1 vs 1 vs 2

Dysphonia (%): 13 vs 16 vs 20

Respiratory infection (%):
19 vs 14 vs 16

Central and peripheral nervous system disorders (%):
18 vs 19 vs 20
Fair
Raphael et al. 199914RCT, DB, DD

399

12 weeks
US

Age ≥ 12 years, mild to severe, not controlled on ICS, smokers excluded

Multicenter, specialty asthma and primary care centers (23)
FP MDI (164)
vs
FP MDI (440)
vs
BDP MDI (336)
vs
BDP MDI (672)
Yes (low, medium, low, medium)FP all vs. BDP all reported for those with two percentages

Overall AEs (%): 9 vs. 15, P = 0.664

Withdrawals due to AEs (%):
3 vs 3 vs 4 vs 2

Oral candidiasis- thrush (%):
1 vs. 4, P = 0.472

Dysphonia (%):
3 vs. 7, P = 0.577

Sore throat (%):
1 vs. 3, P = 0.797

Headache (%):
1 vs. 3, P = 0.721
Fair
Beclomethasone compared with mometasone
Bernstein et al. 199915RCT, DB, DD

365

12 weeks
US

Age ≥ 12, mild to moderate, on ICS, smokers excluded

Multicenter (20)
Mometasone DPI (200)
vs
Mometasone DPI (400)
vs
Mometasone DPI (800)
vs
BDP MDI (336)
vs
placebo
No; only for MOM 400 vs. BDP 336 (both medium)Overall AEs(%): 18 vs 26 vs 28 vs 21 vs 22

Withdrawals due to AEs (%):
5 vs 3 vs 4 vs 8 vs 11

Oral candidiasis- thrush (%):
4 vs 6 vs 15 vs 3 vs 1

Dysphonia (%):
1 vs 1 vs 3 vs 1 vs 1

Cough (%): 1 vs 0 vs 0 vs 0 vs 3

Headache (%): 3 vs 4 vs 4 vs 4 vs 5
Fair
Nathan et al. 200116RCT, DB, DD

227

12 weeks
US

Age ≥ 12, moderate, on ICS, smokers excluded

Multicenter (15)
Placebo
vs
Mometasone DPI (200)
vs
Mometasone DPI (400)
vs
BDP MDI (336)
No; only for MF 200 vs. BDP (both low), MF 400 is mediumOverall AEs: NR

Withdrawals due to AEs(%):
8.8 vs 1.8 vs 3.6 vs 1.8

Oral candidiasis- thrush (%):
0 vs 4 vs 11 vs 5

Dysphonia (%):
0 vs 4 vs 4 vs 2

Headache (%):
2 vs 5 vs 2 vs 4

Hoarseness (%):
2 vs 7 vs 2 vs 0
Fair
Beclomethasone compared with triamcinolone
Berkowitz et al. 199817RCT, DB, DD

339

8 weeks
US

Age 18–65, mild to moderate, on ICS, smokers excluded

Multicenter (17), asthma/allergy centers
BDP MDI (336)
vs
TAA MDI (800)
vs
placebo
Yes (medium)Overall AEs(%): 50 vs 57.4 vs 55.5

Withdrawals due to AEs (%):
9.8 vs 8.3 vs 16.3

Oral candidiasis/thrush (%):
1.8 vs 0 vs 0

Dysphonia (%): 1.8 vs 1.9 vs 0

Cough (%): 3.6 vs 2.8 vs 2.7

Dry throat (%): 0 vs 0.9 vs 0

Death (%): 0 vs 0 vs 0

Pharyngitis (%): 2.7 vs 0.9 vs 2.7
Fair
Bronsky et al. 199818RCT, DB, DD

329

8 weeks
US

Age 18–65, mild to severe, on ICS, smokers excluded

Multicenter
BDP MDI (336)
vs
TAA MDI (800)
vs
placebo
Yes (medium)Overall AEs(%): 48.2 vs 50.9 vs 59.8, P = 0.786 BDP vs. TAA

Withdrawals due to AEs(%):
2.7 vs 8.4 vs 17.9

Oral candidiasis- thrush (%):
0.0 vs 0.9 vs 0.0

Dysphonia (%): 0.9 vs 1.9 vs 0.0

Cough: 0.9 vs 0.9 vs 1.8

Upper respiratory tract infection (%): 2.7 vs 10.4 vs NR, P = 0.027

Death (%): 0.0 vs 0.0 vs 0.0
Fair
Budesonide compared with ciclesonide
Boulet et al. 200619RCT, DB, DD

359

12 weeks
Multinational - Canada and Europe

Age 12–75, mild to moderate, on ICS, heavy smokers or ex- smokers excluded (>10 cigarettes/day)

Multicenter
CIC HFA- MDI (320)
vs.
BUD DPI (320)
No (medium vs. low)Overall AEs(%): 42 vs. 52

Withdrawals due to AEs(%): NR

Oral candidiasis- thrush (%):0.0 vs 0.0

Dysphonia (%): 2 vs. 1

Cough: NR

Sore throat (%): 2 vs. 1

Upper respiratory tract infection (%): 12 vs. 19
Fair
Hansel et al. 200620RCT

554

12 weeks
Multinational - Europe

Age 12–75, mild to severe, on ICS, 9% smokers

Multicenter
CIC HFA- MDI (80)
vs.
CIC HFA- MDI (320)
vs.
BUD DPI (400)
Yes for CIC 80 vs. BUD 400
No for CIC 320 vs. BUD

(low vs. medium vs. low)
Overall AEs(%): 36.8 vs. 40.8 vs. 33.9

Withdrawals due to AEs(%): 4.4 vs. 2.1 vs. 1.7

Oral candidiasis- thrush (%): NR

Dysphonia (%): NR

Increased cough (%): 0 vs. 3.1 vs. 0

Sore throat (%): NR

Headache (%): 3.3 vs. 3.6 vs. 0
p=NR

Upper respiratory tract infection (%): 11.5 vs. 5.1 vs. 7.9
p=NR
Fair
Ukena et al. 200721RCT, DB, DD

399

12 weeks
Germany

Age 12–75, mild to severe, smokers excluded

Multicenter
CIC HFA- MDI (320)
vs.
BUD DPI (400)
No (medium vs. low)See Evidence TableFair
Vermeulen et al. 200722RCT, DB, DD

403

12 weeks
Multinational - Hungary, Poland, Serbia/Montenegro, South Africa, Spain

Age 12–17, severe, not controlled on ICS, excluded smokers

Multicenter
CIC HFA- MDI (320)
vs.
BUD DPI (800)
Yes (medium)Overall AEs(%): 26.5% of patients vs. 18.3%

Withdrawals due to AEs(%): NR

Oral candidiasis- thrush (%): 0 vs. 0

Dysphonia, cough, sore throat, and headache (%): NR

Upper respiratory tract infection (%): 2.2 vs. 2.3

Deaths: 0 vs. 0
Fair
von Berg et al. 200723RCT, DB, DD

621

12 weeks
Multinational - Australia, Germany, Hungary, Poland, Portugal, Serbia and Montenegro, South Africa and Spain

Age 6–11, moderate to severe, smoking status NR

Multicenter
CIC HFA- MDI (160)
vs.
BUD DPI (400)
Yes (low)Overall AEs(%):38% of patients (n=158 in G1, n=78 in G2) experienced an AE

Withdrawals due to AEs(%): 2.9 vs. 1

Oral candidiasis/thrush and dysphonia combined (%): 0.2 vs. 1.5

Cough, sore throat, and headache: NR

Upper respiratory tract infection (%): 3.6% vs. 6.3%

Mean body height increase, in centimeters: 1.18 (p<.0001) vs. 0.70 (p<.0001);
Increase in body height significantly greater in G1 than G2 (difference b/t groups = 0.481 cm, p = .0025, two-sided)
Fair
Budesonide compared with flunisolide
Newhouse et al. 200024RCT

179

6 weeks
Canada

Age 18–75, moderate, on ICS, 5% current smokers

Multicenter (17)
Flunisolide MDI + AeroChamber (1500)
vs.
BUD DPI (1200)
Yes (medium)Overall AEs(%): 48 vs. 54.4

Withdrawals due to AEs: NR

Headache (%): 6.7 vs. 3.8

flu syndrome (%): 4.0 vs. 6.3

Paresthesia (%): 2.7 vs. 0.0

Migraine (%): 2.7 vs. 0.0

Emesis (%): 2.7 vs. 0.0

Insomnia (%): 1.3 vs. 2.5

Back pain (%): 1.3 vs. 2.5
Fair
Budesonide compared with fluticasone
Ayres et al. 199525RCT, DB, DD

671

6 weeks
Multinational (13 countries worldwide)

Age 18–70, severe, on ICS, smokers excluded

Multicenter (66)
FP MDI (1000)
vs
FP MDI (2000)
vs
BUD MDI (1600)
No (high vs high vs medium)Overall AEs: NR

Withdrawals due to AEs: NR

Overall adverse events (%): 61 vs 49 vs 51

Oral candidiasis- thrush (%):3 vs 4 vs 5

Cough (%): 3 vs 6 vs 5

Sore throat (%): 4 vs 4 vs 2

Headache (%): 5 vs 7 vs 6

Upper respiratory tract infection (%): 11 vs 10 vs 6

Respiratory infection (%): 4 vs 1 vs 2

Rhinitis (%): 4 vs 1 vs 3

Hoarseness (%): 6 vs 3 vs 3
Fair
Ferguson et al. 199926RCT, DB, DD

333

20 weeks
Multinational (6 countries worldwide)

Ages 4–12, moderate to severe, on ICS, smoking status NR

Multicenter
FP DPI (400)
vs.
BUD DPI (800)
Yes (medium)Overall AEs(%): NR

Withdrawals due to AEs(%): NR

Oral candidiasis- thrush (%):0 vs. 0

Upper respiratory tract infection (%): 28 vs. 32

Growth: linear growth velocity was statistically greater for FP compared to BUD (adjusted mean increase in height: 2.51 cm vs. 1.89; difference was 6.2 mm (95% CI: 2.9–9.6, P = .0003)
Fair
Heinig et al. 199927RCT, DB, DD

395

24 weeks
Multinational (Belgium, Canada, Denmark, Netherlands)

Age 18–75, severe, not controlled on ICS, 15% current smokers

Multicenter (47)
FP DPI (2000)
vs.
BUD DPI (2000)
No (both are high doses, but relative potency of fluticasone is greater at the given doses)Overall AEs(%): 78 vs. 77

Withdrawals due to AEs: NR
Fair
Hoekx et al. 199628RCT, DB, DD

229

8 weeks
Multinational (4: Netherlands, Sweden, Denmark, Finland)

Children up to 13, mild to moderate, on ICS, smoking status NR

Multicenter (22)
FP DPI (400)
vs.
BUD DPI (400)
No (medium vs. low)Overall AEs(%): 63 vs. 69

Withdrawals due to AEs (%):
2 (1.7%) vs. 3 (2.7%)

Oral candidiasis- thrush (%):
3 vs. < 1

Cough (%): 6 vs. 4

Sore throat (%): 4 vs. 5

Headache (%): 3 vs. 7

Upper respiratory tract infection (%): 12 vs. 15

Rhinitis (%): 11 vs. 12

Hoarseness (%): 0 vs. 4

allergic skin reaction (%): < 1 vs. 5
Fair
Kannisto et al. 200029RCT

75

6 months for lab outcomes, 12 months for growth outcome
Finland

Age 5–15, severity NR, new onset of asthma

tertiary center, University clinic
BUD DPI (800 for 2 months, then 400)
vs.
FP DPI (500 for 2 months, then 200)
vs.
Cromone (non-ICS control)

At 4 months, a subgroup were switched to cromones
Yes

Steroid dosing range: medium, low vs. medium, low
Overall AEs: NR

Withdrawals due to AEs (%): NR

Growth: Greater growth velocity in FP than in BUD group [FP treated children had less growth reduction than BUD treated children (height SD score: 0.03 vs. 0.23; P < 0.05)
Fair
Molimard et al. 20051RCT, open- label

460

12 weeks
France

Age 18–60, moderate to severe persistent, not controlled on ICS, smoking status NR

Multicenter, subspecialty clinics (69 pulmonologists)
BDP MDI (800)
vs
BUD DPI (1600)
vs
FP DPI (1000)
Yes (all high)Overall AEs(%): 38 vs 35 vs 37, P = 0.791 between all

Withdrawals due to AEs (#):
1 vs 1 vs 2

Dysphonia (%): 13 vs 16 vs 20

Respiratory infection (%):
19 vs 14 vs 16

Central and peripheral nervous system disorders (%):
18 vs 19 vs 20
Fair
Ringdal et al. 199630RCT, DB, DD

518

12 weeks
Multinational

Age 18–75, moderate to severe, not controlled on ICS, 19% smokers

Multicenter
FP DPI (800)
vs.
BUD DPI (1600)
Yes (high)Overall AEs(%): 61.7 vs. 61.5

Withdrawals due to AEs (%):
3.9 vs. 5.0

Sore throat (%):
5.9 vs. 4.2

Upper respiratory tract infection (%):
21.5 vs. 24.9

Rhinitis (%):
11.3 vs. 8.0
Fair
Budesonide compared with mometasone
Bousquet et al. 200031RCT, single- blind

730

12 weeks
Multinational (17)

Age ≥ 12, moderate, on ICS, smokers excluded

Multicenter (57)
Mometasone DPI (200)
vs
Mometasone DPI (400)
vs
Mometasone DPI (800)
vs
Budesonide DPI (800)
No (only for MF 400 vs. BUD, both medium)Overall AEs: NR

Withdrawals due to AEs (%):
3 vs < 1 vs 2 vs 4 vs 2

Dysphonia (%):
4.3 vs 2.8 vs 4.8 vs 2.2

The most common treatment-related adverse events were headache (4–8%), pharyngitis (4–5%), and dysphonia (2–5%). Oral candidiasis was uncommon in this study, reported by only 16 patients overall, and had a similar incidence among the treatment groups (N = 4, 6, 4, and 3)
Fair
Corren et al 200332RCT, DB, DD

262

8 weeks
US

Age ≥ 12, moderate, on ICS, smokers excluded

Multicenter (17)
Mometasone DPI (400)
vs
BUD DPI (320)
vs
placebo
No (medium vs. low)Overall AEs(%): 8 vs 9 vs 8

Withdrawals due to AEs: NR

Most frequently reported treatment-related AEs were headache and pharyngitis (both 4% or less: data by treatment arm NR).

There was only one report of oral candidiasis in one MF-reated patient.
Fair
Budesonide compared with triamcinolone
Weiss et al. 200433RCT

945

52 weeks
US

Age ≥18, mild to severe, smoking status NR

Multicenter, patients from 25 managed care plans
BUD DPI (mean dose at start and end: 941.9 and 956.8 mcg/d)
vs.
TAA pMDI (1028.2/1042.9 mcg/d)
Yes, on average both are mediumOverall AEs (%): 85 vs. 86

Withdrawals due to AEs (%):
3.0 vs. 2.5

The most frequently reported AEs were respiratory tract infection, sinusitis, bronchitis, and accident/injury.
Fair
Ciclesonide compared with flunisolide
No systematic reviews or head-to-head trials found
Ciclesonide compared with fluticasone
Bateman 200834RCT

528

6 months
Multinational - Europe, North America, South Africa

Age 12–75, moderate to severe, on ICS, 33% ex-smokers or current smokders

Multicenter
CIC HFA- MDI (640)
vs.
FP HFA-MDI (660)
Yes (high)Overall AEs (N): 373 vs. 401

Withdrawals due to AEs (%): NR

Oral candidiasis- thrush (%): 2.0 vs. 4.8 (numbers from safety set)

Dysphonia (%): 3.1 vs. 9.2 (numbers from safety set)

Cough (%): NR

Sore throat (%):Pharyngolary ngeal pain (numbers from safety set) 4.3 vs. 4.4

Headache (%):2.4 vs. 4.4 (numbers from safety set)

Upper respiratory tract infection (%): 8.2 vs. 7.3% (numbers from safety set)

Hoarseness (%): NR

Deaths: 0
Fair
Boulet 200735RCT

474

12 weeks
Multinational - Austria, Canada, Germany, Hungary, South Africa, Spain

Age 12–75, moderate, 30% ex-smokers or current smokders

Multicenter
CIC HFA- MDI (320)
vs.
FP DPI (400)
Yes (medium)Overall AEs(%): 36.1 vs. 39.3

Withdrawals due to AEs (%): 1.7 vs. 4.2

Oral candidiasis- thrush (%): 0 vs. 3.8; p=0.002 (1-sided)

Dysphonia (N): 5 vs. 6

Cough (%): NR

Sore throat (%): 3.4 vs. 1.7

Headache (%): NR

Upper respiratory tract infection (%): NR

Hoarseness (%): NR
Fair
Buhl 200636RCT

529

12 weeks
Multinational - Germany, Austria, The Netherlands, Spainn, Hungary, Poland, South Africa

Age 12–75, moderate, on ICS, smoking status NR

Multicenter
CIC HFA- MDI (160)
vs.
FP HFA-MDI (176)
Yes (low)Overall AEs (%): 36 vs. 34

Withdrawals due to AEs (%): 2.26 vs. 1.14

Oral candidiasis/thrush or dysphonia: Oral candidiasis or voice alteration occurred in 3 patients treated with fluticasone proprionate but neither occurred in patients treated with ciclesonide

Cough or sore throat: NR

Headache (%): 3 vs. 4

Upper respiratory tract infection (%): 8 vs. 8

Deaths: 0 vs. 0
Fair
Dahl 201037RCT, DB, DD

480

24 weeks
Multinational – Austria, Canada, Germany, Poland, and South Africa

Age 12–75, on ICS, mild to moderate, excluded current and ex-smokers with ≥ 10 pack- year history, 22–31% current or ex-smokers enrolled

Multicenter
CIC HFA- MDI (80)
vs.
FP HFA-MDI (200)
Yes (low)Overall AEs(%): 44 vs. 43

Withdrawals due to AEs (N): 4. Vs. 8

Oral candidiasis- thrush (%): 2.1 vs. 5.0

Cough, sore throat, or headache (%): NR

Upper respiratory tract infection (%): 6.7 vs. 5.0

Hoarseness (%): NR

Deaths (%): 0 vs. 0
Fair
Knox 200738RCT

111

12 weeks
United Kingdom, Belgium

Age 17–75, on ICS, severity NR, 2–3% smokers

Multicenter
CIC HFA- MDI (160)
vs.
FP HFA-MDI (500)
No (low vs. medium)Overall AEs(n): Treatment-emergent AE (TEAE) 42 vs. 49

Withdrawals due to AEs (n): 1 vs. 0

Oral candidiasis- thrush (n): 0 vs. : 1

Cough (%): NR

Sore throat (%): 3.4 vs. 3.8

Headache (%): NR

Upper respiratory tract infection (%): 3.4 vs. 9.4

Hoarseness (%): NR
Fair
Lipworth 200539RCT

164

12 weeks
United States

Age >18, mild to moderate, smoking status NR

Multicenter
Placebo
vs.
CIC HFA- MDI (320)
vs.
CIC HFA- MDI (640)
vs.
FP HFA-MDI (880)
Mixed (NA vs. medium vs. high vs. high)Overall AEs(n): No. of pts/n having at least 1 tx-emergent AE: G1: 35/41 vs. G2/G3: 53/82 vs. G4: 32/41

Withdrawals due to AEs (%): G1: 7 vs. G2/G3: 1.2 vs. G4: 2.4

Oral candidiasis- thrush (%): 0 vs. 2.5% vs. 2.4% vs. 22.0%

Cough, sore throat, URI, or headache (%): NR

Hoarseness (n): G1: 0 vs. G2/G3: 2/82 vs. G4: 3/41
Fair
Magnussen 200740RCT

808

12 weeks
Multinational - Germany, Poland, Czech Republic, France, Italy, The Netherlands, Slovakia, Spain

Age >12, mild to severe, 21–24% ex- and current smokers

Multicenter
CIC HFA- MDI (80)
vs.
CIC HFA- MDI (160)
vs.
FP HFA-MDI (176)
Yes (low)Overall AEs(%): 25.2 vs. 24.4 vs. 27.4

Withdrawals due to AEs (n): 3 vs. 5 vs. 3

Oral candidiasis- thrush, cough, sore throat, headache, or hoarseness (%): NR

Upper respiratory tract infection (%): Reported similar %s for the three groups (from 0.4 to 5.8%) for bronchitis, nasopharyngitis, pharyngitis, and allergic rhinitis
Fair
Pedersen 200941RCT

744

12 weeks
Multinational - Brazil, Germany, Hungary, Poland, Portugal, South Africa

Age 6–11, mild to severe, smoking status NR

Multicenter
CIC HFA- MDI (80)
vs.
CIC HFA- MDI (160)
vs.
FP HFA-MDI (176)
Yes (low)Overall AEs(%): 46.4 vs. 41.7 vs. 47.6

Withdrawals due to AEs (%): 5.2% vs. 2.1 vs. 0.8

Oral candidiasis- thrush (%): 0 vs. 0.43 vs. 0.41

Cough, sore throat, headache, URI, or hoarseness (%): NR
Fair
Pedersen 200642RCT

556

12 weeks
Multinational - 8 countries

Age 6–15, mild to severe, excluded current smokers

Multicenter
CIC HFA- MDI (160)
vs.
FP HFA-MDI (176)
Yes (low)Overall AEs (n): 277 vs. 279

Withdrawals due to AEs (n): 0 vs. 1

Oral candidiasis- thrush (%): NR

Cough, sore throat, or hoarseness (%): NR

Headache (%): 3.6 vs. 2.5

Upper respiratory tract infection (%): 6.9 vs. 6.5
Fair
Ciclesonide compared with mometasone
No systematic reviews or head-to-head trials found
Ciclesonide compared with triamcinolone
No systematic reviews or head-to-head trials found
Flunisolide compared with fluticasone
No systematic reviews or head-to-head trials found for KQ2
Flunisolide compared with mometasone
No systematic reviews or head-to-head trials found
Flunisolide compared with triamcinolone
No systematic reviews or head-to-head trials found
Fluticasone compared with mometasone
O’Connor et al. 200143RCT, DB

733

12 weeks
Multi-national (20)

Age ≥12, moderate, on ICS, excluded smokers

Multicenter, University hospitals
MF DPI (200)
vs
MF DPI (400)
vs
MF DPI (800)
vs
FP DPI (500)
No (only for medium doses of each: MF 400 vs. FP 500)Overall AEs (%):
20 vs 26 vs 30 vs 29

Withdrawals due to AEs (%):
5 vs 3 vs 5 vs 4

Oral candidiasis- thrush (%):
1 vs 7 vs 10 vs 10
Fair
Fluticasone compared with triamcinolone
Baraniuk et al. 199944RCT, DB, triple- dummy

680

12 weeks
US

Age ≥12, not controlled on ICS, excluded smokers

Multicenter, Pulmonary/allergy medicine clinics (50)
FP MDI (196) + Salmeterol (84) vs FP MDI (440)
vs
TAA MDI (1200)
Yes (medium for both ICS-only arms)Overall AEs(%):Drug-related: 14 vs 13 vs 8

Withdrawals due to AEs (%):
4 vs 1 vs 2

Oral candidiasis- thrush (%):
2 vs 2 vs 1

Dysphonia (%): 3 vs 4 vs < 1

Sore throat (%): 3 vs < 1 vs 2
Fair
Condemi et al. 199745RCT, DB, DD

291

24 weeks
US

Age ≥12, persistent asthma, on ICS, excluded smokers

Multicenter (24 outpatient centers)
FP DPI (500)
vs
TAA MDI (800)
vs
placebo
No (medium vs low)Overall AEs(%):15 vs 8 vs 13, P = 0.174

Withdrawals due to AEs:
4 vs 5 vs 8

Oral candidiasis- thrush (%):
8 vs 3 vs 1

Sore throat (%): 3 vs 1 vs 0

Headache (%): 1 vs 0 vs 2

Hoarseness (%): 3 vs 0 vs 0

Candidiasis, unspecified site (%):
2 vs 0 vs 0
Fair
Gross et al. 199846RCT, DB, DD

304

24 weeks
US

Age12, mild to moderate, on ICS, excluded smokers

Multicenter (24 respiratory care or allergy University Clinics)
FP DPI (500)
vs
TAA MDI (800)
vs
placebo
No (medium vs low)Overall AEs (%):
20 vs 5 vs 5, P < 0.001
FP vs TAA

Withdrawals due to AEs (%):
9 vs 7 vs 9

Oral candidiasis- thrush (%):
5 vs 0 vs 0

Sore throat (%): 3 vs 2 vs 2

Headache (%): 1 vs 1 vs2

Hoarseness (%): 3 vs 0 vs 0

Migraine(%): 2 vs 0 vs 0
Fair

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24.
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25.
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44.
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