Transcript Small Airway Inflammation

Targeting Large And Small Airway
Inflammation In Asthma
Ciclesonide – A Small Particle ICS
Presented by Takeda
1
Contents
•
•
•
•
•
•
Small Airway Inflammation
Slides 3 – 15
Targeting Small Airways
Slides 16 – 23
About Ciclesonide
Slides 24 – 33
Efficacy in Large and Small Airways
Slides 34 – 51
Clinical Data on Cortisol Suppression
Slides 52 – 54
Alvesco® EU SmPC
Slides 55 – 56
2
Small Airway Inflammation
3
The bronchial trees in the lungs contain large
and small airways
Conducting zone
First 16-17 branches
Transport air into smaller airways
Respiratory zone
Lower 6-7 branches
Sites of gaseous exchange
4
The majority of bronchial tree generations are
made up of small airways (<2mm diameter)
18
Large airways
16
Small airways
Diameter (mm)
14
12
10
8
6
4
2
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Airway Generation
Figure adapted from: Weibel ER. Morphometry of the Human Lung. 1963.
5
The small airways (<2 mm diameter) account
for ~98.9% of total lung volume1
Cross-sectional area (cm2)
104
103
Large airways
Small airways
Volume: 50mL
Volume: 4500mL
102
10
0
2
4
6
8
10
12
14
Airway generation
1. Virchow JC. Pneumologie 2009;63 Suppl 2:S96-101.
2. Figure adapted from: Weibel ER. Morphometry of the Human Lung. 1963.
16
18
20
23
6
Airflow and airway resistance
The rate of airflow through the lungs can be summarized as follows:
Rate of airflow = Pressure difference (between alveoli and atmosphere)
Resistance
Factors affecting airflow into and out of the lung include: lung compliance,
airway resistance, alveolar surface tension.
Airway resistance
• Affected by the size of the airways, smooth muscle contraction and any
condition that narrows or obstructs the airways
• Since the small airways account for only a small fraction of total airway
resistance, abnormalities in this lung region may not be readily detected
using routine pulmonary function testing.1
1. Wagner EM et al. Am Rev Respir Dis 1990;141:584-8.
7
Methods exist to measure small airway
function
• Abnormalities lead to small airway closure or near closure, causing
peripheral air trapping
• This may be assessed by several methods including:
–
–
–
–
–
Lung function tests (FEF25-75, and RV)
Impulse oscillometry
Alveolar eNO
HRCT
Nitrogen washout
Normal
Air trapping
FVC
FVC
RV
RV
FVC: forced vital capacity; RV: residual volume; CC: closing capacity; CV: closing volume; HRCT: high-resolution computed tomography
eNO: exhaled nitric oxide
Contoli M et al. Allergy 2010;65:141-151.
8
Inflammation is evident in the small airways
and brings about pathological changes1,2
Eosinophils (EG2)/mm2
200
Small
airways
100
An increased eosinophil count
has been observed in the small
airways of asthma patients2
Large
airways
*
n=16
0
>2
<2
Internal airway diameter (mm)
*p<0.05 vs. small airways
1. Contoli M et al. Allergy 2010;65:141-151.
2. Adapted from: Hamid Q, et al. J Allergy Clin Immunol 1997;100:44-51.
9
Small airway inflammation is associated with
several types of asthma
•
•
•
•
•
Nocturnal asthma1,2
Severe asthma3
Allergic asthma4,5
Mild asthma6,7
Exercise-induced asthma8
1. Kraft M, et al. Am J Respir Crit Care Med 1996;154:1505-10; 2. Kraft M, et al. Am J Respir Crit Care Med 2001;163:1551-6;
3. In ‘t Veen JC, et al. Am J Respir Crit Care Med 2000;161:1902-1906; 4. D’Amato G, et al. Eur Respir J 2002;20:763-776;
5. Zeidler MR, et al. J Allergy Clin Immunol 2006;118:1075-1081; 6. Wagner EM, et al. Am Rev Respir Dis 1990;141:584-8;
7. Hyde DM, et al. J Allergy Clin Immunol 2009;124:S72-7; 8. Kaminsky DA, et al. Am J Respir Crit Care Med 1995;152:1784-90.
10
Peripheral resistance relative to controls
(cm H2O/mL/min)
Peripheral resistance is increased in asthma
patients with nocturnal asthma
0.14
Peripheral resistance measured at 4am
*
0.12
0.1
Small airway dysfunction may
explain the increased
symptoms at night in patients
with nocturnal asthma
0.08
0.06
0.04
*
0.02
0
Non-nocturnal asthma
Nocturnal asthma
n=4
n=10
*p<0.05 between the groups
Adapted from: Kraft M, et al. Am J Respir Crit Care Med 2001;163:1551-6.
11
Higher closing volume/vital capacity ratio in patients
with severe asthma suggests small airways disease
200
Stable asthma (n=15)
Difficult-to-control asthma (n=15)
*
% predicted
150
159.5%
113.1%
100
92.9%
100.9%
98.8%
89.0%
50
0
FEV1
RV
CV/VC
*p=0.024 vs. stable asthma
RV: residual volume: CV: closing volume; VC: vital capacity; FEV1: forced expiratory volume in one second
Adapted from: In ‘t Veen JC, et al. Am J Respir Crit Care Med 2000;161:1902-1906.
12
Small size aeroallergens can trigger asthma in
the small airways
Fine particle aeroallergens can enter the smallest airways1–3
Allergen
Origin
Particle size
(µm)
Sub pollen particles
Pet
Rodent
Pet
Mold
Cockroach
Dust mite
Rag weed pollen
Secretions
Secretions, urine
Cat/dog dander
N/A
Secretions
Feces
0.5–4.5
1–5
1–15
2–15
5–10
5–35
5–35
Small size aeroallergens are fine enough to reach the smallest parts of the airways
Small size aeroallergens can reach the smallest airways and cause obstruction and
hyperresponsiveness1–4
1. Zeldin DC, et al. Environ Health Perspect 2006;114:620-6; 2. Bacsi A, et al. J Allergy Clin Immunol 2006;118:844-50;
3. Erwin EA, et al. Immunol Allergy Clin North Am 2003;23:469-481; 4. Zeidler MR, et al. J Allergy Clin Immunol 2006;118:1075-1081;
5. D’Amato G, et al. Eur Respir J 2002;20:763-776; 2.
13
Average peripheral resistance
(cm H2O/mL/min)
Peripheral resistance is significantly increased
even in mild asthma with normal lung function1
0.08
*
0.07
0.069
0.06
0.05
0.04
0.03
0.02
0.01
0
n=15
0.009
Healthy subjects
Patients with mild asthma
*p=0.013 vs. healthy subjects
1. Adapted from: Wagner EM, et al. Am Rev Respir Dis 1990;141:584-8.
2. Hyde DM, et al. J Allergy Clin Immunol 2009;124:S72-7.
14
Cool, dry air stimulation increases peripheral lung
resistance in patients with mild asthma1
Peripheral resistance
(cm H2O/L/sec)
0.3
0.2
*
0.19
0.1
NS
The recruitment of
small airways
determines the severity
of exercise-induced
bronchoconstriction2
0.09
0.07
0.05
0
Pre-challenge
n=14
Post-challenge
Healthy subjects
Pre-challenge Post-challenge
Patients with asthma
*p<0.01 vs. healthy subjects
NS: not significant
1. Adapted from: Kaminsky DA, et al. Am J Respir Crit Care Med 1995;152:1784-90.
2. Anderson SD, et al. Curr Opin Allergy Clin Immunol 2006;6:37-42.
15
Targeting Small Airways
16
Lung deposition depends on particle size and
inhaler type
Distribution of particles with a large particle inhaler
• Large particles are mainly deposited in the large airways, they are not distributed
to the small airways1
• Small particles have greater total lung and small airway deposition2,3
ICS: inhaled corticosteroid
1. Leach CL et al. Chest 2002;122:510-516.
2. Newman S et al. Respir Med 2006;100:375-384.
3. Usmani OS et al. Am J Respir Crit Care Med 2005;172:1497-504.
17
Large particles are more likely to be deposited in
the oropharynx than small particles
Large particles may
become deposited in the
oropharynx1
Smaller particles are
swept down into lungs with
laminar airflow2
ICS: inhaled corticosteroid
1. Martin RJ. J Allergy Clin Immunol 2002;109:S447-S460.
2. Newman S et al. Respir Med 2006;100:375-384.
18
MDIs are able to produce a high proportion of
small particles
Particle size distribution within the fine particle fraction*
FP
BUD
HFA suspension
pMDI
HFA suspension
pMDI
<1.1µm
1.1–3.1µm
3.1–5.0µm
>5µm
BDP
HFA solution
pMDI
Ciclesonide has a larger
proportion of fine particles
(≤5µm) than other ICSs
(% of label claim)1
CIC
HFA solution
pMDI
FP: fluticasone; BUD: budesonide; BDP: beclomethasone; CIC: ciclesonide; MDI: metered-dose inhaler
*30L/min flow rate
1. Adapted from: de Vries TW et al. Respir Med 2009;103:1167-1173.
19
Small particles achieve greater lung deposition and
small airway distribution than larger particles1-3
• Lung deposition of particles from a monodisperse β-agonist aerosol depends on
particle size3
Particle size:
6µm
3µm
1.5µm
Total lung deposition:
46%
51%
56.3%
34.3%
43.9%
Small airway distribution: 24.6%
1. Leach CL et al. Chest 2002;122:510-516.
2. Newman S et al. Respir Med 2006;100:375-384.
3. Usmani OS et al. Am J Respir Crit Care Med 2005;172:1497-504.
20
ICS particle size depends on formulation
Particle size of ICS medications,
Mass Median Aerodynamic Diameter (µm)
DPI1
5.4
• ICS formulations have
different particle sizes
DPI1
4.0
DPI2
3.7
HFA pMDI suspension3
• DPIs and HFA suspension
aerosol formulations
generally have larger
particles than HFA solution
aerosols
2.4
HFA pMDI solution4
1.1
1.1
Ciclesonide HFA solution5
DPI: dry powder inhaler; HFA: hydrofluoroalkane; pMDI: pressurized metered-dose inhaler; ICS: inhaled corticosteroid
1. Martin RJ. J Allergy Clin Immunol 2002;109:S447-S460.
2. Yang TT et al. J Aerosol Med 2001;14:487-494.
3. Cripps A et al. Respir Med 2000;94 Suppl B:S3-9.
4. Leach CL et al. Eur Respir J 1998;12:1346-53. 5. Leach CL et al, J Aerosol Med 2006;19:117-26.
21
Ciclesonide HFA solution pMDI has a small
particle size
• The small particle size allows high lung deposition of ciclesonide and
distribution to the small airways1
DPI: dry powder inhaler; HFA: hydrofluoroalkane; pMDI: pressurized metered-dose inhaler; ICS: inhaled corticosteroid
Leach CL et al. J Aerosol Med 2006;19:117-26.
22
Summary
•
•
•
•
•
ICSs should have a high lung deposition and a low
oropharyngeal deposition
Lung deposition depends on ICS formulation1-3
HFA-propelled solution aerosols (MDIs) provide higher lung
deposition than DPIs
Small particle sizes are able to reach the small airways,
resulting in high deposition2
Ciclesonide HFA solution pMDI has a small particle size
(~1.1µm MMAD), which leads to high lung deposition and
distribution to the small airways4
MMAD: mass median aerodynamic diameter; DPI: dry powder inhaler; ICS: inhaled corticosteroid; HFA: hydrofluoroalkane
1.
2.
3.
4.
Leach CL et al. Chest 2002;122:510-516.
Newman S et al. Respir Med 2006;100:375-384.
Usmani OS et al. Am J Respir Crit Care Med 2005;172:1497-504.
Leach CL et al. J Aerosol Med 2006;19:117-26.
23
About Ciclesonide
24
Ideal properties of an inhaled corticosteroid
(ICS)
For the treatment of asthma, an ICS should:1
•
•
•
•
•
•
Be able to enter and treat large and small airways
Have high receptor binding
Have high pulmonary deposition
Possess prolonged lung activity for once daily dosing
Improve pulmonary function and asthma control
Minimize local and systemic side effects
1. Zitt M. Allergy Asthma Proc 2005; 26:173–182.
25
Ciclesonide has a total lung deposition of 52%, of
which over half is distributed to the small airways
Gamma scintigraphic image of ICS deposition
Small airway deposition with a
small particle inhaler
HFA pMDI ciclesonide
Lung deposition: 52%1
Small airway distribution: 55%1*
HFA: hydrofluoroalkane; pMDI: pressurized MDI; ICS: inhaled corticosteroid
* Of total lung dose
1. Newman S et al. Respir Med 2006;100:375-384.
26
Ciclesonide is a pro-drug
• Ciclesonide is administered as a pro-drug, which has minimal glucocorticoid
activity until it is converted to its active form in the lungs1
• The active metabolite of ciclesonide, des-CIC, has a 100-fold higher GR
affinity than the parent compound 2-4
des-CIC: desisobutyryl-ciclesonide; GR: glucocorticoid receptor
1. Mutch E et al. Biochem Pharmacol 2007;73:1657-1664.
2. Derendorf H. Respir Med 1997;91(suppl A):22-28.
3. Valotis A, et al. J Pharm Sci 2004;93:1337-1350.
4. Dietzel K et al. Prog Respir Res 2001;31:91-93.
27
High lipophilicity prolongs the lung retention of
ciclesonide
Poorly lipophilic drug
Highly lipophilic drug
Extracellular
Plasma membrane
Intracellular
Lipophilic drugs have a high volume of distribution, good tissue penetration and a long duration of
action
Ciclesonide and des-CIC are highly lipophilic, allowing them to cross cell membranes where they
can bind with intracellular glucocorticoid receptors
des-CIC: desisobutyryl-ciclesonide
1. Nonaka T, et al. BMC Pharmacol 2007;7:12.
28
Lipid conjugation may prolong the therapeutic
activity of ciclesonide
In vitro metabolism of CIC in human lung slices
Ciclesonide
des-CIC
Fatty acid conjugates
• Fatty acid conjugates*
Recovered radioactivity (%)
70
can act as a slow-release
pool for the supply of
des-CIC in the lungs1
60
50
60
45.7
40
30
30.1
• Inhaled ciclesonide is
administered once-daily
(80 or 160µg dose)
29.2
20
20.7
10
4.1
0
2 hours
24 hours
des-CIC: desisobutyryl-ciclesonide; CIC: ciclesonide
*M4 metabolites, including palmitic or oleic acid
1. Adapted from: Nave R, et al. Biopharm Drug Dispos 2006; 27: 197–207.
29
Oral bioavailability of commonly used ICS
ICS
Oral bioavailability (%)
Ciclesonide
<1
Fluticasone propionate
<1
Beclomethasone propionate
41
Budesonide
11
Mometasone furoate
<1
• Ciclesonide has low oral bioavailability due to high first pass metabolism1
1. Nave R et al. Clin Pharmacokinet 2004;43:479-486.
2. Affrime MB et al. J Clin Pharmacol 2000;40:1227-1236.
3. Ryrfeldt A et al. Eur J Respir Dis 1982;122(suppl):86-95.
4. Rohatagi S et al. J Clin Pharmacol 1996;36:938-941.
5. Martin LE et al. Postgrad Med J 1975;51:11-20.
30
Unbound drug fractions of common inhaled
corticosteroids1-5
Fraction unbound (%)
25
20
15
12%
10
13%
10%
5
1%
1%
1%
0
CIC
des-CIC MOM
FP
BUD
BDP
• Protein-binding ensures that only 1% of ciclesonide is unbound in the systemic
circulation5
• Only the unbound fraction can exert unwanted systemic pharmacological effects
CIC: ciclesonide; des-CIC: desisobutyryl ciclesonide; MOM: mometasone furoate; FP: fluticasone; BUD: budesonide; BDP: beclomethasone
1. Affrime MB et al. J Clin Pharmacol 2000;40:1227-1236.
2. Ryrfeldt A et al. Eur J Respir Dis 1982;122(suppl):86-95.
3. Rohatagi S et al. J Clin Pharmacol 1996;36:938-941.
4. Martin LE et al. Postgrad Med J 1975;51:11-20. 5. Nave R et al. Clin Pharmacokinet 2004;43:479-486.
31
The fate of inhaled ciclesonide
32
Ciclesonide has a unique pharmacological
profile1
GR: glucocorticoid receptor
1.Derendorf H. J Clin Pharmacol 2007;47:782-789
2.Newman S, et al. Respir Med 2006;100:375-384
3.Richter K, et al. J Clin Pharmacol 2005;45:146-152
4.Nonaka T, et al. BMC Pharmacol 2007;7:12
5.Mutch E, et al. Biochem Pharmacol 2007;73:1657-1664
6.Nave R, et al. Clin Pharmacokinet 2004;43:479-486
7.Stoeck M, et al. J Pharmacol Exp Ther 2004;309:249-258
8.Rohatagi S, et al. Am J Ther 2005;12:385-397
9.Nave R, et al. Pulm Pharmacol Ther 2005; 18:390-396
10.Alvesco® EU SmPC
33
Efficacy in Large and Small Airways
34
A 4-week study of the effects of ciclesonide on
the small airways
Pre-baseline
4 weeks
Baseline
2–3 weeks
Treatment
5–6 weeks
1–2 weeks
Ciclesonide 320µg OD
No ICS
Placebo
Double-blind, randomized, placebo-controlled, parallel-group trial
OD: once-daily
Cohen J et al. Eur Respir J 2008;31:1213–1220.
35
Ciclesonide significantly reduces alveolar eNO
after 5–6 weeks of treatment
Change in alveolar eNO (ppb)
2
1.8
0
Placebo
-2
-4
-6
-8
-8.8
-10
*
Ciclesonide
320µg OD
n=16
*p<0.05 vs. placebo and vs. baseline
Data are presented as median
eNO: exhaled nitric oxide; ppb: parts per billion; OD: once-daily
Adapted from: Cohen J et al. Eur Respir J 2008;31:213–1220.
36
Comparison of ciclesonide and fluticasone
propionate on small airway function
Baseline period
Treatment period
8 weeks
8 weeks
Ciclesonide 200μg OD
Fluticasone 100μg BID
Fluticasone 100μg BID
Randomized, open-label, parallel group study with a treatment period of 8 weeks to compare the effectiveness of
a small particle ICS (ciclesonide) and a large particle ICS (fluticasone DPI) on small airway function
Fluticasone propionate *DPI: particle size 5.4µm diameter
Ciclesonide HFA: particle size of 1.1µm diameter
OD: once-daily; BID: twice-daily; ICS: inhaled corticosteroid; DPI: dry powder inhaler
Hoshino M. Allergol Int 2010;59:59-66.
37
14
-43%
12
NS
12.2%
10
(%)
Eosinophils in late-phase sputum
Ciclesonide significantly reduces eosinophils in latephase sputum compared with fluticasone propionate
8
*
6.9%
6
4
2
n=30
0
Before
After
Ciclesonide
200µg OD
Before
After
Fluticasone propionate
100µg BID
The percentage of early-phase sputum eosinophils remained unchanged in both groups
Data are presented as mean values
*p<0.01 versus baseline
Adapted from: Hoshino M. Allergol Int 2010;59:59-66.
38
Ciclesonide significantly improves Asthma Control
Test™ (ACT) scores compared to fluticasone
propionate
Change in ACT score vs. baseline
2.5
2
*
1.5
1
0.5
NS
0
-0.5
Ciclesonide
200µg OD
-1
Fluticasone propionate
100µg BID
n=30
Data are presented as mean ± SD
*p<0.05 vs. baseline
ACT: Asthma Control Test™; NS: not significant; OD: once-daily; BID: twice-daily
Adapted from: Hoshino M. Allergol Int 2010;59:59-66.
39
Small airway resistance (kPa/L/s)
Ciclesonide reduces small airway resistance
0.01
NS
0
Fluticasone propionate
100µg BID
-0.01
-0.02
-0.02
-0.03
*
Ciclesonide
200µg OD
n=30
R5–R20 as a marker of small airway resistance
Data are presented as means; *p<0.05 vs. baseline
NS: not significant; OD: once-daily; BID: twice-daily
Adapted from: Hoshino M. Allergol Int 2010;59:59-66.
40
Comparison of ciclesonide and fluticasone
propionate on eNO in mild allergic asthma patients
Baseline
Treatment
1–4 weeks
12 weeks
Ciclesonide 80µg OD
Ciclesonide 160µg OD
Salbutamol
as needed
Fluticasone 100µg BID
OD: once-daily; BID: twice-daily; ICS: inhaled corticosteroid; DPI: dry powder inhaler; eNO: exhaled nitric oxide
Zietkowski Z et al. Respir Med 2006;100:1651-1656.
41
Once-daily ciclesonide achieves a greater reduction
in eNO than twice-daily fluticasone propionate
2 weeks
4 weeks
8 weeks
12 weeks
eNO reduction from baseline (%)
0
-10
-20
-30
-40
*
*
-50
FP 200µg BID
*
*
*
*
-60
-70
* CIC 80µg OD
*
CIC 160µg OD
n=35
eNO: exhaled nitric oxide; OD: once-daily; BID: twice-daily; FP: fluticasone propionate
*p<0.05 vs. fluticasone propionate
Adapted from: Zietkowski Z et al. Respir Med 2006;100:1651-1656.
42
Comparison of ciclesonide and fluticasone
propionate in patients with moderate asthma
Baseline period
1–4 weeks
Treatment period
12 weeks
Ciclesonide 320µg OD
Rescue medication or
fluticasone ≤ 250μg/day
or equivalent
Fluticasone 200µg BID
OD: once-daily; BID: twice-daily
International, multicenter, randomized, open-label, parallel group study with a treatment period of 12 weeks
Boulet LP et al. Respir Med 2007;101:1677-1686.
Follow up
If required
Ciclesonide provides equivalent asthma
control to fluticasone propionate
100
90
80
88%
88%
89%
88%
Days (%)
70
85%
84%
60
50
Ciclesonide 320μg OD
40
Fluticasone 200μg BID
30
n=474
20
10
0
Asthma
symptom-free
days
Rescue
medication-free
days
Asthma symptom
and rescue
medication-free
days
OD: once-daily; BID: twice-daily
Reproduced from Respiratory Medicine, vol. 101, Boulet LP, et al. A randomized study comparing ciclesonide and fluticasone propionate in patients with
moderate persistent asthma, 1677-1686, Copyright (2007), with permission from Elsevier.
44
Ciclesonide significantly improves quality of
life in patients with moderate asthma
Quality of life net benefit (%)
25
*
20
21.2%
15
10
5
6.8%
n=474
0
Ciclesonide
320μg OD
Fluticasone
200μg BID
*p=0.005 vs. fluticasone propionate; OD: once-daily; BID: twice-daily
The net benefit in health-related quality of life was calculated as the proportion of patients with an increase of at least 0.5 in the overall AQLQ(S) score
(improvement) minus the proportion of patients with a decrease of at least 0.5 in the overall AQLQ(S)score (deterioration).
Reproduced from Respiratory Medicine, vol. 101, Boulet LP, et al. A randomized study comparing ciclesonide and fluticasone propionate in patients with
moderate persistent asthma, 1677-1686, Copyright (2007), with permission from Elsevier.
45
A 24-week comparison of low-dose ciclesonide and
fluticasone propionate in mild-to-moderate asthma
Baseline period
2–4 weeks
Treatment period
24 weeks
Ciclesonide 80μg OD
Rescue medication only
inhaled salbutamol
100 µg/puff
Fluticasone 100μg BID
OD: once-daily; BID: twice-daily
Study medications were administered via HFA-MDI
No spacer was used, but inhalation technique was reviewed at each visit during the treatment period
Dahl R et al. Respir Med 2010;104:1121-1130.
Change in FEV1 vs. baseline after
24 weeks (L)
Ciclesonide 80µg OD is as effective as fluticasone
propionate 100µg BID in improving FEV1
0.6
0.5
0.4
**
*
0.5
0.46
0.3
0.2
0.1
n=479
0
Ciclesonide
80µg OD
Fluticasone propionate HFA
100µg BID
*p<0.0001 vs. baseline; **p<0.0001 vs. baseline
OD: once-daily; BID: twice-daily; FEV1: forced expiratory volume in one second
Ciclesonide was shown to be non-inferior to fluticasone propionate (p<0.0001)
Adapted from: Dahl R et al. Respir Med 2010;104:1121-1130.
47
Comparison of ciclesonide and fluticasone
propionate BID in patients with moderate-to-severe
asthma
Baseline period
2 weeks
Treatment period
24 weeks
Follow up
if required
Ciclesonide 320µg BID
Fluticasone
500–1000 μg/day
or equivalent
Fluticasone 330µg BID
International, multicenter, randomized, open-label, parallel group study with a treatment period of 24 weeks. Study medication was provided as HFA -MDI.
Salbutamol was used as rescue medication. Use of long-acting β2-agonists (LABAs), oral β2-agonists, theophylline, leukotriene antagonists or lipoxygenase
inhibitors was allowed if the dosage was kept constant throughout the trial
Bateman ED et al. Pulm Pharmacol Ther 2008;21:264-275.
Percentage of patients
Ciclesonide exhibits fewer oropharyngeal
events than fluticasone propionate
14
Total oropharyngeal adverse events
12
-60%
12.8%
10
8
6
*
4
5.1%
2
n=528
0
Ciclesonide
320µg BID
Fluticasone propionate
375µg BID
BID: twice-daily
*p<0.01 vs. fluticasone propionate
Reprinted from Pulmonary Pharmacology Therapy, vol. 21, Bateman ED, et al. Comparison of twice-daily inhaled ciclesonide and fluticasone propionate in
patients with moderate-to-severe persistent asthma, 264-275, Copyright (2008) with permission from Elsevier.
49
Evaluation of the potential of ciclesonide to reduce
oral corticosteroids in patients with severe asthma
Treatment period
Ciclesonide 640µg BID
Ciclesonide 320µg BID
Placebo
Visit 1
Visit 2
Visit 3
Visits 4 to 15
Weeks 1-12
Baseline
Pre-Screening
Screening
Randomization
BID: twice-daily
International, multicenter, randomized, double-blind, placebo-controlled, parallel group study with a treatment period of 12 weeks
Prior to randomization, the lowest effective dose of prednisone was established for each patient
Bateman ED et al. Chest 2006;129:1176–1187.
Ciclesonide significantly reduces the need for oral
corticosteroids in patients with severe, persistent
asthma
Mean change in prednisone dose from
baseline to study end (12 weeks)
Placebo
CIC 640µg
CIC 320µg
•
+4%
•
-47%
Patients using ciclesonide
were able to reduce the dose
of oral steroid needed to
control their asthma by up to
63%
In contrast, patients on
placebo required a mean 4%
increase in oral steroid dose
*
-63%
n=141
**
*p=0.0003 vs. placebo; **p=0.0001 vs. placebo
Adapted from: Bateman ED et al. Chest 2006;129:1176–1187.
51
Clinical Data on Cortisol Suppression
52
Comparison of ciclesonide and fluticasone
propionate on cortisol secretion and AHR
Run in
(up to 3 weeks)
T1
Wash out
(at least 3 weeks)
T2
T3
T4
Follow up
(if required)
T5
T6
Treatments 1–6 (duration of each: 9 days)
Placebo
Ciclesonide
320μg OD
Ciclesonide
640μg OD
Ciclesonide
640μg BID
Fluticasone propionate
440μg BID
Fluticasone propionate
880μg BID
Randomized, double blind, placebo-controlled, double-dummy, 6-period crossover study
Fluticasone was administered via CFC-MDI
OD: once-daily; BID: twice-daily; AHR: airway hyperresponsiveness
Derom E et al. Pulm Pharmacol Ther 2005;18:328-336.
53
Ciclesonide does not significantly affect
cortisol secretion
OD
CIC 320µg
CIC 640µg
BID
CIC 640µg
FP 440µg
FP 880µg
Urinary cortisol level relative to placebo
over 24 hours (nmol/mmol creatinine)
0
n=26
-2
-4
-6
-8
*
-10
-12
*
-14
Data are presented as means. *p=0.0001 vs. placebo.
OD: once-daily; BID: twice-daily
Adapted from: Derom E et al. Pulm Pharmacol Ther 2005;18:328-336.
54
Alvesco® EU SmPC
Alvesco 80 and 160 micrograms pressurised inhalation, solution
ABBREVIATED PRESCRIBING INFORMATION. For more information, please, refer to Summary of Product
Characteristics (SPC) of last revision 18 May 2011 Presentation: Alvesco 80 and 160 micrograms pressurised
inhalation, solution. Each actuation (delivered dose from the mouthpiece) delivers a pressurised inhalation solution
containing either 160 micrograms or 80 micrograms of the active ingredient ciclesonide. The inhalation solution also
contains norflurane (HFA-134a) and ethanol, anhydrous. Therapeutic indications: Treatment to control persistent
asthma in adults and adolescents (12 years and older). Posology and method of administration: The medicinal
product is for inhalation use only. The recommended dose of Alvesco is 160 micrograms once daily, which leads to
asthma control in the majority of patients. However in severe asthmatics, a 12 week study has shown that a dose of
640 micrograms/day (given 320 micrograms twice daily)has demonstrated a reduction in the frequency of
exacerbations but without an improvement in lung function (for more information, see full SPC section 5.1). Dose
reduction to 80 micrograms once daily may be an effective maintenance dose for some patients. Alvesco should
preferably be administered in the evening although morning dosing of Alvesco has also been shown to be effective. The
final decision on evening or morning dosing should be left to the discretion of the physician. Symptoms start to improve
with Alvesco within 24 hours of treatment. Once control is achieved, the dose of Alvesco should be individualised and
titrated to the minimum dose needed to maintain good asthma control. Contraindications: Hypersensitivity to
ciclesonide or any of the excipients. Special warnings and precautions for use: As with all inhaled corticosteroids,
Alvesco should be administered with caution in patients with active or quiescent pulmonary tuberculosis, fungal, viral or
bacterial infections, and only if these patients are adequately treated. As with all inhaled corticosteroids, Alvesco is not
indicated in the treatment of status asthmaticus or other acute episodes of asthma where intensive measures are
required. Alvesco is not designed to relieve acute asthma symptoms for which an inhaled short-acting bronchodilator is
required. Patients should be advised to have such rescue medication available.
55
Alvesco® EU SmPC (cont.)
Systemic Effects: Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged
periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include adrenal
suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma, and more
rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or
aggression (particularly in children). Patients with severe hepatic impairment should be monitored for potential systemic effects.
Interactions: Concomitant administration of potent inhibitors of CYP 3A4 (e.g. ketoconazole, itraconazole and ritonavir or
nelfinavir) should be avoided unless the benefit outweighs the increased risk of systemic side effects of corticosteroids.
Undesirable effects: Approximately 5% of patients experienced adverse reactions in clinical trials with Alvesco given in the dose
range 40 to 1280 micrograms per day. In the majority of cases, these were mild and did not require discontinuation of treatment
with Alvesco. Uncommon effects: nausea, vomiting, bad taste, application site reactions, application site dryness, oral fungal
infections, headache, dysphonia, cough after inhalation, paradoxical bronchospasm, eczema and rash. Rare effects: palpitations,
abdominal pain, dyspepsia, angioedema, hypersensitivity, hypertension. Other effects (unknown frequency): psychomotor
hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural changes (predominantly in children). Paradoxical
bronchospasm may occur immediately after dosing and is an unspecific acute reaction to all inhaled medicinal products. Systemic
effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. Effects on ability to
drive and use machines: Inhaled ciclesonide has no or negligible influence on the ability to drive and use machines. Pregnancy
and lactation: As with other inhaled glucocorticoids, ciclesonide should only be used during pregnancy or lactation if the potential
benefit to the mother justifies the potential risk to the mother, fetus or child. The lowest effective dose of ciclesonide needed to
maintain adequate asthma control should be used. Marketing authorisation holder: Nycomed GmbH, Byk-Gulden-Str. 2, D78467 Konstanz, Germany. Price and packages: For more information about prices and packages please contact the local
Nycomed organization in your country. Legal Category: Prescription Only Medicine.
56