Leonardo M. Fabbri Leonardo M. Fabbri fabbri.leonardo@unimo fabbri.leonardo@unimo .it .it 12th Annual Congress of the 12th Annual Congress of the Turkish Thoracic Society Turkish Thoracic Society Antalya Antalya 8 8 -12 April 2009 -12 April 2009 Sungate Sungate Port Royal Port Royal Beldibi, Antalya Beldibi, Antalya 9 April 2009 9 April 2009 Combination Combination Therapy in Asthma Therapy in Asthma http//pneumologia.unimo.it http//pneumologia.unimo.it
12th Annual Congress of the Turkish Thoracic Society Antalya 8 -12 April 2009. http//pneumologia.unimo.it. Sungate Port Royal Beldibi, Antalya 9 April 2009. Combination Therapy in Asthma. Leonardo M. Fabbri [email protected]. - PowerPoint PPT Presentation
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Combination with higher Combination with higher doses inhaled corticosteroids, doses inhaled corticosteroids, theophylline, antileukotrienestheophylline, antileukotrienes
Avoidance of risk factors, immunotherapyAvoidance of risk factors, immunotherapyFast-acting beta-2 agonists as neededFast-acting beta-2 agonists as needed
BDP/FF vs separate componentsBDP/FF vs separate components• 6-month study6-month study
– BDP/FF vs. BDP + FF in separate inhalers vs. BDP BDP/FF vs. BDP + FF in separate inhalers vs. BDP alonealone
• 3-month study3-month study– BDP/FF vs. BDP aloneBDP/FF vs. BDP alone
BDP/FF vs available ICS/LABA fixed combinationsBDP/FF vs available ICS/LABA fixed combinations• 3-month studies3-month studies
– BDP/FF Vs. Budesonide/formoterolBDP/FF Vs. Budesonide/formoterol– BDP/FF vs. Fluticasone/salmeterolBDP/FF vs. Fluticasone/salmeterol
ObjectivObjectivee
• Clinical equivalence of BDP/FF fixed Clinical equivalence of BDP/FF fixed combination vs BDP CFC 250 μgcombination vs BDP CFC 250 μg + + fformoterol 12 μg ormoterol 12 μg in in separate inhalersseparate inhalers
• Superiority of BDP/FF fixed combination vs Superiority of BDP/FF fixed combination vs BDP CFC 250 μg aloneBDP CFC 250 μg alone
BDP/FF BDP/FF eextrafine combinationxtrafine combinationttotal daily dose of 400 µg extra fine BDP otal daily dose of 400 µg extra fine BDP and and 24 µg formoterol24 µg formoterol
BDP/FF extrafine combination versus the separate BDP/FF extrafine combination versus the separate components and BDP CFC non extrafinecomponents and BDP CFC non extrafine
2-weeks 2-weeks RUN INRUN IN
6 6 MONTHSMONTHS
BDP/FF BDP/FF extrafine combination extrafine combination shows similar shows similar improvement in morning PEF (PRIMARY ENDPOINT) improvement in morning PEF (PRIMARY ENDPOINT) compared to the separate components, and a better compared to the separate components, and a better
outcome compared to BDP aloneoutcome compared to BDP alone
*p<0.001 vs baseline*p<0.001 vs baselineNS between treatmentsNS between treatments##
BDP/FF BDP/FF extrafine combination extrafine combination was significantly superior to the separate components and to was significantly superior to the separate components and to BDP monotherapy with relation to clinical measures of asthma controlBDP monotherapy with relation to clinical measures of asthma control
N. of severe N. of severe exacerbationsexacerbations
BDP/FF extrafine combination demonstrated to be effective in reducing asthma BDP/FF extrafine combination demonstrated to be effective in reducing asthma exacerbationexacerbationss
1.331.33**
1.61.6
2.022.02
N. of overall N. of overall exacerbationsexacerbations
BDP/FFBDP/FF extrafine combination: lack of cortisol suppression extrafine combination: lack of cortisol suppression
BDP 1000 µg CFCBDP 1000 µg CFC
-150-150
-100-100
-50-50
00
5050
100100
150150
200200
-200-200
Morning Serum Cortisol Morning Serum Cortisol (nmol/L)(nmol/L)Changes from Baseline Changes from Baseline to week 24to week 24
--Means and 95% CIMeans and 95% CI--
Mor
ning
Ser
um C
ortis
ol
Mor
ning
Ser
um C
ortis
ol (n
mol
/L)
(nm
ol/L
)C
hang
es fr
om B
asel
ine
Cha
nges
from
Bas
elin
e to
wee
k 24
to w
eek
24
**
Similar improvement in morning PEF and FEVSimilar improvement in morning PEF and FEV11, , compared to the single drugs administered compared to the single drugs administered separately and superiority of BDP/FF fixed separately and superiority of BDP/FF fixed combination versus BDP CFC monotherapy on the combination versus BDP CFC monotherapy on the same parameterssame parameters
Superiority of BDP/FF fixed combination compared Superiority of BDP/FF fixed combination compared to BDP monotherapy, with relation to to BDP monotherapy, with relation to exacerbation frequencyexacerbation frequency
Lack of cortisol suppression with BDF/FF as a Lack of cortisol suppression with BDF/FF as a consequence of a reduced steroid exposureconsequence of a reduced steroid exposure
Superiority in some parameters of 1 vs 2 inhalersSuperiority in some parameters of 1 vs 2 inhalers
BDP/FF extrafine combination versus the separate BDP/FF extrafine combination versus the separate components and BDP CFC non extrafinecomponents and BDP CFC non extrafine
•Randomized, double blind, double dummy, Randomized, double blind, double dummy, multinational, parallel-group design study multinational, parallel-group design study comparing comparing
BDP/FF extrafine combination with BDP/FF extrafine combination with budesonide/formoterol in a 3 months treatmentbudesonide/formoterol in a 3 months treatment
of moderate to severe asthmatic patientsof moderate to severe asthmatic patients
ICAT SY. ICAT SY. BDP/FF extrafine combination vs. budesonide/formoterol combinationBDP/FF extrafine combination vs. budesonide/formoterol combination
216 moderate-to-severe asthmatic patients216 moderate-to-severe asthmatic patients ICS at entry: ICS at entry: 1000 1000 µgµg BDP or equivalent BDP or equivalent Mean FEVMean FEV11 at baseline (% predicted normal) : 69.3%-70.5% at baseline (% predicted normal) : 69.3%-70.5%
*p<0,001 vs baseline*p<0,001 vs baselineNSNS between treatments between treatments
00S
ympt
om s
core
Sym
ptom
sco
re
0.50.5
2.02.0
WeeksWeeks
BaselineBaseline 44 88 1212
1.51.5
1.01.0
**** ** ** ** **
**** **
****
**
ICAT SY. ICAT SY. Asthma symptom score Asthma symptom score Comparable effects of BDP/FF extrafine combination vs budesonide/formoterol Comparable effects of BDP/FF extrafine combination vs budesonide/formoterol
at day and night-timeat day and night-time
##
##
##
– BDP/FF extrafine combination improves lung function BDP/FF extrafine combination improves lung function similarly to budesonide/formoterol with half the dose similarly to budesonide/formoterol with half the dose of inhaled corticosteroidof inhaled corticosteroid
– BDP/FF extrafine combination demonstrated to be not BDP/FF extrafine combination demonstrated to be not significantly different from budesonide/formoterol also significantly different from budesonide/formoterol also in terms of asthma symptoms reduction and in terms of asthma symptoms reduction and exacerbation rateexacerbation rate
SummarySummary
ICAT SY. ICAT SY. BDP/FF extrafine combination vs. budesonide/formoterol combinationBDP/FF extrafine combination vs. budesonide/formoterol combination
•Randomized, double blind, double masking, Randomized, double blind, double masking, multinational, parallel-group design study multinational, parallel-group design study comparing comparing
BDP/FF extrafine combination with BDP/FF extrafine combination with fluticasone/salmeterol in the 3 months treatment fluticasone/salmeterol in the 3 months treatment
of moderate to severe asthmatic patientsof moderate to severe asthmatic patients
216 moderate-to-severe asthmatic patients216 moderate-to-severe asthmatic patients ICS at entry: ICS at entry: 1000 1000 µgµg BDP or equivalent BDP or equivalent Mean FEVMean FEV11 at baseline (% predicted normal) : 66.9%-67.6% at baseline (% predicted normal) : 66.9%-67.6%
*p<0,001 vs baseline*p<0,001 vs baselineNSNS between treatments between treatments
####
##
ICAT SE. ICAT SE. BDP/FF extrafine combination versus fluticasone/salmeterol BDP/FF extrafine combination versus fluticasone/salmeterol
combinationcombination
BDP/FF extrafine combination is equivalent to BDP/FF extrafine combination is equivalent to fluticasone/salmeterol in terms of lung function fluticasone/salmeterol in terms of lung function improvementimprovement
BDP/FF extrafine combination provides a more BDP/FF extrafine combination provides a more rapid bronchodilation in the first hour post rapid bronchodilation in the first hour post dosingdosing
SummarySummary
Estimate Comparative Daily Dosages for Inhaled Glucocorticosteroids Age > 5y
Drug Low Daily Dose Medium Daily Dose High Daily Dose (g) (g) (g)
Beclomethasone-CFC
200-500 500-1000 >1000
Beclomethasone-HFA
100-250 250-500 >500
Budesonide-DPI 200-600 600-1000 >1000
Fluticasone 100-250 250-500 >500
GINA, 2005GINA, 2005 EPR3, 2007EPR3, 2007
GINA Guidelines 2008 www.ginasthma.org
Run-in
SMILE: Study Design
Formoterol/Budesonide + Terbutaline 0.4 mg as reliever n=1141
Formoterol/Budesonide + Formoterol 4.5 µg as reliever n=1140
Formoterol/Budesonide + Formoterol/Budesonide 160/4.5 µg as reliever (SMART) n=1113
Visit: 1 2 3 4 5 6Month: -0.5 0 1 4 8 12
(All patients received Form/Bude 160/4.5 µg bid both during run-in and following Randomisation)
Form/Bude + Terbutaline as reliever R
Enrolled: n=3829
Randomised: n=3394
Rabe KF et al, Lancet. 2006 Aug 26;368(9537):744-53
BDP/FF 1 puff bidBDP/FF 1 puff bid+ SABA prn+ SABA prn
Non fully controlledNon fully controlled
ICS ICS >> 1000 µg 1000 µg
BDP BDP ICS + LABA ICS + LABA
>> 500 µg 500 µg BDP BDP
Study Design: Randomized, Double-Blind, Active Control, Parallel Assignment, Safety/Efficacy Study Study Design: Randomized, Double-Blind, Active Control, Parallel Assignment, Safety/Efficacy Study
Primary Outcome Measures: Number of COPD exacerbations and pre-dose morning FEV1Primary Outcome Measures: Number of COPD exacerbations and pre-dose morning FEV1