Leonardo M. Fabbri [email protected]

Leonardo M. FabbriLeonardo M. Fabbri

[email protected]@unimo.it

12th Annual Congress of the 12th Annual Congress of the Turkish Thoracic SocietyTurkish Thoracic Society

Antalya Antalya 88-12 April 2009-12 April 2009

SungateSungatePort RoyalPort Royal

Beldibi, AntalyaBeldibi, Antalya

9 April 20099 April 2009

Combination Combination Therapy in Asthma Therapy in Asthma

http//pneumologia.unimo.ithttp//pneumologia.unimo.it

http://www.policlinico.mo.it/index.htm

EUROPEAN RESPIRATORY SOCIETYYEAR OF THE LUNG 2009-2010

Shaping the Future of Respiratory Medicine in Europe

Leonardo M. FabbriERS Past-President

[email protected]

Berlin 2008 - RegistrationPlease refer to pages 29 -30 of the Guidelines for detailed

figures

19’356 participantsBiggest Respiratory Congress in the World

Berlin 2008 - Audience

Germany 1’685Italy 1’428United Kingdom

1’397

France 1’170Spain 921Greece 635Netherlands 591United States 588Turkey 566Switzerland 496Sweden 478Belgium 370Russia 356

Brazil 342Denmark 303Japan 298Austria 295Norway 267Poland 263Portugal 262Czech Republic 260India 260Canada 238Romania 210Australia 182China 169

Congress attendance – Top 26 countries

ERS Annual Congress

YearNo of Turkish Participants

2008 566

2007 554

2006 614

ERS Membership

no. of members

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

2001 2002 2003 2004 2005 2006 2007 2008

no. of members

Turkish Members

March Members

2009 2922008 3782007 367*2006 128

* Introduction of the Joint Membership











Persistent asthma may not require regular treatment

Definition of control requires revision

Role of asthmatic inflammation and its suppression remains to be established

LABA/ICS combination for mantainance and reliever therapy is the most effective treatment of

persistent asthma

COMBINATION THERAPY IN COMBINATION THERAPY IN ASTHMAASTHMA

Leonardo M. Fabbri

Management of asthma in untreated Management of asthma in untreated patients, GINA guidelines, 2008patients, GINA guidelines, 2008

Systemic steroidsSystemic steroidsAnti-IgEAnti-IgE

Ast

h ma

sev e

rity

Ast

h ma

sev e

rity

Clin

ical

Fe a

ture

s B

e for

e T r

eatm

ent MildMild

IntermittentIntermittent

Mild Mild PersistentPersistent

Moderate Moderate PersistentPersistent

ModerateModeratePersistentPersistent(Severe?)(Severe?)SevereSevere

PersistentPersistent(Very severe?)(Very severe?)

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

Low-dose inhaled steroidsLow-dose inhaled steroids

Combination of long-acting beta2 Combination of long-acting beta2 agonists with low dose inhaled agonists with low dose inhaled steroidssteroids

GINA Guidelines 2008 www.ginasthma.org

controlled

partly controlled

uncontrolled

exacerbation

LEVEL OF CONTROLLEVEL OF CONTROL

maintain and find lowest controlling step

consider stepping up to gain control

step up until controlled

treat as exacerbation

TREATMENT OF ACTIONTREATMENT OF ACTION

TREATMENT STEPSREDUCE INCREASE

STEP1

STEP2

STEP3

STEP4

STEP5

RED

UC

EIN

CR

EASE

Levels of Asthma Control

Characteristic Controlled Partly controlled(Any present in any week) Uncontrolled

Daytime symptoms None (2 or less / week)

More than twice / week

3 or more features of partly controlled asthma present in any week

Limitations of activities None Any

Nocturnal symptoms / awakening None Any

Need for rescue / “reliever” treatment

None (2 or less / week)

More than twice / week

Lung function (PEF or FEV1)

Normal< 80% predicted or

personal best (if known) on any day

Exacerbation None One or more / year 1 in any week


0

2

4

6

Pre-BD 6 wk

Effects of Inhaled BeclomethasoneEffects of Inhaled BeclomethasoneDipropionate in Clinical AsthmaDipropionate in Clinical Asthma

Bronchial FunctionBronchial Function Bronchial SubmucosaBronchial SubmucosaAsthmaticsymptoms

Seve

rity

0,01

0,1

1

10

100

Pre-BD 6 wk

PC20 methacholine

(mg/ml)m

g/m

l

num

ber o

f cel

ls/m

m2 o

f sub

muc

osa eosinophilsT lymphocytesmast cells

04080

120160200240

720760

Pre-BD6 wk Pre-BD6 wk Pre-BD6 wk

Djukanovic et al, Am Rev Respir Dis 1992 Mar;145(3):669-74

RESCUE USE OF BECLOMETHASONE AND ALBUTEROL

IN A SINGLE INHALER FOR MILD ASTHMA

Papi et al, N Engl J Med 356; 2040-2052 (May 17, 2007)

In patients with mild asthma, the symptom-driven use of inhaled beclomethasone/albuterol

combination in a single inhaler is as effective as regular use of inhaled beclomethasone and is associated with a lower 6-month cumulative

dose of the inhaled corticosteroid

Papi A et al. N Engl J Med 2007;356:2040-52Papi A et al. N Engl J Med 2007;356:2040-52

Study designStudy design

Twice daily inhaled placebo plus Twice daily inhaled placebo plus p.r.n. inhaled 250µg beclomethasone/100 µg salbutamol combinationp.r.n. inhaled 250µg beclomethasone/100 µg salbutamol combination

Twice daily inhaled placebo plusTwice daily inhaled placebo plusp.r.n. inhaled 100 µg salbutamolp.r.n. inhaled 100 µg salbutamol

Twice daily inhaled 250 µg beclomethasone/100 µg salbutamol combination Twice daily inhaled 250 µg beclomethasone/100 µg salbutamol combination plusplus

p.r.n. inhaled 100 µg salbutamolp.r.n. inhaled 100 µg salbutamol

Twice daily inhaled 250 µg beclomethasone plusTwice daily inhaled 250 µg beclomethasone plusp.r.n. 100 µg salbutamolp.r.n. 100 µg salbutamol

BeclomethasoneBeclomethasone(500µg/day)(500µg/day)

Visit 1Visit 1(screening)(screening)

Visit 2Visit 2(randomization)(randomization)

Visit 3Visit 3 Visit 4Visit 4 Visit 5Visit 5 Visit 6Visit 6 Visit 7Visit 7 Visit 8Visit 8(end of (end of

treatment)treatment)

6-month Treatment Period6-month Treatment Period

4-Week Run-in Period4-Week Run-in Period


** * *

360

380

400

420

440

460

prn BDP/S prn S regular BDP regular BDP/S

Baseline Weeks 5-6 Weeks 11-12 Weeks 17-18 Weeks 22-24

Mor

ning

PEF

(lite

rs/m

in)

Missing Values Replaced with the Use of LOCFMissing Values Replaced with the Use of LOCF


0

0,5

1

1,5

2

As neededcombination

As neededalbuterol

Regularbeclomethasone

Regularcombination

Num

ber o

f exa

cerb

atio

ns p

er p

atie

nts/

year


EFFECT OF EXACERBATIONSEFFECT OF EXACERBATIONS


0

20

40

60

80

100

prn BDP/S prn S regular BDP regularBDP/S

****

mg

CUMULATIVE DOSE OF BECLOMETHASONE CUMULATIVE DOSE OF BECLOMETHASONE (BDP)(BDP)

REGULAR VERSUS PRN NEBULISED TREATMENT FOR PRESCHOOL WHEEZE

CHILDREN

Papi et al, submitted, 2008

0

10

20

30

40

50

60

70

80

90

Regular BDP prn combination prn salbutamol

Sym

ptom

-free

day

s (%

)

Run-inwks 1-2wks 3-4wks 5-6wks 7-8wks 9-10wks 11-12


CHILDREN



CHILDREN


Regular beclomethasone but not prn beclomethasone/salbutamol combination increased the percentage of symptom-free

days and reduced exacerbations.

However, prn combination was effective onmost secondary outcomes, convenient and

potentially safer; thus we suggest that it should be explored further

Fig. 5 Quadro anatomo-patologico di un soggetto morto per asma bronchialeIMPORTANCE OF INFLAMMATION IN ASTHMA: pathology of asthma death

AsthmaA

B

C

B

D

COPD

Fabbri LM et al Am J Respir Crit Care Med Fabbri LM et al Am J Respir Crit Care Med 2003;167 418-4242003;167 418-424


Pauwels RA et al., N Engl J Med 1997Pauwels RA et al., N Engl J Med 1997

Higher-dose budesonide plus formoterolLower-dose budesonide plus formoterolHigher-dose budesonideLower-dose budesonide

Changes in FEVChanges in FEV1 1 during the study during the study

90

85

80

75

-1 0 1 2 3 6 9 12Month

FEV 1

(% o

f pre

dict

ed)

FACET

Estimates of severe exacerbation ratesEstimates of severe exacerbation rates

BUD200BUD200h=0.91h=0.91

BUD800BUD800h=0.46h=0.46

BUD200+FBUD200+Fh=0.67h=0.67

BUD800+FBUD800+Fh=0.34h=0.34

FORM: - 26% FORM: - 26% (p=0.014)(p=0.014)p=0.031p=0.031

Pauwels RA et al., N Engl J Med 1997Pauwels RA et al., N Engl J Med 1997

BUDH:BUDH:- 49%- 49%(p<0.001)(p<0.001)

Modulite: extrafine formulations

BDPBDP//FF extrafine combination clinical FF extrafine combination clinical evidenceevidence

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

PatientsPatients 645 moderate-to-645 moderate-to-severe asthmasevere asthmaDurationDuration 6 months6 monthsDesignDesign Double blind, double dummy, parallel groups Double blind, double dummy, parallel groups

First Pivotal StudyFirst Pivotal Study: BDP/FF extrafine combination vs BDP : BDP/FF extrafine combination vs BDP CFC + formoterol DPI vs BDP CFCCFC + formoterol DPI vs BDP CFC

Huchon G, Resp Med 2009Huchon G, Resp Med 2009

645 moderate-to-severe asthmatic patients ICS at entry: 750-1000 µg BDP or equivalent Mean FEV1 at baseline (% predicted normal) : 64.5%-66.2%

BDP CFC BDP CFC total daily dose of 1000 µg non-extrafine BDPtotal daily dose of 1000 µg non-extrafine BDP

BDP CFC BDP CFC ++ fformoterol DPI (separate ormoterol DPI (separate inhalersinhalers))total daily dose of 1000 µg non-extrafine BDPtotal daily dose of 1000 µg non-extrafine BDP andand 24 µg 24 µg formoterolformoterol

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

260260

Mor

ning

PE

F (L

/min

)M

orni

ng P

EF

(L/m

in)

280280

300300

320320

340340

360360

BDP/FF extrafine combinationBDP/FF extrafine combination400/24 µg400/24 µg

380380

00 44 88 2424

Time (weeks)Time (weeks)

BDP CFC+formoterolBDP CFC+formoterol1000/24 µg1000/24 µg

BDP 1000µg CFCBDP 1000µg CFC

1212 1616 2020

# *# *

*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

BDP/FF400/24 µg

BDP CFC+formoterol1000/24 µg

% days free of clinical symptoms

BDP 1000 µgCFC

Perc

enta

ge

0

5

10

15

20

25

30

p < 0.05p < 0.05

35

00

0.40.4

0.80.8

1.21.2

1.61.6

22

2.42.4

BDP/FFBDP/FF400/24 µg400/24 µg

BDP CFC+ formoterolBDP CFC+ formoterol1000/24 µg1000/24 µg

BDP 1000 µg CFCBDP 1000 µg CFC

N. o

f exa

cerb

atio

ns p

er p

atie

ntN

. of e

xace

rbat

ions

per

pat

ient

0.45*0.45*0.660.66

0.750.75

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

** p<0.05 vs. p<0.05 vs. BDP 1000µg BDP 1000µg

CFCCFC

BDP/FFBDP/FF400/24400/24 µgµg

BDP CFC+ formoterolBDP CFC+ formoterol1000/24 µg1000/24 µg

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

SummarySummary

BDPBDP//FF extrafine combination clinical FF extrafine combination clinical evidenceevidence

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

Inhaled Combination Asthma Treatment (ICAT) studies

ICAT SYICAT SY

DAILY DOSESDAILY DOSES:BDP/FF extrafine combinationBDP/FF extrafine combination:: 400 µg BDP + 24 µg formoterol

Vs.

Budesonide/formoterolBudesonide/formoterol 800 µg BUD + 24 µg formoterol

ICAT SE ICAT SE

DAILY DOSES:DAILY DOSES:BDP/FF fixed combinationBDP/FF fixed combination

400 µg BDP + 24 µg formoterol

Vs

Fluticasone/salmeterolFluticasone/salmeterol500 µg fluticasone + 100 µg

salmeterol

•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%

Papi A, Paggiaro PL, Vignola AM, NIcolini G, Fabbri LM.ERJ 2007

Run inRun in

BDP/FF extrafine combinationBDP/FF extrafine combinationdaily dose 400 daily dose 400 µg µg BDP + 24 BDP + 24 µg µg formoterolformoterol

BBudesonide/formoteroludesonide/formoteroldaily dose 800 daily dose 800 µg µg BUD+24 BUD+24 µg µg formoterolformoterol

12 weeks12 weeks

Visit 1Visit 1ScreeningScreening

Visit 2Visit 2RandomizationRandomization

Visit 3Visit 3 Visit 4Visit 4 Visit 6Visit 6end of treatmentend of treatment

4 weeks4 weeks 4 weeks4 weeks 4 weeks4 weeks

2 weeks2 weeks

Visit 5Visit 5

ICAT SY. Study DesignICAT SY. Study Design

12 weeks12 weeks

280280

L/m

inL/

min

290290

300300

310310

320320

330330

340340


350350

BaselineBaseline 44 88 1212

*p<0.001 vs baseline*p<0.001 vs baselineNS between treatmentsNS between treatments

**

**

WeeksWeeks

Budesonide/formoterolBudesonide/formoterol800/24 µg800/24 µg

ICAT SY. Morning PEF ICAT SY. Morning PEF CComparable improvement for both BDP/FF omparable improvement for both BDP/FF extrafineextrafine combination combination

and budesonide/formoteroland budesonide/formoterol

**********

********

**##

##

DaytimeDaytimeasthma symptom scoreasthma symptom score

Night-time Night-time asthma symptom scoreasthma symptom score

00

Sym

ptom

sco

reS

ympt

om s

core

0.50.5

2.02.0

WeeksWeeks


1.51.5

1.01.0

BDP/FF extrafine combinationBDP/FF extrafine combination400/24 µg400/24 µgBudesonide/formoterolBudesonide/formoterol800/24 µg800/24 µg

**** ** ** ** **

**** **

** ** **

*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


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

Inhaled Combination Asthma Treatment (ICAT) studiesInhaled Combination Asthma Treatment (ICAT) studies

ICAT SYICAT SY

DAILY DOSES:DAILY DOSES:BDP/FF extrafine combinationBDP/FF extrafine combination: 400 µg BDP + 24 µg formoterol

Vs.

Budesonide/formoterolBudesonide/formoterol 800 µg BUD + 24 µg formoterol

ICAT SE ICAT SE

DAILY DOSES:DAILY DOSES:BDP/FF fixed combinationBDP/FF fixed combination

400 µg BDP + 24 µg formoterol

Vs.

Fluticasone/salmeterolFluticasone/salmeterol500 µg fluticasone + 100 µg

salmeterol

ICAT SICAT SE.E. BDP/FF extrafine combination versus BDP/FF extrafine combination versus

fluticasone/salmeterol combinationfluticasone/salmeterol 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%

Papi A*, Paggiaro PL*, Vignala AM, Nicolini G, Fabbri LM. Allergy 2007

Run inRun in

BDP/FF extrafine combinationBDP/FF extrafine combinationdaily dose 400daily dose 400 µg µg BDP + 24 BDP + 24 µg µg formoterolformoterol

fluticasone/salmeterolfluticasone/salmeteroldaily dose 500 daily dose 500 µg µg FP + 100 FP + 100 µg µg salmeterolsalmeterol

12 weeks12 weeks

Visit 1Visit 1ScreeningScreening

Visit 2Visit 2RandomizationRandomization

Visit 3Visit 3 Visit 4Visit 4 Visit 6Visit 6end of treatmentend of treatment

4 weeks 4 weeks 4 weeks

2 weeks2 weeks

Visit 5Visit 5

12 weeks12 weeks

ICAT SE. Study DesignICAT SE. Study Design

ICAT SICAT SE. E. Morning PEF comparable improvement for both BDPMorning PEF comparable improvement for both BDP//FF FF

extrafineextrafine combination and fluticasone/salmeterol combination and fluticasone/salmeterol

250250

L/m

inL/

min

270270

290290

310310

330330

350350


*p<0.001 vs baseline*p<0.001 vs baselineNS between treatmentsNS between treatments

WeeksWeeks

260260

280280

300300

320320

340340

Fluticasone/salmeterolFluticasone/salmeterol500/100 µg500/100 µg

**

************

**********

##

##


ICAT SE. ICAT SE. Asthma symptom score Comparable effects of BDP/FF extrafine Asthma symptom score Comparable effects of BDP/FF extrafine

combination and fluticasone/salmeterol at day and night-timecombination and fluticasone/salmeterol at day and night-timeDaytimeDaytime

asthma symptom scoreasthma symptom scoreNight-time Night-time

asthma symptom scoreasthma symptom score

00

Sym

ptom

sco

reS

ympt

om s

core

0.50.5

2.02.0

WeeksWeeks


1.51.5

1.01.0

**

**** ** ** **

****

** ** ** **

00S

ympt

om s

core

Sym

ptom

sco

re

0.50.5

2.02.0

WeeksWeeks


1.51.5

1.01.0

**** ** ** ** **

****

** ** ** **

BDP/FF extrafine combinationBDP/FF extrafine combination400/24 µg400/24 µgFluticasone/salmeterolFluticasone/salmeterol500/100 µg500/100 µg

*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


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

Total No. events Hospitalisations/ER treatment

Terbutal Formoterol Form/BudeMaintenance Form/Bude +

prn

p<0.001

20

60

100

140

194

296

377p<0.01

p<0.001

p<0.05300

200

100

400

70

98115

SMILE Study: Severe Exacerbations

Rabe KF et al, Lancet. 2006 Aug 26;368(9537):744-53

Manteinance and reliever - MART 2

2 week Run in2 week Run in

BDP/FF 1 puff bid + BDP/FF prnBDP/FF 1 puff bid + BDP/FF prn

BDP/FF 1 puff bid + Salbutamol prnBDP/FF 1 puff bid + Salbutamol prn

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

Estimated Enrollment: 825 Estimated Enrollment: 825

Differences between asthma and COPDDifferences between asthma and COPD ASTHMAASTHMA

Sensitizing agentSensitizing agentCOPDCOPD

Noxious agentNoxious agent

Asthmatic airwayAsthmatic airwayinflammationinflammation

CD4+ T-lymphocytesCD4+ T-lymphocytesEosinophilsEosinophils

COPD airway inflammationCOPD airway inflammationCD8+ T-lymphocytesCD8+ T-lymphocytes

MarcrophagesMarcrophagesNeutrophilsNeutrophils

Airflow limitationAirflow limitationCompletelyCompletelyreversiblereversible

CompletelyCompletelyirreversibleirreversibleAirflow limitationAirflow limitation

ASTHMAASTHMA COPDCOPD

Mild Intermittent Mild Intermittent 2 prn 2 prn MildMild 2 prn 2 prn

Mild persistentMild persistent iGCS iGCS Moderate LABAModerate LABA

Moderate persistent Combination Severe Moderate persistent Combination Severe CombinationCombination LABA+iGCS LABA+iGCS LABA+iGCSLABA+iGCS

Severe persistent Oral GCS Very Oxygen, SxSevere persistent Oral GCS Very Oxygen, Sx severesevere SurgerySurgery

Management of COPD and asthma:GOLD and GINA guidelines

CONCLUSIONS

Persistent asthma may not require regular treatment

Definition of control requires revision

Role of asthmatic inflammation and its suppression remains to be established

LABA/ICS combination for mantainance and reliever therapy is the most effective treatment of

persistent asthma

COMBINATION THERAPY IN COMBINATION THERAPY IN ASTHMAASTHMA

Leonardo M. Fabbri











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Leonardo M. Fabbri [email protected]