12th Annual Congress of the Turkish Thoracic Society
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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]

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Leonardo m fabbri fabbri leonardo 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]


Leonardo m fabbri fabbri leonardo unimo it

EUROPEAN RESPIRATORY SOCIETYYEAR OF THE LUNG 2009-2010

Shaping the Future of Respiratory Medicine in Europe

Leonardo M. Fabbri

ERS Past-President

[email protected]


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Berlin 2008 - Registration

Please refer to pages 29 -30 of the Guidelines for detailed figures

19’356 participants

Biggest Respiratory Congress in the World


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Berlin 2008 - Audience

Congress attendance – Top 26 countries


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ERS Annual Congress


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ERS Membership


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Turkish Members

* Introduction of the Joint Membership


Leonardo m fabbri fabbri leonardo 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]


Leonardo m fabbri fabbri leonardo unimo it

COMBINATION THERAPY IN ASTHMA

Leonardo M. Fabbri

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


Management of asthma in untreated patients gina guidelines 2008

Management of asthma in untreated patients, GINA guidelines, 2008

Mild

Intermittent

Avoidance of risk factors, immunotherapy

Fast-acting beta-2 agonists as needed

Mild

Persistent

Low-dose inhaled steroids

Asthma severity

Clinical Features Before Treatment

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

Moderate

Persistent

Moderate

Persistent

(Severe?)

Combination with higher

doses inhaled corticosteroids, theophylline, antileukotrienes

Severe

Persistent

(Very severe?)

Systemic steroids

Anti-IgE


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GINA Guidelines 2008 www.ginasthma.org


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LEVEL OF CONTROL

TREATMENT OF ACTION

REDUCE

maintain and find lowest controlling step

controlled

consider stepping up to gain control

partly controlled

uncontrolled

step up until controlled

INCREASE

exacerbation

treat as exacerbation

REDUCE

INCREASE

TREATMENT STEPS

STEP

1

STEP

2

STEP

3

STEP

4

STEP

5


Levels of asthma control

Levels of Asthma Control


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GINA Guidelines 2008 www.ginasthma.org


Leonardo m fabbri fabbri leonardo unimo it

mast cells

760

720

240

200

160

120

80

40

0

Pre-BD

6 wk

Pre-BD

6 wk

Pre-BD

6 wk

Effects of Inhaled Beclomethasone

Dipropionate in Clinical Asthma

Bronchial Function

Bronchial Submucosa

PC20 methacholine

(mg/ml)

Asthmatic

symptoms

eosinophils

T lymphocytes

number of cells/mm2 of submucosa

Severity

mg/ml

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

RESCUE USE OF BECLOMETHASONE AND ALBUTEROL IN A SINGLE INHALER FOR MILD ASTHMA

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


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Study design

Twice daily inhaled placebo plus

p.r.n. inhaled 250µg beclomethasone/100 µg salbutamol combination

Twice daily inhaled placebo plus

p.r.n. inhaled 100 µg salbutamol

Beclomethasone

(500µg/day)

Twice daily inhaled 250 µg beclomethasone plus

p.r.n. 100 µg salbutamol

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

p.r.n. inhaled 100 µg salbutamol

Visit 1

(screening)

Visit 2

(randomization)

Visit 3

Visit 4

Visit 5

Visit 6

Visit 7

Visit 8

(end of treatment)

4-Week Run-in Period

6-month Treatment Period

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


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*

*

*

Missing Values Replaced with the Use of LOCF

460

Baseline

Weeks 5-6

Weeks 11-12

Weeks 17-18

Weeks 22-24

440

*

420

Morning PEF (liters/min)

400

380

360

prn BDP/S

prn S

regular BDP

regular BDP/S

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


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EFFECT OF EXACERBATIONS

2

1,5

Number of exacerbations per patients/year

1

0,5

0

As needed

As needed

Regular

Regular

combination

albuterol

beclomethasone

combination

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

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


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CUMULATIVE DOSE OF BECLOMETHASONE (BDP)

**

**

100

80

60

mg

40

20

0

prn BDP/S

prn S

regular BDP

regular

BDP/S

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


Regular versus prn nebulised treatment for preschool wheeze children

REGULAR VERSUS PRN NEBULISED TREATMENT FOR PRESCHOOL WHEEZE CHILDREN

Papi et al, submitted, 2008


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REGULAR VERSUS PRN NEBULISED TREATMENT FOR PRESCHOOL WHEEZE CHILDREN

Papi et al, submitted, 2008


Regular versus prn nebulised treatment for preschool wheeze children1

REGULAR VERSUS PRN NEBULISED TREATMENT FOR PRESCHOOL WHEEZE CHILDREN

Regular beclomethasone but not prn beclomethasone/salbutamol combination increased the percentage of symptom-free days and reduced exacerbations.

However, prn combination was effective on

most secondary outcomes, convenient and potentially safer; thus we suggest that it should be explored further

Papi et al, submitted, 2009


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IMPORTANCE OF INFLAMMATION IN ASTHMA: pathology of asthma death

Fig. 5 Quadro anatomo-patologico di un soggetto morto per asma bronchiale


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COPD

Asthma

B

A

B

D

C

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


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GINA Guidelines 2008 www.ginasthma.org


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Changes in FEV1 during the study

90

85

FEV1 (% of predicted)

80

75

Higher-dose budesonide plus formoterol

Lower-dose budesonide plus formoterol

Higher-dose budesonide

Lower-dose budesonide

-1

0

1

2

3

6

9

12

Month

Pauwels RA et al., N Engl J Med 1997

FACET


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Estimates of severe exacerbation rates

BUD200

h=0.91

BUD800

h=0.46

BUD200+F

h=0.67

BUD800+F

h=0.34

BUDH:

- 49%

(p<0.001)

p=0.031

FORM: - 26% (p=0.014)

Pauwels RA et al., N Engl J Med 1997


Modulite extrafine formulations

Modulite: extrafine formulations


Bdp ff extrafine combination clinical evidence

BDP/FF extrafine combination clinical evidence

BDP/FF vs separate components

6-month study

BDP/FF vs. BDP + FF in separate inhalers vs. BDP alone

3-month study

BDP/FF vs. BDP alone

BDP/FF vs available ICS/LABA fixed combinations

3-month studies

BDP/FF Vs. Budesonide/formoterol

BDP/FF vs. Fluticasone/salmeterol


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

Huchon G, Resp Med 2009


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BDP/FF extrafine combination versus the separate components and BDP CFC non extrafine

BDP/FF extrafine combination

total daily dose of 400 µg extra fine BDP and 24 µg formoterol

BDP CFC +formoterol DPI (separate inhalers)

total daily dose of 1000 µg non-extrafine BDPand24 µg formoterol

2-weeks RUN IN

BDP CFC

total daily dose of 1000 µg non-extrafine BDP

6 MONTHS

  • 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%


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BDP/FF extrafine combination shows similar improvement in morning PEF (PRIMARY ENDPOINT) compared to the separate components, and a better outcome compared to BDP alone

BDP 1000µg CFC

BDP/FF extrafine combination

400/24 µg

BDP CFC+formoterol

1000/24 µg

380

360

340

# *

Morning PEF (L/min)

320

300

*p<0.001 vs baseline

280

#

NS between treatments

260

0

4

8

12

16

20

24

Time (weeks)


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% days free

of clinical symptoms

p < 0.05

35

30

25

20

Percentage

15

10

5

0

BDP CFC

+formoterol

1000/24 µg

BDP/FF

400/24 µg

BDP 1000 µg

CFC

BDP/FF extrafine combination was significantly superior to the separate components and to BDP monotherapy with relation to clinical measures of asthma control


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N. of overall exacerbations

N. of severe exacerbations

2.02

1.6

* p<0.05 vs. BDP 1000µg CFC

1.33*

0.75

0.66

0.45*

BDP/FF extrafine combination demonstrated to be effective in reducing asthma exacerbations

2.4

2

1.6

N. of exacerbations per patient

1.2

0.8

0.4

0

BDP CFC+ formoterol

1000/24 µg

BDP 1000 µg CFC

BDP/FF

400/24 µg


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BDP/FF extrafine combination: lack of cortisol suppression

Morning Serum Cortisol (nmol/L)

Changes from Baseline to week 24

-Means and 95% CI-

*

200

150

100

50

Morning Serum Cortisol (nmol/L)

Changes from Baseline to week 24

0

-50

-100

-150

BDP CFC+ formoterol

1000/24 µg

BDP/FF

400/24µg

BDP 1000 µg CFC

-200


Leonardo m fabbri fabbri leonardo unimo it

BDP/FF extrafine combination versus the separate components and BDP CFC non extrafine

Summary

  • Similar improvement in morning PEF and FEV1, compared to the single drugs administered separately and superiority of BDP/FF fixed combination versus BDP CFC monotherapy on the same parameters

  • Superiority of BDP/FF fixed combination compared to BDP monotherapy, with relation to exacerbation frequency

  • Lack of cortisol suppression with BDF/FF as a consequence of a reduced steroid exposure

  • Superiority in some parameters of 1 vs 2 inhalers


Bdp ff extrafine combination clinical evidence1

BDP/FF extrafine combination clinical evidence

BDP/FF vs separate components

6-month study

BDP/FF vs. BDP + FF in separate inhalers vs. BDP alone

3-month study

BDP/FF vs. BDP alone

BDP/FF vs available ICS/LABA fixed combinations

3-month studies

BDP/FF Vs. Budesonide/formoterol

BDP/FF vs. Fluticasone/salmeterol


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Inhaled Combination Asthma Treatment (ICAT) studies

ICAT SY

DAILY DOSES:

BDP/FF extrafine combination:

400 µg BDP + 24 µg formoterol

Vs.

Budesonide/formoterol

800 µg BUD + 24 µg formoterol

ICAT SE

DAILY DOSES:

BDP/FF fixed combination

400 µg BDP + 24 µg formoterol

Vs

Fluticasone/salmeterol

500 µg fluticasone + 100 µg salmeterol


Leonardo m fabbri fabbri leonardo unimo it

Randomized, double blind, double dummy, multinational, parallel-group design study comparing BDP/FF extrafine combination with budesonide/formoterol in a 3 months treatmentof moderate to severe asthmatic patients

ICAT SY.

BDP/FF extrafine combination vs. budesonide/formoterol combination

  • 216 moderate-to-severe asthmatic patients

  • ICS at entry:  1000 µg BDP or equivalent

  • Mean FEV1 at baseline (% predicted normal) : 69.3%-70.5%

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


Leonardo m fabbri fabbri leonardo unimo it

ICAT SY. Study Design

BDP/FF extrafine combinationdaily dose 400 µg BDP + 24 µg formoterol

12 weeks

Run in

2 weeks

Budesonide/formoteroldaily dose 800 µg BUD+24 µg formoterol

12 weeks

4 weeks

4 weeks

4 weeks

Visit 1

Screening

Visit 2

Randomization

Visit 3

Visit 4

Visit 5

Visit 6

end of treatment


Leonardo m fabbri fabbri leonardo unimo it

ICAT SY. Morning PEF Comparable improvement for both BDP/FF extrafine combination and budesonide/formoterol

BDP/FF extrafine combination

400/24 µg

Budesonide/formoterol

800/24 µg

350

*

*

#

*

*

*

340

*

330

*

*

*

*

*

*

320

L/min

310

300

*p<0.001 vs baseline

290

#

NS between treatments

280

Baseline

4

8

12

Weeks


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ICAT SY. Asthma symptom score Comparable effects of BDP/FF extrafine combination vs budesonide/formoterol at day and night-time

Daytimeasthma symptom score

Night-time asthma symptom score

2.0

2.0

1.5

1.5

*

*

*

*

*

#

*

*

*

Symptom score

Symptom score

1.0

1.0

*

*

*

#

*

*

*

*

*

*

*

*

*

0.5

0.5

*

*

*

*

0

0

Baseline

4

8

12

Baseline

4

8

12

Weeks

Weeks

BDP/FF extrafine combination

400/24 µg

*p<0,001 vs baseline

NS between treatments

#

Budesonide/formoterol

800/24 µg


Leonardo m fabbri fabbri leonardo unimo it

BDP/FF extrafine combination improves lung function similarly to budesonide/formoterol with half the dose of inhaled corticosteroid

BDP/FF extrafine combination demonstrated to be not significantly different from budesonide/formoterol also in terms of asthma symptoms reduction and exacerbation rate

ICAT SY.

BDP/FF extrafine combination vs. budesonide/formoterol combination

Summary


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Inhaled Combination Asthma Treatment (ICAT) studies

ICAT SY

DAILY DOSES:

BDP/FF extrafine combination:

400 µg BDP + 24 µg formoterol

Vs.

Budesonide/formoterol

800 µg BUD + 24 µg formoterol

ICAT SE

DAILY DOSES:

BDP/FF fixed combination

400 µg BDP + 24 µg formoterol

Vs.

Fluticasone/salmeterol

500 µg fluticasone + 100 µg salmeterol


Icat s e bdp ff extrafine combination versus fluticasone salmeterol combination

ICAT SE.BDP/FF extrafine combination versus fluticasone/salmeterol combination

Randomized, double blind, double masking, multinational, parallel-group design study comparing BDP/FF extrafine combination with fluticasone/salmeterol in the 3 months treatment of moderate to severe asthmatic patients

  • 216 moderate-to-severe asthmatic patients

  • ICS at entry:  1000 µg BDP or equivalent

  • Mean FEV1 at baseline (% predicted normal) : 66.9%-67.6%

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


Leonardo m fabbri fabbri leonardo unimo it

ICAT SE. Study Design

BDP/FF extrafine combinationdaily dose 400 µg BDP + 24 µg formoterol

12 weeks

Run in

2 weeks

fluticasone/salmeteroldaily dose 500 µg FP + 100 µg salmeterol

12 weeks

4 weeks

4 weeks

4 weeks

Visit 1

Screening

Visit 2

Randomization

Visit 3

Visit 4

Visit 5

Visit 6

end of treatment


Leonardo m fabbri fabbri leonardo unimo it

ICAT SE. Morning PEF comparable improvement for both BDP/FF extrafine combination and fluticasone/salmeterol

BDP/FF extrafine combination

400/24 µg

Fluticasone/salmeterol

500/100 µg

350

*

*

#

*

*

340

*

*

330

*

320

*

*

*

*

310

*

L/min

300

290

280

270

*p<0.001 vs baseline

260

#

NS between treatments

250

Baseline

4

8

12

Weeks


Leonardo m fabbri fabbri leonardo unimo it

ICAT SE. Asthma symptom score Comparable effects of BDP/FF extrafine combination and fluticasone/salmeterol at day and night-time

Daytimeasthma symptom score

Night-time asthma symptom score

2.0

2.0

1.5

1.5

*

Symptom score

Symptom score

*

*

1.0

1.0

*

*

*

*

*

*

#

*

*

*

#

*

*

*

0.5

0.5

*

*

*

*

*

*

*

*

*

0

0

Baseline

4

8

12

Baseline

4

8

12

Weeks

Weeks

BDP/FF extrafine combination

400/24 µg

*p<0,001 vs baseline

NS between treatments

#

Fluticasone/salmeterol

500/100 µg


Icat se bdp ff extrafine combination versus fluticasone salmeterol combination

ICAT SE. BDP/FF extrafine combination versus fluticasone/salmeterol combination

BDP/FF extrafine combination is equivalent to fluticasone/salmeterol in terms of lung function improvement

BDP/FF extrafine combination provides a more rapid bronchodilation in the first hour post dosing

Summary


Leonardo m fabbri fabbri leonardo unimo it

Estimate Comparative Daily Dosages for Inhaled Glucocorticosteroids Age > 5y

Drug Low Daily Dose Medium Daily Dose High Daily Dose

(g) (g) (g)

EPR3, 2007

GINA, 2005


Leonardo m fabbri fabbri leonardo unimo it

GINA Guidelines 2008 www.ginasthma.org


Smile study design

SMILE: Study Design

(All patients received Form/Bude 160/4.5 µg bid both during run-in and following Randomisation)

Formoterol/Budesonide+ Terbutaline 0.4 mg as reliever n=1141

Run-in

Form/Bude + Terbutaline as reliever

R

Formoterol/Budesonide + Formoterol4.5 µg as reliever n=1140

Enrolled: n=3829

Randomised: n=3394

Formoterol/Budesonide+ Formoterol/Budesonide160/4.5 µg as reliever (SMART) n=1113

Visit:1 2 3 4 5 6

Month: -0.5 0 1 4 8 12

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


Leonardo m fabbri fabbri leonardo unimo it

SMILE Study: Severe Exacerbations

Total No. events

Hospitalisations/

ER treatment

p<0.001

p<0.01

400

377

p<0.001

296

p<0.05

300

140

115

194

98

200

100

70

60

100

20

Maintenance Form/Bude + prn

Terbutal

Formoterol

Form/Bude

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


Leonardo m fabbri fabbri leonardo unimo it

Non fully controlled

Manteinance and reliever - MART 2

BDP/FF 1 puff bid + BDP/FF prn

BDP/FF 1 puff bid

+ SABA prn

ICS

> 1000 µg BDP

ICS + LABA

> 500 µg BDP

2 week Run in

BDP/FF 1 puff bid + Salbutamol prn


Leonardo m fabbri fabbri leonardo unimo it

Study Design: Randomized, Double-Blind, Active Control, Parallel Assignment, Safety/Efficacy Study

Primary Outcome Measures: Number of COPD exacerbations and pre-dose morning FEV1

Estimated Enrollment: 825


Leonardo m fabbri fabbri leonardo unimo it

Differences between asthma and COPD

ASTHMA

Sensitizing agent

COPD

Noxious agent

Asthmatic airway

inflammation

CD4+ T-lymphocytes

Eosinophils

COPD airway inflammation

CD8+ T-lymphocytes

Marcrophages

Neutrophils

Airflow limitation

Completely

reversible

Completely

irreversible

Airflow limitation


Leonardo m fabbri fabbri leonardo unimo it

Management of COPD and asthma:GOLD and GINA guidelines

ASTHMA COPD

Mild Intermittent 2 prn Mild 2 prn

Mild persistentiGCS Moderate LABA

Moderate persistent Combination Severe Combination

LABA+iGCS LABA+iGCS

Severe persistent Oral GCS Very Oxygen, Sx

severeSurgery


Leonardo m fabbri fabbri leonardo unimo it

COMBINATION THERAPY IN ASTHMA

Leonardo M. Fabbri

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


Leonardo m fabbri fabbri leonardo 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]


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