1. Roflumilast in aggiunta ai broncodilatatori a lunga durata d’azione1

2. Gli studi M2-124 e M2-125: roflumilast nei pazienti trattati con LABA
Single-blind
Double-blind, randomized,
parallel group
Follow-up
4 weeks
Roflumilast 500µg o.d.
Run-in 4 weeks
Treatment
52 weeks R VE
Visit 0
Follow-up
Speaker notes
Patients enrolled in these 12-month studies were allowed concomitant medications, including short-acting anticholinergics at regular dosing and LABAs, in order to reflect common clinical practice.
Patients were stratified according to treatment with LABAs.
Approximately 50% of patients used a LABA concomitantly with study medication.
Approximately 40% of patients in both treatment arms used a short-acting bronchodilator.
Reference
Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694.
Placebo o.d.
Concomitant medication: LABA or short-acting anticholinergics Targeting a proportion of ~ 50% of all patients on LABA
R = randomization
VE = Visit end
o.d. = Once daily
LABA = Long-acting β2-agonist
Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 2

3. Caratteristiche basali dei pazienti trattati con LABA
Speaker notes
Patient baseline characteristics were similar between the roflumilast and placebo groups in patients treated concomitantly with LABA and those without LABA.
Reference
Bateman ED, Rabe KF, Calverley PMA, et al. Roflumilast with long-acting β2-agonists for COPD: influence of exacerbation history. Eur Respir J 2011, erj d; accepted manuscript, DOI: /
Caratteristiche basali dei pazienti trattati con LABA
Data are expressed as mean (SD), unless otherwise stated
LABA = Long-acting β2-agonist
FVC = Forced vital capacity
FEV1 = Forced expiratory volume in 1 second
Bateman ED, Rabe KF, Calverley PMA, et al. Eur Respir J 2011, 38: 553–560 3

4. Miglioramento della funzionalità respiratoria nei pazienti trattati con roflumilast in aggiunta a LABA
Speaker notes
In addition, analysis of pooled data from M2-124 and M2-125 pivotal 12-month clinical studies revealed the effects of roflumilast on lung function in the LABA subgroup.
Compared with placebo, treatment with roflumilast resulted in a significant improvement in pre- and post-bronchodilator FEV1 in all patients, irrespective of whether they were also receiving a concomitant LABA, suggesting that the beneficial effect of roflumilast on lung function is additive to that achieved with bronchodilators.
Reference
Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694.
LABA = Long-acting β2-agonist
FEV1 = Forced expiratory volume in one second
Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 4 4

5. Riduzione delle riacutizzazioni moderate e gravi
M2-124 & M2-125 – pooled analysis
All
LABA: Yes
LABA: No
 = %
(CI -25;-8)
p =
 = %
(CI -31;-9)
p=0.0011
 = %
(CI -26;-1)
p=0.0387 2
Mean rate of exacerbations (moderate or severe) per patient per year
placebo
roflumilast 1
Key Message: Roflumilast reduced the rate of moderate or severe exacerbations compared with placebo in all patients irrespective of concomitant treatment with long acting bronchodilators.
LABAs were used by 749 (49%) patients in the roflumilast group and 793 (51%) patients in the placebo group in the pooled data set. The change in exacerbation rate with roflumilast vs placebo was –16.9% in the overall population and was not influenced by LABA use, with changes in exacerbation rates of –20.7% and –14.6% in the subgroups of LABA users and non-LABA users, respectively. The larger decrease in exacerbations for the patients who received LABA could be explained by these patients being more symptomatic and therefore were at higher risk of exacerbations. This is also indicated by the higher exacerbation rate in the placebo group in LABA-treated patients versus non LABA-treated patients (1.55 versus 1.17) and thus, treatment effects on exacerbations are easier to demonstrate in these patients.
1.37
1.14
1.55
1.23
1.17
1.00 n:
Rabe KF BrJ Pharmacol 2011 5 5

6. Speaker notes
Approximately 50% of patients in the two 12-month studies continued to use LABAs throughout the roflumilast treatment period.1 Roflumilast reduced the rate of exacerbations irrespective of whether patients were taking concomitant LABA.1
A pre-specified analysis of the effects of roflumilast in the LABA subgroup, revealed approximately 21% lower exacerbation rate in patients receiving roflumilast relative to placebo (p=0.0011).2
R e f e r e n c e s
C a l v e r l e y P M A , R a b e K F , G o e h r i n g U M , e t a l . R o f l u m i l a s t i n s y m p t o m a t i c c h r o n i c o b s t r u c t i v e d i s e a s e : t w o r a n d o m i z e d c l i n i c a l t r i a l s . L a n c e t ; : –
R a b e K F . U p d a t e o n r o f l u m i l a s t , a p h o s p h o d i e s t e r a s e 4 i n h i b i t o r f o r t h e t r e a t m e n t o f c h r o n i c o b s t r u c t i v e p u l m o n a r y d i s e a s e . B r J P h a r m ; :
Roflumilast e LABA: maggiore riduzione delle riacutizzazioni moderate e gravi
Pre-specified analysis of exacerbation rate in LABA subgroup
LABA = Long-acting β2-agonist
Bateman ED, Rabe KF, Calverley PMA, et al. Eur Respir J 2011, 38: 553–560 6

7. Speaker notes
The time to onset of each exacerbation also increased significantly in patients treated with LAMA+ roflumilast compared with LAMA placebo.
Reference
Bateman ED, Rabe KF, Calverley PMA, et al. Roflumilast with long-acting β2-agonists for COPD: influence of exacerbation history. Eur Respir J 2011, erj d; accepted manuscript, DOI: /
Roflumilast e LABA: significativo aumento dell’intervallo di tempo tra riacutizzazioni
LABA = Long-acting β2-agonist
Bateman ED, Rabe KF, Calverley PMA, et al. Eur Respir J 2011, 38: 553–560 7

8. Roflumilast: gli studi registrativi
Early phase III studies1,2
M2-111 (n=1173) M2-112 (n=1513)
Pivotal studies3
M2-124 (n=1523) M2-125 (n=1568)
Supplementary 6-month studies4
M2-127 add on to LABA (n=933) M2-128 add on to LAMA (n=743)
Speaker notes
The supplementary phase III studies were designed to examine the effects of roflumilast when taken on top of long-acting bronchodilators for treatment of COPD.
References
Calverley PMA, Sanchez-Toril F, McIvor A, et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:154–161.
Rennard SI, Calverley PMA, Goehring UM, et al. Reduction of exacerbations by the PDE4 inhibitor roflumilast – the importance of defining different subsets of patients with COPD. Respir Res 2011;12:18.
3 Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694.
4 Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomized clinical trials. Lancet 2009;374:695–703.
LABA = Long-acting β2-agonist
LAMA = Long-acting muscarinic antagonist
1. Calverley PMA, et al. Am J Respir Crit Care Med 2007;176: Rennard et al. Respiratory Research 2011,12: Calverley PMA, et al. Lancet 2009;374:685– Fabbri LM, et al. Lancet 2009;374: 8

9. Studio M2-127: roflumilast e salmeterolo
Speaker notes
P a t i e n t s w e r e r a n d o m l y a s s i g n e d t o r e c e i v e r o f l u m i l a s t ( μ g ) o r p l a c e b o o n c e d a i l y o n t o p o f s a l m e t e r o l ( a L A B A ) , f o r w e e k s .
Reference
Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomized clinical trials. Lancet 2009;374:695–703.
Studio M2-127: roflumilast e salmeterolo
Single-blind
Double-blind, randomized,
parallel group
Follow-up 4 weeks
Run-in 4 weeks
Salmeterol 50µg b.i.d. + roflumilast 500µg o.d.
Treatment
24 weeks R VE
Visit 0
Follow-up
Salmeterol 50µg b.i.d.
+ placebo o.d.
R = randomization
VE = Visit end
b.i.d. = twice daily
o.d. = Once daily
Fabbri LM, Calverley PMA, Izquierdo-Alonso JL , et al. Lancet 2009;374: 9

10. Studio M2-128: roflumilast e tiotropio
Speaker notes
P a t i e n t s w e r e r a n d o m l y a s s i g n e d t o r e c e i v e r o f l u m i l a s t ( μ g ) ( n = ) o r p l a c e b o ( n = ) o n c e d a i l y o n t o p o f t i o t r o p i u m , f o r w e e k s .
Reference
Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomized clinical trials. Lancet 2009;374:695–703.
Studio M2-128: roflumilast e tiotropio
Single-blind
Double-blind, randomized,
parallel group
Follow-up 4 weeks
Run-in 4 weeks
Tiotropium 18µg
+ roflumilast 500µg o.d.
Treatment
24 weeks R VE
Visit 0
Follow-up
Tiotropium 18µg
+ placebo o.d.
R = randomization
VE = Visit end
b.i.d. = twice daily
o.d. = Once daily
Fabbri LM, Calverley PMA, Izquierdo-Alonso JL , et al. Lancet 2009;374: 10

11. Studio M2-128: endpoint clinici
6-MONTH SUPPORTIVE STUDY
PATIENTS (N=743)
COPD associated with chronic bronchitis*
Moderate to severe airflow limitation (FEV1 40–70% of predicted)
TREATMENTS:
Once-daily roflumilast 500µg or placebo added to tiotropium
PRIMARY ENDPOINT:
Pre-bronchodilator FEV1
Speaker notes
This additional 6-month phase III clinical study was conducted to examine the effects of roflumilast in patients with COPD who were taking concomitant therapy with the long-acting inhaled bronchodilator tiotropium (an anti-cholinergic).
Patient inclusion criteria included diagnosed COPD, age ≥40 years, moderate-to-severe airflow limitation and bronchitic symptoms.
Patients were randomly assigned to receive roflumilast (500μg once daily) (n=371) or placebo (n=372) for 24 weeks. The primary endpoints was the change in pre-bronchodilator FEV1 and analysis was by intention to treat.
Reference
Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomized clinical trials. Lancet 2009;374:695–703.
*Chronic productive cough for 3 months in each of the 2 years prior to baseline visit
FEV1: Forced expiratory volume in 1 second
Fabbri LM, Calverley PMA, Izquierdo-Alonso JL , et al. Lancet 2009;374: 11

12. Studi M2-127 e M2-128: aumento del FEV1 post-broncodilatore
M2-127 salmeterol
M2-128 tiotropium
100
 = 60 ml
(CI 38;82)
p <
 = 81 ml
(CI 51;110) p < 80
n=364
n=452 60
Mean change in postFEV1 [ml] 40 20
Key Message
Significant improvements in lung function (post-bronchodilator FEV1) were achieved when roflumilast was used concomitantly with salmeterol or tiotropium as underlying maintenance treatment, compared with either long-acting bronchodilator alone
Roflumilast used concomitantly with salmeterol or tiotropium significantly increased post-bronchodilator FEV1 compared with salmeterol or tiotropium alone in the respective studies. The mean change for roflumilast in M2-127 and M2-128 was 68ml and 74ml respectively which resulted in a treatment difference between roflumilast and placebo of 60ml in study M2-127 and 81ml in study M2-128
Study medication was to be withheld in the morning of study visit days, as was salmeterol for 10 hours and tiotropium for 20 hours, respectively, and reliever medication for at least 4 hours prior to pulmonary function tests. The post-bronchodilator measurement was performed directly after the pre-bronchodilator test by spirometry 30 minutes after inhalation of 4 inhalations of 100 microgram of salbutamol/albuterol (total dose 400 microgram). This test would be discriminative of whether the effect of roflumilast on lung function was independent of bronchodilation by smooth muscle relaxation.
n=460 8 68
n=363 74 -7
-20
salmeterol or tiotropium + placebo
salmeterol or
tiotropium + roflumilast 500 µg
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 12 12

13. Roflumilast e salmeterolo: tempo mediano alla prima riacutizzazione moderata e grave
M2-127 salmeterol
A hazard ratio < 1 means a lower risk for the test treatment
Hazard ratio = 0.6
(IQR 0.4;0.9) p =
0.80
0.85
0.90
0.95
1.00 4 8 12 24 18
Weeks
without exacerbations
Fraction of patients
salmeterol + placebo
salmeterol + roflumilast 500 µg
Note: Data not in paper
Key Message
Roflumilast given concomitantly with salmeterol as underlying maintenance medication significantly increased the time to first exacerbation (moderate and severe exacerbations, ie intervention with systemic corticosteroids and hospitalisation/or death respectively) compared with salmeterol plus placebo. Although the study was only of 6 month duration and thus not designed to evaluate exacerbations over a full year, it showed substantial benefit of roflumilast in reducing the risk of these pivotal events in a population of moderate to severe COPD patients in this post-hoc analysis. These findings are consistent with the one year pivotal trials showing that the benefit of roflumilast in reducing exacerbations is independent of underlying treatment with long-acting bronchodilators
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703, Data on file 13 13

14. Roflumilast e tiotropio: tempo mediano alla prima riacutizzazione moderata e grave
M2-128 tiotropium
1.00
0.95
Probability of not experiencing
an exacerbation
0.90
Hazard ratio = 0.8
(IQR 0.5;1.1) p =
Note: Data not in paper
Key Message
There was a trend for roflumilast, given concomitantly with tiotropium as underlying maintenance medication, to increase the time to first moderate or severe exacerbation over 6 months compared to tiotropium plus placebo with a hazard ratio of 0.8, but it did not reach statistical significance (p=0.196). This was a pre-specified analysis in the statistical analysis plan, although the study was of only 6 month duration and thus not designed to evaluate exacerbations over a full year, the findings are consistent with the one year pivotal studies that the effect of roflumilast in reducing exacerbations is independent of underlying treatment with long-acting bronchodilators. Furthermore the secondary analysis also including mild exacerbations in the analysis showed a significantly reduced hazard ratio
As compared to the salmeterol study (m2-127) this study was also somewhat smaller which can explain a loss of power.
0.85
tiotropium + placebo
tiotropium + roflumilast 500 µg
0.80 4 8 12 18 24
Weeks
A hazard ratio < 1 means a lower risk for the test treatment
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703, Data on file 14 14

15. Tempo mediano alla prima riacutizzazione grave, moderata e lieve
M2-128 tiotropium
1.0
0.9
Probability of not experiencing
an exacerbation
0.8
Hazard ratio = 0.7
(IQR 0.5;1.0) p =
Note: Data not in paper
Key Message
Roflumilast given concomitantly with tiotropium as underlying maintenance medication significantly increased the time to first exacerbation (includes mild, moderate and severe exacerbations) over 6 months (p=0.0264) compared to tiotropium plus placebo
One possible reason why we see an effect on mild, moderate and severe exacerbations in the tiotropium study (M2-128) may be that this study had a highly symptomatic profile as inclusion criteria, and thus an overall greater proportion of more symptomatic patients vs M2-127.
0.7
tiotropium + placebo
tiotropium + roflumilast 500 µg
0.6 4 8 12 18 24
Weeks
A hazard ratio < 1 means a lower risk for the test treatment
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703, Data on file 15 15

16. FEV1 pre-bronchodilator FEV1 post-bronchodilator
S p e a k e r n o t e s
I n s t u d y M , r o f l u m i l a s t s i g n i f i c a n t l y i m p r o v e d p r e - a n d p o s t b r o n c h o d i l a t o r F E V 1 w h e n a d d e d t o t i o t r o p i u m , c o m p a r e d w i t h t i o t r o p i u m p l u s p l a c e b o ( p < ) .
T h e b e n e f i c i a l e f f e c t s o f r o f l u m i l a s t a n d l o n g - a c t i n g b r o n c h o d i l a t o r s a r e a d d i t i v e b e c a u s e t h e y w o r k v i a d i f f e r e n t m o d e s o f a c t i o n , m e a n i n g t h a t t h e a d d i t i o n o f r o f l u m i l a s t p r o v i d e s a d d i t i o n a l b e n e f i t s o v e r a n d a b o v e t h o s e a c h i e v e d u s i n g f i r s t - l i n e C O P D m a i n t e n a n c e t r e a t m e n t a l o n e .
I m p r o v e m e n t s i n l u n g f u n c t i o n w e r e s e e n w i t h i n w e e k s o f r o f l u m i l a s t t r e a t m e n t a n d w e r e s u s t a i n e d t h r o u g h o u t t h e s t u d y p e r i o d .
R e f e r e n c e
F a b b r i L M , C a l v e r l e y P M A , I z q u i e r d o - A l o n s o J L , e t a l . R o f l u m i l a s t i n m o d e r a t e - t o - s e v e r e c h r o n i c o b s t r u c t i v e p u l m o n a r y d i s e a s e t r e a t e d w i t h l o n g - a c t i n g b r o n c h o d i l a t o r s : t w o r a n d o m i z e d c l i n i c a l t r i a l s . L a n c e t ; : –
Roflumilast e tiotropio: aumento significativo del FEV1 pre- e post-broncodilatatore
FEV1 pre-bronchodilator
FEV1 post-bronchodilator
Fabbri LM, Calverley PMA, Izquierdo-Alonso JL , et al. Lancet 2009;374: 16

17. Speaker notes
In each study, an additive effect of roflumilast on reducing exacerbations was shown.
In studies M2-127 and M2-128, and approximately 50% of patients in M2-124/125, this effect was in addition to the benefit already achieved by COPD maintenance therapy with bronchodilators.
Reference
Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharm 2011;163:53-67.
Prevenzione delle riacutizazzioni con roflumilast in aggiunta ai broncodilatatori a lunga durata d’azione
LABA = Long-acting β2-agonist
SAMA = Short-acting muscarinic antagonist
Rabe KF. Br J Pharm 2011;163:53-67. 17

18. Speaker notes
In each study, roflumilast had an additive effect, improving lung function on top of the benefits already achieved with bronchodilator therapy.
Reference
Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharm 2011;163:53-67.
Miglioramento della funzionalità respiratoria con roflumilast in aggiunta ai broncodilatatori a lunga durata d’azione
LABA = Long-acting β2-agonist
SAMA = Short-acting muscarinic antagonist
Rabe KF. Br J Pharm 2011;163:53-67. 18