1. Roflumilast negli studi di Fase III: i dati di efficacia1

2. 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 pivotal phase III studies were designed to confirm the effects of roflumilast in the patient population identified in the analysis of the early studies.
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 longacting 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;374:685–694.
4.Fabbri LM, et al. Lancet 2009;374: 2

3. Gli studi M2-124 e M2-125 (12 mesi di durata)
Single-blind
Double-blind, randomized,
parallel group
Follow-up
4 weeks
Run-in 4 weeks
Roflumilast 500µg o.d.
Treatment
52 weeks R VE
Visit 0
Follow-up
Speaker notes
Patients were randomly assigned to receive roflumilast (500μg once daily) (n=1537) or placebo (n=1554) for 52 weeks.
After randomization, patients were assessed every 4 weeks up to week 12, and every 8 weeks thereafter.
Patients could use short-acting β2-agonists as needed and could continue treatment with long-acting β2-agonists (LABA) or short-acting anti-cholinergic drugs at stable doses. However, inhaled corticosteroids (ICS) and long-acting anti-cholinergic drugs were not allowed during the study.
Analysis was by intention to treat. Patients were stratified according to smoking status, previous use of inhaled corticosteroids (stopped before study start) and treatment with LABAs. Data from the two studies were analyzed separately and in a pooled analysis.
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. 3

4. Studi M2-124 e M2-125: popolazione in studio ed endpoint clinici
TWO PIVOTAL 12-MONTH STUDIES
PATIENTS (POOLED STUDY POPULATION N=3091):
COPD associated with chronic bronchitis*
History of exacerbations
Severe airflow limitation (FEV1 ≤50% of predicted)
TREATMENTS:
Once-daily roflumilast 500µg or placebo
Concomitant use of LABAs or regular short-acting bronchodilators allowed
PRIMARY ENDPOINTS:
Pre-bronchodilator FEV1
Exacerbation rate (moderate to severe)
Speaker notes
In response to observations from the early clinical studies, the pivotal 12-month studies2 were designed to investigate the effects of roflumilast in patients with severe COPD, symptoms of chronic cough and sputum, and a history of exacerbations.
Patient inclusion criteria included diagnosed COPD, severe airflow limitation, age ≥40 years, bronchitic symptoms, and a history of exacerbations.
Patients were randomly assigned to receive roflumilast (500μg once daily) (n=1537) or placebo (n=1554) for 52 weeks.
Primary endpoints were change in pre-bronchodilator FEV1 and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe.
Analysis was by intention to treat. Patients were stratified according to smoking status, previous use of inhaled corticosteroids (ICS, stopped before study start) and treatment with LABAs. Data from the two studies were analyzed separately and in a pooled analysis.
Reference
Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694.
*Chronic productive cough for 3 months in each of the 2 years prior to baseline visit
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

5. Demografia e caratteristiche dei pazienti al basale
Speaker notes
Patients in the roflumilast and placebo groups of the 12-month clinical studies had similar characteristics at baseline.
Around 60% of patients had severe COPD, with around 30% having very severe COPD, as defined by GOLD stages.
Reference
Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694.
Demografia e caratteristiche dei pazienti al basale
Data are expressed as mean (SD), unless otherwise stated
FEV1 = Forced expiratory volume in 1 second
FVC = Forced vital capacity
Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 5

6. Speaker notes
In a pooled analysis of the two 12-month clinical studies, roflumilast was associated with a mean 48mL improvement in pre-bronchodilator FEV1 levels compared with placebo (p<0.0001). This was the co-primary endpoint in the two 12-month clinical studies.
In addition, roflumilast significantly improved post-bronchodilator FEV1 levels compared with placebo (mean change of 55mL, p<0.0001).
The anti-inflammatory mode of action of roflumilast is different to that of bronchodilators. This means that roflumilast offers additional benefits for patients when added to bronchodilator therapy.
Reference
Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694.
Roflumilast: aumento significativo della funzionalità respiratoria dopo 12 mesi di terapia con roflumilast
Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 6

7. Miglioramento della funzionalità respiratoria dopo 4 settimane di terapia con roflumilast
Speaker notes
This graph shows the time-course of lung function in patients in Study M2-124.
Improvements in post-bronchodilator FEV1 were observed after 4 weeks of roflumilast treatment and were sustained throughout the 12-month treatment period.
At all time points between 4 and 52 weeks, post-bronchodilator FEV1 was significantly greater in patients treated with roflumilast than in placebo-treated patients.
Reference
Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694.
*Statistically significant difference from baseline
FEV1: Forced expiratory volume in 1 second
Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 7

8. Roflumilast: riduzione significativa del tasso di riacutizzazioni moderate e gravi
Co-primary endpoint: Exacerbation rate
Speaker notes
In a pooled analysis of the total population of the two 12-month clinical studies, roflumilast significantly reduced the rate of moderate or severe exacerbations by 17% compared with placebo (p=0.0003).
In addition to a significantly lower rate of exacerbations following roflumilast treatment, the time to onset of an exacerbation was significantly longer in patients receiving roflumilast than in patients receiving placebo (Hazard ratio 0.89, p=0.0185).
Reference
Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694.
Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 8

9. Speaker notes
These data were calculated in a post hoc analysis of pooled data from the 12-month roflumilast clinical studies.
Roflumilast significantly reduced the mean exacerbation rate (per patient per year) in all patient groups.
However, the effects of roflumilast were greatest in patients with ≥2 exacerbations in the previous year (1.51 with roflumilast vs 1.95 with placebo, a difference of -22.3%).
These data confirm that roflumilast has the greatest benefits in patients with a history of frequent exacerbations.
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: vantaggi clinici superiori nei pazienti con storia di frequenti riacutizzazioni
M2-124 and M2-125 pooled post hoc analysis
Bateman ED, Rabe KF, Calverley PMA, et al. Eur Respir J 2011, 38: 553–560 9