1. Identificazione del sottogruppo di pazienti responsivi1

2. Fenotipi clinici della BPCO
“a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, and rate of disease progression or death)”
predictive value
prospectively validated for each of the outcomes to which they may relate
able to classify patients into distinct subgroups that provide prognostic information and allow physicians to better determine the most appropriate therapy to improve clinically meaningful outcomes
Han MK et al., AJRCCM 2010

3. Definizione delle riacutizzazioni della BPCO
COPD EXACERBATIONS WERE CLASSIFIED IN CLINICAL STUDIES AS FOLLOWS:
‘Severe’ COPD exacerbation
Requiring hospitalisation and/or leading to death
‘Moderate’ COPD exacerbation
Initiation of oral or parenteral glucocorticosteroid therapy required
Speaker notes
The rate of moderate to severe exacerbations was measured in the roflumilast phase III clinical studies.1-4
This ‘event-based’ classification of exacerbations defines the severity of each exacerbation according to the change in medication needed.5
This type of classification does not capture exacerbations that do not require a change in medications, but is more useful in clinical studies than alternative approaches that use patients’ symptoms to define exacerbation severity.5
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.
Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694.
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.
Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18.
Pauwels R, Calverley P, Buist AS, et al. COPD exacerbations: the importance of a standard definition. Respir Med 2004;98:99–107. 3

4. Gli studi M2-111 e M2-112 R VE Treatment 52 weeks Visit 0 Follow-up
Roflumilast 500µg o.d.
Follow-up
30 days
Placebo o.d.
Treatment
52 weeks VE
Visit 0 R
Follow-up
Baseline
4 weeks
Speaker notes
In two replicate randomized, placebo-controlled, double-blind, parallel-group trials, 2686 patients (1173 in M2-111) and 1513 in M2-112) with COPD (post-bronchodilator FEV1 ≤50% predicted; post-bronchodilator FEV1:FVC ratio ≤70%) were randomized to roflumilast or placebo once-daily for 12 months.
It is important to note that unlike the pivotal 12-month phase III studies, patients in this study were not required to have symptoms of chronic bronchitis or a history of exacerbations.
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. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18.
Placebo o.d.
Allowed concomitant medication: ICSs (≤2000µg BDP or equivalent)
Approximately 60% of all patients were on ICS treatment
R = randomization ICS = Inhaled corticosteroids
VE = Visit end BDP = Beclomethasone dipropionate
o.d. = once daily
Calverley PMA, Sanchez-Toril F, McIvor A, et al. Am J Respir Crit Care Med 2007;176: 4

5. Le analisi per identificare i pazienti responsivi
Speaker notes
In the pooled analysis of M2-111 and M2-112, the effects of roflumilast on the co-primary endpoints (pre-bronchodilator FEV1 and exacerbation rate) were analyzed based on a number of patient characteristics.
Reference
Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18.
Le analisi per identificare i pazienti responsivi
The co-primary endpoints (pre-bronchodilator FEV1 and rate of moderate or severe exacerbations per patient per year) were analyzed additionally in subgroups stratified by:
Sex
Smoking status
Concomitant use of ICS
Concomitant use of anticholinergics
Study completion status
COPD severity (severe, very severe)
History of chronic bronchitis or emphysema (investigator diagnosed)
Cough/sputum score one week before randomization
ICS = Inhaled corticosteroids
Rennard et al, Respiratory Research 2011; 12: 18. 5

6. Roflumilast: riduzione delle riacutizzazoni in base ai sottogruppi
Speaker notes
Among the variables analyzed, the presence of chronic bronchitis (symptoms of chronic cough and sputum) was found to correlate with a greater reduction in exacerbation rate compared with the absence of these symptoms
Presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001)
Presence of cough (20.9% decrease, p = 0.006)
Presence of sputum (17.8% decrease, p = 0.03)
Reference
Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18.
Roflumilast: riduzione delle riacutizzazoni in base ai sottogruppi
Rennard et al, Respiratory Research 2011; 12: 18. 6

7. Patients with chronic brochitis with/without emphysema
Speaker notes
Among the variables analyzed, the presence of chronic bronchitis (symptoms of chronic cough and sputum) was found to correlate with a greater reduction in exacerbation rate compared with the absence of these symptoms.
Overall, patients with chronic bronchitis experienced a 26.2% reduction in exacerbations compared with 1.1% reduction in patients with emphysema only and no chronic bronchitis.
Reference
Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18 .
L’effetto di roflumilast sulle riacutizzazioni nei pazienti con bronchite cronica (tosse ed espettorato)
Patients with
emphysema
Patients with chronic brochitis with/without emphysema
All patients
Rennard et al, Respiratory Research 2011; 12: 18. 7

8. L’evoluzione del programma di sviluppo clinico
IDENTIFICATION OF TARGET PATIENT POPULATION
Confirmatory
1-yr pivotal studies
M2-124, M2-125
Subgroup analyses of
early phase III studies
M2-111, M2-112
Speaker notes
Based on findings from the early clinical studies, patients with chronic bronchitis were identified as the target patient population for the pivotal phase III studies.
Patients also had severe airflow limitation and a history of exacerbations, two additional factors known to increase the risk of exacerbations in patients with COPD.
Hypothesis
Generation
Severe/very severe patients
History of chronic cough and sputum
History of exacerbations 8