1. Roflumilast: il programma di sviluppo clinico1

2. Il programma di sviluppo clinico
Dose ranging 6 month studies:
RECORD

3. RECORD: studio dose-ranging della durata di 6 mesi
S p e a k e r N o t e s
The RECORD study was a phase III, multicentre, double-blind, randomized, placebo-controlled study, undertaken in an outpatient setting.
Patients with COPD were randomly assigned roflumilast 250μg (n=576), roflumilast 500μg (n=555), or placebo (n=280), given orally once daily for 24 weeks.
Primary endpoints were changes in post-bronchodilator FEV1 levels and health-related quality of life (measured by the St George’s Respiratory Questionnaire, SGRQ, score).
The number of exacerbations in each treatment group was measured as a secondary endpoint.
Patient inclusion criteria:
Patients with COPD for ≥12 months and who were ≥40 years of age
Post-bronchodilator FEV1/FVC ≤70% and FEV % of predicted (FEV1 = forced expiratory volume in one second, FVC = forced vital capacity)
Smoking history (≥10 pack years) and current or ex-smoker
No change in COPD treatment in previous 4 weeks.
R e f e r e n c e
Rabe KF, Bateman ED, O’Donnell D, et al. Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2005;366:
RECORD: studio dose-ranging della durata di 6 mesi
Phase III, multicentre, double-blind, randomized, placebo- controlled
1,411 patients with COPD treated for 24 weeks
Run-in period
24 weeks
Follow-up
4 weeks
Roflumilast 500 µg OD
Placebo o.d.
Roflumilast 250 µg OD
Placebo o.d.
OD = Once daily
Rabe KF, Bateman ED, O’Donnell D, et al. Lancet. 2005;366: 3

4. Studio RECORD: miglioramento della funzionalità respiratoria con roflumilast nei pazienti con BPCO moderata e severa
Speaker notes
The RECORD study was a phase III, multicentre, double-blind, randomized, placebo-controlled study, undertaken in an outpatient setting.
Patients with COPD were randomly assigned roflumilast 250μg (n=576), roflumilast 500μg (n=555), or placebo (n=280), given orally once daily for 24 weeks.
Primary endpoints were changes in post-bronchodilator FEV1 levels and health-related quality of life (measured by the St George’s Respiratory Questionnaire, SGRQ, score).
The number of exacerbations in each treatment group was measured as a secondary endpoint.
Post-bronchodilator FEV1 improved significantly by 74mL with roflumilast 250μg and by 97mL with roflumilast 500μg, compared with placebo (p<0.0001).
Health-related quality of life measured by total SGRQ score improved with both doses of roflumilast, although the differences between treatment groups were not significant.
Most adverse events were mild to moderate in intensity, and resolved during the study.
Reference
Rabe KF, Bateman ED, O’Donnell D, et al. Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2005;366:
* p<0.05 vs baseline
Rabe KF, Bateman ED, O’Donnell D, et al. Lancet 2005;366: 4

5. Studio RECORD: riduzione del numero di riacutizzazioni con roflumilast nei pazienti con BPCO moderata e severa
Speaker notes
The mean number of exacerbations (mild, moderate and severe) per patient was significantly lower in patients taking roflumilast 250μg and roflumilast 500μg compared with patients taking placebo (p=0.0029).
Patients taking the higher dose of roflumilast had 34% fewer exacerbations than patients taking placebo.
However, the effect of roflumilast on exacerbations was measured as a secondary endpoint in this study, and required further investigation in phase III studies.
Reference
Rabe KF, Bateman ED, O’Donnell D, et al. Roflumilast - an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2005;366:563–571.
* p<0.05
Rabe KF, Bateman ED, O’Donnell D, et al. Lancet 2005;366: 5

6. Studio RECORD: miglioramento della qualità di vita con roflumilast
Improvement *
-1.0
Placebo
-2.0
***
Change in total SGRQ† score
-3.0
Roflumilast 250µg
Roflumilast 500µg
Speaker Notes
Health-related quality of life was assessed by the St George’s Respiratory Questionnaire (SGRQ).
Total scores significantly improved during the study with all treatments. A difference of 4 SGRQ units is considered clinically relevant, although the suitability of this questionnaire as a tool to measure quality of life in patients with COPD has been debated.
Least squares means were greater with roflumilast 250μg (-3.4 units, SD 0.6, ) and roflumilast 500μg (-3.5 units, SD 0.6) than with placebo (-1.8 units, SD 0.8), although the differences between treatment groups were not significant.
Reference
Rabe KF, Bateman ED, O’Donnell D, et al. Roflumilast - an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2005;366:563–571.
-4.0
***
-5.0 6 12 18 24
Time (weeks)
LS Mean and SEM * p<0.05, *** p< for change versus baseline
† SGRQ = St George’s Respiratory Questionnaire
Rabe KF, Bateman ED, O’Donnell D, et al. Lancet 2005;366: 6

7. Dose ranging 6 month studies: Early phase III studies:
Sviluppo clinico: dagli studi di dose-ranging ai primi studi di Fase III
Dose ranging 6 month studies:
RECORD
Early phase III studies:
M2-111 & M2-112

8. Gli studi M2-111 e M2-112: disegno dello studio
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: 8

9. Speaker notes
The two 12- month, randomized, double-blind, parallel group studies were identical in study design with the exception of the classification used for COPD severity. For M2-111, American Thoracic Society diagnostic criteria were used and for M2-112, the GOLD diagnostic criteria.
Each study began with a 4 week, single-blind run-in period during which patients received placebo. Patients were then randomly assigned to roflumilast 500 µg once daily or placebo for 52 weeks.
Patients were allowed to continue treatment with SAMA and ICS (≤2000µg beclomethasone dipropionate or equivalent) if taken on a regular basis at a constant daily dose for at least 3 months prior to study entry. About 60% of patients concomitantly received ICS during the studies.
The definition of smoking history used in these studies was as follows:
Current or ex-smoker (stopped smoking ≥1 year ago) with a smoking history of ≥10 pack years.
‘Clinically stable’ was defined as no exacerbation and no change in COPD treatment within 4 weeks prior to first baseline visit.
Some of the main exclusion criteria were:
COPD exacerbation indicated by a treatment with systemic glucocorticosteroids not stopped 4 weeks prior to the baseline visit B0
Lower respiratory tract infection not resolved 4 weeks prior to the baseline visit B0
Diagnosis of asthma and/or other relevant lung disease.
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.
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.
Gli studi M2-111 e M2-112
Two 12-month randomized, double-blind, parallel-group studies
Following a 4-week, single blind run-in period, patients were randomized to receive roflumilast 500µg or placebo once daily for 52 weeks
Allowed concomitant medication: ICS and SAMA (if used at stable doses before study entry)
Key inclusion criteria:
Patients ≥ 40 years, current or ex-smoker (≥ 10 pack years)
COPD as defined by ATS (M2-111) or GOLD (M2-112)
Clinically stable with unchanged COPD treatment within 4 weeks of baseline
Post-bronchodilator FEV1 ≤ 50% predicted; post-bronchodilator FEV1:FVC ratio ≤ 0.70
No history of exacerbations required
ICS = Inhaled corticosteroids - SAMA = Short-acting antimuscarinic antagonists
FEV1 = Forced expiratory volume in 1 second - FVC = Forced vital capacity
Rennard et al, Respiratory Research 2011; 12: 18. 9

10. Gli studi M2-111 e M2-112: endpoint primari dell’analisi congiunta
Speaker notes
Co-primary endpoints the pooled analysis of M2-111 and M2-112were:
Pre-bronchodilator forced expiratory volume in 1 second (FEV1)
Number of exacerbations per year
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.
Gli studi M2-111 e M2-112: endpoint primari dell’analisi congiunta
Pre-bronchodilator FEV1
Evaluated using repeated measures of ANCOVA
Rate of moderate or severe exacerbations per patient year
Exacerbations defined by the need for treatment with oral or parenteral corticosteroids (moderate), or requiring hospitalization and/or leading to death (severe)
Evaluated using a Poisson regression model
ANCOVA = Analysis of variance
Rennard et al, Respiratory Research 2011; 12: 18. 10

11. Speaker notes
FEV1 reversibility to short-acting beta2-agonists was similar in both treatment groups.
As the inclusion criteria of FEV1 reversibility to short-acting beta2-agonists ≤15% was defined only in study M2-112, mean reversibility was lower in M2-112 (11%) than in M2-111 (19%).
All other characteristics were comparable between groups.
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.
Studi M2-111 e M2-112: demografia e caratteristiche basali dell’analisi congiunta
Data are expressed as mean (SD), unless otherwise stated; SAMA = Short-acting antimuscarinic antagonists
FEV1 = Forced expiratory volume in 1 second; FVC = Forced vital capacity
Rennard et al, Respiratory Research 2011; 12: 18. 11

12. Speaker notes
For the overall population, pre-bronchodilator and post-bronchodilator FEV1 improved with roflumilast compared to placebo by 51 mL (p<0.0001) and 53 mL (p<0.0001).
The improvement was evident at Week 4 (first measured time point) and maintained throughout the 52 weeks of the studies.
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.
Risultati dell’analisi congiunta: miglioramento del FEV1 pre- e post-broncodilatore
Pre-bronchodilator FEV1
Post-bronchodilator FEV1
FEV1 = Forced expiratory volume in 1 second
Rennard et al, Respiratory Research 2011; 12: 18. 12

13. Speaker notes
No statistically significant differences in exacerbation rate (moderate or severe) were seen between roflumilast and placebo when the early phase III clinical studies were analyzed individually.
The pooled analysis revealed a statistically significant reduction of 14.3% (95% CI -25 to -2; p=0.026) in the exacerbation rate.
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.
Risultati dell’analisi congiunta: riduzione del tasso di riacutizzazioni
Study M2-111
Study M2-112
Pooled analysis post-hoc
*Moderate or severe exacerbations treated with systemic steroids or leading to hospitalization or death
Rennard et al, Respiratory Research 2011; 12: 18. 13