Roflumilast in moderatemoderatetoto-severe COPD treated with longacting bronchodilators: bronchodilators:

Two randomised clinical trials

1. Background


Actual Pharmacotherapy GOLD III-IV III

A. Longacting inhaled Bronchodilator

 a.

agonists (Formoterol and salmeterol  b. anticholinergic drug : tiotropium  c. theophylline  GOLD III-IV : 1-2x a + b (ou c) III1(ou
2

Inhaled glucocorticosteroids
 GOLD
  

IVIV-V 1+ recurrent exacerbations:

symptoms and exacerbations lung function Risk of pneumonia (??)

2. Physiopatho


PhosphodiesterasePhosphodiesterase-4 (PDE4) inhibitors = new class of antiantiinflammatory drugs

roflumilast = second-generation second inhibition of chemotaxis, leucocyte chemotaxis, activation, and cytokine production  neutrophils + eosino in the sputum  both lung function and exacerbations


(independent of the patient s smoking status or use of concomitant medication)

3. Methods A. Setting


A. Salmeterol plus roflumilast (M2-127) (M2

B. Tiotropium plus roflumilast (M2-128) (M2

135 centres in ten countries

85 centres in seven countries

3. Methods B. Patients


a. General Inclusion: Inclusion:

>40 years  Current/former smokers ( 1 year of smoking cessation) (min 10 UPA)  Thiefenaud < 0.70  FEV1 postbronchodilator = 40 70%Pred

 partial

reversibility
(?? Exacerbation ??)

Stable diseases (=4-week run in ?) (=4-

3. Methods B. Patients


b. Specific to tiotropium
chronic cough and sputum production,  frequent use of as-needed shortacting asagonists (>28 puffs/week)  Min 3 months

2

3. Methods C. Interventions


a. 4-week run-in 4runplacebo tablets once a day  Recorded :


 their

(compliance???)

use of shortacting bronchodilators  cough and sputum production



If no evidence of a moderate/severe exacerbation : randomly assigned

 to

roflumilast 500 g/j  Vs placebo for the subsequent 24 weeks

3. Methods D. Assessment


a. When ?
Every 4 weeks up to week 12  Every 6 weeks until week 24


3. Methods D. Assessment


b. What ? Study endpoints

1 : prebronchodilator FEV prebronchodilator  2: postbronchodilator FEV and FVC postbronchodilator

1 1

 Transition

dyspnoea index (TDI score)  Shortness of Breath Questionnaire (SOBQ)  Rate of COPD exacerbations
  

Mild > 3 puffs/day on at least 2 days Moderate : oral corticosteroids ( ATB) Severe : hospital or died

 Rescue

medications

Adherence to taking tablets

3. Methods E. Stastitical Analysis

Intention-toIntention-to-treat analysis  One-sided significance level of 2 5% One


Salmeterol :
 Power=97%

with sample size of 469 patients  = higher statistical power



Tiotropium
 Power=91%with

a sample size of 350 patients

4. Results A. Baseline characteristics

4. Results B. Discontinuation


Probability of discontinuation was patients treated with roflumilast

in

Significant (p=0.0019)

Not Significant (p=0.0864)

4. Results C. Primary + Sec. EP

4. Results D. Adverse Events

??

Total

671

598

373

287

Judged 83(18%) 14 (3%) related TTT

45 (12%) 6 (2%)

5. Conclusion A. Discussion


A) Good Points


Improves lung function

 Pre

+ postbronchodilator FEV suggests additive effect to bronchodilators  Postulate : suppression of inflammation (sputum neutrophils + eosino )  No effect on CRP / [Leuco]sg [Leuco]
1

= Efficacy in moderate-to-severe COPD moderate-towith longacting bronchodilators  PO = increased compliance



5. Conclusion A. Discussion


B) Bad Points


Effect on Lung F = small (~50ml) F

 similar

to by inhaled corticosteroids (on salmeterol) salmeterol) Compliance

Adverse effects of roflumilast (// theoph) theoph)

=

5. Conclusion A. Discussion


C) Controversial
Inclusion for tiotropium = + severe explain best effect in this study ? (avoid comparison btw both)  6-month treatment = too short for exacerbations  Low rate = biais selection ?


5. Conclusion B. Proposition


Comparison


+ inhaled corticosteroids

Comparison
Tiotropium + Salmeterol vs  Tiotropium + Roflumilast vs  Salmeterol + Roflumilast vs  Salmeterol + Tiotropium + Roflumilast