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RoflumilastRoflumilast in moderatein moderate--toto--severe COPD treatedsevere COPD treated
withwith longactinglongactingbronchodilatorsbronchodilators::TwoTwo randomisedrandomised clinicalclinical trialstrials
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1. Background1. Background
ActualActual PharmacotherapyPharmacotherapy GOLD IIIGOLD III--IVIV
A.A. LongactingLongacting inhaledinhaled BronchodilatorBronchodilator
a.a. 22agonistsagonists ((FormoterolFormoterol andand salmeterolsalmeterol
b.b. anticholinergicanticholinergic drugdrug :: tiotropiumtiotropium
c.c. theophyllinetheophylline
GOLD IIIGOLD III--IV : 1IV : 1--2x a + b (2x a + b (ouou c)c)
InhaledInhaled glucocorticosteroidsglucocorticosteroidsGOLD IVGOLD IV--V 1+V 1+ recurrentrecurrent exacerbations:exacerbations:
symptomssymptoms and exacerbationsand exacerbations
lunglung functionfunction
RiskRisk ofof pneumoniapneumonia (??)(??)
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2.2. PhysiopathoPhysiopatho
PhosphodiesterasePhosphodiesterase--4 (PDE4)4 (PDE4)inhibitors = new classinhibitors = new class of antiof anti--
inflammatoryinflammatory drugsdrugs roflumilastroflumilast = second= second--generationgeneration
inhibition ofinhibition of chemotaxischemotaxis,, leucocyteleucocyteactivation, andactivation, and cytokine productioncytokine production
neutrophilsneutrophils ++ eosinoeosino in thein the sputumsputum
both lung functionboth lung function and exacerbationsand exacerbations (independent of the patients smoking status or(independent of the patients smoking status oruse of concomitant medication)use of concomitant medication)
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3.3. MethodsMethodsA. SettingA. Setting
A.A. SalmeterolSalmeterol plusplusroflumilastroflumilast(M2(M2--127)127) 135135 centrescentres in ten countriesin ten countries
B.B. TiotropiumTiotropium plusplusroflumilastroflumilast(M2(M2--128)128) 85 centres in85 centres in sevenseven countriescountries
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a. General Inclusiona. General Inclusion::
>40 years>40 years
Current/former smokers (1 year ofCurrent/former smokers (1 year ofsmoking cessation) (min 10 UPA)smoking cessation) (min 10 UPA)
ThiefenaudThiefenaud
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b.b. SpecificSpecific toto tiotropiumtiotropium
chronic cough and sputum production,chronic cough and sputum production,
frequent use of asfrequent use of as--neededneeded shortactingshortacting 22
agonists (>28 puffs/week)agonists (>28 puffs/week)
Min 3 monthsMin 3 months
3.3. MethodsMethodsB. PatientsB. Patients
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a. 4a. 4--weekweek runrun--inin
placebo tablets once a dayplacebo tablets once a day (compliance???)(compliance???)
Recorded :Recorded : their use oftheir use of shortactingshortacting bronchodilatorsbronchodilators
coughcough andand sputumsputum productionproduction
If noIf no evidence of a moderate/severeevidence of a moderate/severe
exacerbation : randomly assignedexacerbation : randomly assigned toto roflumilastroflumilast 500500 gg/j/j
Vs placebo for the subsequent24 weeksVs placebo for the subsequent24 weeks
3.3. MethodsMethodsC. InterventionsC. Interventions
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a. When ?a. When ?
Every 4 weeks up to week 12Every 4 weeks up to week 12
Every 6 weeks until week 24Every 6 weeks until week 24
3.3. MethodsMethodsD.D. AssessmentAssessment
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b. What ?b. What ? StudyStudy endpointsendpoints
11 :: preprebronchodilatorbronchodilator FEVFEV11
22:: postpostbronchodilatorbronchodilator FEVFEV11
and FVCand FVC TransitionTransition dyspnoeadyspnoea index (TDI score)index (TDI score)
Shortness of Breath Questionnaire (SOBQ)Shortness of Breath Questionnaire (SOBQ)
Rate of COPD exacerbationsRate of COPD exacerbations
Mild > 3 puffs/day on at least2 daysMild > 3 puffs/day on at least2 days Moderate : oral corticosteroids ( ATB)Moderate : oral corticosteroids ( ATB)
Severe : hospital or diedSevere : hospital or died
RescueRescue medicationsmedications
Adherence to taking tabletsAdherence to taking tablets
3.3. MethodsMethodsD.D. AssessmentAssessment
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4.4. ResultsResultsA.A. Baseline characteristicsBaseline characteristics
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4.4. ResultsResultsB. DiscontinuationB. Discontinuation
ProbabilityProbability ofof discontinuation wasdiscontinuation was ininpatients treated withpatients treated with roflumilastroflumilast
Significant (p=0.0019) Not Significant (p=0.0864)
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4.4. ResultsResultsCC.. PrimaryPrimary + Sec. EP+ Sec. EP
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4.4. ResultsResultsDD. Adverse Events. Adverse Events
671 598 373 287
??
Total
Judgedrelated TTT 83(18%) 14 (3%) 45 (12%) 6 (2%)
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5. Conclusion5. ConclusionA. DiscussionA. Discussion
A) Good PointsA) Good Points
ImprovesImproves lunglung functionfunction
PrePre ++ postbronchodilatorpost
bronchodilator FEVFEV
11
suggestssuggestsadditive effect toadditive effect to bronchodilatorsbronchodilators
Postulate :Postulate : suppression of inflammationsuppression of inflammation((sputumsputum neutrophilsneutrophils ++ eosinoeosino ))
NoNo effect on CRP / [effect on CRP / [LeucoLeuco]]sgsg
= Efficacy in moderate= Efficacy in moderate--toto--severe COPDsevere COPDwithwith longactinglongacting bronchodilatorsbronchodilators
PO =PO = increased complianceincreased compliance
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5. Conclusion5. ConclusionA. DiscussionA. Discussion
B) Bad PointsB) Bad Points
EffectEffect on Lung Fon Lung F == smallsmall (~50ml)(~50ml)
similar tosimilar to by inhaled corticosteroids (on
by inhaled corticosteroids (onsalmeterolsalmeterol))
AdverseAdverse effects ofeffects of roflumilastroflumilast (//(// theophtheoph))
= Compliance= Compliance
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5. Conclusion5. ConclusionA. DiscussionA. Discussion
C)C) ControversialControversial
Inclusion forInclusion for tiotropiumtiotropium = + severe= + severe
explain
best effect in this study ? (avoide
xplain
best effect in this study ? (avoidcomparison btw both)comparison btw both)
66--month treatment = too short formonth treatment = too short forexacerbationsexacerbations
Low rate =Low rate = biaisbiais selection ?selection ?
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5. Conclusion5. ConclusionB. PropositionB. Proposition
ComparisonComparison
++ inhaled corticosteroidsinhaled corticosteroids
ComparisonComparison TiotropiumTiotropium ++ SalmeterolSalmeterol vsvs
TiotropiumTiotropium ++ RoflumilastRoflumilast vsvs
SalmeterolSalmeterol ++RoflumilastRoflumilast vsvs
SalmeterolSalmeterol ++ TiotropiumTiotropium ++ RoflumilastRoflumilast