roflumilast in moderate-to-severe copd treated with long acting broncho dilators

8/6/2019 Roflumilast in Moderate-To-severe COPD Treated With Long Acting Broncho Dilators

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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

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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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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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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

roflumilast in moderate-to-severe copd treated with long acting broncho dilators

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