改善UPDRS Ⅲ评分、增加反应持续时间、降低左旋多巴用量、使左旋多巴每日给药次数维持稳定

改善UPDRS Ⅲ评分、增加反应持续时间、降低左旋多巴用量、使左旋多巴每日给药次数维持稳定 改善UPDRS ?评分、增加反应持续时间、降低左旋多巴用 量、使左旋多巴每日给药次数维持稳定 JNeuralTransm(2008)115:843–849DOI10.1007/s00702-008-0025-8 PARKINSON’SDISEASEANDALLIEDCONDITIONS-ORIGINALARTICLE Five-yearef?cacyandsafetyoflevodopa/DDCIandentacaponeinpatientswithParkinson’sdisease ?ki?DavidJ.Brooks?MikaLeinonen?MikkoKuoppama HelenaNissinen Received:16May2007/Accepted:18January2008/Publishedonline:8February2008óSpringer-Verlag2008 AbstractThiswasaretrospectivepooledanalysisofdatafromfourcomparablydesigned,double-blind,placebo-controlled,PhaseIIIstudiesandtheirlong-termopen-labelextensions.Patientsonlevodopaandadopadecarboxylaseinhibitor(DDCI)wererandomizedtoentacaponeortoplacebointhe6-month,double-blindphase,withallpatientssubsequentlyreceivingentacaponeintheexten-sionphase.UPDRSIIImotorscoresimprovedby-2.1pointsduringthe?rst6monthsoflevodopa/DDCIandentacaponetherapy,andremainedbelowbaselineforupto2years.Increaseddaily‘ON’time,togetherwithresponseduration —————————————————————————————————————————————————— ——— toasinglemorningdoseoflevodopaandclinicalglobalevaluation,alsosupportedthelong-termef?cacyoflevodopa/DDCIandentacapone.Themeandailydoseoflevodopadidnotincreaseoverthe5-yearfollow-upperiod. Long-termtherapywithlevodopa/DDCIandentacaponewaswell-tolerated. KeywordsEntacaponeáLevodopaá Parkinson’sdiseaseáLong-termef?cacyáWearing-off Introduction Levodoparemainsthemosteffectiveandbest-toleratedtreatmentforParkinson’sdisease(PD)(Olanowetal.2004),andistheonlyagentwithaprovenpositiv eimpactonthemortalityratesofPDpatients(Rajput2001).Anumberofdouble-blind,levodopa-controlledtrialsofearlydopamineagonistmonotherapyhaveconsistentlyshownthatlevodopaprovidessuperiorsymptomaticef?cacyasassessedbyUni?edParkinson’sDiseaseRatingScale(UPDRS)II(activitiesofdai lyliving[ADL]),III(motor)andtotalscores.However,chronictreatmentwithlevodopaisassociatedwithanincreasedriskofmotorcomplications,suchaswearingoffanddyskinesia(Braccoetal.2004;Hollowayetal.2004;Oerteletal.2006;Rascoletal.2000). LongitudinalstudiesoflevodopainPDpatientsdem-onstrateagradualdeclineinpatientfunction(assessedbyUPDRSscores)overtimeandthecontinualnee—————————————————————————————————————————————————— ——— dtoadjustdopaminergicmedications(Alvesetal.2005;Goetzetal.2000).Withadvancingdisease,PDpatientsareoftenpre-scribedincreasinglyhigherandmorefrequentlevodopadosesinanattempttoprovidethemwithsustainedlevo-dopabioavailabilityandtomaintainsymptomcontroloverthecourseoftheday.However,althoughthesemodi?ca-tionstrategiescanbeusefulintheshort-term,thereisgeneralagreementthattheyareinsuf?cientinthelong-term(Stocchi2006;Olanowetal.2006).Forexample, D.J.Brooks DivisionofNeuroscience,FacultyofMedicine, ImperialCollege,HammersmithHospital,London,UKM.Leinonen 4PharmaAB,Kista,Sweden?kiM.Kuoppama OrionPharma,Turku,Finland ?kiM.Kuoppama DepartmentofNeurology,TurkuUniversityHospital,Turku,Finland H.Nissinen OrionPharma,Espoo,Finland D.J.Brooks(&) HartnettProfessorofNeurology,ImperialCollege, HammersmithHospital,DuCaneRoad,CyclotronBuilding,W120NNLondon,UK e-mail:david.brooks@csc.mrc.ac.uk —————————————————————————————————————————————————— ——— 123 844JNeuralTransm(2008)115:843–849 dosefractionationmayleadtosuboptimallevodopaexposure,whichisoftenassociatedwithwearing-offsymptoms.Ontheotherhand,continuallyincreasingthesizeofindividuallevodopadosesusuallyleadstoincreasedseverityofdyskinesiaswithoutmarkedprolongationoftherapeuticbene?t(Stocchi2006). Fourplacebo-controlled,randomized,double-blind,6-month,PhaseIIIstudieshavedemonstratedthatlevodopa/dopadecarboxylaseinhibitor(DDCI)andentacaponetherapyisaneffectivemanagementstrategyforPDpatientsexperiencingre-emergenceofsymptomsduetowearing-off,providingsigni?cantbene?tsintermsofsymptomcontrolcomparedwithconventionallevodopa/DDCItherapy(Brooksetal.2003;Poeweetal.2002;PSG1997;Rinneetal.1998).Inthesestudies,daily‘ON’-timeincreasedbyupto1.4hcomparedwithlevodop a/DDCIandplacebo,withacorrespondingreductionin‘OFF’-time.Insomeinst ancesthiswasaccompaniedbyuptothree-pointreductionsinUPDRSIIIscoresmeasuredduringthebest‘ON’(Rinneetal.1998).Theseclinicallyrelevantimprovementswereseendespiteeffortstooptimizelevodopaandotherantiparkinsoniantherapypriortoran-domization,andsubsequentreductionsinmeandailylevodopadoseduringthetrials. —————————————————————————————————————————————————— ——— Aspartofthedesignofthesedouble-blindPhaseIIItrials,open-labelsafetyandef?cacyextensionperiodswereincluded.Todate,safetyandef?cacydatahavebeenpublishedfromonlyoneoftheseopen-labelextensionstudiescoveringaperiodof3years(Larsenetal.2003).Herewepresentapooledanalysisofthefourdouble-blindPhaseIIIstudiesandtheiropen-labelextensions,inorder toevaluatetheef?cacyandsafetyoflong-termlevodopa/DDCIandentacaponetherapyinpatientswithPD. MaterialsandmethodsStudydesign Pooleddataoffourcomparablydesigned,randomized,double-blind,placebo-controlledPhaseIIIstudies(Brooksetal.2003;Poeweetal.2002;PSG1997;Rinneetal.1998)andtheirlong-term,open-labelextensions(upto5years),wereanalysed.AnoverviewofthedesignofthesefourstudiesinpresentedinTable1.Theprotocolsoftheoriginalstudieswerealldesignedtoensurethatresultswerere?ectiveofabroadrangeofPDpatientsexperi-encingwearing-offwhilsttreatedwithconventionallevodopaandotherantiparkinsoniantherapies.Allfourstudieshada6-month,double-blindphasewhenpatientsonlevodopa/DDCIwererandomizedtoentacaponeortoplacebo.Followingawashoutperiodofapproximately2weeks,allpatientsconsentingfortheextensionphasesubsequentlyreceivedopen-labellevodopa/DDCIandentacaponetreatmentforupto5years.Theopen-labelextensionphasewasadministrativelyterminatedcount—————————————————————————————————————————————————— ——— ry-by-country,whenmarketingapprovalforthestudymedi-cation(entacapone,OrionPharma,Espoo,Finland)wasgranted.Writteninformedconsentwasobtainedfromeachpatient.ThestudiesfollowedtheguidelinesoftheDecla-rationofHelsinkiandwereapprovedbytheEthicsCommitteesoftheparticipatingcentres. Table1OverviewofthedesignoffourPhaseIIIstudiesevaluatingtheef?cacyandsafetyoflong-termlevodopa/DDCIandentacaponetherapyinpatientswithPDStudy/Author Double-blind(DB)phase Open-labelphase Population NumberofpatientsenrolledinDB/openlabelphaseDB:103+102Open:170DB:85+85Open:132DB:197+104Open:186DB:203+97Open:161 PSG1997 Twoparallelgroups:levodopa/DDCIwithentacaponeorplacebo(1:1)for6monthsTwoparallelgroups:levodopa/DDCIwithentacaponeorplacebo(1:1)for6monthsTwoparallelgroups:levodopa/DDCIwithentacaponeorplacebo(2:1)for6monthsTwoparallelgroups:levodopa/DDCIwithentacaponeorplacebo(2:1)for6months —————————————————————————————————————————————————— ——— Open-labelentacaponewithlevodopa/DDCIforupto60monthsOpen-labelentacaponewithlevodopa/DDCIforupto56monthsOpen-labelentacaponewithlevodopa/DDCIforupto28monthsOpen-labelentacaponewithlevodopa/DDCIforupto24months Levodopa-responsivepatientswithmotor?uctuations Rinneetal.1998 Levodopa-responsivepatientswithmotor?uctuations Poeweetal.2002 Levodopa-responsivepatientswithorwithoutmotor?uctuations(14%withoutmotor?uctuations)Levodopa-responsivepatientswithorwithoutmotor?uctuations(43%withoutmotor?uctuations) Brooksetal.2003 DDCIdopadecarboxylaseinhibitor 123 JNeuralTransm(2008)115:843–849Patientpopulationandstudytreatment Detailsoftheinclusionandexclusioncriteria,similaracrossthefourstudies,havebeenreportedelsewhere(Brooksetal.2003;Poeweetal.2002;PSG1997;Rinneetal.1998).Brie?y,levodopa-responsivepatientswithidiopathicPDaged—————————————————————————————————————————————————— ——— 30–80yearswereincluded.PatientswerealsorequiredtohavePDsymptomsthatwerenotadequatelycontrolledbytheirindividuallytailoredlevo-dopa/DDCItherapy,andotherantiparkinsoniantherapies.Bothcarbidopaandbenserazidepreparationswereallowed.Controlled-release(CR)levodopawaspermittedintwoofthedouble-blindstudies(Brooksetal.2003;Poeweetal.2002)andallsafetyextensionstudies(Larsenetal.2003).Concomitanttreatmentwithamantadine,anticholiner-gics,theMAO-Binhibitorselegilineanddopamineagonists(exceptapomorphine)waspermitted.Thedosesofalltheseantiparkinsoniandrugsalongwithlevodopa/DDCIweretobekeptconstantforatleast4weekspriortorandomization.Theuseofneuroleptics,neurolepticantie-metics,catechol-structureddrugs,MAO-Ainhibitorsornon-selectiveMAOinhibitorswasprohibited. Thelevodoparegimen(andotherindividualantipar-kinsonianmedications)wasoptimizedaccordingtothetreatingphysicians’normalclinicalpracticepriortostudyentry.Entacapone200mg(orplaceboindouble-blindstudies)wasgivenconcomitantlywitheachdailydoseoflevodopa.Duringeachstudy,thelevodopadosecouldbeindividuallyadjusted,whenclinicallyindicated,byeitherchangingthelevodopadoseordosingfrequency. Ef?cacyassessments Long-termef?cacywasassessedbycomparingfollow-updatawithbaselineval—————————————————————————————————————————————————— ——— ues.Baselineforthepatientpopu-lationinthispooledanalysiswasde?nedasthe?rstvisitpriortothestartoflevodopa/DDCIandentacaponetreat-ment(i.e.atthestartofthedouble-blindphaseforpatientsonlevodopa/DDCIinitiallyrandomizedtoreceiveent-acapone,andatthestartofopen-labelphaseforpatientsonlevodopa/DDCIinitiallyrandomizedtoreceiveplacebo).Allpatientsenrolledtotheopen-labelstudieswereinclu-dedintheef?cacyanalysisuntilthetimepointwhenonlytenorfewerpatientswereavailableforfollowup(averageof56months). Herewepresenttheresultsoftheef?cacymeasureswhichwereevaluatedduringboththedouble-blindandopen-labelextensionphases.UPDRSIIImotorscores(n=485atbaseline)wereavailablefromthreeofthestudies(Poeweetal.2002;PSG1997;Rinneetal.1998).UPDRSscoreswererecordedonaverage1.7hafterintakeoflevodopawhenpatientswereattheirbest‘ON’-state. 845 Globalclinicalimpressionscores(n=647atbaseline)andmeandailylevodopadoses(n=649atbaseline)wererecordedinallstudies(Poeweetal.2002;PSG1997;Rinneetal.1998).Theresponsedurationofthe?rstsinglemorningdoseoflevodopa/DDCIandentaca-pone(n=129)wasmeasuredinonedouble-blindstudyanditsopen-labelextensionphase(Larsenetal.2003;Rinneetal.1998). Safetyandtolerability —————————————————————————————————————————————————— ——— Allpatientshavingreceivedatleastonedoseoflevodopa/DDCIandentacaponewereincludedinthesafetyanalysis.Safetyandtolerabilitywereassessedateveryvisitbymonitoringlaboratorysafetyparameters,vitalsigns,ECGandadverseevents(AEs).Particularattentionwaspaidtohepaticsafety,includinganalysesofSGOT/AST(aspartateaminotransferase),SGPT/ALT(alanineaminotransfer-ase),GGT(gamma-glutamyltransferase),alkalinephosphataseandbilirubin.Potentialclinicallysigni?cantincreasesintheseparameterswerede?nedaslevelsthreetimesaboveuppernormallimits.Adverseeventswereclassi?edbySystemOrganClassesandbyPreferredTermusingtheWHOcodingsystem. Statisticalanalysis Thecurrentanalysisincludesallpatientsenrolledinthedouble-blindandopen-labelextensionperiodsofthefourlarge-scalePhaseIIItrials.Alldatawereincludedinalltheef?cacyanalyseswithnoselectionofpatients.Allpatientsenrolledtotheopen-labelstudieswereincludedintheef?cacyanalysisandallpatientswhoreceivedatleastonedoseofstudymedication,regardlessoftheirparticipationintotheextensionstudy,wereincludedinthesafetyanalysis.Onlyobservedcaseswereused,withnoimputa-tionsformissingdata. ResultsBaselinedata Ofthe806patientswhocompletedthedouble-blindperiod,649patients(402—————————————————————————————————————————————————— ——— male,247women)continuedintheopen-labelextensionperiodofthestudies,andwereincludedintheef?cacyanalysis(Fig.1).Atbaseline,themeanage(SD)ofthepatientswas63.1(?9.4)yearsandthedurationofPDwas9.5(?5.2)years.Themeandailydoseoflevodopawas678(?363)mg.Morethanhalfofpatients(54.5%)wereusingdopamineagonistsand41.4%were 123 846Fig.1Patient?owchart usingselegiline.Atotalof83.9%ofpatientsshowedHoehnandYahrstagingof2–3.ThemeanUPDRSpartIII(motor)scorewas24.2(?12.8)pointsatbaselineandthemeanresponsedurationtoamorningdoseoflevodopawas2.2(?0.7)hours(Table2). Ef?cacy PooledanalysisoftheUPDRSIIIscoresshowedaninitialmeanimprovementof-2.1(?7.3)pointsduringthe?rst6monthsoflevodopa/DDCIandentacaponetherapy.Thereafter,UPDRSIIIscoresdeterioratedatarateofapproximately1.0point/year,remainingbelowbaselineforupto2years(Fig.2). Thedurationofresponsetothe?rstsinglemorningdoseoflevodopa/DDCIandentacaponetreatmentincreasedfrom2.2?0.7atbaselineto2.8?0.6hat6months,andwasconsistentlylongercomparedwithbaselinethroughoutthefollo—————————————————————————————————————————————————— ——— w-upperiod(Fig.3). Globalclinicalassessmentindicatedthat,comparedwithbaseline,77.1%ofpatientsonlevodopa/DDCIandentacaponetherapywereeitherimprovedorunchangedat6months.Thisproportionremainedstable(range67.8–84.0%)foru pto52months. Figure4showsthemeandailylevodopadoseinpatientsduringthestudyperiod.Followinginitiationoflevodopa/DDCIandentacapone,themeandailylevodopadosecouldbereducedby68(?169)mgby3monthsandremainedbelowbaselinelevelsforupto56months. Figure5showsthemeannumberofdailylevodopadosesinpatientsduringthestudyperiod.Themeannumberoflevodopadosesremainedstablethroughoutthestudy 123 JNeuralTransm(2008)115:843–849 Table2PatientdemographicsatthestartofentacaponetreatmentParameterEf?cacypopulation(n=649)Age(years) 63.1(9.4)Gender(male/female)62/38DurationofPD(years) —————————————————————————————————————————————————— ——— 9.5(5.2)Durationoflevodopatreatment(years)7.9(4.8)Levodopadose(mg) 678(363)Numberofdailylevodopadoses(mg)5.5(2.0)Dopamineagonistusers(%)55Selegilineusers(%)41Amantadineusers(%)15Anticholinergicsusers(%)14Otheranti-PDmedicationusers(%)1DDCI(carbidopa/benserazide/both)56/38/6CRlevodopauser(%)25H&Ystage2.4(0.7)UPDRSpartIII24.2(12.8)TotalUPDRS37.7(17.7)Responsedurationa(h) 2.2(0.7) Dataaremean(standarddeviation),or%whereindicated a Responsedurationafterasinglemorningdoseoflevodopa/DDCIandentacapone;DDCIdopadecarboxylaseinhibitor,PDParkinson’sdisease,CRcontrolledrelease,H&YHoehnandYahr,UPDRSUni?edParkinson’sDiseaseRating Scale Fig.2ChangeinUni?edParkinson’sDiseaseRatingScale(UP-DRS)partIII(moto r)scorefortheef?cacypopulation;SEMstandarderrorofmean,Bbaseline anddidnotchangebymorethan0.6ofadoseatanytimepointduringthestudy,comparedwithbaseline(Fig.5). Safetyandtolerability —————————————————————————————————————————————————— ——— Atotalof861patientsreceivedatleastonedoseoflevo-dopa/DDCIandentacaponetherapyduringthedouble-blindperiodortheextensionphase,andwereincluded in JNeuralTransm(2008)115:843–849Fig.3Changeinresponsedurationfollowi ngasinglemorningdoseoflevodopaduringtherapywithlevodopa/DDCIandentacapone;SEMstandarderrorofmean,B baseline Fig.4Changeindailylevodopadose;SEMstandarderrorofmean,B baseline thesafetyanalysis.Maximumfollow-uptimeforsafetywasover5years. Adverseeventsandprematurediscontinuation Ingeneral,levodopa/DDCIandentacaponetherapywaswell-tolerated.Table3summarisestheAEsthatoccurredin[10%ofpatients.ThemostcommonlyreportedAEswereaggravationofparkinsonism(worseningofparkin-soniansymptoms),dyskinesiaandnausea.ThemajorityofthedopaminergicAEswereencounteredwithinthe?rst4weeksofexposuretotreatmentandweregenerallymild-to-moderate,transientandoftenmanagedbyadjustmentofthelevodopadose.PatientwithdrawalduetodopaminergicAEswasuncommon,withlo—————————————————————————————————————————————————— ——— wratesofdiscontinuationsduetodyskinesia(2.7%)andnausea(2.0%).Overall,approximatelyonethird(36%)ofdyskinesiaeventsoccurredwithin1weekandaboutone?fth(22%)occurred[1–4weeksafterinitiationofstudymedication .Similarly,the?guresfornauseawereonethird(34%)ofpatientswithin1weekandone?fth(19%)[1–4weeks.Themost 847 Fig.5Changeinnumberofdailylevodopadoses;SEMstandarderrorofmean;Bbaseline Table3Mostcommontreatmentemergentadverseevents([10%)inpatientstreatedwithlevodopa/DDCIandentacaponeduringover5yearsoffollow-upAdverseevent Patients(n=861)n %Parkinsonismaggravated27832.3Dyskinesia26731.0Nausea15918.5Dizziness13015.1Insomnia12514.5Hallucination 12414.4Diarrhoea12114.1Constipation11813.7Depression10011.6Hypokinesia9911.5Tremor9911.5Hyperkinesia9811.4Urineabnormal 9711.3Pain9711.3Fall 94 10.9 —————————————————————————————————————————————————— ——— DDCIdopadecarboxylaseinhibitor commonlyreportednon-dopaminergicAEwasdiarrhoea(14%).Thiswasneverexplosiveandonly1.5%ofpatientsonlevodopa/DDCIandentacaponediscontinuedtreatmentduetodiarrhoeaoverthe5-yearperiod. Duringthe5-yearstudyperiodatotalof478seriousAEs(SAEs),including31deaths,werereportedin274patients(31.8%).ThemostfrequentlyreportedSAEswerefalls(24patients,2.8%)andhallucinations(18patients,2.1%).NocasesofhepatotoxicityorotherunexpectedserioussafetyconcernswerereportedasSAEs. Atotalof248(28.8%)patientsdiscontinuedthestudytreatmentduringthe5-yearstudyperiodduetoanAE,mostofwhichweredopaminergicand/orPD-related in 123 848nature.Anadditionalone?fth(19.5%;n=168)ofpatientsdiscontinuedforotherreasonssuchasprotocoldeviationorwerelosttofollowup.Theremainingdeclineinthenumberofpatientswasnotduetodiscontinuationsbutduetotheadministrativeterminationoftheopen-labelstudyphaseonacountry-by-co—————————————————————————————————————————————————— ——— untrybasis,whenmarketingauthorisationforentacaponewasgranted. Vitalsignsandlaboratoryparameters Duringthe5-yearstudyperiod,mostpatients([80%)showednoclinicallyrelevantchangesinbloodpressureorheartrate.Similarly,fewclinicallysigni?cantchangesinliverfunctiontests,haematologicalparametersorurinaly-sisoccurredduringstudytreatment,withmostchangesbeingtransientinnature(Table4). Discussion Thisanalysisisthe?rsttopresentlong-termef?cacy(n=649)andsafety(n=861)dataforlevodopa/DDCIandentacaponeforaperiodofupto5yearsinalargecohortofPDpatients.Thebene?tsoflevodopa/DDCIandentacaponetherapyseeninthepresentanalysisarecon-sistentwiththe?ndingsreportedinpreviousstudieswithshorterduration(Brooksetal.2003;Larsenetal.2003;Myllylaetal.2001;Poeweetal.2002;PSG1997;Rinneetal.1998). AnalysisoftheUPDRSIIImotorscoresshowedaninitialsigni?cantimprovementoninitiationofentacapone,despiteoptimizationofpatients’conventionallevodopa/DDCIregimenpriortostudyentry.Thereafter,UPDRSIIImotorscoresremainedbelowbaselinevaluesforupto2yearsdespiteprogressionofdisease.AstheUPDRSIIIscoresweredeterminedduringthepatients’best‘ON’-time(a —————————————————————————————————————————————————— ——— meanof1.7hfollowingdrugintake),theresultsindicate Table4Number(%)ofpatientswithclinicallysigni?cantchangesinliverfunctiontests(totalsafetypopulation)Parameter n(%)SGOT/ASTa(n=837)2(0.2)SGPT/ALTa (n=840)3(0.4)GGTa(n=837) 11(1.3)Alkalinephosphatasea (n=838)3(0.4)Totalbilirubinb (n=819) 4(0.5) a[3xupperlimitofnormalb [34.2lmol/L ALTalanineaminotransferase,ASTaspartateaminotransferase,GGTgamma-glutamyltransferase,SGOTserumglutamic-oxaloacetictransaminase,SGPTserumglutamatepyruvatetransaminase 123 JNeuralTransm(2008)115:843–849 thatlevodopa/DDCIandentacaponeimprovedpatients’qualityof‘ON’-time. Aftertwoyearsoftreatment(upto5years),UPDRSIIIscoresdeterioratedbyabout1.0point/year.This?ndingisinlinewiththeaverageannualdete-riorationr—————————————————————————————————————————————————— ——— atereportedpreviouslywithlevodopainasimilarpatientpopulationinnormalclinicalpractice(Goetzetal.2000).Indeed,resultsfromastudybyGoetzetal.demonstratedthatparkinsonianimpairmentwaslin-earovertime,despitesigni?cantincreasesinbothlevodopaanddopamineagonistdosesover4years.Moreover,theseincreaseswereprogressiveovereachyearofthe4-yearstudy(Goetzetal.2000).However,incontrasttothestudybyGoetzetal.,noincreasesinlevodopadosewereobservedinthepresentanalysis,despitethefactthatinvestigatorswereencouragedtoadjusttreatmentoftheirpatientsduringtheopen-labelphaseaccordingtothepatients’clinicalcondition.Overall,themeandailydoseoflevodopawasmaintainedbelowthebaselinelevelsforaperiodofupto56months,extendingthe3year?ndingsfromthestudyreportedbyLarsenetal.(2003).Thus,ingeneral,levodopa/DDCIandentacaponeshowedlong-termef?cacywithoutaneedtoincreaselevodopadoses.Inaddition,thebene?tsoflevodopa/DDCIandentacaponewerewellperceivedbypatientsthroughouttreatment,asre?ectedbythefactthatthenumberofpatientswithsim-ilarorimprovedglobalevaluationscoresremainedatahighlevel(70–80%)throughoutthef ollow-upperiod.Ourpresentresultsindicatethatlevodopa/DDCIandentacaponetreatmentnotonlyimprovedpatients’qualityof‘ON’-time,butalsoincrea sedthedurationof‘ON’-time.Thiswasshownbyassessingtheresponsedurationofthemorningdoseoflevodopa.Previouslypublished3-yearresultsdemonstratedthattheadministrationofasingledoseofentacaponeprolongedthelevodopa-induced‘ON’-timebyapproximately40mincomparedwithbaseline —————————————————————————————————————————————————— ——— (Larsenetal.2003).Our?ndingsfurtherextendtheseresultsdemonstratingthattheprolongedlevodopa-induced‘ON’-timewasmaintainedforupto56mon ths.Itshouldbenotedthatthecurrentanalysisonlyincludes‘ON’-timedataaft erthe?rstmorningdoseoflevodopa.Apreviousdouble-blindstudyfoundthattheproportionof‘ON’-timeincreasedtowardstheendoftheday(PSG1997),sug-gestingthatdeterminingdaily‘ON’-and‘OFF’-timebypatientdiaryduringl ong-termfollow-up(whichwasunfortunatelynotavailableintheextensionstudiesana-lyzedhere)wouldhaveshownthefullbene?tofthestudytreatmentinthisrespect. Thepresentlong-termsafetydatadidnotrevealanynew,unexpectedsafetyconcernsattributabletolevodopa/DDCIandentacapone.Levodopa/DDCIandentacaponewasgenerallywelltoleratedwithmostAEsbeingmildormoderateinintensity.Aggravatedparkinsonismwasoftenreported,butthisismostlikelyduetodiseaseprogression JNeuralTransm(2008)115:843–849ratherthantreatment.Asexpected,the mostcommonAEsreportedwithlevodopa/DDCIandentacaponetherapywerethoseassociatedwithincreaseddopaminergicstimulation(e.g.dyskinesiaandnausea).ThemajorityoftheseAEswereencounteredwithinthe?rst4weeksofexposureand,ingeneral,weretransientandmanagedbylevodopadosereduction,asshownbythelowratesofdiscontinuationsduetodyskinesiaandnau—————————————————————————————————————————————————— ——— seaof2.7and2.0%,respectively.Themostcommonlyreportednon-dopaminergicAEwasdiarrhoea(14%),comparabletotheincidencereportedat6months(Brooksetal.2003;Poeweetal.2002;PSG1997;Rinneetal.1998)and3years(Larsenetal.2003).However,only1.5%ofpatientsdiscontinuedtreatmentwithlevodopa/DDCIandentacaponeduetodiarrhoeaoverthe5-yearassessmentperiod. Analysisofvitalsignsandlaboratoryparametersrarelyrevealedanyclinicallysigni?cantchangesoverthe5-yearperiod.Inparticular,long-termusewithlevodopa/DDCIandentacaponewasonlyrarelyassociatedwithsigni?cantchangesinliverfunctiontests;alloftheseweretransientinnature. Therearelimitationsassociatedwiththeretrospectiveanalysisofthispooleddata.Althoughthedesignsoftheindividualstudieswerecomparable,theywerenotidenticalandtherewerevariationssuchasintheuseofCRlevo-dopa.Inaddition,theopen-labelextensionswereprimarilydesignedforthecollectionoflong-termsafetydata,andthelackofacontrolgroupprecludescomparativestatisticalanalysis.However,boththecurrentef?cacyandsafety?ndingsprovidevaluablelong-termexperiencewithlevo-dopa/DDCIandentacaponetherapythatisrelevanttoclinicalpractice. Inconclusion,thepresentanalysisdemonstratesthatlevodopa/DDCIandent—————————————————————————————————————————————————— ——— acaponetherapyofferslong-termef?cacyforupto5yearsinasafeandwell-toleratedmannerwithouttheneedtoincreaselevodopadoses. AcknowledgmentsStudiesincludedinthispaperweresponsoredbyOrionCorporation,OrionPharma.TheauthorswouldliketothankDiyaLahiriMScPhD,forhereditorialassistance. 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