Unblinded, randomized multicenter trial comparing lamotrigine and valproate combination with controlled-release carbamazepine
monotherapy as initial drug regimen in untreated epilepsy
ByungInLeea,h,*,Soon KeeNob,Sang-DoeYic,Hyang WoonLeed,OkJoonKime, SangHoKimf,MyeongKyuKimg,SungEun Kimh,YoSikKimi,Jae MoonKimj,
Se-JinLeek,DongJinShinl,SungPaParkm,YeongInKimn,KyoungHeoa,YongWonChoc, Yang-JeChoa,Youn NamKimo
aDepartmentofNeurology,YonseiUniversityCollegeofMedicine,Seoul,Korea
bDepartmentofNeurology,BongSengMemorialHospital,Busan,Korea
cDepartmentofNeurology,KeimyungUniversitySchoolofMedicine,Daegu,Korea
dDepartmentofNeurology,EwhaWomansUniversitySchoolofMedicine,Seoul,Korea
eDepartmentofNeurology,CHAUniversity,Seongnam,Korea
fDepartmentofNeurology,Dong-AUniversityCollegeofMedicine,Busan,Korea
gDepartmentofNeurology,ChonnamNationalUniversityMedicalSchool,Gwangju,Korea
hDepartmentofNeurology,InjeUniversityCollegeofMedicine,Busan,Korea
iDepartmentofNeurology,WonkwangUniversitySchoolofMedicine,Iksan,Korea
jDepartmentofNeurology,ChungnamNationalUniversitySchoolofMedicine,Daejeon,Korea
kDepartmentofNeurology,YeungnamUniversityCollegeofMedicine,Daegu,Korea
lDepartmentofNeurology,GachonUniversityMedicalCenter,Incheon,Korea
mDepartmentofNeurology,KyungpookNationalUniversitySchoolofMedicine,Daegu,Korea
nDepartmentofNeurology,TheCatholicUniversityofKoreaCollegeofMedicine,Seoul,Korea
oClinicalTrialCenter,YonseiUniversityHealthSystem,SeveranceHospital,Seoul,Korea
ARTICLE INFO
Articlehistory:
Received20October2017
Receivedinrevisedform26December2017 Accepted28December2017
Keywords:
Monotherapy Combinationtherapy CBZ-CR
LTG+VPA Initialdrugregimen
ABSTRACT
Purpose:Tocomparecontrolled-releasecarbamazepinemonotherapy(CBZ-CR)withlamotrigineand valproate combinationtherapy(LTG+VPA)inequivalenttotaldrugload,asinitialdrugregimenin untreatedpatientswithpartialand/orgeneralizedtonic-clonicseizures(GTCS).
Methods:Thisunblinded,randomized,60-weeksuperioritytrialrecruitedpatientshavingtwoormore unprovokedseizureswithatleastoneseizureduringpreviousthreemonths.Afterrandomizationinto CBZ-CR or LTG+VPA, patients enteredinto eight-week titrationphase (TP), followed by 52-week maintenance phase (MP). Median doses of CBZ-CR and LTG+VPA were 600mg/day and 75mg/
day+500mg/day,respectively.Primaryoutcomemeasurewascompletionrate(CR),aproportionof patientswhohavecompletedthe60-weekstudyasplanned.Secondaryefficacymeasuresincluded seizure-freerate(SFR)for52-weekofMPandtimetofirstseizure(TTFS)duringMP.
Results: Among207 randomized patients, 202underwent outcomeanalysis (104in CBZ-CR,98 in LTG+VPA).CRwas62.5%inCBZ-CRand65.3%inLTG+VPA(p=0.678).SFRduringMPwashigherin LTG+VPA(64.1%)thanCBZ-CR(47.8%)(P=0.034).TTFSwasshorterwithCBZ-CR(p=0.041).Incidenceof adverseeffects(AEs)were57.7%inCBZ-CRand60.2%inLTG+VPAandprematuredrugwithdrawalrates duetoAEswere12.5%and7.1%,respectively,whichwerenotsignificantlydifferent.
Conclusion:CRwascomparablebetweenLTG+VPAandCBZ-CR,however,bothSFRfor52-weekMPand TTFSduringMPwereinfavorofLTG+VPAthanCBZ-CR.ThestudysuggestedthatLTG+VPAcanbean optionasinitialdrugregimenforuntreatedpatientswithpartialseizuresand/orGTCSexceptforwomen ofreproductiveage.
©2017BritishEpilepsyAssociation.PublishedbyElsevierLtd.Allrightsreserved.
* Correspondingauthorat:DepartmentofNeurology,InjeUniversityHaeundaePaikHospital,875Haeundae-ro,Haeundae-gu,Busan,48108,Korea.
E-mailaddress:[email protected](B.I.Lee).
https://doi.org/10.1016/j.seizure.2017.12.008
1059-1311/©2017BritishEpilepsyAssociation.PublishedbyElsevierLtd.Allrightsreserved.
ContentslistsavailableatScienceDirect
Seizure
j o u r n a lh o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y s e i z
1.Introduction
Long-termobservationalstudies[1–3]illuminatedoutcomesof antiepilepticdrug (AED) therapy in epilepsy. Prolongedseizure controlis achieved in 47% of patientsby thefirst drug and in another13%bytheseconddrugtrial[1].Thosepatientswhofailed toadequate trialsof firsttwodrugregimens respondpoorly to furtherdrugtrialstofulfillthecriteriaofdrugresistantepilepsies (DRE)[4]. Therefore, optimization of first drug regimenseems quitecriticaltoachievebetteroutcomeoflong-termpharmaco- therapyofepilepsy[5].
Initial monotherapy is the rule in pharmacotherapy of untreatedepilepsy. Sixteen newAEDshave beenintroduced to the market until recently, however, none of them were found superiortocontrolledreleaseformofcarbamazepine(CBZ-CR)in randomizedclinicaltrials(RCTs)ofinitialmonotherapyinpatients withnewlydiagnosedpartial seizuresand/orgeneralizedtonic- clonicseizures(GTCS)[6].Therefore,anyfurtherimprovementin theoutcomeofinitialmonotherapythanCBZ-CRmonotherapyis unlikelytobeachievedwithcurrentlyavailable25AEDs.
Monotherapyvs.Polytherapyhasbeenthesubjectofendless debatesamongepileptologists,primarilyduetolackofevidence indicatinganydifferencesinoutcome [7].Previouscomparative studiesofsubstitutionmonotherapyandcombinationtherapyin patientswhofailedtomonotherapyfailedtoshowanysignificant differences[8,9].However,KwanandBrodie[9]indicatedthatthe combinationof two drugs, onehaving multiple mechanismsof action (MOA) and the other having sodium-channel blocking effects,carried significantlysuperior efficacy toothercombina- tions,whichhasraisedinterestsformechanisticcombinationsof drugs for synergisticpharmacodynamic interactions. Preclinical studies using isobolographic analysis have provided ample evidence of synergistic interactions of AEDs having different MOA but either additive or infra-additive interactions of AEDs havingsimilar MOA [10]. Clinical experiences also supportthe preclinicaldataofmechanisticcombinations.CombinationofAEDs having different MOA, such as LTG and valproate (VPA) [11], ethosuximideandVPA[12],LTGandtopiramate[13],wereshown tohave synergistic interactions, while combining AEDs having sodium-channel blocking actions were associated with poorer outcomes[14].Amongvariousdrugregimen,combinationofLTG andVPA(LTG+VPA)wassubjectedtointenseclinicalassessments [15–17] and their synergistic interactions are widely accepted amongclinicians[18,19].
A fair comparison ofmonotherapyand combination therapy requires balanced baseline patient characteristics, appropriate dose-titration schedules including initial target dose (ITD), equivalenttotaldrugload(TDL)betweentwogroups,aswellas appropriateselection of drugs for combination, preferablycon- sistingofdrugs carryingsynergisticinteractions. Theserequire- ments are difficult to meet in trials of patients who failed to previousAEDstherapybutfeasibleinnewlydiagnosedpatients.
Deckeretal.[20]conductedastudycomparingCBZmonotherapy withcombinationtherapyofCBZandVPAasinitialtreatmentin patients with untreated epilepsy, which was the only RCT comparingmonotherapywithcombinationtherapyinequivalent TDL.Outcomemeasureswerenumericallyinfavorofcombination therapy, but differences were not statistically significant.
Criticisms against the study include that combination of CBZ andVPAhassignificantpharmacokineticdruginteractionsandno proven synergistic interactions. More importantly, the study is considered not practical because we don’t need combination therapyasinitialdrugregimen.However,ifcombinationtherapy wasconsideredtoprovidea potentialbenefitincertainspecific clinicalscenarios,comparativetrialsofmonotherapyandcombi- nationtherapyasinitialdrugregimenmaybejustifiableunderthe
conceptofindividualpatient-orientedoptimalpharmacotherapy ofepilepsy.
WechoseLTG+VPAasthecomparatorofCBZ-CRmonotherapy ininitialtreatmentofpatientswithuntreatedpartialseizures(PS) and/orgeneralizedtonic-clonicseizures(GTCS).
2.Methods
Thestudywasconductedat14centersinKoreainaccordance with Good Clinical Practice Guidelines. An independent ethics committee at each participating center approved the protocol beforethecommencementofpatient’senrollment.Allparticipants providedwritteninformedconsentbeforeenteringthestudy.
2.1.Patients
Bothinclusionandexclusioncriteriaweresummarizedinthe appendices(TableA.1).
Patients aged16years with newly diagnosed or untreated partial onset seizuresand/or GTCS only were eligible,whereas womenwhowereplanningtobepregnantornotusingappropriate contraceptivemeasureswerenoteligible.Patientswithhistoryof absence seizuresor myoclonic seizures wereexcluded. Seizure typesand epilepsysyndromeswerediagnosedaccordingtothe ILAE Classification System [21,22]. Patients shouldhave experi- enced two or more seizures separated by at least 24h with occurrenceofatleastoneseizureduringpreviousthreemonths.
AllpatientsundertookbothEEGandMRIbeforerandomization.
Patients wereincluded tothe study if theywere either newly diagnosed oruntreatedforatleast12monthsbeforetheindex seizure(thelastseizureepisodeprecipitatedtheirinclusiontothe study).Patientswhohadshort-termAEDstreatment(2weeks) only withorwithout emergencyrescue treatment(with either benzodiazepinesorotherAEDs)wasallowedontheassumption thatashort-termAEDstherapymaynotalterthenaturalcourseor responsivenesstoAEDstherapyoftheirillnesses.
2.2.Studydesign
Dose-titration schedules are summarized in the appendices (Fig. A.1). After one-week screening period, patients were randomlyassignedtoentereight-weektitrationphase(TP)during whichtheyreceivedeitherCBZ-CR100mg/dayorLTG25mg/day forthefirsttwoweeks.Atthirdweek,CBZ-CRwasincreasedto 200mg/dayintwodivideddosesorLTGto50mgonceaday,which wasfurtherincreasedtoCBZ-CR400mg/dayindivideddosesor LTG75mgonceadayduringthenexttwoweeks.At7thweekofTP, CBZ-CRwasfurtherincreasedto600mg/dayintwodivideddoses, whileVPA500mgwasaddedtoLTG75mginonceadaydosing, whichweretheITDof studydrugs. During52-weekofmainte- nancephase(MP),patientswerefollowedatclinicevery4-week intervalandcaringphysicianswereallowedtoescalatethedoseof study drugs if patients had experienced seizure recurrences (includingauraonly)duringpreviousmonth.Maximumdoseof CBZ-CRwas1200mg/dayandLTGwas200mg/day.Doseescala- tionofCBZ-CRwasmadeby200mgat4-weekintervalwhereas LTGwasfirstincreasedto100mg/dayandthenby50mgat4-week interval. VPAwas fixed at500mg/day throughoutMP. In cases developingtolerabilityproblems,CBZ-CRorLTGwasdecreasedto the dose at previous clinic visit. Minimal allowable doses throughoutMPwereCBZ-CR 400mg/dayorLTG 50mg/dayand VPA500mg/day.
2.3.Assessment
AllpatientsrecordedtheirseizuresandAEsusingdailyrecords.
Althoughaurasorsimplepartialseizuresofsubjectivesymptoms wereconsideredasabasisfordose-escalationofstudydrugs,only simplepartialmotorseizureswereincludedtotheseizurecountas complexpartialseizures(CPS)andGTCS.Investigatorswerekeen tothepresenceorabsenceofawarenessduringandaftertheevent fordifferentialdiagnosisofcomplexpartialseizuresfromsimple partial seizures. AEs were assessed at each visit through nonstructured interviews. Blood samples were collected for measurementsofcompletebloodcellcountandchemistry.Blood levelsofstudydrugswerenotmeasured.Compliancewasassessed onthebasisofpatients’dailyrecordandcountingreturnedpillsat eachvisit.Poor-compliancewasdefinedaspillconsumptionless than80%oftheprescribedamountateachvisit.
2.4.Outcomemeasures
Theprimaryoutcomemeasurewascompletionrate(CR),the proportionofpatientswhohascompletedthe60-weekstudy(8- week TP and 52-week MP) as planned. Secondary efficacy measuresincluded (1) SFRduring the entire 52-week MP and (2)Timetofirstseizure(TTFS)fromthestartofMP.Tolerability measuresincludedincidencesofAEsandprematurewithdrawal ratefromstudyduetoAEs.Qualityoflife(QOL)wasmeasuredby QoLIE-31,administeredatthebeginningandtheendofstudy.
2.5.Statisticalanalysis
TherewerenocomparativetrialsofCBZ-CRmonotherapyand LTG+VPA combination therapy. Since the Guideline by ILAE in 1998regarded20%differenceastheminimumoutcomedifference
beingclinicallyimportant[23],weempiricallychoseCRof70%in LTG+VPAand50%forCBZ-CRtocalculatethesamplesizeofthis study.Asamplesizeof94pergroupwasrequiredtoachieve80%
powerwithatwo-tailedsignificancelevelof0.05.Consideringa dropoutrateof15%,weplannedtorecruit110patientspergroup.
Randomization was performed using a block randomization to ensure equal numbersof subjects in each studygroup ateach center.ThegroupswerecomparedusingeitherStudent’st-testor chi-square test. Theprimary outcomewas testedby chi-square test,andKaplan-Meiermethodwasusedforsecondaryoutcomes.
Alog-ranktestwasusedforthegroupcomparisons,andhazard ratioswereestimatedusingtheCoxproportionalhazardsmodel.
MixedmodelanalysiswasperformedforthecomparisonofQoLIE- 31 atthebeginning andthe endof study. Two-tailedvalues of p<0.05wereconsideredstatisticallysignificant.Allanalyseswere performed withSASsoftware,ver.9.2 (SASInstituteInc.).Data wereanalyzedaccordingtotheintention-to-treat(ITT)principle.
3.Results
3.1.Studyprogression
PatientrecruitmentbeganinJuly2008at14centersinKorea and finished in September 2011. A total of 207 patients were recruitedtothestudyandrandomized,whichwasalittlelessthan thatoftheoriginalplan(n=220).However,202of207patients whowererandomizedtookatleastonedoseofstudydrugsand subjectedtodataanalysissets(104inCBZ-CRand98inLTG+VPA), whichwasmorethanthetargetnumberofpatientsrequiredfor the analysis (n=94 per group). The study progression was illustrated in Fig. 1. Thirty-four patients were dropped out prematurely duringTP,14in CBZ-CR [AEsin 8, lackof efficacy (LOE)in1,othersin5]and20inLTG+VPA[non-compliance(NC)in
Fig.1.Adiagramofstudyprogression.
Among202patientswhoreceivedthestudymedications,34patientsweredroppedoutprematurelyduringtitrationand39patientsduringmaintenancephase.
CBZ-CR,controlledrelease-carbamazepine;LTG+VPA,combinationoflamotrigineandvalproate;LOE,lackofefficacy,AEs,adverseevents;NC,non-compliance.
Others*;othercausesofstudydrugwithdrawalduringtitrationphase(TP),whichincludedwithdrawalofconsentsin4patientsandmissedfollow-upvisitin1patientinCBZ- CR,whereasprotocolviolationin2patients,withdrawalofconsentin6patients,andmissedfollow-upvisitin2patientsinLTG+VPA.
Others**;othercausesofstudydrugwithdrawalduringmaintenancephase(MP),whichincludedwithdrawalofconsentin11patientsandmissedfollow-upvisitin4patients inCBZ-CR,whereasprotocolviolationin1patient,withdrawalofconsentin5patients,andmissedfollow-visitin4patientsinLTG+VPA.
2,LOE in2, AEsin 6, othersin 10]. During 52-weekof MP,25 patients from CBZ-CR and 14 patients from LTG+VPA were droppedout.Adherenceratestostudydrugsrangedfrom93.9%
to100%(mean=96.9%)inCBZ-CRand91.5%to100%(mean=98.9%) inLTG+VPA,whichwerenotsignificantlydifferent(p=0.09).
3.2.Patientdemographics
Demographic and clinical characteristics were not different betweentwogroups(Table1).Etiologyofepilepsywasunknown inapproximatelytwo-thirdsofpatients.MRI-lesionswerefoundin 29ofCBZ-CRand23ofLTG+VPA,withfocaltissuelossbeingthe mostfrequent(11and7,respectively),followedbyhippocampal sclerosis(7and5,respectively)andfocalcorticaldysplasia(5and 4,respectively).Among104patientsassignedtoCBZ-CR,80were nevertreated,14hadshort-termtreatment(2weeks)onlywith orwithoutemergencyrescuetreatment,and10hadpriorhistory ofAEDstherapy,whichwere73,12,and13patientsinLTG+VPA, respectively.AmongthoseassignedtoCBZ-CR,89patientswere diagnosedaslocalization-related epilepsy(LRE)and 15patients wereundeterminedepilepsy(UE),whichwere78patientsand20 patientsinLTG+VPA,respectively.Among35patientsclassified intoUE,sixpatients(3patientsineachgroup)showedgeneralized spikes or spikes and waves in EEG and normal MRI but their semiologydescribedclearfocalfeaturesconsistingofvisualauras (2),somatosensoryaura(1),psychicaura(1),spatialdisorientation (2), and additional focal motor symptoms in one patient.
Remaining 29 patients did have either nocturnal Grand Mal seizuresorGTCS withoutfocalfeaturesandrevealednospecific abnormalitiesinEEGandMRI.Meannumberofseizuresduring previoussixmonthswas8.8episodesinCBZ-CRand8.6episodes inLTG+VPAwithmedianseizurenumbersof2ineachgroup.
3.3.Outcomemeasures
Sixty-fivepatients(62.5%)inCBZ-CRand64patients(65.3%)in LTG+VPAcompletedthe60-weekstudyasplanned,whichwere notdifferent(p=0.678)(Fig.2).Proportionsofpatientsremaining at the end of TP were 86.5% in CBZ-CR (n=90) and 79.6% in LTG+VPA(n=78).SFRduringtheentirestudyperiod(60-week)
wasnumericallyhigherinLTG+VPA(40.8%)thanCBZ-CR(35.6%), butstatisticallynotdifferent(RiskDifference,5.2%;95%CI, 8.2%– 18.6%,p=0.444;p=0.717;hazardratio[HR],0.92;95%confidence interval[CI],0.58–1.46;p=0.717).However,SFRduringtheentire 52-weekMPfavoredLTG+VPAthanCBZ-CR,whichwere64.1%and 47.8%, respectively (Risk Difference, 16.3%; 95% CI, 1.5%–31.2%, p=0.034)(Fig.2).TTFSduringMPwasalsoshorterinCBZ-CRthan LTG+VPA(HR,0.50;95%CI,0.27–0.93,p=0.041)(Fig.3).Although asignificantminorityofpatientshadhistoryofpriorAEDsuse(10 patientsinCBZ-CRand13patientsinLTG+VPA),outcomeanalysis after their exclusion did not change the result (Table A.2 and Fig.A.2).Fifty-fivepatientsofCBZ-CRand56patientsofLTG+VPA completedtheQoLIE-31attheendofstudy,whichwerecompared withtheirbaseline scores.Although someimprovements in all categoriesofQOLmeasurewerefoundineachgroup,theywere relativelysmallwithoutanysignificantdifferences(Table2).
3.4.Dosesofstudydrugs
Meandosesofstudydrugattheendofstudyinpatientswho completed study were 650115mg/day (500–1200mg/day) in CBZ-CR and 82.217.5mg/day (53.6–168.8mg/day) of LTG in LTG+VPA.MediandosesofCBZ-CRandLTGwere600mg/dayand 75mg/day,respectively.Sixty-four(67.8%)patientsofCBZ-CRwere kepton600mg/dayduringMPand49of61(80.3%)patientswho achieved SF during MP were taking CBZ-CR600mg/day.
Corresponding numbers of LTG+VPA were 52 (66.7%) patients and46(88.5%)of52patients,respectively.Therefore,dosesator less than ITD were sufficient to achieve seizure freedom in a majorityofpatients.
3.5.Tolerability
A similar proportion of patients in CBZ-CR and LTG+VPA experiencedatleastoneAEduringthetreatmentperiod,withmost eventsbeingmildormoderateinintensity.Sixtyof104(57.7%) patients of CBZ-CR reported 222 AEs, while 59 of 98 (60.2%) patientsof LTG+VPAreported 227 AEs. Investigatorsindicated that67AEsreportedby29(27.9%)patientsinCBZ-CRand52AEs reportedby 27 (27.6%) patients in LTG+VPAwere study drug-
Table1
Baselinedemographicsandclinicalfeaturesofpatients.
Variables CBZ-CR(n=104) LTG+VPA(n=98) P-value
Age(years) Mean(SD) 33.2(14.6) 36.5(13.7) 0.098
Sex Male 53(51.0%) 50(51.0%) 0.993
Bodyweight(kg) Mean(SD) 63.7(9.8) 61.9(11.7) 0.253
BMI(kg/cm2) Mean(SD) 23.3(2.7) 22.6(3.2) 0.115
History Febrileconvulsion 7(6.7%) 8(8.2%) 0.698
Remotebraininsults 7(6.7%) 11(11.2%) 0.326
Familyhistoryofepilepsy 6(5.8%) 3(3.1%) 0.623
AEDstherapy None 80(76.9%) 73(74.5%) 0.709
Emergencyonly 14(13.5%) 12(12.2%)
Previouslytreated 10(9.6%) 13(13.3%)
Neurologicexam Mentalretardation 3(2.9%) 3(3.1%) 0.450
Focalneurologicsigns 3(2.9%) 2(2.0%) 0.195
Totalnumberofseizures For6months:mean(SD) 8.8(27.6) 8.6(27.1) 0.972
median(IQR) 2.0(3.5) 2.0(3.0)
For3months:mean(SD) 5.6(13.8) 5.3(13.7) 0.890
median(IQR) 2.0(3.0) 2.0(2.0)
Epilepsysyndromes Localization–related 89(85.6%) 78(79.6%) 0.261
cryptogenic 54(60.7%) 48(61.5%)
symptomatic 35(39.3%) 30(38.5%)
lesion(+MRI) 30(33.7%) 25(32.5%)
Undetermined 15(14.4%) 20(20.4%)
CBZ-CR,controlledrelease-carbamazepine;LTG+VPA,combinationoflamotrigineandvalproate;SD,standarddeviation;IQR,interquartilerange;BMI,bodymassindex;
AEDs,antiepilepticdrugs;(+MRI),numberofpatientswithlesioninMRI;GTCS,generalizedtonic-clonicseizures;Student’st-test,x2testorFisher’sexacttestifanyfrequency countwas<5.
