Short-term efficacy and safety of zonisamide as adjunctive treatment for refractory partial seizures: A multicenter open-label single-arm trial in Korean patients
KyoungHeoa,Byung InLeea,*,SangDo Yib,Yong Won Chob,DongJin Shinc, Hong KiSongd, OkJoonKime,Sung-Pa Parkf,Sung Eun Kimg, SangHoKimh, JunHong Leei,Kyu-Sik Kimi,Se-Jin Leej
aDepartmentofNeurology,SeveranceHospital,Seoul,RepublicofKorea
bDepartmentofNeurology,KeimyungUniversityDongsanMedicalCenter,Daegu,RepublicofKorea
cDepartmentofNeurology,GachonMedicalSchoolGilMedicalCenter,Incheon,RepublicofKorea
dDepartmentofNeurology,KangdongSacredHeartHospital,Seoul,RepublicofKorea
eDepartmentofNeurology,BundangCHAHospital,Seongnam,RepublicofKorea
fDepartmentofNeurology,KyungpookNationalUniversityHospital,Daegu,RepublicofKorea
gDepartmentofNeurology,InjeUniversityHaeundaePaikHospital,Busan,RepublicofKorea
hDepartmentofNeurology,Dong-AUniversityHospital,Busan,RepublicofKorea
iDepartmentofNeurology,NationalHealthInsuranceCorporationIlsanHospital,Koyang,RepublicofKorea
jDepartmentofNeurology,YeungnamUniversityMedicalCenter,Daegu,RepublicofKorea
1. Introduction
Zonisamide(ZNS)hasbeenapprovedforbroad-spectrumusein Japansince1989andinKoreasince1991,whileitwaslicensedas
anadjunctivedrugforthetreatmentofpartialseizuresmuchlater intheUSA(2000)andEurope(2005).
ZNS’smainpharmacologicaleffectsareduetotheblockadeof neuronalvoltage-gatedsodiumchannelsandlow-voltage-activat- ed(T-type)calciumchannels.1ZNShasafavorablepharmacoki- neticprofile.Itisrapidlyabsorbedfromthegastrointestinaltract, andpeakplasmaconcentrationsareachievedwithin2–5hafter oraldosing.Oralbioavailabilityiscloseto100%,andthekinetics arelinearaftertheadministrationofasingledoseof200–800mg.2 Steady-stateplasmaconcentrationsareachievedwithin14daysof ARTICLE INFO
Articlehistory:
Received27September2011
Receivedinrevisedform6December2011 Accepted8December2011
Keywords:
Antiepilepticdrugs Zonisamide Epilepsy Partialseizures Open-labelstudy Add-ontherapy
ABSTRACT
Objective:Toevaluatetheefficacyandsafetyofadjunctivezonisamide(ZNS)therapyinKoreanadults withuncontrolledpartialepilepsy.
Methods:Studypatientshadanaverageofatleastoneseizureper4-week(averagedovera12-week historicalbaseline)despitetheuseofonetothreeantiepilepticdrugs.ThestartingdoseofZNSwas 100mg/day,andwasincreasedto200mg/dayafter2weeks.Duringthe12-weekmaintenanceperiod, thedose ofZNS was adjusted to 200–400mg/daybased on thephysicians’ discretion. Theglobal evaluationscale(GES)andqualityoflife(QOLIE-31)werealsoevaluated.
Results:Atotalof121patientswereenrolled,ofwhich88patientscompletedthestudy.Themedian percentreductioninweeklyseizurefrequencyoverthetreatmentperiodwas59.0%.The50%and75%
responderrateswere57.3%and38.5%,respectively.Seizurefreedomoverthetreatmentperiodwas observedin25patients,butseizurefreedomthroughoutthe16-weektreatmentperiodwasattainedin only16patients.Oninvestigator’sGES,84patientswereconsideredimproved,with33patientsshowing markedimprovement.InQOLIE-31scale,seizureworryimprovedsignificantlybutemotionalwell-being deteriorated.Treatment-emergentadverseevents(AEs)werereportedin80patients.Themostcommon AEsweredizziness(28.1%),somnolence(24.0%),anorexia(18.2%),headache(14.0%),nausea(13.2%),and weightloss(10.7%).Twenty-twopatientsdiscontinuedthetrialduetodrug-relatedAEs.
Conclusions: OurresultssuggestthatadjunctiveZNS therapyforthetreatmentofrefractorypartial epilepsy,thoughefficacious,isassociatedwithsignificanttolerabilityproblems.
ß2011BritishEpilepsyAssociation.PublishedbyElsevierLtd.Allrightsreserved.
*Correspondingauthorat:DepartmentofNeurology,YonseiUniversityCollege ofMedicine,Severance Hospital,50 Yonsei-ro, Seodaemun-gu,Seoul120-752, RepublicofKorea.Tel.:+82222281603;fax:+8223930705.
E-mailaddress:[email protected](B.I.Lee).
ContentslistsavailableatSciVerseScienceDirect
Seizure
j o urn a l hom e pa g e : ww w . e l se v i e r. c om / l oca t e / y se i z
1059-1311/$–seefrontmatterß2011BritishEpilepsyAssociation.PublishedbyElsevierLtd.Allrightsreserved.
doi:10.1016/j.seizure.2011.12.005
commencing treatmentand are maintained overtime, with a peak-trough fluctuation of only 14% on twice-daily dosing.3 AlthoughinactivationofZNS occurspredominantlybyhepatic metabolism involving CYP3A4-mediated reduction, this drug neitherinducesnorinhibitshepaticcytochromeP450isoenzymes thatare implicated in themetabolism of several antiepileptic drugs (AEDs).4 However, enzyme-inducing AEDs increase its clearance,aninteractionthatmaynecessitateadosageincrease, butwhichwillalsopermitmorerapidattainmentofsteady-state ZNS concentrations. Otherwise, ZNS is essentially devoid of clinicallysignificantinteractionswithother AEDs,oralcontra- ceptives and, indeed, all other classes of therapeutic agents investigatedtodate.5
Theefficacyand safetyof ZNSinpartialepilepsyhave been demonstrated in several pre-registration, randomized, double- blind,placebo-controlledstudiesinwhichthisdrugwasadminis- tered as adjunctive therapy in drug-resistant epileptic patients withpartialepilepsy.6–9Long-termopenstudiesaswellasdouble- blind,placebo-controlledstudieshavedemonstratedthatZNShas agood efficacyand tolerabilityprofile, supportingits useasan adjunctivetherapyforadultepilepticpatients.10–15Along-term open-labelstudy13in317patientswithrefractorypartialepilepsy whocompleteda fixed-dose,randomized,double-blind, add-on trial4showedthatpatientretentionratesat1,2,and3yearswere 65.3%,44.5%and28.8%,respectively,comparabletothosereported for otherAEDs.In indirectcomparisonsof newAEDsbased on meta-analysis of placebo-controlled add-on trials, ZNS had a middle ranking in terms of both response and withdrawal rates.16,17
Inthisstudy,wereporttheresultsofapragmatictrialaimed atassessingtheefficacyandsafetyofZNSasanadd-ontherapy in patients suffering from partial seizures not adequately controlleddespitetreatmentwith uptothreeotherAEDs. We alsoreport theimpactof ZNSonhealth-relatedqualityof life.
We used an open-label methodology, very similar to routine clinical practice, with regard to inclusion criteria and dose escalation.
2. Methods
2.1. Studypopulation
Patients15yearsorolderwithpartialseizures,whetherornot secondarilygeneralized,wereeligibleforenrolment.Patientshad tohavepresentedwithanaverageofatleastonepartialseizureper 4weeks(averagedovera12-weekperiodprecedingstudyentry) despite the use of one or three AEDs. Partial seizures were classifiedaccordingtotheCommissionontheClassificationand Terminology of the International League against Epilepsy.18 Patients were not allowed to be taking more than three concomitantAEDsatthetimeofstudyentry,withbenzodiazepines beingconsideredAEDsiftakenonadailybasisforanyindication.
TheAED regimenwasrequired tohave beenstablefor atleast 4weekspriortostudyentry.Laboratoryvalueslessthantwotimes theuppernormallimitsofserumALT,AST,totalbilirubin,BUN,or creatininelevelswereallowed.Patientswereexcludediftheyhad diseases or conditions expectedto undulycomplicate manage- mentorevaluation.Theseincludedseriouspsychiatricdisorders within the past 5years, uncountable seizures or a history of convulsive status epilepticus within the last year, presence of known psychogenic nonepileptic seizures within the last year, progressive degenerative neurological disease, a history of nephrolithiasis,previousexposuretoZNS,participationinanother clinicalstudyofaninvestigationaldrugordevicewithin12weeks of the selection visit, a history of questionable compliance to scheduled visits or medication intake, pregnant or lactating females, femalesof childbearingpotentialunwillingtoutilizea medicallyacceptablebirthcontrolmethod,andvisualfielddefects relevanttovigabatrinasapreviousorconcomitantAED.
2.2. Studydesign
ThistherapeuticconfirmatoryPhaseIVopen-label,single-arm study of patients with partial seizures began with a 12-week historicalbaselineperiodfollowedbya16-weektreatmentperiod
Fig.1.Studydesign.
in10 Korean centers.Priortostudycommencement, thestudy protocolwasapprovedbytheInstitutionalReviewBoardofeach participatingcenter.ItwasconductedaccordingtotheInterna- tionalConferenceonHarmonisationguidelinesandtheDeclara- tionofHelsinki.
Thestudywasdividedintoanup-titrationperiod(first4weeks) anda maintenanceperiod(last12weeks)asshowninFig.1.At visit1(week0),investigatorsobtainedpatients’writteninformed consent,collecteddemographicdataandmedical/surgical histo- ries, and performed physical and neurological examinations, including vital signs and body mass. During the 4-week up- titrationperiod,patientsinitially receivedZNS100mg/day(V1) (administered qd). The dose was increased to 200mg/day (administered bid) after 2weeks and could be increased to 300mg/day (administeredbid)afteran additional2weeks(V2) atthediscretionoftheinvestigatorifitwasclinicallynecessaryto achieve maximum benefit. During the 12-week maintenance period,theZNSdosewasallowedtobeincreasedfrom200mg/day to300mg/dayorfrom300mg/dayto400mg/dayatV3(week8)if seizurecontrolwasinsufficient,anddecreasedonasingleoccasion inpatientswhowerereceiving300mg/dayifpoorlytolerated.At week16,patientsmadeafifthandfinalvisitoncompletionofthe study,atwhichtimefinaldatawerecollected.Thosewhoelected notto continueZNS therapy had theirdose reduced gradually.
Patientsrecordedthedate,number,andtypeofseizuresonadaily recordcard;eachinvestigatorcodedtheseizuresexperiencedby hisorherpatients. Adverseevents (AEs)wererecordedateach visitbasedonspontaneouspatientreports,investigatorobserva- tions,responsestostandardquestionsaskedbytheinvestigator, andeventsrecordedonthepatientdailyrecordcard.
2.3. Priorandconcomitanttherapy
ThehistoryofpreviousAEDswasinvestigated.Forthepurposes ofstudyevaluation,thepatients’concomitantAEDshadtoremain constantduringthestudy.Additionalmedicationwasallowedto be prescribed for the well-being of the patient; however, medication(otherthanAEDs)affectingthecentralnervoussystem wastobeavoidedunlessthepatienthadbeenonastabledosefor at least the last 6months before the first visit. Concomitant medicationwasmaintained atthesamestabledosethroughout thestudy.
2.4. Efficacyandsafetymeasurements
Efficacy end pointswerebasedon thefrequencyof seizures duringthe16-weektreatmentperiod(titrationandmaintenance) comparedwiththe12-weekbaselineperiodaswellasretention rate.Theprimaryefficacyvariables werethepercent reduction frombaselineinseizurefrequencyperweekandtheretentionrate atweek16,definedasthenumberofsubjectsstilltreatedwithZNS attheendofthe16-weektreatmentperioddividedbythenumber ofpatientsintheintent-to-treat(ITT)population.Otherefficacy variables included the median reduction in the frequency of seizuresandseizuredaysperweek,theresponderrates,andthe numberofseizure-freepatients.Forpatientswhodidnotcomplete the16-weektreatmentperiod,datauptowithdrawalwereusedin theanalysisofefficacy.
Othervariablesincludedglobalevaluationofdiseaseevolution and quality of life. A validated Korean version of the original Quality of Life in Epilepsy Questionnaire (QOLIE-31) instru- ment19,20was filled in at the selection visit and at the end of the16-weektreatmentperiodoruponearlywithdrawal.Follow- ingthecompletionoftreatment,theinvestigatorprovidedaglobal evaluationscaleratingtoassesstheoverallchangeintheseverity ofthepatient’sillnesscomparedtothestartofstudymedication.
The rating was based on overall clinical impression (marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, and marked worsening).Safetywasassessed accordingtoAEs,physicaland neurologicalexaminations, andlaboratoryevaluationsatvisit1 (week0)andvisit 5(week16).Physicalexaminationsincluded measurementofvitalsigns.
2.5. Statisticalmethods
SafetyanalyseswereperformedontheITTpopulation,which includedallpatientswhotookatleastonedoseofZNS.However, four patients who discontinued the study at the early stage withoutanypost-treatmentseizurecountwerenotincludedin theefficacyanalysesbasedonseizurecountduringthetreatment period.Studyvariablesweresummarizedbydescriptivestatis- tics: mean, median, standarddeviation, Q1 andQ3, range for continuous variables, and frequency tables for categorical variables. Baseline characteristics (gender, age, etiology of epilepsy, history of epilepsy,previous and concomitant AEDs) and ZNS exposure were summarized descriptively for theITT population.Weusedthepairedt-test,Wilcoxon’ssignedranktest, Wilcoxon’s rank sum test, or Kruskal–Wallis test to analyze continuousvariablesandthex2testorMcNemar’stesttoexamine categoricalvariables.
3. Results 3.1. Demographics
A total of 121 patients were enrolled and formed the ITT population(Table1).Ofthese,69(57.0%)weremaleand52(43.0%) werefemale.Patients’ ages rangedfrom16 to69years, witha meanage(S.D.)of37.7(11.2)years.AllpatientswereKorean.The meanage(S.D.)atonsetofepilepsywas21.2(12.5)yearsandthe mean duration (S.D.) of epilepsy was 19.0 (11.8) years. The etiologyofepilepsywasunknownin55.4%ofpatientsorattributedto hippocampalsclerosisincludingahistoryofsignificantbraininsultor dual pathology (11.6%), cranial trauma (9.9%), atrophic change withoutahistoryofsignificantbraininsult(9.1%),cerebralinfection (1.7%),malformationofcorticaldevelopment(2.5%),cerebralpalsy without a history of significant brain insult (2.5%), vascular malformation(1.7%),stroke(1.7%),tuberoussclerosis(1.7%),perina- talinjury (0.8%),neurofibromatosis(0.8%),andmentalretardation withoutahistoryofsignificantbraininsult(0.8%).Themedian(Q1–
Q3)baselineseizurefrequencywas0.50(0.25–0.92)perweek.The median (Q1–Q3) seizure days were 0.42 (0.25–0.83) per week.
Ninety-three(76.9%)patientspresentedwithatleastonecomplex partial seizure, 37 (30.6%) patients with atleast one secondarily generalizedtonic–clonicseizure,and13(10.7%)patientswithatleast one simple partial seizure during the baseline 12-week period.
RegardingthehistoryofpreviousAEDtreatment,54(44.6%)patients hadtakentwoormoreAEDspriortoentrytothisstudy.Themajority (85.1%)ofpatientsentered thetrialon twoorthree concomitant AEDs.ThemostfrequentlyusedconcomitantAEDswerelamotrigine, valproicacid,topiramate,andlevetiracetam.
Of the 121 patients, 88 (72.7%) completed the 16-week treatmentand33discontinuedthestudy.Twenty-threepatients withdrew due to an AE, three withdrew because of a lack of efficacy,andsevenwithdrewforotherreasons(protocolviolation infive,lossoffollow-upinone,andwithdrawalofconsentinone).
ThetrialbeganonFebruary04,2008andfinishedonAugust30, 2010.
The121patientswhotookoneormoredosesofZNSreceived thetreatment fora meanduration (S.D.) of94.3(35.9)days withinthestudyperiod.Themeandailydose(S.D.)ofZNSduring
the16-weektreatmentperiodwas233(61)mg,withamediandaily doseof261mg/day.Themeandailydose(S.D.)ofexposureoverthe last8weeksoftheindividualtitrationperiodforsubjectscompleting thestudywas297(69)mg(range,200–400mg).
3.2. Efficacy
The four patients who discontinued the study (AE in two patients,withdrawalofconsentinonepatient,andlackofefficacy inonepatient)withoutanyseizurecountsafterbaselinewerenot included in theefficacy analysis. A totalof 117 patients were therefore analyzed. Overall, 90 patients (76.9%) experienced a reductionfrombaselineinseizurefrequencyperweekoverthe study period; during the last 12weeks, 84 patients (71.8%) experienced a reduction from baseline. In the ITT population (n=117), the median (Q1–Q3) percent reduction in seizure frequency was 59.0% (Q1–Q3, 8.3–89.6%) over the treatment period (range, 3260.0 to 100.0%) (p<0.001); during the last 12weeks (n=102), the median (Q1–Q3) percent reduction in seizurefrequencywas68.5%(Q1–Q3,18.0–96.3%)overthelast12- weektreatmentperiod(range, 4100.0to100.0%)(p<0.001).The frequencyofseizuresdecreasedfromamedian(Q1–Q3)of0.50 (Q1–Q3: 0.33–1.00) per week during the baseline period to a medianof0.25(Q1–Q3:0.06–0.88)perweekoverthetreatment period.Themedianseizurefrequencywas0.25perweekduring the initial 4weeks (n=117, median reduction from base- line=53.8%), remained at 0.24 per week during weeks 4–8 (n=102, median reduction from baseline=68.4%), then was 0.00perweekduringweeks8–12(n=91,medianreductionfrom baseline=100.0%),andremainedat0.23duringthelast4weeks (n=89, median reduction from baseline=84.8%), as shown in Fig.2.
Overthetreatmentperiod,57.3%(67/117)ofpatientshada50%
orgreaterreductioninseizurescount,38.5%(45/117)hadatleasta 75% reduction, and 21.4% (25/117) of patients had a 100%
reduction. During thelast 12weeks, 54.7% (64/117)ofpatients hada50%orgreaterreduction,39.3%(46/117)hada75%orgreater reduction,and21.4%(25/117)ofpatients hada100%reduction.
However, seizure freedom was obtained for a mean of only 6.1weeks(2.0–12.1weeks) inninepatients (AEsinsixpatients, protocolviolationin twopatients, andloss offollow-upin one patient).Themeanweeklybaselineseizurefrequency(S.D.)of16 patientswithseizurefreedomcompletingthestudywas0.34(0.19) whichwassignificantlylowerthan1.32(2.54)oftheotherpatients (n=101)(p<0.001).Themeannumberoflife-timeAEDs(previous andconcomitant)of16patientswithseizurefreedomcompletingthe studywas3.0(1.8)(range,1–7)whichtendedtobelowercompared with3.9(1.8)(range,1–8)oftheotherpatients(n=101)(p=0.054).
The mean daily dose of exposure over the last 8weeks of the individual titration period for 16 patients with seizure freedom completingthestudywas256(63)mg(range,200–400mg)which
Fig.2.Medianweeklyfrequencyofseizure.
Table1
Baselinedemographicandclinicalcharacteristicsofthe121enrolledpatients.
Parameter Value
Age,years(meanS.D.) 37.711.2
Gender,male(%) 57.0
Bodyweight,kg(meanS.D.)a 65.714.0
Height,cm(meanS.D.)a 164.98.7
Bodymassindex,kg/m2(meanS.D.)a 24.04.0
Ageatonset,years(meanS.D.) 21.212.5
Epilepsyduration,years(meanS.D.) 19.011.8 Weeklypartialseizurefrequency
MeanS.D. 1.162.3
Median 0.50
Interquartilerange(Q1–Q3) 0.25–0.92
Min–max 0.25–21.0
No.ofpreviousantiepilepticdrugs(AEDs),n(%)
0 36(30)
1 31(26)
2 23(19)
3 15(12)
4 13(11)
5 3(2)
PreviousAEDstakenby10%ofpatients,n(%)
Valproicacid 35(29)
Carbamazepine 25(21)
Topiramate 23(19)
Pregabalin 17(14)
Phenytoin 16(13)
Clonazepam 13(11)
Oxcarbazepine 13(11)
No.ofconcomitantAEDs,n(%)
1 18(15)
2 58(48)
3 45(37)
ConcomitantAEDstakenby10%ofpatients,n(%)
Lamotrigine 61(50)
Valproicacid 50(41)
Topiramate 43(36)
Levetiracetam 41(34)
Carbamazepine 31(26)
Oxcarbazepine 20(17)
Pregabalin 13(11)
aThesedatawereobtainedfromanalysisof113patients.
