Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia A ...

214 Pages·2015·2.57 MB·English

Research
OriginalInvestigation
Effect of Dextromethorphan-Quinidine on Agitation
in Patients With Alzheimer Disease Dementia
A Randomized Clinical Trial
JeffreyL.Cummings,MD,ScD;ConstantineG.Lyketsos,MD,MHS;ElaineR.Peskind,MD;
AntonP.Porsteinsson,MD;JacoboE.Mintzer,MD,MBA;DouglasW.Scharre,MD;JoseE.DeLaGandara,MD;
MarcAgronin,MD;CharlesS.Davis,PhD;UyenNguyen,BS;PaulShin,MS;PierreN.Tariot,MD;JoãoSiffert,MD
Editorialpage1233
IMPORTANCEAgitationiscommonamongpatientswithAlzheimerdisease;safe,effective
AuthorVideoInterviewand
treatmentsarelacking. JAMAReportVideoat
jama.com
OBJECTIVE Toassesstheefficacy,safety,andtolerabilityofdextromethorphan
Supplementalcontentat
hydrobromide–quinidinesulfateforAlzheimerdisease–relatedagitation.
jama.com
DESIGN,SETTING,ANDPARTICIPANTS Phase2randomized,multicenter,double-blind, CMEQuizat
jamanetworkcme.comand
placebo-controlledtrialusingasequentialparallelcomparisondesignwith2consecutive
CMEQuestionspage1286
5-weektreatmentstagesconductedAugust2012–August2014.Patientswithprobable
Alzheimerdisease,clinicallysignificantagitation(ClinicalGlobalImpressions–Severity
agitationscore(cid:2)4),andaMini-MentalStateExaminationscoreof8to28participatedat42
USstudysites.Stabledosagesofantidepressants,antipsychotics,hypnotics,and
antidementiamedicationswereallowed.
INTERVENTIONS Instage1,220patientswererandomizedina3:4ratiotoreceive
dextromethorphan-quinidine(n=93)orplacebo(n=127).Instage2,patientsreceiving
dextromethorphan-quinidinecontinued;thosereceivingplacebowerestratifiedbyresponse
andrerandomizedina1:1ratiotodextromethorphan-quinidine(n=59)orplacebo(n=60).
MAINOUTCOMESANDMEASURES Theprimaryendpointwaschangefrombaselineonthe
NeuropsychiatricInventory(NPI)Agitation/Aggressiondomain(scalerange,0[absenceof
symptoms]to12[symptomsoccurdailyandwithmarkedseverity]).
RESULTS Atotalof194patients(88.2%)completedthestudy.Withthesequentialparallel
comparisondesign,152patientsreceiveddextromethorphan-quinidineand127receivedplacebo
duringthestudy.Analysiscombiningstages1(allpatients)and2(rerandomizedplacebo
nonresponders)showedsignificantlyreducedNPIAgitation/Aggressionscoresfordextromethorphan-
quinidinevsplacebo(ordinaryleastsquareszstatistic,−3.95;P<.001).Instage1,meanNPIAgitation/
Aggressionscoreswerereducedfrom7.1to3.8withdextromethorphan-quinidineandfrom7.0to
5.3withplacebo.Between-grouptreatmentdifferencesweresignificantinstage1(leastsquaresmean,
−1.5;95%CI,−2.3to−0.7;P<.001).Instage2,NPIAgitation/Aggressionscoreswerereducedfrom
5.8to3.8withdextromethorphan-quinidineandfrom6.7to5.8withplacebo.Between-group
treatmentdifferenceswerealsosignificantinstage2(leastsquaresmean,−1.6;95%CI,−2.9to−0.3;
P=.02).Adverseeventsincludedfalls(8.6%fordextromethorphan-quinidinevs3.9%forplacebo),
diarrhea(5.9%vs3.1%respectively),andurinarytractinfection(5.3%vs3.9%respectively).
Seriousadverseeventsoccurredin7.9%withdextromethorphan-quinidinevs4.7%withplacebo.
Dextromethorphan-quinidinewasnotassociatedwithcognitiveimpairment,sedation,orclinically
significantQTcprolongation.
CONCLUSIONSANDRELEVANCE Inthispreliminary10-weekphase2randomizedclinicaltrial AuthorAffiliations:Author
affiliationsarelistedattheendofthis
ofpatientswithprobableAlzheimerdisease,combinationdextromethorphan-quinidine
article.
demonstratedclinicallyrelevantefficacyforagitationandwasgenerallywelltolerated.
CorrespondingAuthor:JeffreyL.
Cummings,MD,ScD,ClevelandClinic
TRIALREGISTRATION clinicaltrials.govIdentifier:NCT01584440 LouRuvoCenterforBrainHealth,
888WBonnevilleAve,LasVegas,NV
JAMA.2015;314(12):1242-1254.doi:10.1001/jama.2015.10214 89106([email protected]).
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Dextromethorphan-QuinidineforAgitationinPatientsWithAlzheimerDisease OriginalInvestigation Research
A
gitationandaggressionarehighlyprevalentinpa- for statistical analysis plan). All patients or authorized
tientswithdementia1,2andareassociatedwithdis- representativesorcaregiversprovidedwritteninformed
tressforpatientsandcaregivers,greaterriskofinsti- consent.
tutionalization,andacceleratedprogressiontoseveredementia
anddeath.3-5Nonpharmacologicalinterventionsarerecom- Participants
mendedasfirst-linetherapy,butmanypatientsfailtore- Eligiblepatientswereaged50to90yearswithprobable
spond, and pharmaco- Alzheimerdisease(basedon2011NationalInstituteon
CGISClinicalGlobal
therapyisoftenneeded.5-7 Aging–AlzheimerAssociationcriteria)andclinicallysignifi-
Impressions–Severity
Althoughmanyclassesof cantagitation,definedasastateofpoorlyorganizedandpur-
MMSEMini-MentalState
psychotropic drugs are poselesspsychomotoractivitycharacterizedbyatleast1of
Examination
prescribedforagitation, thefollowing:aggressiveverbal(eg,screaming,cursing),
NPINeuropsychiatricInventory
safetyconcernsandmod- aggressivephysical(eg,destroyingobjects,grabbing,fight-
QTcFFridericia-correctedQTinterval
estorunprovenefficacy ing),ornonaggressivephysical(eg,pacing,restlessness)
limittheirutility.Antipsychoticshaveshownbenefitfor behaviors.17Eligiblepatientshadbehavioralsymptomsthat
Alzheimerdisease–relatedpsychosis,buttheiruseisassoci- interferedwithdailyroutine,weresevereenoughtowarrant
atedwithexcessmortality,cerebrovascularevents,seda- pharmacologicaltreatment,scored4orhigher(moderately
tion,falls,cognitiveimpairment,metabolicsyndrome,par- ill)ontheClinicalGlobalImpressions–Severity(CGIS)scale
kinsonism,andtardivedyskinesia.5,8Arecenttrialshowed foragitation,18andhadaMini-MentalStateExamination
thatcitalopram,aselectiveserotoninreuptakeinhibitor, (MMSE)scoreof8to28.StabledosagesofAlzheimerdisease
wasassociatedwithimprovementinagitationinAlzheimer medications(≥2months;memantineand/oracetylcholines-
diseasebutwasassociatedwithprolongedQTcintervaland teraseinhibitors)andspecifiedantidepressants,antipsychot-
mildcognitivedecline.9Safeandeffectivetherapiestarget- ics,orhypnotics(≥1month;includingshort-actingbenzodi-
ingAlzheimerdisease–relatedagitationareneeded.5 azepinesandnonbenzodiazepines)wereallowed;dosages
Thecombinationofdextromethorphanhydrobromide weretoremainstablethroughoutthestudy.
and quinidine sulfate is approved for the treatment of Exclusioncriteriawerenon–Alzheimerdiseasedemen-
pseudobulbar affect in the United States and European tia;agitationnotsecondarytoAlzheimerdisease;hospital-
Union.Dextromethorphanisalow-affinity,uncompetitive izationinamentalhealthcarefacility;significantdepres-
N-methyl-D-aspartatereceptorantagonist,10σ1receptor sion(CornellScaleforDepressioninDementiascore≥10);
agonist,11serotoninandnorepinephrinereuptakeinhibitor,12 schizophreniaorschizoaffectiveorbipolardisorder;myas-
andneuronalnicotinicα β receptorantagonist.13Evidence theniagravis(becausequinidineuseiscontraindicated);
3 4
suggestingapotentialeffectofdextromethorphan-quinidine clinicallysignificant/unstablesystemicdisease;historyof
foragitationcomesfromcontrolledclinicaltrialdatainnon- completeheartblock,QTcprolongation,ortorsadesde
dementedpatientswithpseudobulbaraffect,14published pointes;familyhistoryofcongenitalQTprolongation;his-
casedescriptions,15andanecdotalreportsofimprovement toryofposturalorunexplainedsyncopewithinthelast
inpatientswithdementia,pseudobulbaraffect,andsymp- year; or substance/alcohol abuse within 3 years. First-
tomssuggestiveofagitation. generationantipsychoticsandtricyclicandmonoamineoxi-
Hereinwereporttheresultsofarandomizedclinicaltrial daseinhibitorantidepressantswerenotallowed.
toassesstheefficacyandsafetyofdextromethorphan- Raceandethnicitywereself-reportedorprovidedbya
quinidineformoderatetosevereagitationassociatedwith knowledgeableinformantbasedoncategoriesdefinedby
Alzheimerdisease. the US Food and Drug Administration (FDA) Guidance
forIndustryforCollectionofRaceandEthnicityDatain
ClinicalTrials.
Methods
Interventions
TrialDesignandSetting Instage1,patientswererandomized3:4toreceiveoralad-
Thisrandomized,double-blind,placebo-controlled,10-week ministrationofdextromethorphan-quinidineormatching
trialwasconductedat42USsitesincludingoutpatient placebo.Dextromethorphan-quinidinewasdosedas20/10mg
Alzheimerdiseaseclinicsandassistedlivingandnursing oncedailyinthemorning(withplacebointheevening)for
facilities. This clinical trial was conducted using the week1.Dextromethorphan-quinidinewasincreasedtotwice
Trimentum(PharmacoInvestmentsInc)sequentialparallel dailyforweeks2and3andthenincreasedto30/10mg
comparisondesignmethod,underlicensefromPPDDevel- twicedailyforweeks4and5.Instage2,patientsreceiving
opment LP, consisting of 2 consecutive 5-week stages dextromethorphan-quinidinecontinuedtoreceive30/10mg
toenhancetheabilitytodetectatreatmentsignaleven twicedaily.Patientswhoreceivedplaceboduringstage1were
in the context of a robust placebo response (eFigure in stratifiedbytreatmentresponseandrerandomizedina
Supplement1).16Anindependentdataandsafetymonitoring 1:1ratiotoreceivedextromethorphan-quinidine(dosagees-
boardoversawthestudy,andinstitutionalreviewboards calatedasdescribedabove)ormatchingplacebo.Patientswere
ateachsiteapprovedthestudyprotocolanditsamendments consideredrespondersattheendofstage1iftheirCGISscore
(see Supplement 2 for trial protocol and Supplement 3 foragitationwas3(mildlyill)orlowerandtheirNeuropsychi-
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Research OriginalInvestigation Dextromethorphan-QuinidineforAgitationinPatientsWithAlzheimerDisease
atricInventory(NPI)Agitation/Aggressiondomainscorede- cancelevel,asamplesizeof196patientswouldprovide90%
creasedby25%ormorefrombaseline. powertodetectameandifferenceof2.5points.Thesample
Oral lorazepam (maximum dosage of 1.5 mg/d and sizecalculationwasbasedonaparalleldesignbecausethere
maximumof3daysina7-dayperiod)wasallowedasrescue wasnoprecedentforasequentialparallelcomparisondesign
medicationforagitationifdeemednecessarybythestudy trialofagitationinAlzheimerdisease.
investigator.
Randomization
Outcomes Therandomizationschemewasdesignedbythesponsorand
Theprespecifiedprimaryefficacyendpointwaschange managedbythecontractresearchorganizationusinganin-
frombaselineintheNPIAgitation/Aggressiondomain.Each teractiveWebresponsesystem.Therandomizationinstage1
NPIdomainwasratedbythecaregiverforsymptomfre- wasstratifiedbybaselinecognitivefunction(MMSEscoreof
quency(1-4:occasionally[lessthanonceperweek],often >15vs≤15)andagitationseverity(CGISscoreof4-5vs6-7);
[aboutonceperweek],frequently[severaltimesperweek], blockedrandomizationensuredtreatmentbalanceineachstra-
orveryfrequently[onceormoreperday],respectively)and tum.
severity(1-3:mild,moderate,ormarked,respectively);a
scoreof0indicatednosymptoms.TheNPI’sscoringyields Masking
acomposite(frequency×severity)scoreof1to12foreach Dextromethorphan-quinidineandplacebocapsuleswereiden-
positivelyendorseddomain. ticalinappearance.Thesponsor,patients,caregivers,andin-
Secondaryefficacyendpointsincludedchangesfrom vestigatorswereunawareoftreatmentassignment.Allstudy
baselineinNPItotalscore(range,0-144),individualNPI sites,patients,andcaregiverswereblindedtotheuseofse-
domainscores,andNPIcompositescorescomprisingthe quentialparallelcomparisondesignandunawareofthere-
Agitation/Aggression, Aberrant Motor Behavior, and spondercriteriaandmidstudyrerandomization.
Irritability/LabilitydomainspluseithertheAnxietydomain
(NPI4A)ortheDisinhibitiondomain(NPI4D).AnNPICare- StatisticalAnalysis
giverDistressscoreforeachpositivelyendorsedNPIdomain Thesafetyanalysissetincludedallpatientswhotookatleast
capturedhowemotionallydistressingthecaregiverfound 1doseofstudymedication.Themodifiedintention-to-treat
the behavior (range, 0-5; not at all to very severely or analysissetforefficacyincludedallpatientswithapostbase-
extremely).AlzheimerDiseaseCooperativeStudy(ADCS) lineNPIAgitation/Aggressionassessmentinstage1.Inpri-
ClinicalGlobalImpressionofChangescores(range,1-7; maryanalysis,missingdatawereimputedusinglastobserva-
markedimprovementtomarkedworsening)andPatient tioncarriedforward;insensitivityanalysis,missingdatawere
GlobalImpressionofChangescores,ratedbyacaregiver handledusingamixed-effectsmodelassumingamissing-at-
(range,1-7;verymuchimprovedtoverymuchworse),were randommechanism.
assessedatweeks5and10andprovidedmeasuresofclini- Primaryandsecondaryefficacyendpointswereana-
cal meaningfulness. Additional secondary end points lyzedbasedonpublishedsequentialparallelcomparisonde-
included the ADCS Activities of Daily Living Inventory signmethods16,23analyzingdatafromboth5-weekstageswith
(range, 0-54; higher scores signifying better function); 1:1weightingusingordinaryleastsquaresandincludingallpa-
Cornell Scale for Depression in Dementia (range, 0-38; tientsinstage1andonlythererandomizedplacebononre-
higherscoressignifyingmoreseveredepression);Caregiver spondersinstage2.Theprimarystudyend-pointanalysiswas
StrainIndex(range,0-13;higherscoressignifyinghigher prespecified;nocorrectionwasperformedtoaddressmulti-
stress levels); Quality of Life–Alzheimer Disease score plicityinthesecondaryendpoints.Dextromethorphan-
(range,13-52;higherscoressignifyingbetterqualityoflife); quinidineandplacebogroupswerecomparedusing2-sided
andpsychotropicmedicationchanges/rescueuseofloraze- testsattheα=.05levelofsignificance.Additionally,analysis
pam.CognitionwasassessedusingtheMMSE(range,0-30; ofcovariancewithtreatmentasthefixedeffectandbaseline
lowerscoressignifyinggreatercognitiveimpairment)and asthecovariatewasusedtocomparetreatmentgroupmeans
theAlzheimerDiseaseAssessmentScale–CognitiveSubscale ateachstageandvisit,separately.Tosimulatea10-weekpar-
(range, 0-70; higher scores signifying greater cognitive allel-groupdesign,wealsoconductedaprespecifiedcompari-
impairment).Safetyoutcomesincludedadverseevents, sonofNPIAgitation/Aggressionscoresbetweenpatientswho
vitalsigns,clinicallaboratorytestresults,andelectrocar- were randomized to receive only dextromethorphan-
diographicfindings.ResultsforQTintervalwerecorrected quinidinevsonlyplacebofortheentire10weeksofthetrial
forvariationinheartrateandcalculatedaccordingtothe (regardlessofresponderstatus).Allstatisticalanalyseswere
formulaofFridericia(QTcF):(QT/3(cid:2)[RR]).19 performedusingSASversion9.1orhigher(SASInstituteInc).
Giventheuseofsequentialparallelcomparisondesign
SampleSizeCalculation methodsandtoensurefindingsfromtheprimaryanalysis,ad-
Inpublishedtreatmentstudiesfordementia-relatedagita- ditionalexploratorysensitivityanalysesoftheprimaryend
tion,standarddeviationestimatesforchangeinNPIAgitation/ pointwerecarriedout.Oneusedtherepeated-measuresmodel
Aggressionscoresrangefrom3.1to5.2points.20-22Assuming (prespecified)describedbyDorosetal24totestthepotential
anSDof5.0pointsandbasedona2-sided,2-samplecompari- statisticaleffectofmissingdataandtheexclusionofreran-
sonofmeansfromindependentsamplesatthe.05signifi- domizedplacebo“responders”instage2.Thismodelusesall
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Dextromethorphan-QuinidineforAgitationinPatientsWithAlzheimerDisease OriginalInvestigation Research
availabledatafromtheNPIAgitation/Aggressiondomain.Three to3.8(SD,3.1)withdextromethorphan-quinidineandfrom
separatemodelswereusedtoestimatetreatmenteffectand 6.7 (SD, 2.8) to 5.8 (SD, 3.8) with placebo, with a least
includeddatacollectedatbaseline,endofstage1,andendof squaresmeantreatmentdifferenceof−1.6(95%CI,−2.9to
stage2,withageneralmodelthatallowsinclusionofdatafrom −0.3;P=.02)(Figure2B).Theprespecifiedcomparisonof
intermediatevisits.BasedonanFDArecommendation,thesec- NPIAgitation/Aggressionscoresbetweenpatientswhowere
ondsensitivityanalysisoftheprimaryendpoint,usingthe randomizedtoreceiveonlydextromethorphan-quinidine
seeminglyunrelatedregressionmethod24-26inthesequen- (n=93)vsonlyplacebo(n=66)fortheentire10weeksof
tialparallelcomparisondesigninsteadoftheordinaryleast the trial (regardless of responder status, simulating a
squaresmethod,wasconductedafterunblindingofthestudy parallel-groupdesign)alsofavoreddextromethorphan-
toaddresswhethermissingdatacouldbemissingnotatran- quinidineoverplacebo(leastsquaresmeantreatmentdif-
dom.Inaddition,aprespecifiedexploratoryanalysisofthepri- ference,−1.8;95%CI,−2.8to−0.7;P=.003)(Table2and
maryendpointwascarriedoutthatusedthesamesequen- Figure2C).Responsetodextromethorphan-quinidinecom-
tialparallelcomparisondesignmethoddescribedaboveforthe paredwithplacebodidnotappeartodifferbydiseasestage.
primaryanalysisbutincludingbothplaceborespondersand ThestratifiedrandomizationbybaselineMMSEscore(>15
nonresponderswhowerererandomizedinstage2. vs≤15)andbaselineCGISscore(4or5vs6or7)resultedin
balancedtreatmentgroupsforbothagitationandcognitive
function.Supplementalanalysesconductedtoassessthe
potentialinfluenceofthesefactorsdidnotsuggestadiffer-
Results
enceinresponse.
Patients Therepeated-measuresmodelandseeminglyunrelatedre-
PatientswererecruitedbetweenJuly23,2012,andMay22, gressionsensitivityanalysesoftheprimaryendpointcorrobo-
2014;thelastpatientcompletedthestudyonJuly31,2014, ratedthestatisticalsignificanceobservedintheprimaryeffi-
andthestudyclosedAugust30,2014,atexpirationofthe cacy analysis (eTable in Supplement 1). The additional
30-daysafetyreportingwindow.All220randomizedpatients prespecifiedanalysisthatincludedbothplaceboresponders
(126womenand94men)wereincludedinthesafetyanalysis andnonresponderswhowerererandomizedinstage2didnot
set;218patientscomprisedthemodifiedintention-to-treat alterthesignificanceormagnitudeofeffectoftheprimary
analysissetforefficacy,and194(88.2%)completedthestudy analysis.
(Figure1).Withthesequentialparallelcomparisondesign
andrerandomizationoftheplacebogrouponentryintostage SecondaryOutcomes
2, a total of 152 patients received dextromethorphan- Sequentialparallelcomparisondesignanalysisofprespeci-
quinidine(93startingfromstage1andanadditional59 fiedsecondaryoutcomes(Table2andTable3)showedsig-
rerandomizedfromtheplacebogroupinstage2)and127 nificantimprovementfavoringdextromethorphan-quinidine
patientsreceivedplacebo,resultinginanapproximately onglobalratingscores(PatientGlobalImpressionofChange
26.7%greaterexposuretodextromethorphan-quinidine andADCSClinicalGlobalImpressionofChange),NPItotal,
(1153patient-weeks)thantoplacebo(911patient-weeks).Sev- NPIAberrantMotorBehaviordomain,NPIIrritability/Lability
enteenpatients(11.2%)discontinuedthestudywhilereceiv- domain,NPI4AandNPI4Ddomaincomposites,NPICare-
ingdextromethorphan-quinidineand9(7.1%)whilereceiv- giverDistress(asrelatedtoboththeNPIAgitation/Aggression
ingplacebo,including8(5.3%)and4(3.1%)foradverse domainscoreandNPItotalscore),CaregiverStrainIndex,
events,respectively.Patientcharacteristicswerewellbal- andCornellScaleforDepressioninDementia.Resultsfor
ancedacrosstreatmentgroups(Table1). changesintheQualityofLife–AlzheimerDiseasescore,ADCS
ActivitiesofDailyLivingInventory,MMSE,andAlzheimer
EfficacyOutcomes DiseaseAssessmentScale–CognitiveSubscale(anexploratory
PrimaryEndPoint outcome)werenotsignificantvsplacebo.Posthocanalyses
Dextromethorphan-quinidinesignificantlyimprovedthe showedsimilarimprovementinNPIAgitation/Aggression
NPIAgitation/Aggressionscorecomparedwithplaceboin scoreswithdextromethorphan-quinidineinpatientstaking
theprimarysequentialparallelcomparisondesignanalysis concomitantacetylcholinesteraseinhibitors,memantine,
(ordinaryleastsquareszstatistic,−3.95;P<.001).Results antidepressants,orantipsychoticscomparedwiththosenot
foreachstagealsofavoreddextromethorphan-quinidine receivingtheseagents.Lorazepamrescuemedicationwas
over placebo (Table 2). In stage 1, mean NPI Agitation/ usedby10of152patients(6.6%)duringtreamentwith
Aggressionscoreswerereducedfrom7.1(SD,2.6)to3.8(SD, dextromethorphan-quinidine and by 13 of 125 patients
3.3)withdextromethorphan-quinidineandfrom7.0(SD, (10.4%)duringtreatmentwithplacebo.
2.4)to5.3(SD,3.2)withplacebo,withaleastsquaresmean
treatmentdifferenceof−1.5(95%CI,−2.3to−0.7;P<.001). SafetyandTolerability
Differentialresponsewasnotedbyweek1(leastsquares Treatment-emergentadverseeventswereattributedbased
mean,−0.8;95%CI,−1.5to−0.03;P=.04)(Figure2A).In on treatment assignment at the time of occurrence.
stage2(placebononrespondersrerandomizedtoeither Treatment-emergentadverseeventswerereportedby93of
dextromethorphan-quinidine or placebo), mean NPI 152patients(61.2%)and55of127patients(43.3%)(safety
Agitation/Aggressionscoreswerereducedfrom5.8(SD,3.0) set)duringtreatmentwithdextromethorphan-quinidineor
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Figure1.ParticipantFlowinaTrialofDextromethorphan-QuinidineforAlzheimerDisease–RelatedAgitation
383Patients assessed for eligibility
163Excluded
128Did not satisfy inclusion criteria or met
exclusion criteria a
17Patient withdrawals
6Investigator decision
2Adverse events
2Caregivers no longer wanted to participate
2Lost to follow-up
6Other
220Randomized
STAGE 1 (WEEKS 1-5)
127Randomized to receive placebo 93Randomized to receive
127Received placebo as randomized dextromethorphan-quinidine
93Received
dextromethorphan-
quinidine as randomized
8Discontinued during stage 1 10Discontinued during stage 1
3Adverse event 5Adverse event
3Protocol deviation 2Protocol deviation
2Withdrawal by patient or guardian 1Withdrawal by patient
1Other
1Lost to follow-up
119Completed stage 1 83Completed stage 1
125Included in primary SPCD analysis 93Included in primary
2Excluded (no postbaseline data SPCD analysis
for efficacy end point)
STAGE 2 (WEEKS 6-10)
119Continued to stage 2
30Placebo responders 89Placebo nonresponders 83Continued to stage 2
rerandomized rerandomized
15Rerandomized to receive 15Rerandomized to receive 45Rerandomized to receive 44Rerandomized to receive
placebo dextromethorphan-quinidine placebo dextromethorphan-quinidine
15Received placebo as 15Received 45Received placebo as 44Received
randomized dextromethorphan- randomized dextromethorphan-
quinidine as randomized quinidine as randomized
15Completed stage 2 15Completed stage 2 44Completed stage 2 40Completed stage 2 80Completed stage 2
1Discontinued during stage 2 4Discontinued during stage 2 3Discontinued during stage 2
(adverse event) 2Adverse event 1Adverse event
2Withdrawal by patient 1Withdrawal by patient
1Other
45Included in primary 44Included in primary
SPCD analysis SPCD analysis
SPCDindicatessequentialparallelcomparisondesign.Themodified aMostcommonreasonsforexclusionsrelatedtoinclusionorexclusioncriteria
intention-to-treatpopulationincluded218patients(placebo,n=125; werenothavingaMini-MentalStateExamininationscorebetween8and28,
dextromethorphan-quinidine,n=93).Attheendofstage1,responsefor inclusive(n=26);nothavingaCGISscoreforagitationofatleast4(n=25);
placebogroupstratificationwasdefinedashavingaClinicalGlobal havingapersonalhistoryofcompleteheartblock,QTcprolongation,or
Impressions–Severity(CGIS)scoreforagitationof3orlower(mildlyill)anda torsadedepointes(n=21);havingcoexistentclinicallysignificantorunstable
NeuropsychiatricInventoryAgitation/Aggressiondomainscoredecreaseof systematicdisease(n=18);takingadisallowedmedication(n=5);andtakingan
25%ormorefrombaseline. allowedmedicationbutatanunstabledoseorduration(n=5).
placebo, respectively. The most commonly occurring urinarytractinfection(5.3%vs3.9%),anddizziness(4.6%
treatment-emergentadverseevents(>3%andgreaterthan vs 2.4%) for dextromethorphan-quinidine vs placebo,
placebo)werefalls(8.6%vs3.9%),diarrhea(5.9%vs3.1%), respectively.Seriousadverseeventsoccurredin12patients
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Dextromethorphan-QuinidineforAgitationinPatientsWithAlzheimerDisease OriginalInvestigation Research
Table1.BaselineDemographicandClinicalCharacteristicsa
Dextromethorphan-Quinidine Placebo
Characteristics (n=93)b (n=127)b
Age,mean(SD),y 77.8(8.0) 77.8(7.2)
Age≥75y 68(73.1) 86(67.7)
Women 52(55.9) 74(58.3)
Race
White 84(90.3) 118(92.9)
BlackorAfricanAmerican 5(5.4) 6(4.7)
Asian 3(3.2) 1(0.8)
NativeHawaiianorotherPacificIslander 1(1.1) 0
Other 0 2(1.6)
Ethnicity
HispanicorLatino 7(7.5) 13(10.2)
Residence
Outpatient 82(88.2) 111(87.4)
Assistedliving 5(5.4) 10(7.9)
Nursinghome 6(6.5) 6(4.7)
Concomitantmedications
Acetylcholinesteraseinhibitors 67(72.0) 95(74.8)
Memantine 43(46.2) 66(52.0)
Antidepressants 57(61.3) 65(51.2)
Antipsychotics 16(17.2) 29(22.8)
Benzodiazepines 6(6.5) 12(9.5)
Benzodiazepine-likederivatives 6(6.5) 12(9.5)
Historyoffalls 16(17.2) 16(12.6)
Ratingscalescores,mean(SD)c
ClinicalGlobalImpressions–Severityscore 4.4(0.6) 4.5(0.7)
foragitation
No.(%)withscore
4(moderatelyill) 61(65.6) 77(61.6)
5(markedlyill) 28(30.1) 38(30.4)
6or7(severelyilloramongthemostextremely 4(4.3) 10(8.0) Abbreviations:NPI4A,thesumof
illpatient) NeuropsychiatricInventory
NeuropsychiatricInventory Agitation/Aggression,
Irritability/Lability,AberrantMotor
Agitation/Aggressiondomain 7.1(2.6) 7.0(2.4)
Behavior,andAnxietydomainscores;
Totalscore 40.1(19.6) 38.0(18.7) NPI4D,thesumofNeuropsychiatric
AberrantMotorBehaviordomaind 4.0(0-8) 2.0(0-6) InventoryAgitation/Aggression,
Irritability/Lability,AberrantMotor
Irritability/Labilitydomain 5.8(3.7) 5.4(3.2)
Behavior,andDisinhibitiondomain
NPI4Acomposite 20.9(9.4) 20.1(8.3) scores.
NPI4Dcomposite 19.8(9.1) 18.5(9.2) aDataareexpressedasNo.(%)of
Caregiverdistress participantsunlessotherwise
indicated.
Agitation 3.3(0.9) 3.0(1.0)
bSafetyanalysissetatrandomization.
Totalscore 17.9(8.0) 17.0(8.3)
cModifiedintention-to-treatanalysis
CaregiverStrainIndex 6.9(3.2) 6.8(3.6) setforefficacyanalysis
CornellScaleforDepressioninDementia 5.9(2.4) 5.8(2.4) (dextromethorphan-quinidine,
n=93;placebo,n=125)atstage1
QualityofLife–AlzheimerDiseasescale
baseline.
Patient 36.5(7.4) 37.2(6.4)
dPresentedasmedian(interquartile
Caregiver 30.9(6.0) 30.1(6.0) range).Atbaseline,themean
Mini-MentalStateExamination 17.4(6.0) 17.2(5.8) NeuropsychiatricInventory
AberrantMotorBehaviordomain
AlzheimerDiseaseAssessmentScale–CognitiveSubscale 30.6(14.1) 32.0(15.2)
scoreswere4.3(SD,4.4)for
AlzheimerDiseaseCooperativeStudy–Activities 35.8(11.9) 34.1(12.8) dextromethorphan-quinidineand
ofDailyLivingInventory
3.5(SD,4.2)forplacebo.
(7.9%) receiving dextromethorphan-quinidine and in 6 (n=2),anemia,acutemyocardialinfarction(occurring2
(4.7%)receivingplacebo.Seriousadverseeventsinpatients daysafterdosingended),bradycardia,kidneyinfection,
receivingdextromethorphan-quinidineincludedchestpain femurfracture,dehydration,coloncancer,cerebrovascular
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Table2.SummaryofEfficacyOutcomeMeasuresintheModifiedIntention-to-TreatPopulation
No.ofParticipants ChangeFromBaseline,Mean(95%CI)
LeastSquaresMean
OutcomeMeasureand Dextromethorphan- Dextromethorphan- PValue TreatmentDifference PValue
StudyStagea Quinidine Placebo Quinidine Placebo byStageb (95%CI)c bySPCDb,d
NPIAgitation/
Aggressiondomaine
Stage1a 93 125 −3.3(−3.9to−2.6) −1.7(−2.3to−1.2) <.001 −1.5(−2.3to−0.7)
<.001
Stage2a 44 45 −2.0(−3.0to−1.0) −0.8(−1.9to0.2) .02 −1.6(−2.9to−0.3)
10wkf 93 66 −3.6(−4.3to−2.9) −1.9(−2.8to−1.0) .001 −1.8(−2.8to−0.7) .003
NPItotalscoree
Stage1a 93 125 −13.5(−17.1to−9.9) −8.5(−11.0to−5.9) .03 −4.2(−8.0to−0.4)
.01
Stage2a 44 45 −6.0(−9.7to−2.2) −2.5(−6.0to1.1) .15 −3.8(−9.0to1.4)
10wkf 93 66 −16.0(−19.5to−12.5) −10.1(−14.7to−5.5) .02 −5.7(−10.7to−0.7) NA
NPIAberrantMotor
Behaviordomaine
Stage1a 93 125 −1.2(−2.0to−0.4) −0.4(−1.1to0.3) .39 −0.4(−1.3to0.5)
.03
Stage2a 44 45 −0.8(−1.6to−0.1) 0.4(−0.6to1.3) .04 −1.2(−2.4to−0.1)
10wkf 93 66 −1.3(−2.1to−0.5) 0.1(−0.7to0.8) .03 −1.0(−1.9to−0.1) NA
NPIIrritability/
Labilitydomaine
Stage1a 93 125 −2.2(−3.0to−1.4) −1.2(−1.8to−0.6) .09 −0.7(−1.5to0.1)
.03
Stage2a 44 45 −1.0(−2.0to0.04) −0.7(−1.8to0.5) .14 −0.9(−2.2to0.3)
10wkf 93 66 −2.4(−3.3to−1.6) −1.8(−2.8to−0.7) .38 −0.4(−1.4to0.6) NA
NPI4Acompositee
Stage1a 93 125 −7.3(−9.1to−5.4) −4.5(−6.0to−3.0) .03 −2.4(−4.6to−0.2)
.001
Stage2a 44 45 −4.8(−6.9to−2.7) −1.4(−3.8to1.0) .01 −3.9(−7.0to−0.9)
10wkf 93 66 −8.5(−10.4to−6.7) −5.0(−7.4to−2.5) .01 −3.4(−6.1to−0.7) NA
NPI4Dcompositee
Stage1a 93 125 −7.6(−9.4to−5.7) −4.0(−5.5to−2.6) .006 −3.0(−5.1to−0.9)
<.001
Stage2a 44 45 −4.6(−6.8to−2.4) −1.9(−4.2to0.4) .02 −3.5(−6.5to−0.5)
10wkf 93 66 −8.3(−10.1to−6.5) −5.0(−7.4to−2.6) .02 −3.0(−5.5to−0.4) NA
NPICaregiverDistress
agitationscoree
Stage1a 93 125 −1.4(−1.6to−1.0) −0.6(−0.8to−0.4) <.001 −0.7(−1.0to−0.3)
.01
Stage2a 44 45 −0.5(−0.9to−0.004) −0.7(−1.2to−0.2) .49 −0.2(−0.8to0.4)
10wkf 93 66 NA NA NA NA NA
NPICaregiverDistress
totalscoree
Stage1a 93 125 −6.6(−8.2to−5.0) −3.6(−4.8to−2.5) NA NA
.01
Stage2a 44 45 −2.6(−4.3to−1.0) −2.0(−3.8to−0.3) NA NA
10wkf 93 66 NA NA NA NA NA
CaregiverStrainIndexe
Stage1a 93 125 −1.2(−1.7to−0.7) −0.6(−0.9to−0.2) .03 −0.6(−1.2to−0.1)
.05
Stage2a 44 45 −0.2(−0.7to0.3) 0.1(−0.5to0.6) .42 −0.3(−1.0to0.4)
10wkf 93 66 −1.2(−1.7to0.6) −0.4(−0.9to1.3) .04 −0.8(−1.6to−0.02) NA
CornellScaleforDepression
inDementiag
Stage1a 88 123 −1.0(−1.8to−0.3) 0.6(−0.1to1.3) .002 −1.6(−2.5to−0.6)
.02
Stage2a 43 44 −0.9(−1.8to−0.004) −0.7(−1.5to0.1) .75 −0.2(−1.3to0.9)
10wkf 88 64 −1.2(−2.0to−0.4) 0.4(−0.6to1.5) .03 −1.3(−2.6to−0.1) NA
ADCSClinicalGlobal
Impressionof
Changescoreforagitationh
Stage1a 88 123 3.0(2.8to3.3) 3.6(3.4to3.8) <.001 −0.6(−0.9to−0.3)
<.001
Stage2a 42 42 3.3(2.9to3.6) 3.7(3.3to4.2) .07 −0.5(−1.0to0.1)
10wkf 82 59 2.7(2.3to3.1) 3.3(3.0to3.7) .02 −0.5(−0.9to−0.1) NA
(continued)
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Dextromethorphan-QuinidineforAgitationinPatientsWithAlzheimerDisease OriginalInvestigation Research
Table2.SummaryofEfficacyOutcomeMeasuresintheModifiedIntention-to-TreatPopulation(continued)
No.ofParticipants ChangeFromBaseline,Mean(95%CI)
LeastSquaresMean
OutcomeMeasureand Dextromethorphan- Dextromethorphan- PValue TreatmentDifference PValue
StudyStagea Quinidine Placebo Quinidine Placebo byStageb (95%CI)c bySPCDb,d
PatientGlobalImpression
ofChangei
Stage1a 88 123 3.1(2.8to3.3) 3.6(3.4to3.8) .001 −0.6(−0.9to−0.2)
.001
Stage2a 43 44 3.2(2.8to3.6) 3.8(3.3to4.2) .04 −0.6(−1.1to−0.1)
10wkf 81 59 2.9(2.7to3.2) 3.5(3.2to3.8) .007 −0.6(−1.0to−0.2) NA
QualityofLife–
AlzheimerDisease
scale
Patienth
Stage1a 87 116 1.3(−0.03to2.6) 0.0(−1.0to0.9) .14 1.1(−0.4to2.6)
.16
Stage2a 40 40 1.5(−0.1to3.1) 0.7(−0.7to2.0) .50 0.7(−1.4to2.7)
10wkf 87 61 0.7(−0.7to2.1) 0.5(−1.1to2.0) .96 −0.1(−2.0to1.9) NA
Caregiverh,j
Stage1a 88 123 0.4(−0.5to1.3) 0.3(−0.5to1.1) .63 0.3(−0.9to1.5)
.47
Stage2a 43 43 −0.3(−1.5to0.9) 0.9(−0.4to2.2) .24 1.1(−2.8to0.7)
10wkf 88 64 1.3(0.2to2.4) 0.9(−0.5to2.4) .28 0.9(−0.7to2.6) NA
ADCSActivities
ofDailyLiving
Inventoryh
Stage1a 88 123 −0.9(−1.8to−0.04) −0.8(−1.5to−0.1) .90 −0.1(−1.2to1.1)
.16
Stage2a 43 44 −2.0(−3.4to−0.5) −0.6(−1.7to0.4) .12 −1.4(−3.1to0.4)
10wkf 88 64 −0.8(−1.8to0.2) −1.8(−2.9to0.7) .17 1.0(−0.5to2.5) NA
Mini-MentalState
Examination
totalscoreg
Stage1a 88 122 0.2(−0.4to0.9) −0.3(−0.8to0.2) .20 0.5(−0.3to1.3)
.05
Stage2a 42 44 0.3(−0.5to1.2) −0.5(−1.3to0.2) .15 0.8(−0.3to2.0)
10wkf 88 63 0.1(−0.5to0.8) −0.6(−1.5to0.3) .21 0.7(−0.4to1.8) NA
AlzheimerDisease
AssessmentScale–
CognitiveSubscaleh
Stage1a 87 121 −0.9(−2.5to0.6) 0.3(−5.7to1.3) .11 −1.4(−3.0to0.3)
.20
Stage2a 42 43 0.3(−1.4to1.9) 0.8(−0.7to2.3) .64 −0.5(−2.8to1.7)
10wkf 81 58 −0.7(−1.9to0.7) 1.2(−0.2to2.4) .07 −1.7(−3.5to0.2) NA
Abbreviations:ADCS,AlzheimerDiseaseCooperativeStudy;NA,notassessed; dSequentialparallelcomparisondesign(SPCD)analysiswasprotocolspecified
NPI,NeuropsychiatricInventory;NPI4A,thesumofNeuropsychiatricInventory fortheprimaryefficacyanalysisandcombinesresultsfromallpatientsinstage
Agitation/Aggression,Irritability/Lability,AberrantMotorBehavior,andAnxiety 1andfromplacebononrespondersrerandomizedinstage2basedona50/50
domainscores;NPI4D,thesumofNeuropsychiatricInventory weightingoftheNPIAgitation/Aggressiondomainforeachstageofthestudy.
Agitation/Aggression,Irritability/Lability,AberrantMotorBehavior,and eAssessedatbaselineandweeks1,3,5,6,8,and10.
Disinhibitiondomainscores.
fThe10-weekanalysisincludesonlypatientswhocontinuedtheiroriginal
aStage1includesallpatientsandmeasureschangefromstage1baselineto treatmentfortheirentirestudyparticipation(ie,tookonly
week5foreachoutcome.Stage2includesonlyrerandomizedplacebo dextromethorphan-quinidineoronlyplacebo,therebysimulatinga
nonrespondersfromstage1andmeasureschangefromstage2baseline(week parallel-groupdesign)andmeasureschangefromstage1baselinetoweek10.
5)toweek10foralloutcomesexceptthePatientGlobalImpressionofChange,
gAssessedatscreeningandweeks5and10.
whichmeasureschangefromoriginalstage1baselinetoweek10.
hAssessedatbaselineandweeks5and10.
bPvaluebystagefordextromethorphan-quinidinevsplaceboisbasedon
analysisofcovariancewithtreatmentasfixedeffectandbaselineascovariate; iAssessedatweeks5and10.
PvalueforSPCDanalysisisbasedonordinaryleastsquares. jFortheQualityofLife–AlzheimerDiseasescale’scaregiverresponse,the
cTreatmentdifference=dextromethorphan-quinidine−placebo. caregiverratesthepatient’squalityoflife.
accident,aggression,andhematuria(n=1each).Serious discontinuedtreatmentowingtoadverseevents,including
adverseeventsinpatientsreceivingplaceboincludedidio- 4 (2.6%) and 2 (1.6%), respectively, for serious adverse
pathicthrombocytopenicpurpura,vertigo,pneumonia, events.Nodeathsoccurredduringthestudy.
gastroenteritis,contusion,transientischemicattack,and Ofthe13patientswhofellwhilereceivingdextromethorphan-
agitation (n = 1 each). Eight patients (5.3%) receiving quinidine,9hadahistoryoffalls.Threefell2to4daysafter
dextromethorphan-quinidineand4(3.1%)receivingplacebo studycompletion,and1patientfelltwicewithin24hoursof
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Figure2.MeanNeuropsychiatricInventoryAgitation/AggressionDomainScoresbyStageandVisitforPatientsIncludedintheSequentialParallel
ComparisonDesignand10-WeekAnalyses
A Stage 1 analysis B Stage 2 analysis C 10-Week analysis
8 8 8
% CI) 6 Placebo % CI) 6 Placebo % CI) 6 Placebo
5 5 5
9 9 9
e ( 4 e ( 4 e ( 4
an Scor 2 Dqueixntirdoimneethorphan- an Scor 2 Dqueixntirdoimneethorphan- an Scor 2 Dqueixntirdoimneethorphan-
e e e
M M M
0 0 0
Baseline 1 3 5 Baseline 6 8 10 Baseline 1 3 5 6 8 10
Week (5) Week Week
No. of participants a
Dextromethorphan- 93 93 90 83 44 44 44 44 93 93 90 90 83 82 83
quinidine
Placebo 125 124 121 119 45 45 45 45 66 65 65 65 60 60 60
A,Stage1(weeks1-5);B,stage2(weeks6-10)forplacebononresponders −1.5to−0.03;P=.04),week3,−1.0(95%CI,−1.8to−0.2;P=.01),andweek5,
rerandomizedafterstage1;C,10-weekresults(the10-weeksecondary −1.5(95%CI,−2.3to−0.7;P<.001);forstage2,week6,0.7(95%CI,
analysisincludesonlypatientswhocontinuedthesametreatmentassignment −0.4to1.9;P=.19),week8,−0.1(95%CI,−1.3to1.2;P=.93),andweek10,
throughoutstudyparticipation;ie,wererandomizedtoreceiveonly −1.6(95%CI,−2.9to−0.3;P=.02);for10-weekanalysis,week1,−0.9(95%CI,
dextromethorphan-quinidineoronlyplacebo[excludespatientswho −1.8to−0.04;P=.047),week3,−1.3(95%CI,−2.2to−0.3;P=.01),week5,
werererandomizedfromplacebotodextromethorphan-quinidineinstage2], −1.8(95%CI,−2.7to−0.9;P<.001),week6,−0.9(95%CI,−2.0to0.1;
thussimulatingaparallel-groupdesign).Analysis-of-covariancemodels P=.06),week8,−1.3(95%CI,−2.4to−0.3;P=.01),andweek10,
withtreatmentasfixedeffectandbaselineascovariatewereusedtocompare −1.8(95%CI,−2.8to−0.7;P=.003).
meanchangefrombaselinebetweengroupsateachtimepoint.Baseline aObservedcases.
forstage2isthepatients’scoresatthestartofstage2.Leastsquares
meantreatmentdifferencesareasfollows:forstage1,week1,−0.8(95%CI,
receivinglorazepamrescueinbothinstances;nopatientwho der.Agitatedbehaviorsmayincludeexcessivemotoractivity,
fellwhilereceivingplacebohadahistoryoffalls.Twofalls verbalaggression,orphysicalaggression.27Baselineagita-
wereassociatedwithseriousadverseevents;femurfracture tionseverityandNPIAgitation/Aggressionscoreswerealsogen-
inthedextromethorphan-quinidinegroupandcontusionin erallyconsistentwiththoseofparticipantsintheCitalopram
theplacebogroup. forAgitationinAlzheimerDiseasestudy.9Treatmentwith
Noclinicallymeaningfulbetween-groupdifferencesin dextromethorphan-quinidineinthisstudydemonstratedsta-
electrocardiographicfindingswereobserved.Themeanchange tisticallysignificantefficacyontheprimaryendpointandthe
inQTcFwas5.3(SD,14.06)millisecondsamongpatientsre- majorityofsecondaryendpointsacrossmultiplemeasures
ceivingdextromethorphan-quinidine(n=138)and−0.3(SD, ratedbybothcliniciansandcaregivers.
12.96)millisecondsamongpatientsreceivingplacebo(n=60) ImprovementintheNPIAgitation/Aggressiondomainwas
at the final visit. Fifteen patients (10.3%) receiving statisticallysignificantatweek1andateverytimepointuntil
dextromethorphan-quinidine(n=145)and8(6.7%)receiving studyend,withexceptionofweeks6and8(duringstage2).
placebo(n=120)hadaQTcFincreaseofatleast30millisec- Theeffectswereconsideredtobeclinicallymeaningfulasre-
ondsatanyvisit;1patientreceivingplacebohadaQTcFin- flectedbyimprovementinADCSClinicalGlobalImpressionof
creaseofgreaterthan60milliseconds.NopatienthadaQTcF ChangeandPatientGlobalImpressionofChangescores,aswell
greaterthan500milliseconds. asonthemeasuresofCaregiverStrainIndexandNPICare-
giverDistressscore.Attheendofthe10-weektreatment,45.1%
of participants treated only with dextromethorphan-
quinidine(n=82)werejudgedtohavea“moderate”or
Discussion
“marked”improvementonADCSClinicalGlobalImpression
Inthisplacebo-controlledrandomizedtrialofdextromethorphan- ofChangevs27.1%ofparticipantswhotookonlyplacebo
quinidineforagitationinAlzheimerdisease,weenrolledpa- (n=59;P=.008).SimilarresultswerealsoobservedforPa-
tientswithmoderatetoseveresymptomswhorequiredphar- tientGlobalImpressionofChange.Percentageimprovement
macologicalintervention.TheAlzheimerdisease–related ontheNPIAgitation/Aggressionscoresfrombaselineandpro-
agitationcharacteristicsofpatientsinthisstudyweregener- portionofpatientsachievingstandardthresholdsofre-
allyconsistentwiththerecentlyproposeddefinitionofagita- sponse(eg,30%or50%response)werealsousedtogaugerel-
tionfromtheInternationalPsychogeriatricAssociation(IPA),27 evanceofclinicalresponse.TheNPImanual(http://npitest
althoughpatientemotionaldistresswasnotdirectlymea- .net/faqs.html),forinstance,suggeststhata30%decreasein
sured.Asinthecurrentstudy,theIPAdefinitionrequiresthe scoresisgenerallyclinicallymeaningful.
presenceofbehaviorscausingexcessdisabilitythatarenotdue Inthisstudy,patientstreatedwithonlydextromethorphan-
toanothermedical,psychiatric,orsubstance-relateddisor- quinidinehadamean50.7%reductionintheNPIAgitation/
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Table3.SummaryofCategoricalEfficacyOutcomeintheModifiedIntention-to-TreatPopulation
No.(%)ofParticipants
StudyStage CategoricalResponse Dextromethorphan-Quinidine Placebo
ClinicalGlobalImpressions–SeverityScoreforAgitation
Baseline Moderatelyill 61(65.6) 77(61.6)
Markedlyill 28(30.1) 38(30.4)
Severelyill 4(4.3) 9(7.2)
Amongthemostextremelyill 0 1(0.8)
AlzheimerDiseaseCooperativeStudy–ClinicalGlobalImpressionofChangeScoreforAgitation
Stage1a Markedimprovement 8(9.1) 1(0.8)
Moderateimprovement 22(25.0) 13(10.6)
Minimalimprovement 28(31.8) 43(35.0)
Nochange 22(25.0) 48(39.0)
Minimalworsening 7(8.0) 12(9.8)
Moderateworsening 1(1.1) 6(4.9)
Markedworsening 0 0
Stage2b Markedimprovement 0 4(9.5)
Moderateimprovement 11(26.2) 2(4.8)
Minimalimprovement 15(35.7) 8(19.0)
Nochange 11(26.2) 19(45.2)
Minimalworsening 4(9.5) 6(14.3)
Moderateworsening 1(2.4) 2(4.8)
Markedworsening 0 1(2.4)
10wkc Markedimprovement 9(11.0) 6(10.2)
Moderateimprovement 28(34.1) 10(16.9)
Minimalimprovement 27(32.9) 18(30.5)
Nochange 14(17.1) 15(25.4)
Minimalworsening 2(2.4) 9(15.3)
Moderateworsening 1(1.2) 0
Markedworsening 1(1.2) 1(1.7)
PatientGlobalImpressionofChangeScore
Stage1a Verymuchimproved 10(11.4) 2(1.6)
Muchimproved 24(27.3) 23(18.7)
Minimallyimproved 20(22.7) 30(24.4)
Nochange 20(22.7) 40(32.5)
Minimallyworse 13(14.8) 23(18.7)
aStage1includesallpatientsand
Muchworse 1(1.1) 4(3.3)
measureschangefromstage1
Verymuchworse 0 1(0.8)
baselinetoweek5foreach
Stage2b Verymuchimproved 3(7.0) 3(6.8) outcome.
Muchimproved 10(23.3) 4(9.1) bStage2includesonlyrerandomized
Minimallyimproved 14(32.6) 11(25.0) placebononrespondersfromstage1
andmeasureschangefromstage2
Nochange 10(23.3) 13(29.5)
baseline(week5)toweek10forall
Minimallyworse 4(9.3) 9(20.5) outcomesexceptthePatientGlobal
Muchworse 2(4.7) 4(9.1) ImpressionofChange,which
measureschangefromoriginal
Verymuchworse 0 0
stage1baselinetoweek10.
10wkc Verymuchimproved 9(11.1) 5(8.5) cThe10-weekanalysisincludesonly
Muchimproved 26(32.1) 9(15.3) patientswhocontinuedtheir
Minimallyimproved 25(30.9) 17(28.8) originalassignedtreatmentfortheir
entirestudyparticipation(ie,took
Nochange 13(16.0) 14(23.7)
onlydextromethorphan-quinidine
Minimallyworse 5(6.2) 10(16.9) oronlyplacebo,therebysimulating
Muchworse 3(3.7) 4(6.8) aparallel-groupdesign)and
measureschangefromstage1
Verymuchworse 0 0
baselinetoweek10.
Aggressionscoresfrombaselinetoweek10comparedwith specttostandardresponsethresholds,inthe10-weekanaly-
26.4%treatedwithonlyplacebo(P=.001);thisplacebore- sis,55.9%ofpatientstreatedwithonlydextromethorphan-
sponsewouldnotbedeemedclinicallymeaningful.Withre- quinidineexperiencedatleasta50%reductionintheNPI
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