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MorphineSulfateandNaltrexoneHydrochlorideExtendedReleaseCapsulesinPatientswithChronicOsteoarthritisPain

NathanielKatzMD,MS,MartinHaleMD,DavidMorrisPhDJosephStaufferDO,MBA

Tocitethisarticle:NathanielKatzMD,MS,MartinHaleMD,DavidMorrisPhDJosephStaufferDO,MBA(2010)MorphineSulfateandNaltrexoneHydrochlorideExtendedReleaseCapsulesinPatientswithChronicOsteoarthritisPain,PostgraduateMedicine,122:4,112-128

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Morphine Sulfate and Naltrexone Hydrochloride Extended Release Capsules in Patients with Chronic Osteoarthritis Pain

NathanielKatz,MD,MS1,2

MartinHale,MD3

DavidMorris,PhD4

JosephStauffer,DO,MBA5,6

1TuftsUniversitySchoolofMedicine,Boston,MA;2AnalgesicSolutions,Natick,MA;3GoldCoastResearch,LLC,Plantation,FL;4WebbWrites,Durham,NC;5DURECTCorporation,Cupertino,CA;6JohnsHopkinsSchoolofMedicine,Baltimore,MD

Correspondence: Nathaniel Katz, MD, MS, President and CEO, Analgesic Solutions,

232 Pond Street,

Natick, MA 01760.

Tel: 781-444-9605 x124

Fax: 781-444-9608

E-mail:

Abstract

Objective:Toassesstheefficacyandsafetyofmorphinesulfateandnaltrexonehydrochlorideextendedreleasecapsules(EMBEDA®;MS-sNT),whichcontainmorphinesulfatepelletswithasequesterednaltrexonecore,intreatingpatientswithchronic,moderate-to-severeosteoarthritis (hiporknee)pain.PatientsandMethods:Thisphase3studyhadanenriched-enrollment,randomized-withdrawal,double-blind,multicenterdesign.Patients(N547)weretitratedtoaneffectivedoseofMS-sNT(20–160mg/day).Responders(n344)wererandomizedto12 weeksmaintenancewithaneffectiveMS-sNTdoseorweretaperedtoplaceboover2weeks. Theprimaryefficacymeasurewasthechangefrombaseline(CFB)indiaryaverage-painscores(0–10scale,BriefPainInventory[BPI])fromrandomizationtothelast7daysofthemain-tenanceperiod.SecondaryefficacymeasuresincludedtheremainingBPIscoresandWesternOntarioandMcMasterUniversities(WOMAC)OsteoarthritisIndex.Opioidwithdrawalsymp-tomswereassessedbytheClinicalOpiateWithdrawalScale(COWS)andSubjectiveOpiateWithdrawalScale(SOWS).ThestudyranfromJanuary10,2007throughNovember8,2007.Results:MS-sNTmaintainedpaincontrolbetterthanplacebo(meanCFB,diaryaverage-pain score,–0.21.9vs0.32.1;P0.045).ChangefrombaselineforMS-sNTpain-diaryscore (worst,least,average,current)wassuperiorduringthemaintenanceperiodvisits,weeks2to12 (P,0.05).WOMACcompositescoreCFBwassuperioratmostvisits.MS-sNTwasgenerally welltolerated,withatypicalmorphinesafetyprofile.NopatienttakingMS-sNTasdirected experiencedwithdrawalsymptoms.Conclusion:MS-sNTprovidedeffectiveanalgesiainpatientswithchronic,moderate-to-severeosteoarthritispain,withasafetyprofiletypicalof morphine-containingproducts.NaltrexonesequesteredinMS-sNThadnoclinicallyrelevant effect when MS-sNT was taken as directed.

Keywords:chronic pain; opioids; morphine; extended release; opioid withdrawal

Introduction

Controlofchronicpainisanimportanttherapeuticchallenge.Suboptimalcontrolofchronicpaincanleadtosubstantialsuffering,productivityloss,andincreasedhealthcarecosts,andisaleadingreasonfordisabilityinworkingadults.1Manypatientswithmoderate-to-severepainfailtoobtainadequatepainreliefwithnonopioidagentsand, asaresult,opioidanalgesicsarefrequentlyusedeitherinmonotherapyorasadd-on therapy.1Becauseoftheiranalgesicefficacyacrossmultiplepainstates,opioidsremainamainstayofchronicpainmanagement.2,3IthasbeenestimatedthatbetweenFebruary1998andSeptember2006,.4.3millionadultsintheUnitedStatesregularlyusedopioidsinanygivenweek.1,3,4Immediate-releaseopioidformulationsrequire dosingevery3to4hourswhenadministeredorally,whereasextended-releaseoral

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71508e

Morphine Sulfate and Naltrexone HCI Extended Release

formulationscanprovideeffectivepainreliefoverperiods up to24hours.1

Despitetheirdemonstratedefficacy,theuseofopioidanalgesicstotreatchronicpainisoftenlimitedbythefearofpotentialabuseandconcernamonghealthcareproviders aboutbeingaccusedofopioidover-prescribing.2,3,5Multiple datasourcesindicatethatthemisuse,abuse,anddiversion ofopioidsareincreasing.Resultsfromthe2008NationalSurveyonDrugUseandHealthindicatedthatthenumberof“current”(withinthepreviousmonth)abusersofprescriptionpainrelievers(4.7million)surpassedthenumberofcurrent abusersofcocaine(1.9million)andheroin(0.2million).6In2008,thespecificdrugcategorieswiththelargestnumber ofpast-yearinitiatesamongpeopleaged$12yearswereprescriptionpainrelieversandmarijuana(approximately2.2millioninitiateseach).6Themostcommonroutesofadmin-istrationofabusedopioidsareoral,snorting,andinjection.7Extended-releaseformulationsmaybegreatertargetsfor abusecomparedwithshorter-acting,immediate-releasefor-mulationsduetotheirhigheropioidcontent.Tamperingwithextended-releaseformulationsmayresultinreleaseofthe largeunitdoseofopioidatonce,whichincreasestheriskof seriousandlife-threateningsideeffects.1Asaresult,severalpharmaceuticalformulationstrategieshavebeenproposedtodeterabuseofextended-releaseopioids.1Theabuseliability ofsuchproductsisexaminedusingvariousmethodologies thatmayincludebenchtoptesting(invitro)toanalyzetherobustnessofaformulationundervariousattemptsattamper-ing,preclinicalstudies(eg,self-administration),andclini-calabusepotentialtesting(commonlyreferredtoasabuse liabilityorlikeabilitystudies)usingsurrogatemarkers(eg, reinforcing effects, drug liking, and euphoria). To establish whetheranyoftheseproductsaretrulyabuse“deterrent” or“resistant,”furtherpost-marketingepidemiologicalstud- iesarerequiredtodeterminewhethertheyarelessabusedinthecommunitycomparedwithsimilarproductsthatare morereadilyabused.Italsoremainsimportant,however,todemonstratethattheseformulationsareeffectiveinachievingtheirprimarypurpose:effectivenessinpainmanagement.Morphinesulfateandnaltrexonehydrochloridecapsules(EMBEDA®)containpolymer-coatedpelletsofextended-releasemorphinesulfate,eachwithasequesteredcoreoftheopioidantagonistnaltrexone(morphinesulfatewithsequesterednaltrexone[MS-sNT]).8MS-sNTwasdevelopedbasedontheextended-releaseformulationusedinmorphinesulfateextended-release(KADIAN®)capsules,whichdonotcontainnaltrexone.Thepolymercoatingofdefinedthick-nessandporositycontrolstherateofmorphinedissolution

inapH-dependentmannerasthepelletspassthroughthe gastrointestinaltract.9,10MS-sNTcapsulesareindicatedforthemanagementofchronic,moderate-to-severepainwhenacontinuous,around-the-clockopioidanalgesicisneededfor anextendedperiodoftime.8WhenMS-sNTistakenorallyasdirected,thereleaseofmorphineprovidesanalgesicactiv-ity,whereasthenaltrexoneremainssequesteredwithonlytracesystemicexposure.8Crushingthepelletsanddissolvingthemincertainsolventsreleasesnaltrexone,11whichhasbeenshowntosuccessfullymitigatethemorphine-induced, subjectiveeffectsinpatientswithahistoryofrecreational opioidabuse.12

Whentakenwhole,asintended,MS-sNTexhibiteda comparablepharmacokineticprofile,efficacy,tolerability,andsafetyinanactive-controlledtrialcomparedwithamarketedformulationofextended-releasemorphinesulfate (KADIAN®)10inpatientswithchronicosteoarthritis(OA) pain.13Thecurrentstudywasdesignedtoevaluatetheeffi-cacyandsafetyofMS-sNTcomparedwithplacebointhetreatmentofpatientswithchronic,moderate-to-severepain associated with OA of the hip or knee.

Patients and Methods

Menandwomenaged$21yearswithOAofthehiporkneewhowereotherwiseingenerallygoodhealthwereeligibleiftheyrequiredtreatmentofchronicjointpainwithinthelast90daysandwereunabletoconsistentlycontroljointpainwitheithernonopioidanalgesics,tramadol,oranotheropioidatadoseequivalentto#40mg/dayoforalmorphine.Eli- giblepatientshadanaverage24-hourpainintensityscoreof

$5onthe11-pointpainscale(0nopain;10painasbad asyoucanimagine)atthebaselinevisitfollowingcessation ofpreviousmedications,aprimarydiagnosisoffunctionalclassI–IIIOAofthehiporknee,andalsometAmericanCol-legeofRheumatologyclinicalclassificationcriteriaforOA pain of the hip or knee.14,15Patients with $1 joint pain whometthesecriteriawereaskedtochoosethemostpainfulareatoserveasthetargetjointforassessingtreatmentefficacy.

Exclusioncriteriaincludedhistoryofdrugoralcohol abuseordependencewithinthepast5years;apositiveurine toxicologytestforillicitdrugsornonprescribedcontrolled substances at screening; allergy, intolerance, or nonrespon-sivenesstoopioids;establishedhistoryofuncontrolledmajordepressivedisorder;anyconditionthatwouldinterferewith orconfoundthestudyresultorposepatientrisk;injurytothetargetjointwithin12weekspriortoscreening;anddocu-mentedhistoryofrheumatoidarthritis,inflammatoryarthritis,ornonsteroidalanti-inflammatorydrug(NSAID)-dependent

Katz et al

inflammatoryarthritis.Womenofchildbearingpotentialwererequiredtohaveanegativeurinepregnancytestatscreeningand be practicing an appropriate method of birth control.

Study Design

Thisrandomized,double-blind,placebo-controlled,multi- centeroutpatientstudy(SponsorstudyALO-KNT-301)was conductedinaccordancewiththeprinciplesoftheDecla- rationofHelsinkianditsamendmentsandincompliance withtheInternationalConferenceonHarmonisationprin- ciplesofGoodClinicalPracticeandallnationalregulatory requirements.Theprotocolandrelatedstudymaterialswere approvedbyaninstitutionalreviewboardorindependentethicscommitteeforeachsitebeforepatientswereenrolled. Allpatientsprovidedwritteninformedconsentbeforeany study-related procedures were conducted.

Thestudyfollowedanenriched-enrollment,randomized-withdrawal(EERW)design.16,17Thestudyconsistedof3periods:washout,titration,andmaintenance(Figure1).TheEERWtrialdesignmorecloselyreflectsclinicalpractice,anddiffersfromthatoftraditionalrandomizedclinicaltrialsinthatallparticipantsundergoopen-labeldosetitrationtoeffectivedosepriortorandomization.16,17Thosepatientswhodidnotrespondtoordidnottoleratethestudydrugwerediscontin-uedfromthetrial.PatientswhoreachedanoptimaleffectiveanalgesicdosewererandomizedeithertocontinuedMS-sNTortaperedtoplacebo.TheoutcomeassessedintheEERWtrialdesignislossofanalgesicefficacyafterremovaloftherapyratherthan reduction ofpain upon institutionof therapy.18

Duringeachperiod,rescuemedicationwithacetamino-phen(#500mgevery6hours)wasallowed.Patientswere instructedtorefrainfromtakingnonstudypainmedications;however,dailyaspirin#325mgforcardiovascularprophy-

laxiswaspermitted.Throughoutthestudy,patientsusedanelectronicdiarydailytoanswerquestionsabouttheirpainintensityandrescuemedicationuse.Patientswerescreenedforeligibilityupto14daysbeforeabaselineassessment,afterwhichtheyentereda1-to7-daywashoutperiod,anddiscontinuedallprohibitedandpainmedications.Whentherequired24-hourpainintensitywasattained(score$5onthe11-pointpainintensityscale),thepatientwasinstructedtoreturntotheclinicwithin72hoursforthebaselineassessment,whichconsistedof standardclinical andlaboratorytestingandreconfirmationofpatienteligibility.Acetaminophenwasprohibitedduringthe24-hourperiodbeforethisbaselinevisit.Patientswithapainintensityscoreof,5andthosewhocouldnottoleratetheirpainwiththemaximumalloweddoseofacetaminophenwerediscontinuedfromthestudy.

Eligiblepatientsenteredatitrationperiodlastinguptoa maximumof45days,duringwhichthedoseofopen-label MS-sNTwastitrateduntilaneffectivetwice-dailyregimen wasachieved.ThestartingdoseofMS-sNTwas20mgat bedtimeinopioid-naïvepatients,and20mgtwicedailyin thosepreviouslytreatedwithopioids,althoughinvestigator discretionwasallowedforthestartingdoseneededforpain controlinopioid-experiencedpatients.Dosetitrationswere performedweeklyandincreasesweremadeinincrements of20mg/dayupto120mg/day,withafinalincreasefrom120to160mg/dayifneeded.Amaximumof2back-titrationswasallowed,ifnecessary,toestablishaneffectivetolerated dose.Duringthetitrationperiod,patientswereseenweeklyforpainintensityandsafetyassessments.Patientswereconsideredresponderswhentheiraverage-painintensityscoreontheBriefPainInventory(BPI)scaleoverthelast4 daysbeforetheclinicvisitwas#4andhaddeclinedby$2pointsfrombaseline.Onceidentifiedastreatmentresponders,

Figure 1. Study design.

aWashoutperiod was 1 to 7days prior to initiation oftitration;b2-week taper to placeboin double-dummy fashion.

Abbreviation: MS-sNT, morphine sulfate with sequestered naltrexone.

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patientswereallowedtocontinuedosetitrationforincreasedpainreliefprovidedthemaximumMS-sNTdoseandtitra-tionperioddurationwerenotexceeded.Patientswhodid notachieveaneffectiveanalgesicdoseaftertitrationtothe maximum dose or by 45 days were discontinued.

Treatmentrespondersenteredthedouble-blindmainte- nance period during which they were randomly assigned toreceivetheeffectivedoseofMS-sNTdeterminedduringtitra-tionordosagetitrationdowntoplacebo.Theoutpatientsite contactedtheInteractiveWebResponseSystemtoreceivea randomizationnumberandtreatmentassignment(MS-sNT attheeffectivedoseorplacebo).Randomizationwasstrati- fiedbytargetjoint(hiporknee),thefinaltotaldailydoseofthetitrationperiod(#80mg,.80mg),andsite.Both drugandplacebowerepackagedsoastobeblindedtothe investigator, study clinic personnel, and patients.

TheminimumdoseofMS-sNTallowedatrandomizationwas20mgtwicedaily.Patientsrandomizedtotheplacebo groupweretaperedgraduallyinablindedmannerover2 weeksusingadouble-dummydesign.Duringthemainte- nanceperiod,patientsattendedclinicvisitsatweeks0,1, 2,4,6,8,10,and12forefficacy,tolerability,andsafetyassessments.Patientswhodiscontinuedprematurelyfromthetitrationormaintenanceperiodcompletedanearlytermina-tionassessment,whichincludedthesameproceduresspeci-fiedfortheweek12clinicvisit:vitalsigns,adverseevents (AEs),andefficacyassessments.Patientswhocompletedthemaintenanceperiodentereda2-weektaperingperiod, afterwhichtheyweretransitionedtothestandardofcareappropriate for their existing OA condition.

EfficacyAssessments

Patientsrecordedpainintensitydailyintheirelectronicdiaryusing4itemsfromtheBPIShortFormQuestionnaire19:painatitsworstandleastinthelast24hours,painonaveragein thelast24hours,andthecurrentlevelofpain,allassessed ona0-to-10–pointscale(0nopain;10painasbadas youcanimagine).Theprimaryefficacyoutcomewasthechangeindiaryaverage-painscoresfromrandomizationbaseline(averageofpast24-hourpainscoresfromthelast7daysbeforerandomization)tocompletionofthemaintenanceperiod(forcompleters,thefinal7daysofthe12-weekstudy).Prespecifiedsecondaryefficacyoutcomemeasureswere:

in-clinicpainintensity;weeklydiaryworst-,least-,current-,andaverage-painscoresoverthepast24hours;diaryaverage-painscoresaveragedovertheentiremaintenanceperiod;andpatient-completedassessmentsonthefollowinginstruments:

1)WesternOntarioandMcMasterUniversities(WOMAC)

OsteoarthritisIndex,with3subscales(pain,stiffness,and physicalfunction)andacompositeindexscore.Eachofthe 24itemsontheWOMACOsteoarthritisIndexhasascoreof 0(none)to4(extreme);scoreswerethenstandardizedona 0-to-100–pointscale20; 2) Medical Outcomes Study (MOS) SleepScale,consistingof12itemswith7subscalescores (scorerange,0–100points);withtheexceptionofsleepade-quacysubscale,higherscoresindicategreaterimpairment21,22;

3)BeckDepressionInventory(BDI),a21-item,multichoicequestionnairetoevaluatedegreeofdepression(eachitemhasascaleof0–3points;0minimal,3severe;totalscore range0–63).23TheWOMACOsteoarthritisIndexandMOSSleepScalewereevaluatedatscreeningbaseline,lastvisit oftitration(sameasfirstdayofmaintenanceperiod),and duringmaintenance.TheBDIwasadministeredatscreen- ingbaselineandatweeks4,8,and12ofthemaintenanceperiod.ThestudyprotocolincludedanassessmentofPatientGlobalImpressionofChange(PGIC)bya7-pointscalefrom“verymuchimproved”to“verymuchworse”sincelastvisit.However,afterconsiderationoftheanalyses,inwhichthefirstreportedtimewasatrandomizationbaselinewithvaluesreflectingchangefrommultiplepresentations(2,4,6,8, 10,and12weeksofmaintenance)ratherthanchangefrom baseline,thedatawereconsidereduninterpretableandare not reported here.

Aprespecifiedresponderanalysiswasalsoperformedonin-clinic,24-houraverage-painintensityscoresatthecompletionofthetitrationandmaintenanceperiods.Forpatientswhocompletedthetitrationperiodandquali-fiedforrandomization,therangeofpercentdecreasesforin-clinic,24-houraverage-painintensityfrom0%to100%(inincrementsof10%)betweenthescreeningbaselineandrandomizationbaselinewascalculated.Patientswhodiscontinuedduringthetitrationperiodorwhofailedtoqualifyforrandomization(ie,patientswhodidnotachieveaneffectiveanalgesicdose[definedasanaverage-painintensityscoreof#4ontheBPIoverthelast4daysbeforetheclinicvisitandadeclineof$2pointsfrombaseline])aftertitrationtothemaximumdoseorby45dayswereconsiderednonresponders.Forpatientswhoenteredthemaintenanceperiod,thecumulativeproportion ofresponderswasbasedonthepercentdecreaseinin-clinic, 24-houraverage-painintensityfromscreeningbaselineto studycompletion(12weeksofmaintenance).Patientswho discontinued from the study during the maintenance period were considered nonresponders.

Useofrescuemedication(1tablet[500mg]ofsponsor-providedacetaminophenevery6hours,ifneeded)was

Katz et al

allowedforethicalreasons.Theaverageweeklyuseofrescuemedicationwascalculatedateachvisitfrompillcountssummedover7-dayintervalsandwasusedfordescriptive purposes only.

Safety Assessments

Safetywasassessedbytheincidenceoftreatment-emergentadverseevents(TEAEs)andbychangesinvitalsigns,clini-callaboratoryparameters,andphysicalexaminationfindingsatclinicvisits.Treatment-emergentadverseeventswereevaluatedaccordingtointensityandsuspectedrelationshiptostudytreatmentbytheinvestigator,andcodedtotheMedi-calDictionaryforRegulatoryActivities.Inaddition,since exposuretonaltrexonecanprecipitateopioidwithdrawalinopioid-dependentindividuals,theClinicalOpiateWith-drawalScale(COWS)andSubjectiveOpiateWithdrawalScale(SOWS)wereusedtoassessopioidwithdrawalduringthemaintenanceperiod.24,25InvestigatorsusedtheCOWS11-itemscaletoassessapatient’slevelofopioidwithdrawal,withtotalscoresof5to12indicativeofmildwithdrawal;13to24,moderatewithdrawal;25to36,moderatelyseverewithdrawal;and.36,severewithdrawal.TheCOWScanbeadministeredseriallytoidentifychangesintheseverityofthesignsandsymptomsofopiatewithdrawal.24TheCOWSwasadministeredatweeks0,1,and2ofthemaintenance period,aswellasatthefinalvisitofthemaintenanceperiod

oranearlyterminationvisit.Patientsalsoratedintensity ofwithdrawalsymptomsusingtheSOWS,whichrates16withdrawalsymptomsonascalefrom0(notatall)to4(extremely).25TotalSOWSscoresof6to16weredefinedasmildwithdrawal;17to32,moderatewithdrawal;33to48,moderatelysevere;and.48,severewithdrawal.TheSOWSwascompleteddailyduringthefirst2weeksofmaintenance period by electronic diary.

Statistical Analysis

TheprimaryefficacymeasurewasthechangeindiaryBPIaverage-painscorefromrandomizationbaselinetothelast7daysofthemaintenanceperiod.Randomizationbaselinewasdefined asthediaryaverage-painscore overthelast7days ofthetitrationperiod.Forpatientswhodiscontinued,pain scoreswereimputedbasedontreatmentgroupandreason for discontinuation (Table 1).

Theprimaryefficacyanalysis(changefromrandomiza-tionbaselineinaverage-painscores)wasconductedinthe intent-to-treatpopulation,definedasallpatientswhowere randomizedintothemaintenanceperiodandwhoreceived

$1doseofdouble-blindstudymedication.Comparisons betweentheMS-sNTandplacebogroupsfortheprimaryefficacymeasureweremadebyananalysisofcovariance(ANCOVA)withtreatmentasacategoricalfactorandtherandomizationbaselinescoreascovariate.Assumingan

Table 1.Imputation Rules to Account for Patients Who Discontinued From the Study

Reason for DiscontinuationImputedValueEffect on Analysis Primary analysis

AEsScreening baseline scoreAssigns no benefit to study drug for patients who

discontinue due to AEs

Lack of efficacy, administrative reasonsDiary average-pain scores

during last 7 days on study drug

Actual last pain scores are carried forward for these dropouts

If discontinued due to withdrawal

(COWSatdiscontinuation.randomizationbaselinewithatleastamoderatescore

[$ 13])(patientsonplacebo)

Discontinuation due to withdrawal while taking MS-sNT

Randomization baseline scoreAssignsfullefficacybenefittopatients

on placebo who discontinue due to withdrawal

Screening baseline scoreAssigns nobenefit tostudy drugfor patientswho

discontinued due to withdrawal regardless of pain scores

Additional imputation methods for sensitivity analysis

Alternative Method 1:

All patients who discontinued Alternative Method 2:

All patients who discontinued due toAEorlack ofefficacyAll patients who discontinued for any other reason Alternative Method 3:

All patients who discontinued

Randomization baseline score

Screening baseline score Randomization baseline score Screening baseline score

Assignsfullefficacybenefittoalldropouts

Assigns nobenefit tostudy drugfor thesedropouts

Assignsfullefficacybenefittothesedropouts Assigns nobenefittostudydrug

Abbreviations:AE, adverseevent; COWS,Clinical OpiateWithdrawal Scale;MS-sNT, morphinesulfate withsequestered naltrexone.

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effectsize(meandifferencebetweentreatmentsdividedbythepooledstandarddeviation[SD])of0.33andtypeIerrorof0.05fora2-tailedtest,asamplesizeof200patientspertreatmentgroupwasestimatedtoobtain90%statisticalpowerfortheprimaryefficacyanalysis.However,aninterimrecalculationofpower,basedonapublishedstudywithsimilartrialdesignthatappearedafterthestartofthestudy,18indicatedthatthiswouldhaveprovided.99%powerfortheprimary efficacymeasure withthis sample size,whichraisedethicalconcernsaboutexposingadditionalpatientstotheprotocol.Therefore,enrollmentwasdiscontinuedafter344patientshadbeenrandomized.

Toaccountforpatientswhodiscontinued,painscoreswereimputedbasedontreatmentgroupandreasonfordiscontinuation.Theconcernthatpatientsrandomizedtoplacebocouldexperiencewithdrawalsymptomsmanifest-ingasareturnofbaselinepain,therebyadverselyaffectingefficacyscorespriortostudydiscontinuation,wasaddressedwiththeseimputationrules.ScreeningbaselinevaluewasusedforpatientswhodiscontinuedduetoAEsandforpatientstakingMS-sNTcapsuleswhodiscontinuedduetowithdrawalsymptoms;randomizationbaselinewasusedforpatientsonplacebowhodiscontinuedduetowithdrawalsymptoms;andlast-observation-carried-forwardmeth-odologywasusedinallotherinstances(Table1).Threeadditionalsensitivityanalysesusingalternativemethodsfordataimputation(Table1)werealsoconductedtoconsiderthepossibleimpactofstudydiscontinuationontheprimaryefficacyvariable.Theseweredesignedtobesupportiveefficacy analysesof theprimary endpoint.

Continuoussecondaryefficacymeasuresweresumma-rizedateachvisitbytreatmentusingdescriptivestatisticsandanalyzedusingamixed-effectsrepeated-measuresmodel,withfixed-effectstermsincludingdaysonstudy,treatment,andtheirinteraction;randomizationbaselinevaluewasthecovariate.Noadjustmentformultipleanaly-seswasmadebecausethereisonly1primaryefficacyend-pointanalysis.Secondaryanalyseswerereportedaschangesfrombaselinetoparalleltheprimaryoutcome.

Thecumulativeproportionofpatientswhowererespondersbasedonin-clinic,24-houraverage-paininten-sity scoreswassummarizedin10-pointincrements.26Dif-ferencesbetweentheMS-sNTandplacebogroupsintheproportionofpatientswhoreported$20%,30%,40%,or50%improvementinthemaintenanceperiodwereassessedusingtheFisherexacttest.

Safetyassessments,includingCOWSandSOWS,were summarizedbytreatmentusingdescriptivestatisticsforall

patientswhoreceiveddouble-blindstudymedicationduring themaintenanceperiod.ThefrequencyofTEAEsbetweentreatment groups was compared using the Fisher exact test. Inaddition,aposthocdeterminationoftheproportionofpatientswhodiscontinuedduringthemaintenanceperiodforanyreason,forAEs,orforlackofefficacywasperformedanddisplayedgraphicallyovertime.Thelog-ranktestwasusedtotesttreatmentdifferencesintimetodiscontinuation

foreachoftheabovereasons.

Results

Patient Disposition and Baseline Characteristics

ThefirstpatientwasenrolledJanuary10,2007,andthelast patientwascompletedNovember8,2007.Atotalof547 patientsenteredthetitrationperiodandreceived$1dose ofMS-sNT.Whenenrollmentwasconcluded,344patients (62.9%)hadsuccessfullycompletedthetitrationperiodand proceededtorandomization.Duringthetitrationperiod,themostcommonreasonsfordiscontinuationwereAEs(124/547patients;22.7%)andlackofefficacy(22/547;4%)(Figure2).Atrandomization,173patientswereswitchedtoplacebo and171patientscontinuedtheirtitrateddoseofMS-sNT (Figure2).Duringthemaintenanceperiod,AEswerealso themostcommonreasonfordiscontinuationintheMS-sNT group(18/171patients;10.5%),althoughtheincidencewas muchlowerthaninthetitrationperiod.Incomparison,lack ofefficacy (32/173 patients; 18.5%) was themost commonreason for discontinuation in the placebo group (Figure 2). Demographiccharacteristicsofpatientsinthetitration periodandthosesubsequentlyrandomizedtotreatmentin themaintenanceperiodwerecomparable(Table2).Three- quartersoftheenrolledpatientshadnotusedopioidanalge-sicswithin30dayspriortoenteringthisstudy;however,nearlyallpatientshadpreviouslyusedothermedicationsforanalgesia,mostcommonlyibuprofen(32.4%),acetaminophen(23.8%),andnaproxensodium(11.9%).Forpatientswhowererandom-ized,nosignificantdifferencesindemographicvariablesorbaselineopioiduse,painlocation,orpainscoreswereevidentbetweenpatientsintheMS-sNTandplacebogroups(Table2).

Effect of MS-sNT During Titration Period

Forrandomizedpatientswhoreportedscoresatbothscreen- ingandrandomizationbaseline,themeandecreaseindiary worst-,least-,average-,andcurrent-painscoresisshownin Table3.Scoresforcompositeindexandthe3subscalesof theWOMACOsteoarthritisIndexdecreasedfromtitration baselinetofinaltitrationvisit(Table3).TheMOSSleep

Katz et al

Figure2.Patientdisposition.

Abbreviations: MS-sNT, morphine sulfate with sequestered naltrexone.

Table 2.Demographic and Clinical Characteristics

Characteristic / Titration Period / Maintenance Period / PValuea
MS-sNT (N 547) / Placebo (n 173) / MS-sNT (n 171)
Sex, n (%) / 0.191
Men / 215 (39.3) / 78 (45.1) / 65 (38.0)
Women / 332 (60.7) / 95 (54.9) / 106 (62.0)
Mean age, y (SD) / 55.7 (12.3) / 54.7 (12.9) / 54.2 (11.6) / 0.703
Race, n (%) / 0.336
White / 413 (75.5) / 121 (69.9) / 128 (74.9)
Black / 89 (16.3) / 30 (17.3) / 29 (17.0)
Asian / 26 (4.8) / 15 (8.7) / 9 (5.3)
American Indian or Alaska Native / 8 (1.5) / 4 (2.3) / 2 (1.2)
Other / 11 (2.0) / 3 (1.7) / 3 (1.8)
Hispanic ethnicity, n (%) / 100 (18.3) / 40 (23.1) / 36 (21.1) / 0.697
Mean BMI,kg/m2(SD)b / 32.1 (6.4) / 31.8 (6.3) / 32.5 (6.9) / 0.310
Primary area of OA, n (%) / 0.789
Right hip / 70 (12.8) / 24 (13.9) / 20 (11.7)
Left hip / 57 (10.4) / 16 (9.2) / 17 (9.9)
Right knee / 244 (44.6) / 83 (48.0) / 77 (45.0)
Left knee / 176 (32.2) / 50 (28.9) / 57 (33.3)
Prior opioid use, n (%) / n 171 / n 167 / 1.000
Opioid naïve / 407 (75.4) / 129 (75.4) / 125 (74.9)
Opioid experienced / 133 (24.6) / 42 (24.6) / 42 (25.1)

aPvalueformaintenanceperiodMS-sNTvsplacebofromtheFisherexacttestforcategoricalvariablesandANOVAforcontinuousvariables.Racewascategorizedaswhite vs nonwhite for testing.

bTitrationperiod, n 530; maintenance period, n 167 for both placebo and MS-sNT.

Abbreviations:ANOVA,analysisofvariance;BMI,bodymassindex;SD,standarddeviation;MS-sNT,morphinesulfatewithsequesterednaltrexone;OA, osteoarthritis.

118© Postgraduate Medicine,Volume 122, Issue 4, July 2010, ISSN – 0032-5481, e-ISSN – 1941-9260

Morphine Sulfate and Naltrexone HCI Extended Release

Scalescoresattitrationbaselineandatthefinaltitration visitdidnotindicateseveresleepproblemsinthesepatients ateithertime(Table3).Theaverageweeklyuseofrescue medication(acetaminophen,500mg)duringthetitration period (n 482) was 12.5 tablets.

Therewere317of547(58%)patientswhoreportedscoresdemonstrating$30%improvementinin-clinicpain scores;293(53.6%)with$40%improvement;and247(45.2%)with$50%improvementduringthetitrationperiod.

PrimaryEfficacyAnalysis

Meanaverage-painscoresatrandomizationbaselineandstudycompletionareshowninTable4.Themeanchange fromrandomizationbaselinewasstatisticallysignificantwithMS-sNTcomparedwithplacebo(–0.21.9vs0.3

2.1;P0.045).PatientstakingMS-sNTexperiencedan

additionalsmalldeclineinpainscores,whilethosetaking placeboexperiencedasmallincreasecomparedwithran- domization baseline.

Treatmentgroupdifferencesfromthe3prespecifiedalternativemethodsofimputation,conductedassup-portiveefficacyanalysestoexplorethepotentialimpactofopioidwithdrawalontheprimaryoutcomemeasure,

weredirectionallyconsistentwiththeprimaryanalysis(Table4).

SecondaryEfficacyOutcomesDuringtheMaintenancePeriod

ReductioninaveragepainfromscreeningbaselinewasmaintainedduringthemaintenanceperiodtoagreaterdegreeinpatientstakingMS-sNTthaninthosetakingpla-cebo(Figure3).Changesfromrandomizationbaselineforeachofthe4painintensityitemsstatisticallyfavoredtheMS-sNTgroupovertheplacebogroupatallvisitsduringthemaintenanceperiod(P,0.05,exceptfortheweek1average-painscore;P0.067).Patientstakingplaceboalsohadagreaterincreasefromrandomizationbaselineindiaryaverage-painscore(0.71.5)thanthosetakingMS-sNT(0.11.4)whenscoreswereaveragedovertheentiremaintenanceperiod.

ResponderanalysisatthetimeofcompletionofthemaintenanceperiodisillustratedinFigure4.MorepatientsonMS-sNTthanonplaceboexperienced$30%improvementfromthetitrationbaselinevisitin-clinicassessmentofpainscores(124/171[72.5%]vs100/173[57.8%];P0.005).Thenumericallyhigherratesforthose

Table 3.Effects of MS-sNT During Titration: Mean Change From Screening Baseline Score to Score at Final Titration Visit

(score range, 0–10)

aIncludes only patients with scores reported at both screening baseline and randomizationbaseline visits.

bn 277 except for average pain (n278) and current pain (n 276).

Abbreviations:MOS,MedicalOutcomesStudy;MS-sNT,morphinesulfatewithsequesterednaltrexone;SD,standarddeviation;WOMAC,WesternOntarioandMcMaster Universities.

Katz et al

Table 4.PrimaryEfficacy Outcome:Diary Average-PainScoresaandMean ChangeFrom Baseline

Pain Assessment Mean (SD) / Placebo (n 173) / MS-sNT (n 170) / P Value
Randomization-baseline pain / 3.2 (1.1) / 3.3 (1.3)
(score range, 0–10)
Primary imputation method
Final visit / 3.5 (2.1) / 3.1 (2.0)
Change from baseline
Protocol-specified sensitivity analyses Method1b
Final visit / 0.3 (2.1)
3.1 (1.6) / –0.2 (1.9)
2.9 (1.6) / 0.045
Change from baseline
Method2c
Final visit / –0.2 (1.3)
3.9 (2.4) / –0.4 (1.3)
3.3 (2.1) / 0.122
Change from baseline
Method3d
Final visit / 0.7 (2.2)
4.3 (2.5) / 0 (1.9)
3.9 (2.5) / 0.005
Change from baseline / 1.1 (2.4) / 0.6 (2.3) / 0.049

aDiary average-pain scores: 7-day mean of daily average-pain scores.

bRandomization baseline score for those who discontinued.

cScreening baseline score if due to AEs/lack of efficacy; randomization baseline score if dueto other.

dScreening baseline score.

Abbreviations:AE,adverseevent; SD,standarddeviation;MS-sNT, morphinesulfatewithsequestered naltrexone.

with$20%(133/171[77.8%]vs118/173[68.2%]),40%

(110/171[64.3%]vs96/173[55.5%])and50% (97/171

[56.7%]vs82/173[47.4%])improvementwerenotsta-tisticallysignificant.

SignificantdifferencesfromrandomizationbaselinefavoringMS-sNTversusplacebo(P,0.05)wereobservedatmostvisitsduringthemaintenanceperiodforthecomposite indexandphysicalfunctionsubscalescoresofWOMAC. ChangesfromrandomizationbaselineinWOMACcom-positeindexandpainsubscalescoressignificantlyfavoredMS-sNToverplacebo(P0.031andP0.023,respectively)atweek12ofmaintenance(Table5).Atweek12ofmain-tenance,changesfromrandomizationbaselineinstiffness andphysicalfunctionsubscalescoreswerenotsignificantlydifferent from the placebo group (Table 5).

Meanchangesfrombaselinetoweek12ofthemaintenanceperiodwerenotsignificantlydifferentbetweentreatmentgroupsforMOSSleepScale(randomizationbaselinetoweek12)orBDIscores(titrationbaselinetoweek12).TheBDIscoresattitrationbaselineandallassessmentsduringthemaintenanceperiodwere,6,indicatingonlymilddepressionthroughoutthestudy(Table5).

Duringthemaintenanceperiod,127patients(74.3%)intheMS-sNTgroupand125patients(72.3%)intheplacebogroupusedrescuemedication(acetaminophen)forbreakthroughpain.Inbothgroups,thenumberoftabletsperweekwaslow(mean

SD,5.36.1vs6.25.7tablets;median,2.4vs4.4tablets).Figure5demonstratesaposthocanalysisofthepropor- tionofpatientswhodiscontinuedduringthemaintenance

periodforanyreasonovertimeoverall(A),aswellasthosewhodiscontinuedduetoAEs(B),orlackofefficacy(C).TimetodiscontinuationduetoanyreasonorAEsdidnotdifferbetweentheMS-sNTandplacebogroups,butthetimetodiscontinuationforlackofefficacywasshorterforplaceboversusMS-sNT(P,0.001,log-ranktest).Thisdifferencewasconsistentwiththehigherproportionofpatientswhodiscontinuedduetolackofefficacyduringthemaintenanceperiod inthe placebogroup (18.5%)versus thosetakingMS-sNT(3.5%;P,0.0001,Fisherexacttest).

Safety and Tolerability

ThetitrationperiodwithMS-sNTlastedfor19.613.8days(meanSD).PatientsstartedMS-sNTatanaveragedailydoseof 25.3 9.7 mg (range, 20–120 mg) and ended at an aver- agedailydoseof43.531.7mg(range,20–160mg).After enteringthemaintenanceperiod,exposuretodouble-blindtreatmentwasnumericallylongerintheMS-sNTgroupthanin the placebo group (mean, 74.2 vs 66.4 days).

Themajorityofpatients(347/547,63.4%)experienced$1AEduringthe titration period,mostcommonly constipation, nausea,andsomnolence(Table6).Threepatients(0.5%)hadseriousAEs(SAEs)duringthetitrationperiod;ofthese,1event(hypotension)wasconsideredbytheinvestigatortobepossiblyorprobablyrelatedtothestudydrug.Oftheother2events,atrialfibrillationwas considered unrelated tostudy treatment and concussion wasconsideredunlikelytobetreatmentrelated.Duringthetitrationperiod,38patients(6.9%)hadAEsthatwerejudgedtobesevere,mostfrequentlyconstipation(1.8%)andsomnolence

Morphine Sulfate and Naltrexone HCI Extended Release

Figure 3. Mean diary average-pain scores from baseline through the maintenance period (imputation method 1).

*P,0.01,MS-sNTvsplacebo,changefromrandomizationbaseline.

Abbreviations:MS-sNT,morphine sulfatewith sequesterednaltrexone;SEM standarderror ofmean.

(1.5%).Atotalof130patients(23.8%)discontinuedfromthestudyduringthetitrationperiodduetoAEs,mostcommonlynausea(4.2%),constipation(3.7%),somnolence(2.7%),and

vomiting(2.7%).

Duringthemaintenanceperiod,theincidenceofAEswassimilarbetweentheMS-sNTandplacebogroups(53.2%

and48.6%,respectively,P0.391),withthemostcom- moneventsbeingdiarrheaandnausea(Table6).Compared with the titration period, the most common AEs, except for diarrhea,occurredatlowerratesduringthemaintenanceperiod.SixpatientstakingMS-sNTexperiencedSAEs(pancreatitisandrenalcellcarcinoma,malignantlung

Figure 4. Proportion of responders from screening baseline through completion of the maintenance period.

Abbreviations: MS-sNT, morphine sulfate with sequestered naltrexone.

Katz et al

Table 5.Summary ofPrespecified SecondaryEfficacy Outcomes: MeanChange FromBaselineatoMaintenance Week 12

Scores

Placebo (n 173)MS-sNT (n 171)PValuec,d

Mean(SD)b

Diary pain scores (score range, 0–10)

BaselineWeek 12ChangeBaselineWeek 12Change

vsPlacebod

Worst pain / 3.5 (1.6) / 4.4 (2.3) / 0.9 (2.0) / 3.6 (1.6) / 3.9 (2.1) / 0.3 (2.0) / 0.003
Least pain / 1.9 (1.3) / 2.7 (2.0) / 0.8 (1.8) / 2.1 (1.4) / 2.4 (1.9) / 0.3 (1.8) / 0.036
Average pain / 2.6 (1.2) / 3.5 (2.1) / 0.9 (1.9) / 2.8 (1.3) / 3.1 (2.0) / 0.3 (1.9) / 0.003
Current pain / 2.4 (1.5) / 3.3 (2.2) / 0.9 (2.1) / 2.6 (1.6) / 3.0 (2.1) / 0.4 (2.0) / 0.026
In-clinic pain (score / 2.8 (1.5) / 4.3 (2.5) / 1.5 ( 2.3) / 2.8 (1.4) / 3.5 (2.2) / 0.7 (2.3) / 0.002
range, 0–10)
Diary average-pain score / 2.6 (1.2) / 3.3 (1.7) / 0.7 (1.5) / 2.7 (1.3) / 2.9 (1.5) / 0.1 (1.4) / 0.001
averaged over the entire maintenance period WOMAC subscales (score
range, normalized, 0–100) Composite index / 30.4 (15.4) / 36.2 (18.3) / 5.8 (16.8) / 31.2 (15.3) / 32.8 (20.0) / 1.6 (18.0) / 0.031
Pain / 29.4 (15.6) / 35.1 (18.3) / 5.7 (17.1) / 29.7 (15.5) / 31.1 (19.9) / 1.4 (18.9) / 0.023
Stiffness / 34.5 (18.9) / 39.8 (21.0) / 5.3 (22.0) / 35.1 (18.4) / 36.2 (22.5) / 1.1 (21.1) / 0.063
Physical function / 29.3 (16.4) / 35.5 (19.8) / 6.2 (17.8) / 30.7 (16.3) / 32.9 (21.1) / 2.3 (18.4) / 0.064
MOS Sleep Scale
(score range, 0–100) Sleep disturbance / 22.7 (19.1) / 28.3 (22.2) / 5.6 (17.7) / 23.0 (21.1) / 25.3 (22.0) / 2.4 (15.3) / 0.068
Snoring / 30.1 (29.9) / 32.8 (31.8) / 2.8 (22.6) / 26.7 (28.8) / 29.2 (31.8) / 2.5 (20.6) / 0.687
Awaken with / 12.3 (23.1) / 11.8 (23.0) / –0.5 (25.3) / 8.5 (16.4) / 10.7 (21.0) / 2.2 (17.9) / 0.699
shortness of breath/headache Sleep quantity / 6.8 (1.5) / 6.6 (1.4) / –0.2 (1.3) / 6.8 (1.7) / 6.8 (1.8) / 0.0 (1.9) / 0.079
Optimal sleep / 0.5 (0.5) / 0.4 (0.5) / –0.1 (0.5) / 0.5 (0.5) / 0.5 (0.5) / 0.0 (0.5) / 0.325
Sleep adequacy / 62.9 (25.7) / 57.5 (27.4) / –5.4 (24.5) / 65.8 (25.8) / 63.6 (26.9) / –2.2 (21.4) / 0.068
Somnolence / 29.4 (24.3) / 26.9 (23.2) / –2.5 (17.9) / 27.8 (22.5) / 27.0 (24.0) / –0.7 (13.8) / 0.407
BDI / 4.7 (4.3) / 3.7 (4.5) / –0.9 (3.9) / 5.5 (5.5) / 4.0 (4.8) / –1.4 (4.5) / 0.675
(score range, 0–63)

aForpain, in-clinic pain,WOMAC Osteoarthritis Index, and MOS Sleep Scale, baseline visit israndomization baseline visit; for BDI baseline is screening baseline visit day 0.

bImputation rules used for missing secondary endpoints were the same as those used for primary endpoints.

cChange from baseline.

dP value is based on based on mixed-effects, repeated-measures model.

Abbreviations:BDI,BeckDepressionInventory;MOS,MedicalOutcomesStudy;MS-sNT,morphinesulfatewithsequesterednaltrexone;SD,standarddeviation;WOMAC, Western Ontario and McMaster Universities.

neoplasm,cholelithiasis,intestinalblockage,viralgas-troenteritis,andbasalcellcarcinoma);3patientsonplaceboexperiencedSAEs(chestpain,abdominalpain,andtransientischemicattack).Only1SAE(abdominalpaininapatienttakingplacebo)wasconsideredbytheinvestigatortobetreatmentrelated.Twentypatients,including11patients(6.4%)intheplacebogroupand9patients(5.3%)intheMS-sNTgroup,hadsevereAEs.Duringthemaintenanceperiod,18patients(10.5%)intheMS-sNTgroupand13patients(7.5%)intheplacebogroupindicatedAEsasthereasonfordiscontinuation;however,11patients(6.4%)intheplacebogroupand14patients(8.2%)intheMS-sNTgrouphadprematurediscontinuationofstudydrugindicatedastheactiontakenontheAEcasereportform.ThemostcommonAEs leading to discontinuation were nausea (3 MS-sNT[1.8%],2placebo[1.2%])andvomiting(1MS-sNT

[0.6%],2placebo[1.2%]).Twopatientseach(1.2%)

discontinuedduetoconstipationandsomnolenceintheMS-sNTgroup.

Overall,themajorityofAEsinthetitrationandmaintenanceperiodswerejudgedbytheinvestigatorstobemildtomoderateinintensity.AnalysisoflaboratoryandvitalsignsdatarevealednoclinicallyrelevantresultswithMS-sNTcomparedwithplacebo.

WithdrawalSymptoms

SymptomsandsignsofopioidwithdrawalwereevaluatedusingCOWSandSOWSandanalyzedaccordingtothedoseofMS-sNT(#80and.80mg/day)atrandomiza-tion.Inbothsubsets,themeanCOWSscoreattheran-domizationbaselinewaslow(#0.7).Duringthestudy,nopatientexperiencedopioidwithdrawalwhiletakingMS-sNTasdirected.Duringtitration,anopioid-naïvepatienttakingadailydoseofMS-sNT160mghadasingleCOWSassessmentwithascoreof16atanearlytermi-

Morphine Sulfate and Naltrexone HCI Extended Release

Figure 5. Proportion of patients who discontinued during the maintenance period due to (A) any reason, (B) AEs, or (C) lack of efficacy.

Duration of trial for some patients was extended beyond 12 weeks based on the actual time of the nominal 12-week visit.

Abbreviations:AE, adverseevent; MS-sNT,morphine sulfate withsequestered naltrexone.

nationvisitpriortorandomization;thepatienthadbeencompliantuntiltitrationweek5,thentook5capsulesin10daysbetweentheweek5visitandtheearlyterminationvisit(Table7).Duringthemaintenanceperiod,2patientshadscoresof23(moderatewithdrawal)duringtapertoplacebo:anopioid-experiencedpatienttaking120mg/daywhohadaCOWSscoreof23atweek2ofmaintenance,continuedinthestudy,thendiscontinuedatweek6ofmaintenance duetolack ofefficacy(COWS scoreatthattimewas1);andanopioid-naïvepatienttaking60mg/daywhohadaCOWSscoreof23atweek1ofmaintenance

anddiscontinuedduetolackofefficacy.Thelatterpatientwashandledasadropoutduetoopioidwithdrawalduringtheimputationprocess,perprespecifiedrules.Anaddi-tionalopioid-naïvepatienttaperingfrom160mg/daytoplacebohadaCOWSscoreof13(moderate)duringweek1 of taper,which was reduced to 8(mild) at week 2. Thispatientcompletedthestudy.Oneopioid-naïvepatienttaking120mg/dayofMS-sNTabruptlystoppedtreatmentonday49ofmaintenance,experienceddrugwithdrawalsymptomsonday52,andhadascoreof28(moderatelyseverewithdrawal)onday54.Theeventresolvedonthesamedayafterthepatientwasdiscontinuedfromthestudyandtreatedwithlorazepam.Aswasprespecifiedfortheefficacyanalysis,painscoreswereimputedusingthescreeningbaselinevalue(Table7).

SOWSdatawerecollectedduringthefirst2weeksofthemaintenanceperiod.Attherandomizationbase-line,themeanSOWSscoresintheplaceboandMS-sNTgroupsaveraged4.7and4.4,respectively,inthesubsetwitharandomizationdoseof#80mg,and6.7and7.9,respectively,inthesubsetwitharandomizationdoseof.80mg.Overdays4to6,themeanworstscoreonSOWSincreasedto9.3and8.8intheplaceboandMS-sNTgroups,respectively,inthesubsetwitharandomizationdoseof#80mg,andto11.9inbothgroupsinthesubsetwitharandomizationdoseof.80mg.Overall,theSOWSscoresdidnotdifferappreciablybetweentheMS-sNTandplacebogroups.

ThreeadditionalpatientsreportedindividualsymptomsconsistentwithwithdrawalasanAEduringthestudy(Table7).Onepatientreportedwithdrawalsymptomsduringtheweek4titrationvisit.Thepatienthadtakenrescuemedicationinsteadofstudydrugduringthepre-viousweek,andwasdiscontinuedfromthestudyduetononcompliance.TheCOWSscorewas7forthispatientatthestudyterminationvisit1weeklater.Twopatientsreportedsymptomsnotedasdrugwithdrawalsymptomsbeginningontheseconddayoftaperingaftercompletionofthe12-weekmaintenanceperiod,whichthereforedidnotinfluencetheanalysesofanyoutcomemeasures.OneofthesepatientshadbeentakingMS-sNT20mgtwicedailyandexperienceddiarrhea,vomiting,andrestlesslegssyndrome;allclassifiedasmildandunrelatedtostudydrug.Shewastreatedwith10mgoralmorphinesulfateasneededfor3days.TheCOWSscorehadbeen0thepriorday.Thesecondpatienthadbeentakingpla-cebooverthe12-weekmaintenanceperiodandreportedwithdrawal symptoms of moderate intensity identified as

Katz et al

Table 6.TEAEs During theTitration and Maintenance Periodsa

AE, n (%) / Titration / Maintenance
MS-sNT / Placebo / MS-sNT
(N 547) / (n 173) / (n 171)
Patients with TEAEs / 347 (63.4) / 84 (48.6) / 91 (53.2)
Patients with drug-relatedTEAEsb / 313 (57.2) / 45 (26.0) / 56 (32.7)
Patients with SAEs / 3 (0.5) / 3 (1.7) / 6 (3.5)
Patients with drug-relatedSAEsb / 1 (0.2) / 1 (0.6) / 0
TEAEs leading to discontinuation Most common TEAEs
Constipation / 130 (23.8)
167 (30.5) / 11 (6.4)
7 (4.0) / 14 (8.2)
12 (7.0)
Nausea / 115 (21.0) / 13 (7.5) / 20 (11.7)
Somnolence / 78 (14.3) / 5 (2.9) / 2 (1.2)
Vomiting / 50 (9.1) / 4 (2.3) / 12 (7.0)
Dizziness / 47 (8.6) / 3 (1.7) / 3 (1.8)
Pruritus / 38 (6.9) / 1 (0.6) / 1 (0.6)
Headache / 33 (6.0) / 6 (3.5) / 12 (7.0)
Dry mouth / 31 (5.7) / 2 (1.2) / 3 (1.8)
Diarrhea / 15 (2.7) / 21 (12.1) / 21 (12.3)
Rhinorrhea / 2 (0.4) / 12 (6.9) / 4 (2.3)

aAllTEAEsoccurringin$5%ofpatientsduringthetitrationperiodorin$5%ofpatientsineithergroupofthemaintenanceperiod.

bDrug-related events were judged to be possibly, probably, or definitely related to study treatment by the investigator.

Abbreviations:AE,adverseevent;MS-sNT, morphinesulfatewithsequesterednaltrexone; SAE,seriousadverseevent; TEAE,treatment-emergentadverseevent.

Table 7.All Patients With Potential Opioid Withdrawal

Patient DescriptionTotal MS-sNT Daily Dose (mg)

Withdrawal assessment based onCOWS scorea

Treatment Period at Occurrence

COWS

Scorea

Outcome

Opioid-naïveman,aged58years;
noncompliant with dose prior to termination / 160 / Titration period
(Early termination visit) / 16 / Discontinued medication after
day37oftitration;AE
of severe worsening of anxiety
Opioid-naïve woman, aged 56 years / 60 tapering / Maintenance period / 23 / Premature discontinuation on
to placebo / (Week 1 taper to placebo) / maintenanceday7;lack
Opioid-naïve man, aged 42 years / 160 tapering / Maintenance period / 13 / ofefficacy
Completed study (week 2
to placebo / (Week 1 taper to placebo) / taperto placebo,COWS8;
Opioid-experienced man, aged 45 years / 120 tapering / Maintenance period / 23 / week 12, COWS 1) Premature discontinuation
to placebo / (Week 2 taper to placebo) / onmaintenance day42; lack
of efficacy(COWS1 onday
Opioid-naïvewoman,aged51years; / 120 / Maintenance period / 28 / of discontinuation) Discontinued;experienced
abruptly stopped taking dose / (Early termination visit) / withdrawal symptoms reported
on day 49 of maintenance
Withdrawal reported as an AE
Opioid-experiencedman,aged69years; / 80 / Titration period (Early / 7b / as AE on maintenance day 52
Discontinued due to
reported withdrawal symptoms / termination visit), 1 week / noncompliance (failed to
and drug withdrawal syndrome
Opioid-naïvewoman,aged55 years;reported / 40 / after study withdrawal Day 2 of tapering at / 0c / take study drug)
Treated with 10 mg morphine
mild diarrhea, vomiting, nighttime restless / completion of / sulfateasneeded;vomiting
legs syndrome, and withdrawal symptoms / maintenance week 12 / resolved, but diarrhea and
restless legs syndrome were
Opioid-naïvewoman,aged49years; / Placebo over / Day 2 of tapering at / 0c / ongoing
Symptoms resolved
reported moderate-intensity drug / the maintenance / completion of maintenance
withdrawal syndrome / week 12

aCOWSscore5–12mildwithdrawal;13–24moderatewithdrawal;25–36moderatelyseverewithdrawal;.36=severewithdrawal.

bWithdrawal as an AE lasted 6days and was first reported 7days prior to the last COWSscore.

cWithdrawal as an AE was reported 1 day after the last COWS score was taken.

Abbreviations:AE, adverseevent; COWS,Clinical OpiateWithdrawal Scale;MS-sNT, morphinesulfate withsequestered naltrexone.

Morphine Sulfate and Naltrexone HCI Extended Release

definitelyrelatedtostudydrug.Thepatient’sCOWSscorehadbeen 0 throughoutthestudy.Thesymptomsresolvedthefollowingday.

Discussion

This studydemonstrated that MS-sNTissignificantlymoreefficaciousthanplaceboinmaintainingreliefofchronic,moderate-to-severepainassociatedwithOAofthehipandkneeinpatientswhohadnotbeenabletoconsistentlycontroltheirpainwithpreviousmedications,includingNSAIDs,COX-2inhibitors,tramadol,andlow-doseopioids.

Inthisstudy,patientswerefirsttitratedtoaneffec-tivedoseofMS-sNTandthenrandomizedtocontinueMS-sNTorswitchtoplacebo.Theopen-labeltitrationperiodallowedforslowdoseincreasesoveraprolongedperiod(upto45days).Usingthisprotocol,thetreatmentwaseffectivein62.9%ofpatients(344/547),basedonprespecifiedefficacycriteriaandtolerability.Therelativelyhighrateofrespondersduringtitrationwassimilartothatinothertrialsofopioidsinwhichtherewas a gradualpro-cesstostabilizepatientsontheoptimaldose.18,27Thediaryaverage-painscoreinthelast24hourswasreducedfrom