Therapeutic Goods Administration

Firstroundevaluationreport:31August2013
Secondroundreport:2January2014
AusPARAttachment1
ExtractfromtheClinicalEvaluationReportforSuvorexant
ProprietaryProductName:Belsomra
Sponsor:MerckSharpe and DohmeAustraliaPtyLtd

AbouttheTherapeuticGoodsAdministration(TGA)

  • TheTherapeuticGoodsAdministration(TGA)ispartoftheAustralianGovernmentDepartmentofHealth,andisresponsibleforregulatingmedicinesandmedicaldevices.
  • TheTGAadministerstheTherapeuticGoodsAct1989(theAct),applyingariskmanagementapproachdesignedtoensuretherapeuticgoodssuppliedinAustraliameetacceptablestandardsofquality,safetyandefficacy(performance),whennecessary.
  • TheworkoftheTGAisbasedonapplyingscientificandclinicalexpertisetodecision-making,toensurethatthebenefitstoconsumersoutweighanyrisksassociatedwiththeuseofmedicinesandmedicaldevices.
  • TheTGAreliesonthepublic,healthcareprofessionalsandindustrytoreportproblemswithmedicinesormedicaldevices.TGAinvestigatesreportsreceivedbyittodetermineanynecessaryregulatoryaction.
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AbouttheExtractfromtheClinicalEvaluationReport

  • Thisdocumentprovidesamoredetailedevaluationoftheclinicalfindings,extractedfromtheClinicalEvaluationReport(CER)preparedbytheTGA.ThisextractdoesnotincludesectionsfromtheCERregardingproductdocumentationorpostmarketactivities.
  • Thewords[Informationredacted],wheretheyappearinthisdocument,indicatethatconfidentialinformationhasbeendeleted.
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Submission PM-2013-00325-1-1 Extract from the Clinical Evaluation Report for Rivuley/ Silumbra/Vispli/Belsomra / Page 1 of 72

Therapeutic Goods Administration

Contents

List of commonly used abbreviations

1.Clinical rationale

2.Contents of the clinical dossier

2.1.Scope of the clinical dossier

2.2.Paediatric data

2.3.Good clinical practice

3.Pharmacokinetics

3.1.Studies providing pharmacokinetic data

3.2.Summary of pharmacokinetics

3.3.Evaluator’s overall conclusions on pharmacokinetics

4.Pharmacodynamics

4.1.Studies providing pharmacodynamic data

4.2.Summary of pharmacodynamics

4.3.Pharmacodynamic effects

4.4.Secondary pharmacodynamic effects

4.5.Evaluator’s overall conclusions on pharmacodynamics

5.Dosage selection for the pivotal studies

5.1.Study P006

5.2.Evaluator’s overall conclusions on dose selection

6.Clinical efficacy

6.1.Primary insomnia

6.2.Evaluator’s conclusions on clinical efficacy for primary insomnia

7.Clinical safety

7.1.Studies providing evaluable safety data

7.2.Pivotal studies that assessed safety as a primary outcome

7.3.Patient exposure

7.4.Phase 2 Studies

7.5.Phase 3 studies

7.6.Adverse events

7.7.Laboratory tests

7.8.Post-marketing experience

7.9.Evaluator’s overall conclusions on clinical safety

8.First round benefit-risk assessment

8.1.First round assessment of benefits

8.2.First round assessment of risks

8.3.First round assessment of benefit-risk balance

9.First round recommendation regarding authorisation

10.Clinical questions

10.1.Pharmacokinetics

10.2.Pharmacodynamics

10.3.Efficacy

10.4.Safety

11.Second round evaluation of clinical data submitted in response to questions

11.1.Pharmacokinetics

11.2.Safety

11.3.Additional questions from delegate

12.Second round benefit-risk assessment

12.1.Second round assessment of benefits

12.2.Second round assessment of risks

12.3.Second round assessment of benefit-risk balance

13.Second round recommendation regarding authorisation

Listofcommonlyusedabbreviations

Abbreviation / Meaning
AASM / AmericanAcademyofSleepMedicine
AE / Adverseexperience
ANOVA / Analysisofvariance
ANCOVA / Analysisofcovariance
APAT / AllPatientsasTreated
APTS / Allpatientstreatedset
AUC / Areaundertheconcentration-timecurve
AUC0-inf / Areaundertheconcentration-timecurvefromtime0toinfinity
AUC0-last / Areaundertheconcentration-timecurvefromtime0tolastobservation
BMI / Bodymassindex
BP / Bloodpressure
BUN / Bloodureanitrogen
BZD / Benzodiazepine
CI / Confidenceinterval
CL / Clearance
Cmax / Maximumconcentration
COAD / Chronic obstructive airway disease
COPD / Chronic obstructive pulmonary disease
CRT / ChoiceReactionTime
CSSRS / ColumbiaSuicideSeverityRaringScale
CV / Coefficientofvariation
DBP / DiastolicBloodPressure
DSCT / DigitSymbolCopyTest
DSM-IVTR / DiagnosticandStatisticalManualofMentalDisorder-CategoryIV-TextRevision
DSST / DigitSymbolSubstitutionTest
ECG / Electrocardiogram
FAS / Fullanalysisset
FDR / Falsediscoveryrate
FSG / Fastingserumglucose
GCP / Goodclinicalpractice
GI / Gastrointestinal
GMR / Geometricmeanratio
hCG / Humanchorionicgonadotropin
HR / Heartrate
HRT / Hormonereplacementtherapy
IA / Interimanalysis
IEC / IndependentEthicsCommittee
IM / Intramuscular
IN / Intranasal
IP / Intraperitoneal
IRB / InstitutionalReviewBoard
ISI / InsomniaSeverityIndex
IUD / Intrauterinedevice
IV / Intravenous
IVRS / InteractiveVoiceResponseSystem
KSS / KarolinskaSleepinessScale
LLOQ / Lowerlimitofquantitation
LOCF / Lastobservationcarriedforward
LPLV / Lastpatientlastvisit
LPS / Latencytopersistentsleep
LREM / LatencytoREM
LSmeans / Least-squaresmeans
LSWS / Latencytoslowwavesleep
MAR / Missingatrandom
MED / Minimaleffectivedose
MRM / Multiplereactionmonitoring
MSE / Meansquareerror
msec / millisecond
MVAV / MotorVehicleAccidentsandViolations
NAW / Numberofawakenings
NOA / Numberofarousals
NREM / Non-REM
NSAID / Nonsteroidalanti-inflammatorydrug
NSS_W_1 / Numberofstageshiftstowakeorstage1
NSSL / Numberofshiftstolighterstagesofsleep
OTC / Overthecounter
PBO / Placebo
PSG / Polysomnography
PD / Pharmacodynamic
PDLOC / Predefinedlimitsofchange
PK / Pharmacokinetic
QIDS / QuickInventoryofDepressiveSymptomatology
QTcB / CorrectedQTinterval,Bazets
QTcP / PopulationspecificratemethodofcorrectingQTinterval
RBC / Redblood(cell)count
REM / Rapideyemovement
SBP / SystolicBloodPressure
SC / Subcutaneous
SD / Standarddeviation
SDLP / StandardDeviationofLateralPosition
SDS / SheehanDisabilityScale
SE / Sleepefficiency
SEM / Standarderrorofthemean
siDMC / Standinginternaldatamonitoringcommittee
sNAW / Subjectivenumberofawakenings
SOL / SleepOnsetLatency
SRT / SimpleReactionTime
sTSO / Subjectivetimetosleeponset
sTST / Subjectivetotalsleeptime
SWA / Slowwaveactivity
sWASO / Subjectivewakeaftersleeponset
SWS / Slowwavesleep
t½ / Half-life
TIB / Timeinbed
Tmax / Timetomaximumeffectorconcentration
TSO / Timetosleeponset
TST / TotalSleepTime
TTA / Totaltimeawake
ULN / Upperlimitofnormal
VAS / Visualanalogscale
Vss / Volumeofdistributionatsteadystate
WASO / Wakeaftersleeponset
WBC / Whiteblood(cell)count

1.Clinicalrationale

Insomniaiscommonlyreportedasasymptom.TheSponsorarguesthat“Chronicinsomniaaffectsabout10%to30%ofthetotalpopulation(uptoone-thirdoftheadultpopulation),withmorethan50%ofcasesexperiencingsignificantdaytimeconsequencessuchasreducedenergy,memoryproblems,anddifficultyconcentrating.”Thecurrentlyavailabletreatmentsforinsomniaareunsatisfactorybecauseoftheproblemsoftolerance,habituationandabuse.TheseagentsinducesleepthroughglobalCNSdepressionbyactingontheneurotransmitterGABA.Hence,thereisaneedforalternativetreatmentsforinsomnia.

2.Contentsoftheclinicaldossier

2.1.Scopeoftheclinicaldossier

Thesubmissioncontainedthefollowingclinicalinformation:

  • 32clinicalpharmacologystudies,including25thatprovidedpharmacokineticdataand15thatprovidedpharmacodynamicdata.
  • Onepopulationpharmacokineticanalysis.
  • Twopivotalefficacy/safetystudies.
  • Onedose-findingstudy.
  • One long-term (12 month) /safety and efficacy study.
  • Additional pooled analyses, Integrated Summary of Efficacy, Integrated Summary of Safety, and a tabulation of pooled safety data.

2.2.Paediatricdata

Thesubmissiondidnotincludepaediatricdata.

2.3.Goodclinicalpractice

ThesponsorhasstatedthatGoodClinicalPractice(GCP)hasbeenconformedtoforeachoftheclinicalstudiesincludedinthedossier.

3.Pharmacokinetics

3.1.Studiesprovidingpharmacokineticdata

Table 1showsthestudiesrelatingtoeachpharmacokinetictopicandthelocationofeachstudysummary.

Table1.Submittedpharmacokineticstudies.

PKtopic / Subtopic / StudyID
PKinhealthyadults / GeneralPK-Singledose / StudyP001
StudyP011
StudyP002
MassBalance / StudyP012
StudyP018
Multi-dose / StudyP003
Bioequivalence†-Singledose / StudyP007
StudyP041
StudyP051
Foodeffect / StudyP020
StudyP042
PKinspecialpopulations / Targetpopulation§-Singledose[1]
Multi-dose1
Hepaticimpairment / StudyP017
Renalimpairment / StudyP023
Neonates/infants/children/adolescents / Nodata
Elderly / StudyP004
Elderly / StudyP027
Japanese / StudyP005
Japanese / StudyP022
Genetic/gender-relatedPK / Malesversusfemales / StudyP004
PKinteractions / Ketoconazole / StudyP008
CombinedOralContraceptive / StudyP013
Midazolam / StudyP015
Digoxin / StudyP016
Warfarin / StudyP024
Paroxetine / StudyP026
Rifampin,diltiazem / StudyP038
Ethanol / StudyP010
PopulationPKanalyses / Healthysubjects / StudyP018[2]

*Indicatestheprimaryaimofthestudy.

†Bioequivalenceofdifferentformulations.

§Subjectswhowouldbeeligibletoreceivethedrugifapprovedfortheproposedindication.

Noneofthepharmacokineticstudieshaddeficienciesthatexcludedtheirresultsfromconsideration.

3.2.Summaryofpharmacokinetics

Theinformationinthefollowingsummaryisderivedfromconventionalpharmacokineticstudiesunlessotherwisestated.

3.2.1.Physicochemicalcharacteristicsoftheactivesubstance

ThefollowinginformationisderivedfromtheSponsor’ssummariesinModule2.

Suvorexant(USANadoptedname,WHOrINN),alsoknownasMK-4305,isanorallyactive,potent,andreversibleorexinreceptorantagonist(ORA)andisanticipatedtobethefirstinclassORAforthetreatmentofpatientswithinsomnia.ThechemicalformulaforsuvorexantisC23H23ClN6O2andthechemicalnameis5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazole.Suvorexantisawhitetooff-whitepowderthatisinsolubleinwater,veryslightlysolubleinheptane,andsolubleinmethanol.

3.2.2.Pharmacokineticsinhealthysubjects
3.2.2.1.Absorption
3.2.2.1.1.Sitesandmechanismsofabsorption

Therewerenostudiesaddressingthisissue.

3.2.2.2.Bioavailability
3.2.2.2.1.Absolutebioavailability

Absolutebioavailabilitydecreasedwithincreasingdose.Absolutebioavailabilitywasestimatedusingapopulationpharmacokineticmodel(Report611).Themean(5thand95thpercentile)bioavailabilityfora10mgoraldosewas0.82(0.74to0.89),fora20mgdosewas0.62(0.55to0.69)fora40mgdosewas0.47(0.41to0.53)andforan80mgdosewas0.37(0.31to0.42).

Inasubsequentpooledanalysis(Report613),theSponsorestimatedbioavailabilityforaneveningdose,usingthe10mgdoselevelasareference,tobe83.9%fora20mgdose,80.3%fora30mg,69.9%fora40mg,and52.0%fora60/80-mgdose.

3.2.2.2.2.Bioavailabilityrelativetoanoralsolutionormicronisedsuspension

Thiswasnotaddressedinthesubmission.

3.2.2.2.3.Bioequivalenceofclinicaltrialandmarketformulations

StudyP007wasconductedaspartofformulationdevelopment.ThreedifferentpotentialPhaseIIBformulationsweretestedagainsttheearlydevelopmentformulation.TheSponsorelectedtoproceedwiththeP2formulationintoPhaseIIBdevelopmentbecausethePKprofilewassimilartotheearlydevelopmentformulation,anditexhibitedlessvariabilitythanotherpotentialformulations.Inaddition,theabsorptionwasnotinfluencedbyfood.

InStudyP041theSponsorcomparedthreeformulationswiththePhase3formulation.FormulationAwasbioequivalenttoformulationC(thereference,orPhase3formulation),andmayalsohavebeenabsorbedmorerapidlyasmedianTmaxwas1.3hourscomparedwith1.8hoursforthePhase3formulation.

3.2.2.2.4.Bioequivalenceofdifferentdosageformsandstrengths

StudyP051comparedthebioavailabilityofthe15mgand30mg;andthe20mgand40mgdoseforms.The15mgand30mgdoseformswerebioequivalent:GMR(95%CI)2x15mg/30mgforAUC0-infwas99.66(96.52to102.91)%andforCmaxwas108.74(101.10to116.95)%.The20mgand40mgdoseformswerebioequivalent:GMR(95%CI)2x15mg/30mgforAUC0-infwas102.33(98.80to105.99)%andforCmaxwas96.58(90.96to102.55)%.

3.2.2.2.5.Bioequivalencetorelevantregisteredproducts

Thiswasnotrelevanttothepresentapplication.

3.2.2.2.6.Influenceoffood

Incomparisonwiththefastedstate,followingahighfatbreakfast,forthesuvorexant40mgFMItablet,thegeometricmeanratio(90%CI)fed/fastedforAUC0-infwas0.98(0.91to1.07)andforCmaxwas1.09(0.90to1.33).However,Tmaxwasincreasedinthefedstateincomparisonwiththefasted:median(range)3.0(1.0to6.0)hoursforfedcomparedwith2.0(1.0to4.0)hoursforfasted.

InJapanesesubjectsincomparisonwiththefastedstate,followingastandardJapanesebreakfast,forthesuvorexant40mgFMItablet,thegeometricmeanratio(90%CI)fed/fastedforAUC0-infwas1.10(1.02to1.19)andforCmaxwas1.23(1.02to1.49).Tmaxwasincreasedinthefedstateincomparisonwiththefasted:median(range)3.0(1.0to6.0)hoursforfedcomparedwith1.5(1.0to3.0)hoursforfasted.

InStudyP001,atthe10mgdoselevelAUCwassimilarbutCmaxwasdecreasedinthefedstate:GMR(90%CI)fed/fastedforAUC0-inf0.93(0.79to1.09)andforCmax0.55(0.45to0.66).

InyounghealthyJapanesemalestherewasanincreaseoverallexposureinthefedstateatthe10mgdoselevel,buttherewasadecreaseinCmax(StudyP005).GMR(90%CI)fed/fastedforAUC0-inf1.34(1.15to1.56)andforCmax0.88(0.73to1.05).

3.2.2.2.7.Doseproportionality

InStudyP018thereappearedtobedoseproportionalityforAUCandCmaxintheintravenousdosingrangeof5mgto30mg,andintheoraldosingrangeof10mgto80mg.[3]

InStudyP001doseproportionalitywasnotdemonstratedoverthedoserange4mgto120mg.Theslopeestimate(95%CI)was0.78(0.74to0.83)forAUC0-infand0.67(0.61to0.74)forCmax,ieAUCandCmaxdecreasedrelativetoincreasingdose.

InStudyP011doseproportionalitywasnotobservedoverthedoserange120mgto240mginfemalesand150mgto240mginmales,withlittleincrementalabsorptioninthehigherdoselevels.

InStudyP005inyounghealthyJapanesemales,doseproportionalitycouldnotbeconcludedoverthedoserange4mgto100mg.Therewasdecreasingexposurerelativetodose.

InStudyP002,inhealthymalevolunteers,singleoraldosesofsuvorexantdidnotexhibitdoseproportionalityinthe10mgto100mgrangeduringeveningadministration.Therewasdecreasedexposurerelativetodoseasthedoseincreased.

InStudyP022inhealthyvolunteersthePKparametersforsuvorexantwerenotdoseproportionalinthedoserange60mgto240mg,withdecreasingexposurerelativetodosewithincreasingdosesize.

3.2.2.2.8.Bioavailabilityduringmultiple-dosing

InStudyP003thesingledoseandmultipledosePKparameterswerenotdoseproportionalintherangeof10mgto100mgoncedailyfor14days.Steadystatewasreachedin3days.TheaccumulationratioforAUCover14daysrangedfrom1.27forthe10mgdoseto1.60forthe80mgdose.Therewasnoapparentautoinductionofmetabolism.

InStudy013,inhealthyyoungfemales,adailydoseof40mgsuvorexantresultedinanaccumulationratio(95%CI)over18daysof1.53(1.43to1.65)forAUC0-24and1.36(1.15to1.60)forCmax.Timetosteadystatewasapproximately3days.

3.2.2.2.9.Effectofadministrationtiming

InStudyP001,atthe76mgdoselevelAUCwassimilarbutCmaxwasdecreasedwitheveningcomparedtomorningdosing:GMR(90%CI)PM/AMforAUC0-inf1.00(0.84to1.18)andforCmax0.64(0.52to0.78).

InyounghealthyJapanesemalestherewasnodifferenceinoverallexposurebetweenmorningandeveningdosingatthe76mgdoselevel,buttherewasadecreaseinCmax(StudyP005).GMR(90%CI)PM/AMforAUC0-inf1.05(0.91to1.22)andforCmax0.71(0.59to0.86).

3.2.3.Distribution
3.2.3.1.Volumeofdistribution

InStudyP018intheintravenousdoserange5mgto30mgtheVssrangedfrom36.5Lto57.33L.

3.2.3.2.Plasmaproteinbinding

Theplasmaproteinbindingofsuvorexantisapproximately 99%.InStudyP017themean(SD)fractionunboundwas0.77(0.18)%insubjectswithhepaticfailureand1.01(0.43)%inhealthyvolunteers.

3.2.4.Metabolism
3.2.4.1.Interconversionbetweenenantiomers

Therewerenoclinicaldataregardinginterconversionbetweenenantiomers.

3.2.4.2.Sitesofmetabolismandmechanisms/enzymesystemsinvolved

SuvorexantundergoesextensivehepaticmetabolisminvolvingCYP3A4,CYP2C19andglucuronidation.

3.2.4.3.Non-renalclearance

CLrangedfrom48.60to80.62mL/min,andapparentterminalhalf-lifefrom8.9hoursto13.5hours.

3.2.4.4.Metabolitesidentifiedinhumans

3.2.4.4.1.Activemetabolites

Suvorexantdoesnotappeartohaveactivemetabolites.

3.2.4.4.2.Othermetabolites

TheproposedmetabolicpathwaysaredisplayedinFigure1.InStudyP012theprimarycomponentsinplasmaweresuvorexant(39.1%[4]ofcirculatingsuvorexantmaterial)andtheM9metabolite(36.5%).TheprimarymetabolitesweretheM4(21.1%ofdose),M18(10.6%),M9(9.5%)andM10a(9.2%).

Figure1.ProposedMajorMetabolicPathwaysofMK-4305

3.2.4.5.Pharmacokineticsofmetabolites

InStudyP003theAUCandCmaxfortheM9metabolitewerenotdoseproportionalinthedoserange10mgto100mg,eitherassingledoseormultipledailydoseover14days,withlessthanexpectedexposurewithincreasingdose.TherewasnoaccumulationoftheM9metaboliteover14days.

3.2.4.6.Consequencesofgeneticpolymorphism

Therewerenoclinicaldatawithregardtopharmacogenetics.

3.2.5.Excretion

3.2.5.1.Routesandmechanismsofexcretion

Suvorexantundergoesextensivehepaticmetabolismwithbiliaryandrenalexcretionofitsmetabolites.

3.2.5.2.Massbalancestudies

Inthemassbalancestudy(StudyP012)thetotalrecoveryofradioactivitywas90%inurineandfaeces,with82%recoveredinthefirst144hourspost-dose.Themajorrouteofexcretionwasfaecal(66%ofdoserecovered).Recoveryinurinewas23%ofdose.Unchanged(parent)suvorexantwasnotdetectedinurineandonlyatracewasdetectedinfaeces.

3.2.5.3.Renalclearance

Thereisnosignificantrenalclearanceofparentsuvorexant.

3.2.6.Pharmacokineticsinthetargetpopulation

Thetargetpopulationintheclinicaltrialswasotherwisehealthypatientswithprimaryinsomnia.Hence,thehealthyvolunteerPKdataisapplicabletothispopulation.

3.2.7.Pharmacokineticsinotherspecialpopulations

3.2.7.1.Pharmacokineticsinsubjectswithimpairedhepaticfunction

TherewasnoeffectofmoderatehepaticimpairmentonthePKofsuvorexantortheM9metabolite.InStudyP017therewasnodifferenceinPKparametersbetweensubjectswithmoderatehepaticimpairmentandhealthyvolunteers.TheGMR(90%CI)hepaticinsufficiency/healthywas1.03(0.74to1.43)forAUC0-infand0.94(0.68to1.29)forCmax.Mean(SD)AUC0-infforM9insubjectswithmoderatehepaticfailurewas17.24(6.53)μM•hourandinhealthyvolunteerswas12.50(2.32)μM•hour.Mean(SD)CmaxforM9insubjectswithmoderatehepaticfailurewas0.517(0.256)μMandinhealthyvolunteerswas0.594(0.127)μM.

3.2.8.Pharmacokineticsinsubjectswithimpairedrenalfunction

Insevererenalimpairment(creatinineclearance≤30mL/min)therewasa22%increaseinAUC0-infcomparedwithmatchedhealthycontrols:GMR(90%CI)severerenalfailure/healthy1.22(0.93to1.60)(StudyP023).Therewasa15%increaseinCmax:GMR(90%CI)severerenalfailure/healthy1.15(0.98to1.34).ForM9therewasa12%decreaseinAUC0-inf0.88(0.71to1.09).

3.2.9.Pharmacokineticsaccordingtoage

Overallexposurewassimilarforhealthyelderlymalescomparedwithyoungmales,butCmaxwas28%lower.HealthyelderlymalesfromStudyP004werecomparedwithhealthyyoungmalesfromStudyP001,andthedosenormalizedGMR(90%CI)forAUC0-infwas0.92(0.71to1.19)andforCmaxwas0.72(0.58to0.89).

InStudyP027inhealthyelderlyvolunteerstherewasnoindicationoftimedependentchangesinthePKofsuvorexant.Forsuvorexant40mgorallyafter7daysthemean(95%CI)forAUC0-infwas17.88(15.25to20.96)andforCmaxwas1.336(1.132to1.575).Forsuvorexant40mgover7daystheaccumulationratio(90%CI)forAUC0-infwas1.34(1.26to1.42)andforCmaxwas1.17(1.04to1.32).Forsuvorexant30mgorallyafter21daysthemean(95%CI)forAUC0-infwas14.93(12.94to17.21)andforCmaxwas1.133(0.960to1.337).Forsuvorexant40mgover21daystheaccumulationratio(90%CI)forAUC0-infwas1.45(1.35to1.56)andforCmaxwas1.21(1.08to1.35).

Apooledanalysis(Study616)estimatedthatat9hourspost-dosetheplasmaconcentrationinanelderlysubjectfollowinga30mgdosewouldbesimilartothatinanon-elderlysubjectfollowinga40mgdose.

3.2.10.Pharmacokineticsrelatedtogeneticfactors

Nodatawerepresentedrelatingtopharmacogeneticfactors.

3.2.11.GenderEffectsonPharmacokinetics

InStudyP004,themeanAUC0-infwas55%higherinhealthyelderlyfemalescomparedtohealthyelderlymales,andCmaxwas29%higher:GMR(90%CI)1.29(1.08to1.54)[5]forAUC0-infand1.29(1.08to1.54)forCmax.ExposuretotheM9metabolitewasalso30%greaterinthefemales:GMR(90%CI)1.38(1.05to1.81)forAUC0-infand1.05(0.92to1.19)forCmax.

3.2.12.Pharmacokineticinteractions

3.2.12.1.Pharmacokineticinteractionsdemonstratedinhumanstudies

InStudyP008,co-administrationofketoconazolewithsuvorexantincreasedAUC0-infby179%andCmaxby23%.TheGMR(90%CI)suvorexant+ketoconazole/suvorexantwas2.79(2.35to3.31)forAUC0-inf,and1.23(1.05to1.44).FortheM9metabolite,ketoconazoleincreasedAUC0-infby80%anddecreasedCmaxby39%.TheGMR(90%CI)suvorexant+ketoconazole/suvorexantforM9was1.80(1.64to1.98)forAUC0-inf,and0.71(0.64to0.80).ThisindicatessignificantmetabolismofsuvorexantbyCYPenzymes.[6]

Inhealthyyoungfemalesmultipledailydosesuvorexant40mgdidnotsignificantlyaffectthePKofthecombinedoralcontraceptivepill(StudyP013).ForethinylestradioltheGMR(90%CI)was1.07(0.99to1.16)forAUC0-infand0.94(0.83to1.06)forCmax.FornorelgestromintheGMR(90%CI)was1.16(1.11to1.20)forAUC0-infand1.08(0.95to1.23)forCmax.

AtsteadystatesuvorexantexhibitsweakinhibitionofCYP3A4.InStudyP015asingledoseofsuvorexantdidnotalterthePKofmidazolambutatsteadystatesuvorexantincreasedAUCby47%.ForsingledosesuvorexantGMR(90%CI),midazolam+suvorexant/midazolam,forAUC0-infwas0.96(0.84to1.08)andforCmaxwas0.83(0.72to0.95).ForsteadystatesuvorexantGMR(90%CI),midazolam+suvorexant/midazolam,forAUC0-infwas1.47(1.30to1.67)andforCmaxwas1.23(1.07to1.41).

InStudyP016,exposuretodigoxinwasincreasedwithco-administrationofsuvorexant,butthiswasnotduetoalteredrenalclearance.TheGMR(90%CI)digoxin+suvorexant/suvorexantwas1.27(1.12to1.43)forAUC0-last,and1.21(1.05to1.40)forCmax.However,theGMR(90%CI)digoxin+suvorexant/suvorexantforrenalclearanceofdigoxinwas0.94(0.82to1.08).Thefractionofdigoxindoseexcretedunchangedintheurinewas23.04%whenco-administeredwithsuvorexantand26.02%whenadministeredalone.

SuvorexanthadnoeffectonthePKparametersforeitherR-warfarinorS-warfarin(StudyP024).TheGMR(90%CI)warfarin+suvorexant/warfarinforR-warfarinforAUC0-lastwas0.99(0.95to1.04)andforCmaxwas0.95(0.87to1.03).TheGMR(90%CI)warfarin+suvorexant/warfarinforS-warfarinforAUC0-lastwas0.99(0.95to1.04)andforCmaxwas0.95(0.86to1.05).

ParoxetinehadnosignificanteffectonthePKparametersforsuvorexant(StudyP026).TheGMR(90%CI)suvorexant+paroxetine/suvorexantwas0.97(0.92to1.03)forAUC0-24and1.05(0.96to1.15)forCmax.

Exposuretosuvorexantwasgreatlydecreasedwithrifampinco-administration(StudyP038).TheGMR(90%CI)suvorexant+rifampin/suvorexantwas0.12(0.11to0.14)forAUC0-inf,and0.36(0.31to0.42)forCmax.ExposuretotheM9metabolitewasalsodecreased:GMR(90%CI)suvorexant+rifampin/suvorexantwas0.23(0.21to0.25)forAUC0-inf,and0.77(0.70to0.86)forCmax.

Exposuretosuvorexantwasdoubledwithdiltiazemco-administration(StudyP038).TheGMR(90%CI)suvorexant+diltiazem/suvorexantwas2.05(1.82to2.30)forAUC0-inf,and1.22(1.09to1.36)forCmax.ExposuretotheM9metabolitewasalsoincreased:GMR(90%CI)suvorexant+diltiazem/suvorexantwas1.36(1.27to1.47)forAUC0-inf,and0.85(0.79to0.92)forCmax.

InStudyP010ethanolhadnosignificanteffectuponthePKparametersforsuvorexant.TheGMR(90%CI)suvorexant+ethanol/suvorexantforsuvorexantwere1.09(1.04to1.16)forAUC0-infand1.05(0.98to1.12)forCmax.TheGMR(90%CI)suvorexant+ethanol/ethanolforethanolwere0.99(0.95to1.03)forAUC0-lastand0.99(0.95to1.03)forCmax.SuvorexanthadnosignificanteffectonthePKofethanol:median(range)ratioforAUC0-last0.95(0.84to1.36)andforCmax0.96(0.80to1.34).

3.3.Evaluator’soverallconclusionsonpharmacokinetics

Suvorexantwaswellabsorbedorallybutbioavailabilitydecreasedwithincreasingdose.Themean(5thand95thpercentile)bioavailabilityfora10mgoraldosewas0.82(0.74to0.89),fora20mgdosewas0.62(0.55to0.69)fora40mgdosewas0.47(0.41to0.53)andforan80mgdosewas0.37(0.31to0.42).TheclinicaltrialformulationswerebioequivalenttotheFMI.The15mgand30mgdoseformswerebioequivalent.The20mgand40mgdoseformswerebioequivalent.

Fooddidnotsignificantlyaffectexposuretosuvorexant.AUCwassimilarfastedversusfed,butCmaxwasdecreasedbyfood.[7]SuvorexantPKwerenotdose-proportional[8],asexposuredecreasedwithincreasingdose.AUCwassimilarbetweenmorningandeveningdosingbutCmaxwasdecreasedintheevening.

Timetosteadystatewasapproximately3days.Suvorexantmetabolismwasnotautoinduced.Intheintravenousdoserange5mgto30mgtheVssrangedfrom36.5Lto57.33L.Theplasmaproteinbindingofsuvorexantis99%.Themean(SD)fractionunboundwas0.77(0.18)%insubjectswithhepaticfailureand1.01(0.43)%inhealthyvolunteers.CLrangedfrom48.60to80.62mL/min,andapparentterminalhalf-lifefrom8.9hoursto13.5hours.Suvorexantundergoesextensivehepaticmetabolismwithbiliaryandrenalexcretionofitsmetabolites.TheenzymesinvolvedincludeCYP3A4,CYP2C19andglucuronidation.

ThePKofsuvorexantwasnotsignificantlyalteredineithermoderatehepaticimpairmentorsevererenalimpairment.At9hourspost-dosetheplasmaconcentrationinanelderlysubjectfollowinga30mgdosewassimilartothatinanon-elderlysubjectfollowinga40mgdose.

InhibitionofCYPenzymesbyketoconazoleincreasedexposuretosuvorexantbymorethandouble.Hence,incombinationwithdrugsthatinhibitCYP3A4andCYP2C19thedoseofsuvorexantwillneedtobereduced.Verapamilco-administrationalsoincreasedexposuretosuvorexanttoasimilarextent.[9]

4.Pharmacodynamics

4.1.Studiesprovidingpharmacodynamicdata

Table 2showsthestudiesrelatingtoeachpharmacodynamictopicandthelocationofeachstudysummary.

Table2.Submittedpharmacodynamicstudies.

PDTopic / Subtopic / StudyID
PrimaryPharmacology / Effectonsleep / StudyP003
StudyP011
StudyP005
StudyP002
SecondaryPharmacology / EffectonQTc / StudyP022
AbusePotential / StudyP025
EffectonDrivingAbility / StudyP035
StudyP039
RespiratorySafety:healthy / StudyP040
RespiratorySafety:COPD / StudyP031
RespiratorySafety:OSA / StudyP036
GenderothergeneticandAge-RelatedDifferencesinPDResponse / Effectofage / StudyP004
PDInteractions / Warfarin / StudyP024
Paroxetine / StudyP026
Ethanol / StudyP010
PopulationPDandPK-AE analyses / Healthysubjects[10] / Report615

*Indicatestheprimaryaimofthestudy.

‡Andadolescentsifapplicable.

Noneofthepharmacodynamicstudieshaddeficienciesthatexcludedtheirresultsfromconsideration.

4.2.Summaryofpharmacodynamics

Theinformationinthefollowingsummaryisderivedfromconventionalpharmacodynamicstudiesinhumansunlessotherwisestated.

4.2.1.Mechanismofaction

Fromthein-vitrostudies,suvorexantisahighlyselectivereversiblehighaffinityorexinreceptorantagonistatOX1R(Ki0.55nM)andOX2R(Ki0.35nM)receptors.Theorexinneuropeptidesignallingsystemisacentralpromoterofwakefulness.Orexinproducingneuronalcellbodiesarelocalisedspecificallyinthehypothalamusandprojecttothewakefulnessmediatingneuronsofthebrain.

4.3.Pharmacodynamiceffects

4.3.1.Primarypharmacodynamiceffects

InStudyP003,conductedatthedoserange10mgto100mg,therewasadosedependentdecreaseinalertnessthatlastedfrom2to12hourspostdoseforthe40mgdoselevel,buttherewascarry-overeffectduringthedayforthe80mgand100mgdoselevels.Therewasnoconsistentchange,ordoseeffect,incontentednessorcalmness.TherewasalsoadosedependentdecreaseinKarolinskaSleepinessScale(KSS)thatlastedfrom2to12hourspostdoseforthe40mgdoselevel,buttherewasalsocarry-overeffectduringthedayforthe80mgand100mgdoselevels.TherewasnosignificanteffectonDSST,ImmediateWordRecallorDelayedWordRecall.

InStudyP011,thedoserange150mgto240mgwasinvestigatedinmalesand120mgto240mginfemales.Between1.5hoursand4hourspost-dose,ChoiceReactionTimeincreasedinadosedependentmanner;andDividedAttentionTestscoredecreasedinadosedependentmanner.Visualanaloguescorefordrowsinessalsoincreasedinadosedependentmanner,withdrowsinesspersistinginthe240mggroupforupto24hours.TherewasadosedependentincreaseinKSSthatpersistedforupto24hoursinthe240mggroupinmales,andatallthedoselevelsinfemales.

InStudyP005inyounghealthyJapanesemales,therewasadosedependentdecreaseinalertnessthatpersistedforupto24hoursatthehigherdoselevels.Therewasnoeffectoncalmnessorcontentedness.ForKSStherewasalsoadosedependentincreasebuttherewasalsoanunexpectedincreaseafter12hoursinthePMplacebogroup.

InStudyP002theeffectsonsleepofsingledosesofsuvorexantwerestudiedinthedoserange10mgto100mg.TherewaslittleeffectonSWA,evenupto100mg.However,thedurationofREM2increasedinadosedependentmanner.Sleeplatencydecreasedsignificantlyinadosedependentmannerupto100mg.WASOimprovedwithsuvorexantbutnotinadosedependentmanner.Sleepefficiencyalsoincreasedinadosedependentmannerupto100mg.CRT,DSSTandSRTalldeterioratedinadosedependentmanner.

4.4.Secondarypharmacodynamiceffects

4.4.1.EffectsonQTprolongation

StudyP022wasathoroughQTstudyperformedtoamaximumdoselevelof240mgsuvorexant.The90%CIforincreaseinQTcFandQTcPfrombaselinerelativetoplacebowerelessthan10msecforsuvorexant.Themaximumdoseofsuvorexantusedinthestudywasreducedfrom240mgto150mgbecauseofissueswithtolerability.Thepositivecontrolwasmoxifloxacin400mg,whichshowedamaximummean(90%CI)QTcFchangefrombaselinerelativetoplaceboof11.06(8.99to13.16)msec.ThemaximumincreaseinQTcFforthehighdosesuvorexant(240mg/150mg)wasmean(90%CI)(changefrombaselinerelativetoplacebo)4.13(2.03to6.23)msecat8hourspostdose.ThemaximumincreaseinQTcPforthehighdosesuvorexant(240mg/150mg)wasmean(upper90%CI)(changefrombaselinerelativetoplacebo)3.17(5.33)msecat8hourspostdose.

4.4.2.Abusepotential

InStudyP025asingledoseofsuvorexantinthedoserange40mgto150mghadsignificantlygreaterabusepotentialcomparedwithplacebo,usingtheDrugLikingVAS.However,atthehighestdoseofsuvorexant(150mg)therewaslesserabusepotentialcomparedwiththehigherdoseofzolpidem(30mg).Forotherpharmacodynamicmeasuresofabusepotential,suvorexanthadgreaterabusepotentialthanplacebo.TherewasnosignificantdifferenceforabusepotentialcomparedwithzolpidemexceptforlessHighincomparisonwithzolpidem30mg,lesseffectscomparabletoMorphineBenzedrineGroup(MBG)andgreaterdrowsinessforsuvorexantcomparedwithzolpidem.

4.4.3.Drivingability

Suvorexant20mgand40mgresultedinsignificantimpairmentindrivingperformancethedayaftereveningdosing.InStudyP035,forStandardDeviationofLateralPosition(SDLP)therewasanincreaseincomparisontoplaceboforalltheactivetreatmentsatbothDay1andDay9.Theeffectforsuvorexant40mgwassimilartothatforzopiclone7.5mg.ForCarDrivingSDStherewassignificantimpairmentforalltheactivetreatmentsatDay1,butonlyforsuvorexant40mgatDay9.TherewassignificantimpairmentofwordrecalltimeatDay1forsuvorexant40mgandzopiclone7.5mg,butnotatDay9.Bodysway,eyesopen,wassignificantlyimpairedatDay2forallthreeactivetreatmentsrelativetoplaceboatDay2butnotatDay9.TheDrivingInstructorVASfordrivingqualityindicatedsignificantimpairmentforbothdosesofsuvorexantatDay2,butonlythe40mgdoseatDay9.TheDrivingInstructorVASforsedationdemonstratedimpairmentforsuvorexant20mgand40mgatDay2andDay9.Therewasnosignificantimpairmentindrivingqualityorsedationforzopiclone.

Inelderlysubjectssuvorexantatthe15mgand30mgdoselevelsdidnotsignificantlyimpairdrivingperformance.InStudyP039,inelderlysubjects,neitherthesuvorexant15mgnorthe30mgdosesresultedinsignificantimpairmentinSDLPorCarDrivingSDSatDay2orDay9.Zopiclone7.5mgresultedinsignificantimpairmentinbothparametersatbothDay2andDay9.Therewerenosignificanteffectsofsuvorexantonwordlearningtests,bodyswayorDrivingInstructorVAS.

4.4.4.Respiratorysafety

Suvorexantdidnotimpairrespiratorysafetyduringsleepatdosesupto150mginhealthyvolunteers.InStudyP040therewasnoimpairmentofmeanSaO2duringtotalsleeptime,duringwaketime,NREMorREM.Therewasnoimpairmentoftheapnoea-hypopneaindex.

Insubjectswithchronicpulmonaryobstructivediseasetherewasnosignificantimpairmentofsleepsafetywithsuvorexant.InStudyP032,onDay1therewasnoclinicallyorstatisticallysignificantdifferencebetweensuvorexantandplaceboformeanSa02duringtotalsleeptime,NREM,REMorwaketime;percentageoftotalsleeptimewithSa02<90%or85%,orinapneoa-hypopneaindex.OnDay4,therewasnoclinicallyorstatisticallysignificantdifferencebetweensuvorexantandplaceboformeanSa02duringtotalsleeptime,NREMorREM;orpercentageoftotalsleeptimewithSa02<90%.DuringwaketimeSa02washigherwithsuvorexant.However,thepercentageoftotalsleeptimewithSa02<85%washigherwithsuvorexant:LSmean(95%CI)0.32(0.06to0.58)%comparedwith0.01(-0.26to0.28)%;LSmeandifference(95%CI)suvorexant–placebo0.32(0.00to0.63)%.Theapnoea-hypopneaindexwashigherwithsuvorexantthanplacebo:LSmean(95%CI)8.27(5.71to10.84)%comparedwith6.22(3.61to8.83)%;LSmeandifference(95%CI)suvorexant–placebo2.05(0.33to3.77)%.

RespiratorysafetywasstudiedinsubjectswithmildtomoderateobstructivesleepapnoeainStudyP036.Apnoea-hypopneaindexwashigherinthesuvorexantgroupatDay4:LSmean(95%CI)17.07(13.30to20.84)comparedwith14.41(10.61to18.22);LSmeandifference(90%CI)2.66(0.22to5.09).TherewasnosignificantdifferenceinmeanSaO2duringtotalsleeptime,NREM,REM,orwaking;orinthepercentageoftotalsleeptimethatSaO2was<90%or<85%.TherewasnodifferencebetweenthegroupsinanyoftherespiratorysafetyparametersatDay1.

4.4.5.Timecourseofpharmacodynamiceffects

TheSponsorperformedapooledanalysisofthePKPDrelationshipbetweennextdayplasmaconcentrationsofsuvorexantandsomnolence(Study615).Thisstudyestimatedarateofnext-daysomnolenceof7.9%with20mg,10.6%with40mgand14.2%withthe80mgdoselevel.Thestudyestimatedthatelderlysubjectswouldhavesimilarratesofsomnolenceandfatiguetonon-elderlysubjects.

4.4.6.Relationshipbetweendrugconcentrationandpharmacodynamiceffects

Theplasmaconcentrationat9hourspostdosecorrelatedwithnextdaysomnolence.

4.4.7.Genetic-,gender-andage-relateddifferencesinpharmacodynamicresponse

InStudyP004,ata16mgsingledoselevel,intheelderlyfemalevolunteerstherewasadecreaseinalertnessVASat2hourspost-dose,butnosignificanteffectforthemales.TherewerenosignificantchangesincalmnessorcontentednessVAS.ForKSStherewasalsoanincreaseinsleepinesscomparedtoplacebo,butnotforthemalegroup.TherewasnochangeinDigitSymbolSubstitutionTest(DSST).TherewasanimpairmentinPowerofAttentionbutnotinContinuityofAttention,QualityofWorkingMemory,QualityofEpisodicMemoryorSpeedofMemory.

Inelderlysubjects,suvorexantincreasedbodysway,eyesopen,at1.5hourspostdosecomparedwithplacebobuttoalesserextentthanzolpidem5mg(StudyP021).At1.5hourspostdose,therewasasignificantincreaseinbodysway,eyesopen,incomparisonwithplaceboofapproximately50%:GMR(95%CI)suvorexant/placebo1.49(1.04to2.14).Therewaslesserincreasecomparedwithzolpidem:GMR(95%CI)suvorexant/zolpidem0.76(0.53to1.08).Therewasnosignificantdifferencecomparedtoplaceboforbodysway,eyesclosed.Totalreactiontimeincreasedinthesuvorexantgroupat1.5hourspostdosebyLSmean(95%CI)67.91(24.11to111.71)mseccomparedtoplaceboand62.15(17.13to107.18)mseccomparedtozolpidem.Therewerenodifferencesbetweenthetreatmentsforimmediatewordrecall,ordelayedwordrecall.Therewerenosignificantdifferencesinanyoftheparametersat4or8hourspostdose.

4.4.8.Pharmacodynamicinteractions

SuvorexanthadnoclinicallysignificanteffectonthePDparametersforwarfarin(StudyP024).TheGMR(90%CI)warfarin+suvorexant/warfarinforINRAUC0-168hourswas1.06(1.03to1.04)andforIMRmaxwas1.09(1.05to1.14).Hence,theremaybeasmall,butnotclinicallysignificant,increaseinINRwithco-administrationofsuvorexantwithwarfarin.

InStudyP026therewasanincreaseindigitreactiontimewithsuvorexantthatincreasedslightlywithparoxetineco-medication:LSmean(90%CI)suvorexant+paroxetine–suvorexantalone3.58(-9.08to16.23).Thisadditiveeffectwouldnotbeclinicallysignificant,andwasnotstatisticallysignificant.Therewasnosignificanteffectonwordrecallordigitsubstitutiontest.

InStudy010suvorexantandalcoholexhibitedasignificantadditiveeffectonimpairmentincognitivefunctionthatlastedforupto9hourspost-ingestion.Fordigitreactiontime,targetsdetectedcorrectly,wordscorrectlyrecalled,numericworkingmemorysensitivityindexandalertnesstherewassignificantadditiveimpairment.

4.5.Evaluator’soverallconclusionsonpharmacodynamics

ThetimecourseofsingledosesuvorexantwasexaminedinfourPDstudiesatdosesupto240mg.Theredidnotappeartobepersistenceofeffectbeyond8hoursforthe10mgdoselevel,somepersistenceforthe20mganddefinitepersistenceforthe40mg.Therateofnext-daysomnolencewasestimatedtobe7.9%with20mg,10.6%with40mgand14.2%withthe80mgdoselevel.Athighdoses(>100mg)theeffectspersistedforupto24hours.InathoroughQTcstudyatdosesupto240mg(maximumtolerated)therewasnoQTcprolongationofregulatoryconcern.Therewaslesserabusepotentialcomparedwithzolpidem.Therewassignificantnextdaydrivingimpairmentwithsuvorexant,similartothatforzopiclone,innon-elderlysubjectsbutnosignificantimpairmentinelderlysubjects.Suvorexantdidnotimpairsleepsafetyinnormalvolunteers,subjectswithchronicobstructivepulmonarydiseaseorsubjectswithobstructivesleepapnoea.Suvorexantandalcoholexhibitedasignificantadditiveeffectonimpairmentincognitivefunctionthatlastedforupto9hourspost-ingestion.

5.Dosageselectionforthepivotalstudies

5.1.StudyP006

StudyP006wasamulticentre,randomised,doubleblind,placebocontrolled,twoperiodadaptive, crossoverpolysomnographystudytoevaluatethesafetyandefficacyofsuvorexantinsubjectswithprimaryinsomnia.Thestudywasconductedat41centresfromNovember2008toDecember2009.

Theinclusioncriteriaincluded:

  • Maleorfemalebetween18and<65yearsofage
  • DSM-IV-TRdiagnosisofPrimaryInsomniabasedontheinvestigator’sjudgmentandthepatient’ssleephistoryasassessedontheSleepDiagnosticInterview/SleepHistory
  • Completedatleast6yearsofformaleducation;obtainsascore6thgradelevelonReadingSubtestofWideRangeAchievementTestVersion4(WRAT-4)atscreening,oracomparablemeasureapprovedbySponsor
  • Goodphysicalandmentalhealth
  • Totalsleeptimeof≤6.5hoursonatleast3outof7nightseachweekwithinthe4weekspriortoVisit1,whennotmedicatedonahypnoticagent
  • Sleeplatencyof≥30minutesonatleast3outof7nightseachweekwithinthe4weekspriortoVisit1,whennotmedicatedonahypnoticagent
  • ≥1hourofwakefulnessaftersleeponset
  • 6.5to9hoursnightlyinbed
  • Regularbedtimebetween9PM(21:00)and12AM(00:00)
  • Willingtorefrainfromnapping
  • Willingtolimitalcoholto2drinksaday,atleast3hoursbeforegoingtobedonnon-PSGvisitdays,andrefrainsfromdrinkingalcoholonallPSGvisitsandatleast24hourspriortoaPSGvisit.(Adrinkisdefinedasa12-ouncebottle/canofbeer(~14gramsalcohol)ora4-ounceglassofwine(~12gramsalcohol)or1ounceofliquor(80proofor40%alcohol,~9gramsalcohol).)
  • Willingtolimitcaffeineconsumptionto5standard6-ouncecupsofcaffeinatedbeveragesaday,or600mgcaffeine,avoidcaffeineafter4PM(16:00)onnon-PSGnights,andavoidcaffeineafter1PM(13:00)onPSGvisits
  • Femalepatientsofreproductivepotentialarenon-pregnantandagreetoremainabstinentortouseappropriatedoublebarriercontraception
  • AtscreeningthesubjectmustalsohaveLPS>20minutesandWASO>45minutes
  • AtBaselinethesubjecthasLPS>20minutesatbothScreeningandBaselineandameanWASO60minutesonthecombinedScreeningandBaselinenights,whereneithernightis45minutes.

Theexclusioncriteriaincluded:

  • Historyorcurrentevidenceofanycondition,therapy,lababnormalityorothercircumstancesthatmightconfoundtheresultsofthestudy
  • Historyofaneurologicaldisorder,includingbutnotlimitedtoseizuredisorder,epilepsy,stroke,transientischemicattack,multiplesclerosis,cognitiveimpairment,significantheadtraumawithsustainedlossofconsciousness,orclassicalmigraineheadachesinthelast10years
  • Historywithinthepast6monthspriororcurrentevidenceofaclinicallysignificantcardiovasculardisorder,including,butnotlimitedto:leftventricularhypertrophy,mitralvalveprolapse,acutecoronarysyndrome,unstableangina,congestiveheartfailure(e.g.,ejectionfraction(EF)<40%),cardiogenicsyncope,orsymptomaticarrhythmia
  • ECGclinicallysignificantAVconductiondisturbance(e.g.,secondorthirddegreeAVblock),sicksinussyndrome,bradycardia(restingpulse<40),accessorybypasstract(e.g.,Wolff-Parkinson-White)
  • ECGorphysicalexamahistoryorcurrentevidenceoflongQTsyndrome,Torsadesdepointe,oraQTcintervalof>450msec
  • SBP>160mmHg,DBP>100mmHgorpulserate>100beats/min
  • Patientistaking,orplanstotake,oneormoreofthefollowingmedications(non-inclusive),withinthespecifiedwashoutperiods:

–ClinicallyrelevantCYP3A4InhibitorsandInducers:4weeks

–Centrallyactinganticholinergicsorantihistamines:2weeks

–Melatonin:2weeks

–Antidepressants:2weeks

–Fluoxetine:4weeks

–Anxiolytics:2weeks

–Benzodiazepines:2weeksor5t½lives(whicheverislonger)

–Hypnotics:2weeksor5t½lives(whicheverislonger)

–AnyCNSdepressants:2weeks

–Over-the-countermedicationsthatcouldaffectsleep(e.g.,kava-kava,valerian,Benadryl[diphenhydramine]St.John’swort):2weeks

–Stimulants:2weeks

–Dietpills:2weeks

–Antihistamines(sedating):2weeks

  • Positiveprestudyurinedrugscreen
  • ActiveAxisIorIIdisorderasdefinedintheDSM-IV-TRandasassessedbytheMiniInternationalNeuropsychiatricInterview,otherthanPrimaryInsomnia
  • Evidenceofongoingdepressionasdeterminedbyascore20ontheQuickInventoryofDepressiveSymptomatology–SelfReportScale(QIDS-SR16),orscores2ontheQIDS-SR16suicideitem#12,orinthejudgmentoftheinvestigatorthepatientisimpaired,suicidalorotherwiseinsuchawayastobeunabletocompletethestudyproceduresinasafeandappropriatefashion
  • Historyofsubstanceabuseordependence(includingalcohol,marijuana,hypnotics,anddrugsofabuse,butexcludesnicotinedependence)
  • Historyoftransmeridiantravel(across>3timezones)orshiftwork(definedaspermanentnightshiftorrotatingday/nightshiftwork)withinthepast2weeksoranticipatesneedingtotravel(across>3timezones)atanytimeduringthestudy
  • Subjectconsumestheequivalentof>15cigarettesaday,andthePrimaryInvestigatorconfirmsthatthepatient’ssleepdisturbanceisinparttheresultofthisconsumptionandthepatientisunabletorefrainfromsmokingduringthenight
  • Historyofanyoffollowingconditions:narcolepsy,cataplexy,circadianrhythmsleepdisorder,parasomnia(includingnightmaredisorder,sleepterrordisorder,sleepwalkingdisorder,andREMbehaviourdisorder),sleep-relatedbreathingdisorder,periodiclimbmovementdisorder,orrestlesslegssyndrome
  • Historyofmalignancy≤5yearspriortosigninginformedconsent,exceptforadequatelytreatedbasalcellorsquamouscellskincancerorinsitucervicalcancer.Melanoma,leukaemia,lymphomaandmyeloproliferativedisordersofanydurationareexcluded
  • HistoryofuncontrolleddiabetesasdefinedbyHbA1cofgreaterthan8%
  • Difficultysleepingduetoamedicalcondition
  • BMI>40kg/m2
  • Commencedaweight-lossdietinthepast30days
  • Atscreening,anunderlyingpathologyofsleepidentifiedduringthescreeningPSG:ApneaHypopneaIndex>10,or>10periodiclegmovementsassociatedwithanarousalperhourofsleep
  • Positivealcoholbreathtestasanalyzedbyabreathalyzermachine[11].

Thetreatmentgroupswere:

1.Suvorexant10mg

2.Suvorexant20mg

3.Suvorexant40mg

4.Suvorexant80mg

Treatmentswereadministered30minutesbeforebedtimeonPSGnightsandimmediatelypriortobedtimeonnon-PSGnights.SubjectswererandomisedbyIVRSto4weeksactiveorwith4weeksplacebo,withcrossovertothealternativetreatment(activeorplacebo)[12].

TheprimaryefficacyoutcomemeasurewasSE,derivedfromTSTfromthePSG.Thesecondaryefficacyoutcomemeasureswere:

  • WASO
  • LPS

Theexploratorysubjectiveassessmentsofsleepwere:

  • sWASO
  • sTSO
  • sNAW
  • sTST
  • SheehanDisabilityScale
  • InsomniaSeverityIndex

Safetyoutcomemeasureswere:AEs,laboratorysafetytests,vitalsigns,ECG,TyrerWithdrawalSymptomQuestionnaireviatheeDiaryeveningquestionnaire,DigitSymbolSubstitutionTest,andDigitSymbolCopyTest.

Atotalof254subjectswereallocatedtotreatmentgroup:62inthesuvorexant10mggroup,61inthe20mg,59inthe40mgand61inthe80mg.Ofthese228subjectscompleted.Therewere148(58.3%)females,106(41.7%)males,andtheagerangewas18to64years.Thetreatmentgroupsweresimilarindemographiccharacteristics.MorningeDiarycompliancewas99.7%andeveningdiarycompliancewas98.3%.

ForSEonNight1,thedifferencefromplaceboincreasedwithdoseuptothe80mgdoselevel(Table3).Therewasnosignificantdifferencebetweentheactivetreatments.In Week 4,thedifferencewasgreatestforthe20mgdoselevel,andsimilarforthe40mgand80mgdoselevel.Therewasnosignificantdifferencebetweenthetreatments.While there was no formal pair-wise comparison for WASO,onNight1therewasaprogressivedecreasewithincreasingdoseincomparisonwithplacebo,butin Week 4thegreatestdecreasewaswiththe40mgdoselevel.ForLPS,onNight1therewasaprogressivedecreasewithincreasingdoseincomparisonwithplacebo,butthiswasonlysignificantforthe40mgand80mgdoselevels.InWeek 4theonlysignificantdecreasecomparedtoplacebowaswiththe20mgdoselevel.TherewaslesseffectonLPSin Week 4thanonNight1forthe40mgand80mgdoselevels.

Table3.AnalysisofSleepEfficiency(SE)(%),WakefulnessafterPersistentSleepOnset(WASO)(minutes)andLatencytoOnsetofPersistentSleep(LPS)(minutes)(FullAnalysisSet/Data-as-Observed)

Theresultsfortheexploratoryendpointswere:

  • TotalsleeptimeincreasedwithdoseonbothNight1andWeek 4.TheestimateddifferencesinTSTbetweenNight1andbaselinewere:52.4,85.3,83.7,113.8and104.5minutesforplacebo,suvorexant10mg,20mg,40mgand80mg,respectively;andin Week 4were59.2,89.8,91.8,97.9and95.1minutesrespectively
  • TheestimateddifferencesinTTAbetweenNight1andbaselinewere:-52.4,-85.3,-83.7,-114and-105minutesforplacebo,suvorexant10mg,20mg,40mgand80mg,respectively;andin Week 4were:-59.2,-89.8,-91.8,-97.9and-95.1minutesrespectively
  • SOLwassignificantlydecreasedonlyonNight1forthe40mgand80mgdoselevels:-15.3minutesand-12.7minutesrespectively
  • Therewasnodoseeffectfornumberofnon-REMepochsbeforeREM
  • TherewasnodoseeffectonlatencytoREM
  • Numberofawakeningsafteronsetofpersistentsleepwasdecreasedonlyforthe80mgdoseonNight1:-3.3awakenings
  • TherewasnoapparenteffectontheratioofNAWtoTST
  • NumberofarousalswasincreasedforalldosesofsuvorexantonbothNight1andWeek 4(intherange3.1to6.3)relativetoplacebo,buttherewasnodoseeffect
  • TherewasnoconsistenteffectfortheratioofNOAtoTST
  • ThenumberofshiftstoWakeorStage1fromlightsouttolightsonincreasedrelativetoplaceboforallthesuvorexantdoses(intherange1.6to7.6),withnoapparentdoseeffect

Theresultsofthesubjectiveendpointswere:

  • Subjectivetotalsleeptime(sTST)atWeek4wasonlyincreasedrelativetoplaceboforthe40mgand80mgdoses:mean(95%CI)29.6(17.1to42.1)minutesand19.4(7.1to31.7)minutesrespectively
  • Timetosleeponset(sTSO)atWeek4wasonlydecreasedrelativetoplaceboforthe40mgand80mgdoses:mean(95%CI)-17.4(-24.1to-10.7)minutesand-7.7(-14.3to-1.1)minutesrespectively
  • WakeaftersleeponsetatWeek4wasonlydecreasedrelativetoplaceboforthe40mgand80mgdoses:mean(95%CI)-20.5(-29.2to-11.7)minutesand-12.4(-21.2to-3.5)minutesrespectively
  • NumberofsleepawakeningsatWeek4wasonlydecreasedrelativetoplaceboforthe40mgand80mgdoses:mean(95%CI)-0.3(-0.5to-0.1)and-0.2(-0.4to-0.0)respectively
  • QualityofsleepatWeek4decreasedrelativetoplaceboforthe40mgand80mgdoses:mean(95%CI)-5.5(-9.7to-1.4)and-5.7(-9.8to-1.6)respectively
  • Suvorexant80mg,40mgand20mghadgreaterimprovementofinsomniacomparedtoplaceboasassessedbythetotalscorefortheInsomniaSeverityIndex.Themeanchange(95%CI)fromBaselinetoDay28,relativetoplacebowas-0.4(-1.7to1.0)for10mg,-2.0(-3.4to-0.6)for20mg,-1.8(-3.2to-0.4)for40mgand-1.6(-3.0to-0.2)for80mg
  • TheShehanDisabilityScalewasonlydecreasedrelativetobaselineandplaceboforthe20mgdoselevel.

5.2.Evaluator’soverallconclusionsondoseselection

Althoughthedata,withtheexceptionofLPS,weresupportiveofefficacyforthe10mgdoselevel,thestrongestsupportwasforthe20mgdoselevel.Fortheobjectiveendpoints(PSG):SEsupportedthe20mgdoselevel,WASOsupportedthe40mg,andLPSsupportedthe20mgdoselevel.Thesubjectiveendpointsweremostsupportiveofthe40mgdoselevel,exceptfortheISIwhichsupportedthe20mgdoselevel.

6.Clinicalefficacy

6.1.Primaryinsomnia

6.1.1.Pivotalefficacystudies

6.1.1.1.StudyP028

6.1.1.1.1.Studydesign,objectives,locationsanddates

StudyP028wasamulticentre,randomised,parallelgroup,PhaseIIIstudytoevaluatesafetyandefficacyofsuvorexantinsubjectswithprimaryinsomnia.Thesubjectswererandomizedintwocohorts:QuestionnaireonlyandPSG+Questionnaire.Thestudywasconductedat91centresin16countriesfromMay2010toNovember2011.Therewasanoptional3monthextensionphase,andarun-outphase.ThestudydesignissummarisedinFigure2.

Figure2.StudyFlowDiagramStudyP028

6.1.1.1.2.Inclusionandexclusioncriteria

Theinclusioncriteriaincluded:

  • Maleorfemaleand≥18yearsofage
  • DSM-IV-TRdiagnosisofPrimaryInsomniabasedontheInvestigator’sjudgmentandthepatient’ssleephistoryasassessedontheSleepDiagnosticInterview/SleepHistory
  • Forsubjects≥65years:MiniMentalStateExamination(MMSE)scoreof≥25
  • Goodphysicalandmentalhealthintheopinionoftheinvestigator
  • Femalesubjectsofchildbearingagearenotpregnantandagreetouseacceptablecontraception
  • Totalsleeptimeof<6.5hoursonatleast3outof7nightseachweek
  • Sleeplatencyof≥30minutesonatleast3outof7nightseachweek
  • ≥1hourofwakefulnessaftersleeponsetonatleast3outof7nights
  • Forsubjectschronicallyusingahypnoticoranxiolyticfortreatmentofinsomnia(definedasuseof4times/week),a4-weekwashout(or5t½lives,whicheverisgreater)isrequired
  • 6.5to9hoursnightlyinbedonatleast3outof7nightseachweekduringthe4weeks
  • Regularbedtimeisbetween9pm(21:00)and1am(01:00)
  • Subjectiswillingtorefrainfromnapping
  • Willingtolimitalcoholto2drinksadayandatleast3hoursbeforegoingtobed
  • Willingtolimitcaffeineconsumptionto5standard6-ouncecupsofcaffeinatedbeveragesaday,or600mgcaffeine,andavoidcaffeineafter4pm(16:00)
  • Willingtolimitnicotine.

ForthosesubjectsinthePSGcohort,theadditionalinclusioncriteriawere:

  • WillingtostayovernightatasleeplaboratoryforPSGtestingvisits
  • Willingtostayinbedforatleast8hourseachnightwhileatthesleeplaboratory
  • WillingtorefrainfromdrinkingalcoholonallPSGvisitdays,andatleast24hourspriortoaPSGvisit
  • Willingtoavoidcaffeineafter1pm(13:00)onPSGvisitdays
  • Atbaseline:LPS20minutesonbothScreeningandBaselinePSGnightsandameanWASOof≥60minutesonthecombinedScreeningandBaselinePSGnights,whereneithernightcanbe≤45minutes.

TheexclusioncriteriawerethesameasforStudyP006.

6.1.1.1.3.Studytreatments

Thestudytreatmentswere:

1.Suvorexanthighdose:40mgforsubjects<65yearsand30mgforsubjects≥65years

2.Suvorexantlowdose:20mgforsubjects<65yearsand15mgforsubjects≥65years

3.Placebo

6.1.1.1.4.Efficacyvariablesandoutcomes

Theprimaryefficacyoutcomemeasureswere:

  • Sleepmaintenance:

–Suvorexanthighdose:ChangefrombaselineinsTSTandsWASO[13]onthedailye-diaryatMonth1andMonth3

–Suvorexanthighdose:Changefrombaselineinwakefulnessafterpersistentsleeponset(WASO)byPSGatMonth1andMonth3.

  • SleepOnset:

–Suvorexanthighdose:Changefrombaselineinmeansubjectivetimetosleeponset(sTSOm)bydailye-diaryatMonth1andMonth3

–Suvorexanthighdose:Changefrombaselineinlatencytoonsetofpersistentsleep(LPS)byPSGatMonth1andMonth3.

Thesecondaryefficacyoutcomemeasureswereevaluatedforbothhighdoseandlowdose:

  • Sleepmaintenance:

–Changefrombaselineinmeansubjectivetotalsleeptime(sTSTm)onthedailye-diaryatWeek1

–Changefrombaselineinwakefulnessafterpersistentsleeponset(WASO)byPSGatNight1

  • Sleeponset:

–Changefrombaselineinmeansubjectivetimetosleeponset(sTSOm)bydailye-diaryatWeek1

–Changefrombaselineinlatencytoonsetofpersistentsleep(LPS)byPSGatNight1.

Theexploratoryoutcomemeasureswere[14]:

  • Meansubjectivenumberofawakenings(sNAWm)
  • Meansubjectivesleepquality(sQUALm)
  • Meansubjectiverefresheduponawakening(sREFRESHEDm)
  • Responderanalysisendpoints:

–Percentageofpatientsachieving≥6pointimprovementfrombaselineinISItotalscore

–PercentageofpatientsrespondingtotreatmentbaseduponthecumulativefrequenciesofpercentchangefrombaselineinsTSTmonthedailysleepdiary

–PercentageofpatientsrespondingtotreatmentbaseduponthecumulativefrequenciesofpercentchangefrombaselineinsWASOmonthedailysleepdiary

–PercentageofpatientsrespondingtotreatmentbaseduponthecumulativefrequenciesofpercentchangefrombaselineinsTSOmonthedailysleepdiary

  • NREMstage1duration(S1)(minutes)fromLights-OfftoLights-On
  • NREMstage1percent(PS1):definedasS1dividedbyTST
  • NREMstage2duration(S2)(minutes)fromLights-OfftoLights-On
  • NREMstage2percent(PS2):definedasS2dividedbyTST
  • NREMstage3duration(SWS)(minutes)fromLights-OfftoLights-On
  • NREMstage3percent(PSWS):definedasS3/4dividedbyTST
  • REMduration(REM)(minutes):durationofstageRfromLights-OfftoLights-On
  • REMpercent(PREM):definedasREMdividedbyTST
  • OtherPSGsleepparameters:

–Totalsleeptime(TST)(minutes)

–Numberofawakenings(NAWPS2E)

–Rateofawakenings(RNAWPS2E):100*NAWPS2E/TST.

–Sleeponsetlatency(SOL1)(minutes):durationoftimemeasuredfromlightsofftothefirstepochof3consecutivestageS1oranyepochofstageS2,SWS,orstageR

–Non-REMepochstoREM(LREM2):numberofnon-REMsleepepochsfromlightsofftothefirstepochofREMsleep

–LatencytoREM(LREM3):Durationoftimemeasuredfromonsetofsleep(SOL1)tothefirstepochofStageR

–NumberofArousals(NOA):Numberoftimes–beginningfromlightsofftolightson–thatthepatientarousesfromStageS2,SWS,orstageRasevidencedbyashifttoStageS1ortoStagewakewithadurationoflessthan2epochs

–RateofArousals(RNOA):100*NOA/TST

–WakefulnessAfterpersistentSleepOnset(WASO)byhour

–Durationofwakefulness(minutes)afteronsetofpersistentsleep

–WakefulnessAfterpersistentSleepOnsetbythirdsofnight(WASO1T1,WASO1T2,WASO1T3)

  • InsomniaSeverityIndex
  • ClinicalGlobalImpressions–SeverityofIllness(CGI-S)
  • PatientGlobalImpressions–SeverityofIllness(PGI-S)
  • ClinicalGlobalImpressions–Improvement(CGI-I)
  • PatientGlobalImpressions–Improvement(PGI-I).

Thesafetyoutcomemeasureswere[15]:

  • Laboratoryevaluations(hematology,chemistry,urinalysis)
  • Urinedrugscreen
  • Alcoholbreathtest(PQ-cohortonly)
  • Physicalexamination
  • Electrocardiogram(ECG)
  • Vitalsigns
  • TyrerWithdrawalSymptomQuestionnaireviatheeveninge-diaryquestionnaire
  • DigitSymbolSubstitutionTest(PQ-cohortonly)
  • ColumbiaSuicideSeverityRatingScale
  • MotorVehicleAccidentsandViolations.

ForthePSGcohort,polysomnographywasperformedatscreening,atbaseline,onNight1,atendofMonth1,atendofMonth3andatrun-out.

6.1.1.1.5.Randomisationandblindingmethods

RandomisationwasperformedcentrallybyIVRS,withstratificationbystratifiedbycohortandbyagegroup(<65years,≥65years).Subjectswererandomised3:2:3tohighdose,lowdoseorplacebo.Attheendofthetreatmentphase(s)thesuvorexantsubjectswerere-randomisedtoeitherthesamedoseofsuvorexantorplacebo.[16]Thestudywasdouble-blindwithin-houseblindingthroughuseofmatching-imageplacebotabletsofsuvorexant.Itwouldhavebeenpossibleforthesubjectstodiscriminatebetweenhighdoseandlowdosegroups tabletsbutnotfortheirrespectiveplacebos.

6.1.1.1.6.Analysispopulations

TheFASconsistedofallrandomizedpatientswhoreceivedatleastonedoseofstudymedicationandhadanypost-randomizationefficacyassessmentdata.TheFAS-PSGpopulationconsistedofallrandomizedpatientswhohadatleastonepost-randomizationPSGobservationsubsequenttoadministrationofatleastonedoseofstudytreatment;andBaselinedataforthoseanalysesthatrequirebaselinedata.Thee-diaryFASpopulationconsistedofallrandomizedpatientswhohadatleastonepost-randomizatione-diaryobservationsubsequenttoadministrationofatleastonedoseofstudytreatment;andBaselinedataforthoseanalysesthatrequirebaselinedata.Thesafetypopulationwasallsubjectsastreated.

6.1.1.1.7.Samplesize

ThesamplesizecalculationwasbasedontheeffectsizesfromStudyP006.Thesamplesizecalculationassumedadropoutrateof1%atNight1,5%atWeek1,10%atmonth1and20%atMonth3.Theestimatedsamplesizewas360subjectsinthehighdoseandplacebogroups,and240inthelowdosegroup,with75%subjectsinthePSGstrataand25%inthequestionnairealonestrata.

6.1.1.1.8.Statisticalmethods

Hypothesistestswereperformedusingalongitudinaldataanalysismodel.MultiplicitywasaddressedbyusingaBonferroniapproach,withineachindication,andafixedsequentialtestingprocedurewasusedtomovefromthefirstsetofprimaryhypotheses(Month1)tothenextsetofprimaryhypotheses(Month3).

6.1.1.1.9.Participantflow

Atotalof2878subjectswerescreenedand1022randomisedtotreatment:254tolowdose,383tohighdose,and385toplacebo.Ofthesesubjects230(90.6%)lowdose,345(90.1%)highdoseand341(88.6%)placebocompletedtreatment.Therewere423subjectsthatproceededintotheextensionphase:172inthehighdosegroup,100inthelowdoseand151intheplacebo.Ofthesesubjects377completedandcontinuedintotherun-outphase.Atotalof862subjectsenteredtherunoutphase,andonlyonesubjectfromeachtreatmentgroupdiscontinued.

Therewere775(75.8%)subjectsrandomizedto[17]thePSGcohort:291tohighdose,193tolowdoseand291toplacebo.Onesubjectintheplacebogroupdidnotreceivetreatment,andtherewere774subjectsintheFAS.

6.1.1.1.10.Majorprotocolviolations/deviations

Therewere114subjectsidentifiedasprotocolviolators.

6.1.1.1.11.Baselinedata

Therewere637(62.4%)females,384(37.6%)malesandtheagerangewas18to87years.Therewere429(42.0%)subjectsaged≥65years.Thetreatmentgroupsweresimilarindemographicandphysicalcharacteristicsatbaseline.Theefficacymeasuresatbaselineweresimilarforthethreetreatmentgroups.Therewere301(78.6%)subjectsinthehighdosegroup,202(79.5%)inthelowdoseand300(78.1%)intheplacebowithahistoryofpriormedicalconditions.Priormedicationhistorywassimilarforthethreetreatmentgroups.Concomitantmedicationsweresimilarforthethreegroupsexceptforahigherusageofsexhormonesandmodulatorsofthegenitalsysteminthelowdosegroup.

6.1.1.1.12.Resultsfortheprimaryefficacyoutcome

SleepmaintenancewasimprovedbyhighdosesuvorexantincomparisonwithplacebothroughtoMonth3(Figure3).AtMonth3,theimprovementinsTST,mean(95%CI)relativetoplacebo,was19.7(11.9to27.6)minutes,p<0.00001,sWASOwas-6.9(-11.9to-2.0)minutes,p=0.00565;andWASOwas-22.0(-29.6to-14.4)[18]minutes,p<0.0001.

Figure3.PointEstimatesand95%ConfidenceIntervalsforSleepMaintenanceEfficacyEndpointsMK-4305HighDose(HD)versusPlacebo(LDA/FullAnalysisSet/Data-as-Observed)

SleeponsetwasimprovedbyhighdosesuvorexantincomparisonwithplacebothroughtoMonth3.AtMonth3,theimprovementinsTSOwas-8.4(-12.8to-4.0)minutes,p=0.00019;andinLPSwas-9.4(-14.6to-4.3),p=0.00037.

Figure4.PointEstimatesand95%ConfidenceIntervalsforSleepOnsetEfficacyEndpointsMK-4305HighDose(HD)versusPlacebo(LDA/FullAnalysisSet/Data-as-Observed)

Thesubgroupanalysisshowednodifferenceineffectbyagegroup(Figures5and6).Inthehighdosegroupincomparisonwithplacebo,forthe<65yearsagegroup,atMonth3themean(95%CI)improvementinsTSTwas21.0(10.7to31.3)minutes,sWASOwas-8.0(-14.4to-1.5)minutes,WASOwas-27.5(-37.4to-17.6)minutes,sTSOwas-7.8(-13.5to-2.0)minutes,andLPSwas-7.1(-13.9to-0.2)minutes.Forthe≥65yearsagegroup,atMonth3themean(95%CI)improvementinsTSTwas18.1(6.0to30.1)minutes,sWASOwas-5.6(-13.1to2.0),WASOwas-16.9(-28.3to-5.4),sTSOwas-9.3(-16.1to-2.5)minutes,andLPSwas-12.4(-20.3to-4.4)minutes.Therewerenosubgroupeffectsforgenderorbaselineseverity.TherewasgreaterefficacyforsTSTforWhitesthannon-Whites:25.9(16.2to35.7)minutescomparedwith8.3(-4.8to21.3)minutesfornon-Whites;forsWASO-9.9(-16.0to-3.7)and-1.5(-9.7to6.7)respectively.IntheAsian/EasternEuropean/AfricaregiontherewasactuallyadeteriorationinsTSTwithhighdosesuvorexant:-13.5(-54.4to27.5)minutes;andinsWASO9.5(-16.0to35.0)minutes.HoweverforWASOtheimprovementwassimilarforWhitesandnon-Whites:-19.3(-27.4to-11.3)minutescomparedwith-41.4(-60.7to-22.2)minutesfornon-Whites;andtherewasnoregionalvariation.ForLPS,theimprovementwasgreaterforWhitesandnon-Whites:-11.1(-16.6to-5.5)minutescomparedwith-3.9(-17.2to9.5)minutesfornon-Whites.

Figure5.PointEstimatesand95%ConfidenceIntervalsforChangefromBaselineforMaintenanceEndpointsMK-4305HighDose(HD)versusPlaceboatMonth3bySubgroupFactors(LDA/FullAnalysisSetE-Diary/Data-as-Observed)

Figure6.PointEstimatesand95%ConfidenceIntervalsforChangefromBaselineforOnsetEndpointsMK-4305HighDose(HD)versusPlaceboatMonth3bySubgroupFactors(LDA/FullAnalysisSetE-Diary/Data-as-Observed)

Foralltheprimaryefficacyoutcomemeasuresthereweresubstantialimprovementsintheplacebogroupovertime(Figures7-11).Therewaslittleapparentdoseeffectbetweenthehighdoseandlowdosegroups,particularlyforthePSGendpoints.TherewasalsolessapparenteffectforsuvorexantbysubjectivemeasurescomparedtoPSG.

Figure7.AdjustedMeansand95%ConfidenceIntervalsforChangefromBaselineinMeanSubjectiveTotalSleepTime(sTSTm;minutes)byTimePointDuringtheTreatmentPhase(FullAnalysisSetE-Diary/Data-as-Observed)

Figure8.AdjustedMeansand95%ConfidenceIntervalsforChangefromBaselineinMeanSubjectiveWakeTimeAfterSleepOnset(sWASOm;minutes)byTimePointDuringtheTreatmentPhase(FullAnalysisSetE-Diary/Data-as-Observed)

Figure9.AdjustedMeansand95%ConfidenceIntervalsforChangefromBaselineinWakefulnessAfterPersistentSleepOnset(WASO;minutes)byTimePoint(FullAnalysisSetPSG/Data-as-Observed)

Figure10.AdjustedMeansand95%ConfidenceIntervalsforChangefromBaselineinMeanSubjectiveTimetoSleepOnset(sTSOm;minutes)byTimePointDuringtheTreatmentPhase(FullAnalysisSetE-Diary/Data-as-Observed)

Figure11.AdjustedMeansand95%ConfidenceIntervalsforChangefromBaselineinLatencytoOnsetofPersistentSleep(LPS;minutes)byTimePoint(FullAnalysisSetPSG/Data-as-Observed)

6.1.1.1.13.Resultsforotherefficacyoutcomes

SleepmaintenancewasinitiallyimprovedbylowdosesuvorexantincomparisonwithplacebobutthebenefitwasnotsustainedthroughtoMonth3.AtMonth3,theimprovementinsTST,relativetoplacebo,was10.7(1.9to19.5)minutes,p=0.01711;sWASOwas-2.4(-7.9to3.1)minutes,p=0.38819;andWASOwas-16.3(-24.7to-7.8)[19].

SleeponsetwasnotimprovedtothesameextentbylowdosesuvorexantincomparisonwithplacebothroughtoMonth3.TheimprovementinsTSOwasapproximately5minutesandmarginallystatisticallysignificant:-5.2(-10.2to-0.3)minutes,p=0.03771.TheimprovementinLPSwas-7.3(-13.0to-1.5),p=0.01347[20].

Fortheremainingsecondaryefficacyoutcomemeasures:

  • TherewerenosignificantdifferencesinsNAWmatanytimepoint
  • AtMonth3,sQUALmwassignificantlyimprovedinthehighdosegroupcomparedwithplacebo:mean(95%CI)0.08(0.01to0.15),p=0.02434
  • AlthoughtherewereimprovementsinsREFRESHEDatMonth1,thesewerenotsustainedtoMonth3
  • AtMonth3,ISIwassignificantlyimprovedcomparedwithplacebo:mean(95%CI)-1.4(-2.1to-0.7),p=0.00013forhighdose,-1.2(-1.9to-0.4),p=0.00371forlowdose
  • AtMonth3,CGI-Swassignificantlyimprovedcomparedwithplacebo:mean(95%CI)-0.3(-0.5to-0.2),p=0.0001forhighdose,-0.3(-0.5to-0.1),p=0.00159forlowdose
  • AtMonth3,CGI-Iwassignificantlyimprovedcomparedwithplacebo:mean(95%CI)-0.4(-0.6to-0.3),p<0.00001forhighdose;-0.4(-0.5to-0.2),p=0.00002forlowdose
  • AtMonth3,PGI-Swassignificantlyimprovedcomparedwithplacebo:mean(95%CI)-0.4(-0.6to-0.3),p<0.00001forhighdose;-0.3(-0.5to-0.1),p=0.00036forlowdose
  • AtMonth3,PGI-Iwassignificantlyimprovedcomparedwithplacebo:mean(95%CI)-0.5(-0.6to-0.3),p<0.00001forhighdose;-0.4(-0.5to-0.2),p=0.00004forlowdose
  • TheresponderanalysisforISIreportedaclinicallymeaningfulresponseatMonth3in168(51.1%)subjectsinthehighdosegroup,115(52.0%)inthelowdoseand129(39.3%)intheplacebo.ForsTST,therewasa≥15%improvementfrombaselinein190(54.6%)subjectsinthehighdosegroup,102(44.7%)inthelowdoseand143(42.2%)intheplacebo.ForsWASO,therewasa≥15%improvementfrombaselinein266(76.7%)subjectsinthehighdosegroup,172(75.4%)inthelowdoseand238(70.2%)intheplacebo.ForsTSO,therewasa≥15%improvementfrombaselinein262(75.3%)subjectsinthehighdosegroup,152(66.7%)inthelowdoseand231(68.1%)intheplacebo
  • AtMonth3,relativetoplacebo,therewasanincreaseinNREMStage1durationof3.8(1.2to6.4)minutesinthehighdosegroupand3.1(0.2to6.0)minutesinthelowdose;NREMStage2durationof13.3(6.6to20.0)minutesinthehighdosegroupand13.2(5.8to20.6)minutesinthelowdose;REMdurationof12.7(8.5to17.0)minutesinthehighdosegroupand9.2(4.4to13.9)minutesinthelowdose.TherewasnosignificantchangeinSlowWaveSleep(SWS).

Intheextensionphase,theimprovementinsTSTwasnotsustainedthroughtoMonthsix,andwasactuallybetterintheplacebogroup:4.3(-9.2to17.9)minutesforhighdoseand-8.7(-24.5to7.0)forlowdose.TherewasnosignificantimprovementinsWASO:5.7(-2.2to13.6)minutesforhighdoseand6.9(-2.4to16.1)minutesforlowdose.AtMonth6,themean(95%CI)changeinsTSOrelativetoplacebowas-3.7(-11.2to3.8)minutesforhighdoseand0.6(-8.1to9.3)minutesforlowdose.

6.1.1.2.StudyP029

6.1.1.2.1.Studydesign,objectives,locationsanddates

StudyP029wassimilarindesigntoStudyP028.Itwasamulticentre,randomised,parallelgroup,PhaseIIIstudytoevaluatesafetyandefficacyofsuvorexantinsubjectswithprimaryinsomnia.Thesubjectswerealsorandomizedintwocohorts:QuestionnaireonlyandPSG+Qestionnaire.Thestudywasconductedat114centresin19countriesfromJuly2010toOctober2011.Althoughtherewasarun-outphase,unlikeStudyP028therewasnooptional3monthextensionphase.

6.1.1.2.2.Inclusionandexclusioncriteria

TheinclusioncriteriawerethesameasforStudyP028.

TheexclusioncriteriawerethesameasforStudyP006.

6.1.1.2.3.Studytreatments

ThestudytreatmentswerethesameasforStudyP028:

1.Suvorexanthighdose:40mgforsubjects<65yearsand30mgforsubjects≥65years

2.Suvorexantlowdose:20mgforsubjects<65yearsand15mgforsubjects≥65years

3.Placebo

6.1.1.2.4.Efficacyvariablesandoutcomes

TheefficacyandsafetyoutcomemeasuresweresimilartothoseforStudyP028:

Theprimaryefficacyoutcomemeasureswere:

  • Sleepmaintenance:

–Suvorexanthighdose:ChangefrombaselineinsTSTonthedailye-diaryatMonth1andMonth3

–Suvorexanthighdose:ChangefrombaselineinWASObyPSGatMonth1andMonth3

  • SleepOnset:

–Suvorexanthighdose:ChangefrombaselineinmeansTSObydailye-diaryatMonth1andMonth3

–Suvorexanthighdose:ChangefrombaselineinLPSbyPSGatMonth1andMonth3.

Thesecondaryefficacyoutcomemeasureswereevaluatedforbothhighdoseandlowdose[21]:

  • Sleepmaintenance:

–ChangefrombaselineinmeansubjectivetotalsleeptimesTSTmandsWASO[22]onthedailye-diaryatWeek1

–ChangefrombaselineinWASObyPSGatNight1.

  • Sleeponset:

–ChangefrombaselineinmeansTSObydailye-diaryatWeek1

–ChangefrombaselineinLPSbyPSGatNight1.

Theexploratoryoutcomemeasureswere:

  • Meansubjectivenumberofawakenings(sNAWm)
  • Meansubjectivesleepquality(sQUALm)
  • Meansubjectiverefresheduponawakening(sREFRESHEDm)
  • Responderanalysisendpoints:

–Percentageofpatientsachieving≥6pointimprovementfrombaselineinISItotalscore

–PercentageofpatientsrespondingtotreatmentbaseduponthecumulativefrequenciesofpercentchangefrombaselineinsTSTmonthedailysleepdiary

–PercentageofpatientsrespondingtotreatmentbaseduponthecumulativefrequenciesofpercentchangefrombaselineinsWASOmonthedailysleepdiary

–PercentageofpatientsrespondingtotreatmentbaseduponthecumulativefrequenciesofpercentchangefrombaselineinsTSOmonthedailysleepdiary

  • NREMstage1duration(S1)(minutes)fromLights-OfftoLights-On
  • NREMstage1percent(PS1):definedasS1dividedbyTST
  • NREMstage2duration(S2)(minutes)fromLights-OfftoLights-On
  • NREMstage2percent(PS2):definedasS2dividedbyTST
  • NREMstage3duration(SWS)(minutes)fromLights-OfftoLights-On
  • NREMstage3percent(PSWS):definedasS3/4dividedbyTST
  • REMduration(REM)(minutes):durationofstageRfromLights-OfftoLights-On
  • REMpercent(PREM):definedasREMdividedbyTST.
  • OtherPSGsleepparameters:

–Totalsleeptime(TST)(minutes)

–Numberofawakenings(NAWPS2E)

–Rateofawakenings(RNAWPS2E):100*NAWPS2E/TST.

–Sleeponsetlatency(SOL1)(minutes):durationoftimemeasuredfromlightsofftothefirstepochof3consecutivestageS1oranyepochofstageS2,SWS,orstageR

–Non-REMepochstoREM(LREM2):numberofnon-REMsleepepochsfromlightsofftothefirstepochofREMsleep

–LatencytoREM(LREM3):Durationoftimemeasuredfromonsetofsleep(SOL1)tothefirstepochofStageR

–NumberofArousals(NOA):Numberoftimes–beginningfromlightsofftolightson–thatthepatientarousesfromStageS2,SWS,orstageRasevidencedbyashifttoStageS1ortoStagewakewithadurationoflessthan2epochs

–RateofArousals(RNOA):100*NOA/TST

–WakefulnessAfterpersistentSleepOnset(WASO)byhour

–Durationofwakefulness(minutes)afteronsetofpersistentsleep

–WakefulnessAfterpersistentSleepOnsetbythirdsofnight(WASO1T1,WASO1T2,WASO1T3)

  • InsomniaSeverityIndex
  • ClinicalGlobalImpressions–SeverityofIllness(CGI-S)
  • PatientGlobalImpressions–SeverityofIllness(PGI-S)
  • ClinicalGlobalImpressions–Improvement(CGI-I)
  • PatientGlobalImpressions–Improvement(PGI-I).

Thesafetyoutcomemeasureswere[23]:

  • Laboratoryevaluations(haematology,chemistry,urinalysis)
  • Urinedrugscreen
  • Alcoholbreathtest(PQ-cohortonly)
  • Physicalexamination
  • Electrocardiogram(ECG)
  • Vitalsigns
  • TyrerWithdrawalSymptomQuestionnaireviatheeveninge-diaryquestionnaire
  • DigitSymbolSubstitutionTest(PQ-cohortonly)
  • ColumbiaSuicideSeverityRatingScale
  • MotorVehicleAccidentsandViolations.

ForthePSGcohort,polysomnographywasperformedatscreening,atbaseline,onNight1,atendofMonth1,atendofMonth3andatrun-out.

6.1.1.2.5.Randomisationandblindingmethods

RandomisationwasperformedcentrallybyIVRS,withstratificationbystratifiedbycohortandbyagegroup(<65years,≥65years).Questionnairesubjectswererandomised1:1:1;andPSGsubjectswererandomised2:1:2tohighdose,lowdoseorplacebo.Attheendofthetreatmentphase(s)thesuvorexantsubjectswerere-randomisedtoeitherthesamedoseofsuvorexantorplaceboina1:1ratio[24].Thestudywasdouble-blindwithin-houseblindingthroughuseofmatching-imageplacebotabletsofsuvorexant.Itwouldhavebeenpossibleforthesubjectstodiscriminatebetweenhighdoseandlowdosebutnotfortheirrespectiveplacebos.

6.1.1.2.6.Analysispopulations

TheanalysispopulationswerethesameasforStudyP028.

6.1.1.2.7.Samplesize

ThesamplesizecalculationwassimilartothatforStudyP028andwasbasedontheeffectsizesfromStudyP006.Thesamplesizecalculationassumedadropoutrateof1%atNight1,5%atWeek1,10%atmonth1and20%atMonth3.Theestimatedsamplesizewas360subjectsinthehighdoseandplacebogroups,and240inthelowdosegroup,with71%subjectsinthePSGstrataand29%intheQuestionnairealonestrata.

6.1.1.2.8.Statisticalmethods

ThehypothesistestswereperformedinthesamemannerasforStudyP028.

6.1.1.2.9.Participantflow

Atotalof2876subjectswerescreenedand1019wererandomisedtotreatment:240tolowdose,392tohighdose,and387toplacebo.Ofthesesubjects205(85.4%)lowdose,346(88.3%)highdoseand330(85.3%)placebocompletedtreatment.Atotalof876subjectsenteredtherunoutphase,andsix(0.7%)subjectsdiscontinued.

Therewere751(73.7%)subjectsrandomizedto[25]thePSGcohort:302tohighdose,150tolowdoseand299toplacebo.Fivesubjectsdidnotreceivetreatment:threeinthehighdosegroupandtwointheplacebo.Afurther21subjectswereexcludedfromtheFAS,leaving725(71.1%)subjects:fivefromthehighdosegroup,fivefromthelowdoseandelevenfromtheplacebo.

6.1.1.2.10.Majorprotocolviolations/deviations

Therewere116subjectsidentifiedasprotocolviolators.

6.1.1.2.11.Baselinedata

Therewere671(66.5%)females,338(33.5%)malesandtheagerangewas18to86years.Therewere410(40.6%)subjectsaged≥65years.Thetreatmentgroupsweresimilarindemographicandphysicalcharacteristicsatbaseline.Theefficacymeasuresatbaselineweresimilarforthethreetreatmentgroups.Therewere309(79.8%)subjectsinthehighdosegroup,177(74.1%)inthelowdoseand305(79.6%)intheplacebowithahistoryofpriormedicalconditions.Priormedicationhistorywassimilarforthethreetreatmentgroups.Concomitantmedicationsweresimilarforthethreegroupsexceptforahigherusageofsexhormonesandmodulatorsofthegenitalsysteminthehighdosegroup.

6.1.1.2.12.Resultsfortheprimaryefficacyoutcome

SleepmaintenancewasimprovedbyhighdosesuvorexantincomparisonwithplacebothroughtoMonth3(Figure12).AtMonth3,theimprovementinsTST,mean(95%CI)relativetoplacebo,was25.1(16.0to34.2)minutes,p<0.00001,sWASOwas-8.9(-14.4to-3.4)minutes,p=0.00167);andWASOwas-29.4(-36.7to-22.1)minutes,p<0.00001.

SleeponsetwasimprovedbyhighdosesuvorexantincomparisonwithplacebothroughtoMonth3(Figure13).AtMonth3,theimprovementinsTSOwas-13.2(-19.4to-7.0)minutes,p=0.00003;andinLPSwas-3.6(-10.1to2.8),p=0.26510.

Figure12.PointEstimatesand95%ConfidenceIntervalsforSleepMaintenanceEfficacyEndpointsMK-4305HighDose(HD)versusPlacebo(LDA/FullAnalysisSet/Data-as-Observed)

Figure13.PointEstimatesand95%ConfidenceIntervalsforSleepOnsetEfficacyEndpointsMK-4305HighDose(HD)versusPlacebo(LDA/FullAnalysisSet/Data-as-Observed)

Thesubgroupanalysisshowednodifferenceineffectbyagegroup.Inthehighdosegroupincomparisonwithplacebo,forthe<65yearsagegroup,atMonth3themean(95%CI)improvementinsTSTwas25.7(13.9to37.6)minutes,sWASOwas-5.2(-12.4to2.1)minutes,WASOwas-27.0(-36.7to-17.3)minutes,sTSOwas-15.7(-23.7to-7.6)minutes,andLPSwas-3.8(-12.3to4.7)minutes.Forthe≥65yearsagegroup,atMonth3themean(95%CI)improvementinsTSTwas24.1(10.0to38.3)minutes,sWASOwas-14.1(-22.7to-5.6),WASOwas-32.5(-43.7to-21.4),sTSOwas-9.8(-19.4to-0.1)minutes,andLPSwas-3.5(-13.3to6.3)minutes.Therewerenosubgroupeffectsforgender.TherewasgreatereffectinsubjectswithgreaterseverityatbaselineforWASO,sWASOandsleeponset.

Forallprimaryefficacyoutcomemeasuresthereweresubstantialimprovementsintheplacebogroupovertime(Figures14-18).Therewaslittleapparentdoseeffectbetweenthehighdoseandlowdosegroups,particularlyforthePSGendpoints.TherewasalsolessapparenteffectforsuvorexantbysubjectivemeasurescomparedtoPSG.AlthoughatNight1therewasimprovementinsleeponset,therewasnoapparentbenefitatMonth3.

Figure14.AdjustedMeansand95%ConfidenceIntervalsforChangefromBaselineinMeanSubjectiveTotalSleepTime(sTSTm;minutes)byTimePointDuringtheTreatmentPhase(FullAnalysisSetE-Diary/Data-as-Observed)

Figure15.AdjustedMeansand95%ConfidenceIntervalsforChangefromBaselineinMeanSubjectiveWakeTimeAfterSleepOnset(sWASOm;minutes)byTimePointDuringtheTreatmentPhase(FullAnalysisSetE-Diary/Data-as-Observed)

Figure16.AdjustedMeansand95%ConfidenceIntervalsforChangefromBaselineinWakefulnessAfterPersistentSleepOnset(WASO;minutes)byTimePoint(FullAnalysisSetPSG/Data-as-Observed)

Figure17.AdjustedMeansand95%ConfidenceIntervalsforChangefromBaselineinMeanSubjectiveTimetoSleepOnset(sTSOm;minutes)byTimePointDuringtheTreatmentPhase(FullAnalysisSetE-Diary/Data-as-Observed)

Figure18.AdjustedMeansand95%ConfidenceIntervalsforChangefromBaselineinLatencytoOnsetofPersistentSleep(LPS;minutes)byTimePoint(FullAnalysisSetPSG/Data-as-Observed)

6.1.1.2.13.Resultsforotherefficacyoutcomes

SleepmaintenancewasinitiallyimprovedbylowdosesuvorexantincomparisonwithplacebobutthebenefitwasnotsustainedthroughtoMonth3.AtMonth3,theimprovementinsTST,relativetoplacebo,was22.1(11.5to32.6)minutes,p=0.00004;sWASOwas-7.7(-14.1to-1.3)minutes,p=0.01885;andWASOwas-31.1(-40.1to-22.2).

SleeponsetwasnotimprovedtothesameextentbylowdosesuvorexantincomparisonwithplacebothroughtoMonth3.TheimprovementinsTSOwasapproximately5minutes[26]andmarginallystatisticallysignificant:-7.6(-14.7to-0.4)minutes,p=0.03894.TheimprovementinLPSwas-0.3(-8.3to7.6),p=0.93219.

Fortheremainingsecondaryefficacyoutcomemeasures:

  • TherewerenosignificantdifferencesinsNAWmforsuvorexantincomparisonwithplacebo.
  • sQUALmwassignificantlyimprovedcomparedwithplaceboatalltimepoints:AtMonth3,incomparisonwithplacebo,mean(95%CI)0.1(0.1to0.2),p=0.00030forhighdose;0.1(0.00to0.2),p=0.00520forlowdose.
  • sREFRESHEDwasalsoimprovedincomparisonwithplacebothroughtoMonth3.AtMonth3,incomparisonwithplacebo,mean(95%CI)0.1(0.0to0.3),p=0.00510forhighdose;0.2(0.00to0.3),p=0.00658forlowdose.
  • AtMonth3,ISIwassignificantlyimprovedcomparedwithplacebo:mean(95%CI)-2.3(-3.1to-1.6)p<0.00001forhighdose,and-1.3(-2.2to-0.4)p=0.00380forlowdose.
  • AtMonth3,CGI-Swassignificantlyimprovedcomparedwithplacebo:mean(95%CI)-0.6(-0.8to-0.4)p<000001forhighdose,and-0.3(-0.5to-0.1)p=0.00304forlowdose.
  • AtMonth3,CGI-Iwassignificantlyimprovedcomparedwithplacebo:mean(95%CI)-0.5(-0.7to-0.4)p<000001forhighdose,and-0.4(-0.6to-0.3)p<000001
  • AtMonth3,PGI-Swassignificantlyimprovedcomparedwithplacebo:mean(95%CI)-0.5(-0.6to-0.3)p<000001forhighdose,and-0.3(-0.5to-0.1)p=0.00691forlowdose
  • AtMonth3,PGI-Iwassignificantlyimprovedcomparedwithplacebo:mean(95%CI)-0.5(-0.7to-0.4)p<000001forhighdose,and-0.3(-0.5to-0.1)p=0.00222forlowdose
  • TheresponderanalysisforISIreportedaclinicallymeaningfulresponse(≥6pointimprovement)atMonth3in192(58.7%)subjectsinthehighdosegroup,113(59.5%)inthelowdoseand140(45.2%)intheplacebo.ForsTST,therewasa≥15%improvementfrombaselinein182(54.2%)subjectsinthehighdosegroup,111(56.3%)inthelowdoseand133(41.3%)intheplacebo.ForsWASO,therewasa≥15%improvementfrombaselinein263(78.5%)subjectsinthehighdosegroup,150(76.1%)inthelowdoseand220(68.8%)intheplacebo.ForsTSO,therewasa≥15%improvementfrombaselinein264(77.6%)subjectsinthehighdosegroup,145(73.6%)inthelowdoseand207(63.7%)intheplacebo.
  • AtMonth3,relativetoplacebo,therewasanincreaseinNREMStage1durationof6.0(3.4to8.7)minutesinthehighdosegroupand2.3(-1.0to5.5)minutesinthelowdose;NREMStage2durationof18.5(11.5to25.4)minutesinthehighdosegroupand18.3(9.7to26.8)minutesinthelowdose;REMdurationof11.7(7.7to15.7)minutesinthehighdosegroupand8.3(3.4to13.3)minutesinthelowdose.TherewasnosignificantchangeinSlowWaveSleep(SWS).

6.1.2.Otherefficacystudies

6.1.2.1.StudyP009

StudyP009wasamulticentre,randomized,doubleblind(within-houseblinding),placebocontrolled,parallelgroupofsuvorexantinsubjectswithprimaryinsomnia.Thestudywasconductedat106centresfromDecember2009toAugust2011.

Theinclusioncriteriaincluded:

  • Maleorfemaleand≥18yearsofage
  • DSM-IV-TRdiagnosisofPrimaryInsomniabasedontheInvestigator’sjudgmentandthepatient’ssleephistoryasassessedontheSleepDiagnosticInterview/SleepHistory
  • Patientisabletoread,understandandcompletequestionnairesanddiaries,includingoperationofthee-diary
  • Subjects≥65yearsofagescores≥25ontheMiniMentalStateExamination(MMSE),toruleoutcognitiveimpairment
  • Femaleswhoarenotpregnantandagreetouseacceptablecontraception.

Theexclusioncriteriaincluded:

  • Femalesubjectswhoarepregnantorlactating
  • Patienthasahistoryofhypersensitivityoridiosyncraticreactiontomorethantwochemicalclassesofdrugs
  • Historyorcurrentevidenceofanycondition,therapy,laborECGabnormalityorothercircumstancesthatmightconfoundtheresultsofthestudy,orinterferewiththepatient’sparticipationforthefulldurationofthestudy
  • Recentand/oractivehistoryofaconfoundingneurologicaldisorder,includingbutnotlimitedto:seizuredisorder(otherthansingleepisodesofchildhoodfebrileseizures),stroke,transientischemicattack,multiplesclerosis,cognitiveimpairment,orsignificantheadtraumawithsustainedlossofconsciousnessandresidualimpairmentwithinthelast10years
  • Historywithinthepast6monthspriortotheScreeningVisit1orcurrentevidenceofanunstableorotherwiseclinicallysignificantcardiovasculardisorder,includingbutnotlimitedto:acutecoronarysyndrome;unstableangina;congestiveheartfailure;cardiogenicsyncope;cardiomyopathy;oranysymptomaticarrhythmia
  • ClinicallysignificantECGabnormalitysuchasAVconductiondisturbance(e.g.secondorthirddegreeAVblock),sicksinussyndrome,bradycardia,accessorybypasstract(e.g.,Wolff-Parkinson-White),orcurrentevidenceoflongQTsyndromeorTorsadesdepointe
  • Abnormalscreeninglaboratoryvaluesincluding:ALT,ASTorbilirubin>1.5xULNorserumcreatinine≥2mg/dL
  • Taking,orplanstotake,oneormoreofthefollowingmedications(non-inclusive)withinthewashoutperiods:

–ClinicallyrelevantCYP3A4InhibitorsandInducers:2weeksor5t½lives(whicheverislonger)

–Centrallyactinganticholinergicsorantihistamines:2weeks

–Melatonin:2weeks

–Anticonvulsants:2weeks

–Antipsychotics:2weeks

–Anxiolytics:2weeks

–Benzodiazepines:2weeksor5t½lives(whicheverislonger)

–Hypnotics:2weeksor5t½lives(whicheverislonger)

–AnyCNSdepressants:2weeks

–Over-the-countermedicationsthatcouldaffectsleep(e.g.,kava-kava,valerian,Benadryl[diphenhydramine]St.John’sWort):2weeks

–Stimulants:2weeks

–Dietpills:2weeks

  • Positivescreeningurinedrugscreen(e.g.,positiveforbenzodiazepines,cannabinoids,cocaine,etc.).
  • Anyofthefollowing:

–Alifetimehistoryofbipolardisorder,apsychoticdisorder,orposttraumaticstressdisorder;

–Apsychiatricconditionrequiringtreatmentwithaprohibitedmedication

–Othercurrentpsychiatricconditionthat,intheinvestigator’sopinion,wouldinterferewiththepatient’sabilitytoparticipateinthestudy

–Evidenceofsuicidality

  • Historyofsubstanceabuseordependence
  • IntheopinionoftheInvestigator,difficultysleepingduetotobacco,caffeine,oralcoholuse
  • Historyofmalignancy5yearspriortosigninginformedconsent,exceptforadequatelytreatedbasalcellorsquamouscellskincancerorinsitucervicalcancer
  • Historyoftransmeridiantravel(across3timezonesor3hourtimedifference)withinthepast2weeks
  • Historyofshiftwork(definedaspermanentnightshiftorrotatingday/nightshiftwork)withinthepast2weeksoranticipatesneedtoperformshiftworkduringthestudy
  • Historyordiagnosisof:narcolepsy;cataplexy,CircadianRhythmSleepDisorder;parasomniaincludingnightmaredisorder,sleepterrordisorder,sleepwalkingdisorder,andREMbehaviourdisorder;Sleep-relatedBreathingDisorder(obstructiveorcentralsleepapneasyndrome,centralalveolarhypoventilationsyndrome);PeriodicLimbMovementDisorder;RestlessLegsSyndrome;orPrimaryHypersomia
  • IntheopinionoftheInvestigator,difficultysleepingduetoaconfoundingmedicalcondition.NOTE:MedicalConditionsmayincludechronicpainsyndromes,chronicmigraines,cardiacdisease,nocturia(>3times/night),asthma,gastroesophagealrefluxdisease(GERD),orhotflashes
  • BMI40kg/m2.

Thestudytreatmentswere:

1.Suvorexant40mgforsubjectsaged<65yearsand30mgforsubjectsaged≥65years

2.Placebo

Thetreatmentswereadministeredorallyatbedtime.Subjectstreatedwithsuvorexantwerere-randomisedintheratio1:1tosuvorexantorplaceboduringthe2monthdiscontinuationphase.[27]Treatmentdurationwasfor12months,followedbya2monthdiscontinuationphase.

Thestudywasprimarilyasafetyandtolerabilitystudy,butthefollowingefficacyoutcomemeasureswereobtained:

  • Morninge-diary

–subjectivetotalsleeptime(sTST)

–subjectivetimetosleeponset(sTSO)

  • ClinicalGlobalImpressions-Severity(CGI-S)scale
  • ClinicalGlobalImpressions-Improvement(CGI-I)scale
  • PatientGlobalImpressions-Severity(PGI-S)scale
  • PatientGlobalImpressions-Improvement(PGI-I)scale
  • QuickInventoryofDepressiveSymptomatologySelf-Report(QIDS-SR16)
  • InsomniaSeverityIndex(ISI).

Thesafetyoutcomemeasureswere:laboratoryevaluations,urinedrugscreen,physicalexamination,ECG,vitalsigns,ColumbiaSuicideSeverityRatingScale(C-SSRS),reboundinsomniaandpotentialwithdrawalsymptomswillbeassessedusingthee-diarycontainingthemorningquestionnaireandtheTyrerWithdrawalSymptomQuestionnaire(administeredintheevening)duringtheDouble-BlindRun-outPhase.