IBD&me: Optimizing Selection of Biologic and Small Molecule

Therapies in IBD

Proposal submitted by: Brennan M.R. Spiegel, MD, MSHS Gil Y. Melmed, MD, MS Christopher V. Almario, MD, MSHPM Cedars-Sinai Center for Outcomes Research and Education F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Cedars-Sinai Medical Center Los Angeles, CA October 12, 2017

COVERPAGETITLE:IBD&me:OptimizingSelectionofBiologicandSmallMoleculeTherapiesinIBDMAINCOLLABORATORS:BrennanM.R.Spiegel,MD,MSHSGilY.Melmed,MD,MSChristopherV.Almario,MD,MSHPMCedars-SinaiCenterforOutcomesResearchandEducationF.WidjajaFoundationInflammatoryBowelandImmunobiologyResearchInstituteCedars-SinaiMedicalCenterLosAngeles,CAABSTRACT:Biologicsremainthemainstayoftreatmentforthosewithmoderate-to-severeinflammatoryboweldisease(IBD).However,drugdevelopmentinIBDisdynamic;manyadditionaltherapieswithnovelmechanismsofactionareinthepipeline.Forexample,anoveloralJanuskinaseinhibitorcalledtofacitinibwasrecentlyshowntobeefficaciousinulcerativecolitis.

Currently,therearemultiplefirst-lineIBDtherapies,anditcanbedifficultforpatientstonavigatethearrayoftreatmentoptions.Moreover,thedecision-makingprocesswillbecomeevenmorecomplexasadditionaleffectivetherapiesaredeveloped,tested,andapprovedforuseinclinicalpractice.Tofacilitateshareddecision-making(SDM)focusedonIBDtreatments,ourresearchgroupcreatedIBD&me(ibdandme.org)–afree,online,unbrandedresourcethatoffersanimmersiveandinteractivedecisionaidthatsupportspatientsinselectingatreatmentthatiscongruentwiththeirpreferencesandbeliefs.IBD&mealsousesconjointanalysistogenerateauniquepersonalizedreportdesignedtohelpdoctorsefficientlyandeffectivelyunderstandtheirpatients’treatmentpreferences.

Aspartofthisstudy,weaimtoassesstheimpactofIBD&meonpatientperceptionsofSDMandsatisfactionwhencomparedtoastandardizededucationarminamulticenterrandomizedcontrolledtrialinpartnershipwithIBDQorus.Moreover,inaseparateaim,wewillassesshowIBDpatientsnavigateandmakedecisionswhenselectingamongcurrentandemergingIBDtherapies(i.e.,smallmolecules)usingconjointanalysis;theseresultswillinformfutureupdatestotheIBD&medecisiontoolasnewtherapiesareapprovedforuseinclinicalpractice.

TABLEOFCONTENTSMainProposal....................................................................................................................... 4

References............................................................................................................................ 18

OrganizationalDetail............................................................................................................ 22

LeadershipandStaffCapacity.............................................................................................. 24

DetailedBudget.................................................................................................................... 25

StaffBiosketches.................................................................................................................. 28

LettersofCommitment........................................................................................................ 41

Appendix.............................................................................................................................. 44

MAINPROPOSAL

OVERALLGOALS&OBJECTIVES

Inflammatoryboweldisease(IBD)isachronicconditionthatleadstosignificantmorbidityanddecreasedhealth-relatedqualityoflife(HRQOL).1,2Althoughtherearemanytreatmentoptionsavailableforpatientswithulcerativecolitis(UC)andCrohn’sdisease(CD),biologictherapiesremainthemainstayoftreatmentforthosewithmoderate-to-severeIBD.3,4However,drugdevelopmentinIBDisdynamic;manyadditionaltherapieswithnovelmechanismsofactionareinthepipeline.Forexample,tofacitinib,anoralsmallmoleculeJanuskinaseinhibitor,wasshowntobeeffectiveininducingandmaintainingremissioninUCvs.placebo.5

WhiletheavailablebiologicsandsmallmoleculetherapiesareeffectiveintreatingIBD,therehavebeenfewmajorhead-to-headtrialsofthesecommonly-prescribedtherapeutics.Becauseofthelackofcomparativeeffectivenessdata,IBDcarepathwaysendorseseveralfirst-linetherapies.6,7Asaresult,itisoftendifficultforpatientstonavigatethearrayoftreatmentoptionswiththeirphysicianandtochooseatherapythatalignswiththeiruniquetreatmentpreferences.Moreover,thedecision-makingprocesswillbecomeevenmorecomplexasadditionaleffectivetherapiesaredeveloped,tested,andapprovedforuseinclinicalpractice.

Becausetherearemultiplefirst-lineIBDtherapies,itisvitaltoelicitpatientpreferencesbyengaginginshareddecision-making(SDM),aprocessinwhichcliniciansandpatientsmakehealthcarechoicestogetherbybalancingrisksandexpectedoutcomeswiththepatient’spreferencesandvalues.8-11InIBD,employingSDMhaspotentialtostrengthenthepatient-providerdialogueinawaythatfacilitatesalignmentbetweentreatmentdecisionsandpatientpreferences.Wheneffectivelyemployed,SDMcanimprovemedicationadherence,enhanceHRQOLandclinicaloutcomes,andlowerhealthcarecostscomparedtoalesspersonalizedapproachofassigningtherapy.12-15

TofacilitateSDMfocusedonIBDtreatments,ourresearchgroupcreatedIBD&me(ibdandme.org)–afree,online,unbrandedresourcethatoffersanimmersiveandinteractivedecisionaidthatsupportspatientsinselectingatreatmentthatiscongruentwiththeirpreferencesandbeliefs.IBD&meenablespatientstoexplorebiologicrisksandbenefits,andthenguidesthemthroughasurveycalledtheIBD&meDecisionTree.Oncepatientscompletethesurvey,whichisbasedonanunderlyingconjointanalysissoftwareprogram,thewebsitegeneratesauniquepersonalizedreportdesignedtohelpdoctorsefficientlyandeffectivelyunderstandtheirpatients’treatmentpreferences.BasedontheSDMliterature,wehypothesizethatuseofIBD&meanditstailoredreportscanfacilitateamoreinformeddiscussioninclinicbetweenpatientsandclinicians,improveSDM,andbetteralignmedicalcarewithpatients’uniquepreferencesandvalues.16,17Ofnote,IBD&mewillbefeaturedatacontinuingmedicaleducationsymposiumattheCrohn’s&ColitisCongressinJanuary2018andisinrevisionfortheupcoming“PuttingPatientsFirst”specialissueoftheAmericanJournalofGastroenterology.

WhileSDMtoolshavepotentialtoenhancepatient-centeredcareandimprovethepatient-providerinteraction,18IBD&mehasnotyetbeensubjecttoprospectivevalidation.Aspartofthisstudy,Aim1willassesstheimpactofIBD&meonpatientperceptionsofSDMand

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satisfactionwhencomparedtoastandardizededucationarminamulticenterrandomizedcontrolledtrial(RCT).Here,wewillpartnerwithandrecruitpatientsthroughIBDQorus,aground-breakinginitiativebytheCrohn’s&ColitisFoundationwith30community-basedandacademicIBDcenterscommittedtoimprovingthequalityofcaredeliveredtoIBDpatients.PleaseseeaccompanyingLetterofSupportfromIBDQorusleadership(Dr.CoreySiegel,Co-PrincipalInvestigator;AlandraWeaver,DirectorofIBDQorus,Crohn’s&ColitisFoundation).

InadditiontotestingtheimpactofIBD&meonpatient-reportedoutcomes,wehaveanopportunitythroughthisgranttopreparethetoolforwiderdisseminationandapplicabilitytoupcomingtherapeuticoptions.AswithanySDMtool,IBD&memuststayrelevantovertime,particularlyinIBDgiventhegrowingpipelineofIBDtherapiesandincreasingglobalprevalenceofCDandUC.Toachievethis,wewillassesswhetherthereareculturaldifferencesindecisionmakingwhenpatientsnavigateamongcurrentandemergingIBDtherapies;theseresultswillallowfutureupdatestothetool.Specifically,Aim2willuseconjointanalysis,atechniquethatdetermineshowrespondentsmakecomplexdecisionsunderconditionsofuncertainty,toexaminehowpatientswithmoderate-to-severeIBDbothinsideandbeyondNorthAmericaselectamongavailablebiologicaswellasupcomingsmallmoleculetherapies.ThisinformationwillinformupdatestoIBD&measwellasotherdecisionaidsoncenewmedicationsbecomeavailableforuseineverydayclinicalpractice.

CURRENTASSESSMENTOFNEEDINTARGETAREA

WhilethetestedbiologicsandsmallmoleculetherapiesareeffectiveintreatingIBDcomparedtoplacebo,thereisstillalackofcomparativeeffectivenessdata,resultingincarepathwaysthatendorseseveralfirst-linetherapies.6,7Addingtothecomplexityisthesubstantialvariationamongbiologicsandupcomingsmallmoleculeswithrespecttomechanismofaction,modeofadministration,andsideeffects,amongotherattributes.Forexample,thetherapiescanbecategorizedasanti-tumornecrosisfactor(TNF),anti-integrin,anti-interleukin(IL)12/anti-IL23agents,orJanuskinaseinhibitors.5,19,20

Asidefrommechanismofaction,IBDtherapiesalsodifferinboththeroute(intravenousvs.subcutaneousvs.oral)andfrequencyofuse.IBDtherapeuticsalsohavevaryingside-effectprofiles,astherearedifferentialratesoffatigue,skinrash,lymphoma,infections,andhyperlipidemia.5,21Asaresult,itisoftendifficultforpatientstonavigatethearrayoftreatmentoptionswiththeirphysiciansandtochooseatherapythatalignswiththeiruniquetreatmentpreferences.Moreover,thedecision-makingprocesswillbecomemorecomplexasadditionaldrugsaredevelopedandapproved.

Ourgrouprecentlyconductedastudyusingconjointanalysis–atechniquethatdetermineshowrespondentsmakecomplexdecisionsunderconditionsofuncertainty–thatfoundsystematicallydifferentapproachestobiologictherapydecisionmakingbetweenpatientswithUCandCD(manuscriptinrevisionatAmJGastroenterol)(Figure1).22Moreover,acrossconditionswefoundwidelydivergentindividualpatientpreferenceswhenselectingamongbiologics.Inattemptingtoidentifypredictorsofindividualpatientchoice,wefoundthatdemographicandIBDcharacteristicswerelargelyunhelpful;98%ofrespondentshaduniquedecision-makingprofiles,againemphasizingthehighlypersonalizednatureofdecisionmaking.

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Becauseofthehighly-individualizednatureofdecisionmakinginIBD,alongwithhealthcare’sincreasedemphasisonSDM,itiscriticalforclinicianstoidentifywhatmattersmosttopatientswhenchoosingamongtherapeuticoptions;thisenablespatientstoselecttherapiesthatalignwiththeirvalues–aneedthatisrecognizedbypatientsandphysiciansalike.23,24Yet,itcanbechallengingtoaccuratelyestablishapatient’suniquepreferenceprofileinthecontextofabriefclinicvisitbecausenotwoIBDpatientsarealike.Inthefaceofburgeoningadministrativeandclinicaltasks,gastroenterologistsoftenlacktimeandresourcestoengageindetaileddiscussionsaroundtherapies’risks,benefits,andtradeoffs.Thus,thereisaneedforsimpleandefficienttoolsthatelicitindividualpreferencesandsupportthepatient-providerinteraction.

Toaddressthisgap,weconvertedourconjointanalysisintoadecisionaidcalledIBD&me(ibdandme.org).IBD&meisanovel,onlinetooltoenhanceSDMbetweenIBDpatientsandtheirproviderswhennavigatingamongtheavailableIBDtherapies.Theprogramenablespatientstoexploretherisksandbenefitsofthedifferenttherapies,andthenguidesthemthroughaconjointsurveycalledtheIBD&meDecisionTree.Oncepatientscompletethesurvey,thewebsitegeneratesauniquepersonalizedreportthatcanbesharedwithadoctor.SeebelowforfulldetailsonIBD&me.

FIGURE1.AverageattributeimportanceforUCandCDpatients.Theaverageimportanceofeachbiologicattributeisbasedonpart-worthutilities.ForUCpatients,remission,modeofadministration,andlymphomariskaccountedfor15.6%,15.3%,and13.7%ofdecisionmaking.ForCDpatients,short-termimprovement(15.1%),lymphomarisk(14.7%),andmodeofadministration(13.7%)weremostimportant(N=336CD;334UC;datainrevisionatAmJGastroenterol).

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Whiledecisionsaidshavebeenshowntoincreaseparticipants’knowledgeandaccuracyofriskperceptions,decreasedecisionalconflict,andpositivelyimpactpatient-cliniciancommunication,18thecapacityofIBDdecisionaids,suchasIBD&me,toimprovepatientoutcomesislesswelldefined.Weaimtoaddressthisgapbyconductingapragmatic,multicenterRCTinpartnershipwithIBDQorusinstitutionscomparingtheimpactofIBD&meonSDMandpatientsatisfactionwhencomparedtostandardizededucation.

AIM1.RCTOFIBD&MEVS.STANDARDIZEDEDUCATION.

TARGETAUDIENCE

WewillrecruitIBDpatientsfromparticipatingIBDQorusinstitutionstoparticipateinanRCTcomparinguseofIBD&mevs.standardizededucation.IBDQorusisaconsortiumof30community-basedandacademicIBDcenterscommittedtoimprovingthequalityofcaredeliveredtoIBDpatientsandprovidesaccesstoover1,000potentialstudyparticipants.Eligiblepatientswillincludethosewhoare:(i)age≥18years;(ii)havemoderate-to-severeUCorCD;and(iii)consideringstartingorswitchingbiologicsfortreatinghisorherIBD.IndividualswithmildIBDorwhoarestableontheirbiologictherapywillbeineligible.Pleaseseethe“ProjectDesignandMethods”sectionfordetailsonrecruitmentplan.

PROJECTDESIGNANDMETHODS

Approach.TomeasuretheefficacyofIBD&meinclinicalpractice,wewillconductapragmatic,multicenterRCTcomparingprovisionofIBD&mevs.standardizededucation.WewillrecruitpatientsseenincentersthathaveconsentedtobepartofIBDQorus.Eligiblepatientswillbeofferedparticipationinthestudy1weekpriortotheirnextscheduledappointment–aperiodwhentheynormallycompleteastandardizedIBDQorusquestionnaire.Patientsinterestedinparticipatingwillbedirectedtothestudywebsitewheretheywillelectronicallyconsentandthenundergorandomizationtoaccesseitheroneoftwowebsites:(i)IBD&me;or(ii)standardized,high-qualityeducationalmaterialfromtheCrohn’s&ColitisFoundation.Seebelowforfulldescriptionsofthetwoarms.WehypothesizethatIBD&me,throughoptimizingSDMandimprovingthepatient-providerinteraction,willprovideincrementalbenefitsbeyondthoseprovidedbyhigh-qualityeducationalmaterialwithoutanSDMtool.

PatientsrandomizedtoIBD&mewillbedirectedtocompletetheIBD&meDecisionTreepriortotheirappointment.Bypresentingthesitetopatientsinthismanner,ratherthanrequestingthatpatientscompletetheSDMtoolinclinicimmediatelyprecedingtheirvisit,weintendtoallowforsufficienttimetoreviewtheeducationcontentandcompletetheconjointsurveyathome,attheirownpace.Thisrecruitmentprocesswillalsobypassthebusyclinicianofficeandnotrelyonprovidersenrollingpatients–apragmaticdesignwehavedevelopedfromothertrialswehaveperformedofpre-cliniconlinetools.25-27PatientswhocompleteIBD&mewillbeaskedtoprintouttheirpersonalizedreportandbringitwiththemtotheirupcomingvisit.Asapragmatictrial,wewilltrackallpatientswhoenrollusinganintention-to-treatprincipal,includingthosewhodecidenottousethesite,orthosewhodonotbringtheirreportwiththemtothevisit.Asasecondaryanalysis,wewillalsoevaluateper-protocolsubjects,focusingonthosewhocompletedtheDecisionTreeandbroughtthereporttotheirappointment.

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Onedayafterthevisit,subjectswillreceiveafollow-upemailtoaskabouttheirperceptionofSDMduringthevisit,theirsatisfactionduringtheirvisit,whethertheycompletedandbroughttheirpersonalizedreporttothevisit,andtheperceivedutilityofIBD&meinfacilitatingthediscussionand/orimpactingtherapeuticdecisions.Twomonthslater,afollow-upemailwilldirectsubjectstoreportchangesintreatment,andinclinicaloutcomesincludingdiseaseactivityandHRQOL.Seethe“EvaluationDesign”sectionbelowforadditionaldetailsontheoutcomemeasurementsandrelatedpsychometrics.

Intervention:IBD&me–ADigitalTooltoEnhanceSDMforIBDBiologics.IBD&me(ibdandme.org)isanonline,freely-availabletoolthatallowspatientstoexploredecisionmakingaroundbiologictherapiesforIBDattheirownpace.FundingforthedevelopmentofthesitewasthroughcollaborativeresearchandeducationalgrantsmanagedbytheCedars-SinaiOfficeofContinuingMedicalEducation,whichoversawdevelopmentofthecontentusingafairandbalanced,peer-reviewprocess.

IBD&meenablespatientstoexplorebiologicrisksandbenefitsbyfirstintroducinguserstoa“LearnMore”section,whichwasiterativelydevelopedbycontentexpertsatCS-COREandtheCedars-SinaiIBDCenter(Figure2).Here,thesiteaddressescommonquestionslike:Whatarebiologics?Howtotakebiologics?And,whatistheriskoflymphoma?

FIGURE2.IntheIBD&me“LearnMore”section,patientslearnaboutimportanttermsandconceptsrelatedtobiologics.Inthepagebelow,individualsareinformedoftheclinically-availablebiologictherapiesandtheirmechanismsofaction.

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Afterwards,userscompleteaconjointsurveycalledtheIBD&meDecisionTree;seeFigure3forasamplescreenshot.Basedontherespondent’sanswertothefirstcomparison,analgorithmselectsanewsidebysidecomparisonandaskstherespondenttoselectthepreferredprofile.Theprocesscontinuesuntiltherespondentrevealsinternalconsistencyandthetechniquecollectssufficientdatatorankpreferences.

OnceuserscompletetheDecisionTree,thewebsitethengeneratesauniqueIBD&mepersonalizedreportthattheycanreviewandsharewiththeirdoctor.Notworeportsarethesame.Thereporthasbeendesignedtohelpcliniciansefficientlyunderstandwhatismostimportanttotheirpatientwhenselectingabiologicmedicine.TheexamplereportinFigure4revealsthetypeofinformationavailabletopatientsandtheirproviders,andhas4sections:(1)AboutThisReport;(2)MyImportanceScores;(3)WhatDoesThisMean?;and(4)OtherHelpfulInformation.The“AboutThisReport”sectiondescribeshowthereportmaybeusefultopatientsandalsoinstructsthemtoprintitoutandbringittotheirnextclinicvisit(anemailoptionisalsoavailable).The“MyImportanceScores”sectionincludesthepatients’part-worthutilityscoresforthedifferentbiologiccharacteristics;thehigherthescore,themoreimportantthecharacteristicistothepatientwhenchoosingamongmedicines.IntheexampleinFigure4,modeofadministrationisthemostimportantfactorasitaccountsfor19%ofthispatient’sbiologicdecisionmaking.Inthe“WhatDoesThisMean?”section,patientsseetheirtop3mostimportantfactorsinthedecision-makingprocess.Italsohighlightsthepatient’spreferredrouteofadministrationandhowoftenthepatientpreferstoreceivethemedicine.Finally,inthe“OtherHelpfulInformation”section,bothpatientsandclinicianscanreviewrelevant,tailoredinformationthatmaybehelpfulwhendiscussingthedifferentbiologicoptionsinclinic.Forinstance,intheprovidedexample,thereportdescribeshoweachofthecurrentlyavailablebiologicsareadministeredsincethepatientprioritizedmodeofadministrationwhennavigatingtheIBD&meDecisionTree.

FIGURE3.InthisexamplefromtheIBD&meDecisionTree,apatientneedstoweighthetradeoffofincreasedeffectivenessofthebiologicininducingremissionwithanincreasedriskoflymphoma.

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FIGURE4.SampleIBD&mePersonalizedReportthatdetailsthepatient’sprioritieswhenselectinganIBDtherapy.

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Comparator:Crohn’s&ColitisFoundationEducationMaterial.ThepurposeoftheRCTistodeterminewhetherprovisionofanSDMtoollikeIBD&meoffersincrementalbenefitsoverandabovehighqualityeducationalmaterialintheabsenceofanSDMtool.Thus,wewillcompareIBD&meagainstanactivecontrolthatemploysstandardized,high-qualityeducationalmaterialfromtheCrohn’s&ColitisFoundation.WewillusetheFoundation’sBiologicTherapiesonlineresource(www.crohnscolitisfoundation.org/resources/biologic-therapies.html),whichisawell-researchedandclearlypresentedoverviewofIBDbiologictherapies,butwithoutanactiveSDMcomponent.SeeFigure5forascreenshotofthesite,whichincludesinformationonthedifferentbiologics,theirmechanismsofaction,andfrequencyofdosing.Thesitealsodescribestherisksandspecialconsiderationsforbiologictherapies.

CovariateData.Inadditiontooutcomesdata(see“EvaluationDesign”sectionfordetails),wewillcollectpatientdemographics,includingage,gender,race/ethnicity,education,maritalstatus,employmentstatus,andincome.Wewillalsoaskquestionsregardingparticipants’IBD,includingthetypeofIBD(UCorCD),durationofIBD,priorIBD-relatedsurgery,IBD-relatedsymptomsexperiencedinthepast30days,IBDseverityasdeterminedbytheShortInflammatoryBowelDiseaseQuestionnaire(SIBDQ),28andcurrentandpriorIBDtherapyuse(steroids,aminosalicylates,immunomodulators,antibiotics,biologics,andsmallmolecules).

EVALUATIONDESIGN

PrimaryandSecondaryOutcomes.OurprimaryoutcomewillbeSDMasmeasuredbythevalidated9-itemSharedDecisionMakingQuestionnaire(SDM-Q-9;Appendix1).29Patientsatisfactionasmeasuredbytheshort-formPatientSatisfactionQuestionnaire(PSQ-18;Appendix2)willserveasasecondaryoutcome.30Onedayaftertheclinicvisit,patientswillbesentanemailbyresearchstaffinvitingthemtocompletetheSDM-Q-9andPSQ-18onREDCap,asecurewebapplicationformanagingonlinesurveysanddatabases.Theywillbeinstructedto

FIGURE5.Crohn’s&ColitisFoundationBiologicTherapieseducationalmaterial.

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answerthequestionsthinkingaboutdiscussionsthattookplaceduringthevisit,ifany,regardingbiologictherapeuticoptions.Twomonthslater,afollow-upemailwilldirectsubjectstoreportchangesintreatment,andinclinicaloutcomesincludingdiseaseactivity(SIBDQ)andHRQOL(NIHPROMIS10GlobalHealthquestionnaire).

StatisticalAnalysis.Allanalyseswillbeconductedfromanintention-to-treatperspective.Asrandomizationwillbalancemeasurableandunmeasurablevariablesbetweengroups,wewilluseStudent’st-testtoassessforsignificantdifferencesinSDM-Q-9scoresbetweentheIBD&meandstandardizededucationgroups.Wewillalsoperformmultivariablelinearregressiontoidentifypatient(age,sex,race/ethnicity,educationlevel,etc.),provider(yearsofexperience,leveloftraining[physician,nursepractitioner,physicianassistant]),andprocess(IBD&mevs.educationmaterialcomparator)characteristicsthatareindependentpredictorsofhigherSDM-Q-9scores.

SampleSize.WhiletheSDM-Q-9isawidelyused,validatedmeasure,weareunawareofdatameasuringtheminimallyclinicallyimportantdifferenceonthescale.Therefore,thesamplesizewascalculatedtoachieveamoderateeffectsizeof0.5(ahalfstandarddeviationdifference,whichgenerallycorrelateswiththeminimallyclinicallyimportantdifference)inmeanSDM-Q-9scoresbetweengroups.31,32Assumingatwo-tailed5%significancelevelwith80%power,theminimumsamplesizeneededtoshowaneffectsizeof0.5is64patientspergroup.

PlansforDissemination.Uponcompletionofthestudy,wewilldisseminatethefindingsthroughabstractssubmittedtoeithertheCrohn’s&ColitisCongressorDigestiveDiseaseWeek(DDW).Wewillalsoprepareandsubmitamanuscriptforpeer-reviewatahigh-impactmedicaljournal,employoursocialmediachannelsatCedars-Sinai(12K+followers)andthePI(Dr.Spiegel~5.6Kfollowers),andworkwithourmediacontactstodriveawarenessaboutthetrialresults.

DETAILEDWORKPLANANDDELIVERABLESSCHEDULE

ForAim1,weanticipatea12-monthtimeline.Thiswillbeginwithakickoffin-personmeetingthatwillincludeallmembersoftheresearchteamatCedars-Sinai,principalinvestigatorsofIBDQorus,andrepresentationfromtheCrohn’sandColitisFoundationincludingtheDirectorofIBDQorus.Thismeetingwillserveasthelaunchofthestudy,ensureallpersonnelrolesareclarified,andthatthetimelineandstudyplanarereviewed.Immediatelyfollowingthismeeting,wewilldeveloppatientrecruitmentmaterials,andupdatetheIBD&mesiteforuseinaresearchcapacity.Wewillthendevelopandtestoutcomesurveystoclarifydeterminantsofsuccess.RegulatorydocumentswillbepreparedandsubmittedforreviewthroughtheusualmechanismsofIBDQorusregulatorysubmission,utilizingDartmouth-HitchcockasthecentralInstitutionalReviewBoard(IRB)forthemajorityofsites,andanyadditionalinterestedsitesnotrelyingonDartmouthwillbeprovidedtherelevantregulatorydocumentsforlocalsubmissions.Weanticipatearapidapprovalforthislow-riskstudybasedonourpriorexperiencewithIBD&me,andexpectpatientenrollmenttobeginwithin4monthsofstudykickoffafterrequisiteregulatoryapprovals.Patientenrollmentwillcontinuefor5months,duringwhichtime,enrollmentwillbeactivelymonitoredandstrategiesforboostingenrollmentwillbesoughtasneeded,withactivecollaborationwiththeIBDQorusleadershipteam.Patientswill

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completeallstudy-relatedsurveys2monthsfollowingenrollment,foratotalof7monthsofdatacollectionfromthefirstpatientenrolledtothelastpatientforwhomdataiscollected.Wethenanticipatea2-3monthdataanalysisperiod,followedbyabstractandmanuscriptpreparationforsubmissiontoaninternationalGImeetingandahigh-impactmedicaljournal.

AIM1:TimelineandMilestones.

TaskMonth

1 2 3 4 5 6 7 8 9 10 11 12

Kickoffmeeting ¡ IRBsubmissionandapproval

¡ ¡ ¡

Developpatientrecruitmentstrategyandmaterials

¡ ¡

Developandtestoutcomesurveys

¡ ¡

RecruitpatientsthroughIBDQorus ¡ ¡ ¡ ¡ ¡

Datacollectionandanalyses ¡ ¡ ¡ ¡ ¡ ¡ ¡

Prepareandsubmitabstracts&

manuscript ¡ ¡ ¡

AIM2.EXAMININGIBDPATIENTS’MAINDRIVERSOFDECISIONMAKINGWHENSELECTINGAMONGBIOLOGICSANDSMALLMOLECULES.

TARGETAUDIENCE

InadditiontotestingtheimpactofIBD&meonpatient-reportedoutcomes,wealsoaimtopreparethetoolforwiderdisseminationandapplicabilitytoupcomingtherapeuticoptions.AswithanySDMtool,IBD&memustremainrelevantovertime,especiallygiventhegrowingpipelineofIBDtherapiesandincreasingworldwideprevalenceofIBD.Toachievethis,wewilluseconjointanalysistoassesshowIBDpatientsbothwithinandbeyondNorthAmericachooseamongbothcurrentandfutureIBDtherapeuticprofiles.EligiblepatientswillincludethosewithIBDrecruitedthroughCint(www.cint.com),aninternationalsurveyresearchfirm,theCedars-SinaiGastrointestinalPatientReportedOutcomeMeasurementInformationSystem(PROMIS®)researchdatabase,33andtheMucosalImmunologyRepositoryforInflammatoryandDigestiveDiseases(MIRIAD)database.Eligibleindividualswillbethosewhoare18yearsofageorolderwithevidenceofrecentlyactiveIBDsymptomsinthepast30days,includingabdominalpain,diarrhea,constipation,bowelincontinenceorleakage,nauseaand/orvomiting,jointpain,and/orbloodinstool.

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PROJECTDESIGNANDMETHODS

ConjointAnalysis–Overview.Conjointanalysisisaformoftradeoffanalysisthatelucidateshowpeoplemakecomplexdecisionsbybalancingcompetingfactors.34Itwasfirstwidelyusedinmarketing,35butthetechniquehassincespreadtoproductdesign,socialsciences,andhealthcare.Recentstudiesfromourgroupandothershaveusedconjointtoexamineclinicaldecisionmakinginrheumatology,36surgery,37diabetesmanagement,38useoftransfusionsindialysis-relatedanemia,39andevenIBD.40-45Giventhepenetrationofthistechniqueintohealthcare,theInternationalSocietyforPharmacoeconomicandOutcomesResearch(ISPOR)createdataskforcetodevelopguidelinesforhealthcareconjointanalysis,34indicatingbroadacceptanceofthisapproachforquantifyinghowpatientsmakedifficultdecisionsunderconditionsofuncertainty.

Conjointanalysisposesaseriesofsidebysidecomparisonsofcompetingproductprofilesandasksrespondentstoselectwhichprofileispreferable(Figure3).Basedontherespondent’sanswertothefirstcomparison,analgorithmselectsanewsidebysidecomparisonandaskstherespondenttoselectthepreferredprofile.Theprocesscontinuesuntiltherespondentrevealsinternalconsistencyandthetechniquecollectssufficientdatatorankpreferences.

ConjointAnalysisSurveyforBiologicandSmallMoleculesDecisionMaking.ToquantifyandrankpreferencesregardinguseofbiologicsandsmallmoleculesinIBD,wewillusetheadaptiveconjointanalysisplatformdevelopedbySawtoothSoftware(Sawtooth,NorthOrem,Utah).Conjointanalysisassumesthatdecisionmakingdependsuponattributes,eachofwhichhaslevels.Forexample,selectingamongIBDbiologicsandsmallmoleculesmaydependuponmanyattributes,includingmechanismofaction,routeofdelivery,frequencyofadministration,efficacyatinducingremission,tolerabilityofsideeffects,andrisksforlymphoma,seriousinfection,rash,fatigue,andhyperlipidemia.Eachattributecanbemeasuredacrossseverallevels.Asanexample,levelsformechanismofactionareanti-TNF,anti-integrin,anti-IL12/23,andJanuskinaseinhibitors.Formodeofadministration,levelscanincludeoral,intravenous,andsubcutaneous.Ofnote,ouroriginalconjointanalysisfocusedsolelyonbiologics,22anddidnotincludeoraladministrationofmedications;thismaybeapriorityformanypatientswithmoderate-to-severeIBDwhenselectingamongthedifferenttherapyoptions.

Oncetheattributesandlevelsaredefined,theconjointanalysissoftwaredisplayssetsofsidebysidetherapeuticprofiles,eachwithvaryinglevelsforeachattribute(Figure3).Foreachtherapeuticprofileinthesepaircomparisons,respondentsdecidewhichtherapyispreferable,ifany.Thecomparisonsbecomeincreasinglycomplexastherespondentprogressesandcontinuesuntilresponsesachieveinternalconsistency.

Inadditiontoconjointvignettes,thesurveywillincludestand-alonequestionsregardingpatientdemographics,includingage,gender,race/ethnicity,education,maritalstatus,employmentstatus,andincome.Wewillalsoaskquestionsregardingparticipants’IBD,includingthetypeofIBD(UCorCD),durationofIBD,priorIBD-relatedsurgery,IBD-relatedsymptomsexperiencedinthepast30days,IBDseverityasdeterminedbytheSIBDQ,28andcurrentandpriorIBDtherapyuse(steroids,aminosalicylates,immunomodulators,antibiotics,biologics,andsmallmolecules).Theresponsestothesequestionswillbeusedtoidentifypotentialdemographicorclinicalpredictorsofdecisionmaking.Wehypothesizethatbiologic

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andsmallmoleculepreferencesmightvarypredictably,forexample,byIBDseverity,patientage,orcountry.

Approach.WewillrecruiteligiblepatientstocompletetheconjointanalysissurveythroughCint,aglobalsurveyresearchfirm,andthroughtheCedars-SinaiGastrointestinalPROMIS®andMIRIADdatabases.Cintpartnerswithpanelcompaniesandresearchpanelsacrosstheworld,andalltogetherhasaccesstoover40millionpotentialresearchparticipantsinover80countries.Forthisstudy,wewillfocusonrecruitingpatientsfromNorthAmericanandEuropeancountrieswithahighprevalenceofIBD,includingtheU.S.,Canada,andUnitedKingdom.46ThePROMIS®databaseincludesover150IBDpatientsevaluatedinclinicsatCedars-SinaiMedicalCenter,theWestLosAngelesVeteransAffairsMedicalCenter,theUniversityofMichigan,andUCLA.33TheMIRIADdatabaseincludesover15,000IBDpatientswhohaveconsentedtobecontactedforfutureresearchstudiesincludingsurveys.

CintwillsendpotentialsubjectsamessagethroughtheCintportalinvitingthemtocompletetheconjointsurvey.Aftertheyprovideonlineinformedconsent,participantswillthenbeshowna“blinded”screenerquestionthatasksthemiftheyhavebeendiagnosedbyaphysicianwithoneormoreofthefollowingmedicalconditions:(i)UC;(ii)CD;(iii)rheumatoidarthritis;(iv)ankylosingspondylitis;(v)psoriasis;(vi)psoriaticarthritis;or(vii)noneoftheabove.OnlythosewhoclickUCorCDwillbeallowedtoproceedthroughtheconjointexercise.Byusinga“blinded”screenerthatincludesUCandCDalongwithotherinflammatoryconditions,itwillhelpmaximizethelikelihoodthatrespondentshad,infact,beendiagnosedwithIBDandarenotsimplyseekingcompensationbyparticipatinginasurvey.AsforthepatientsincludedinourPROMISandMIRIADdatabases,allofwhomhavephysician-confirmedIBD,researchstaffwilldirectlyemailpotentialparticipantsalinktotheconjointanalysissurvey.

EVALUATIONDESIGN

ConjointAnalysisOutcomes–Part-WorthUtilitiesandImportanceScores.Afterrespondentscompletethesurvey,theconjointsoftwareuseshierarchicalBayesregressiontoestimateindividual-levelutilitycoefficients.41,47Thesecoefficientsarecalledpart-worthutilities,andtheyaregeneratedforeachattributelevel.Levelsthathavegreaterimportanceinthedecision-makingprocessareassociatedwithhigherpart-worths,andthepart-worthutilitiesforthelevelswithineachattributesumtozero.Inadditiontocalculatingpart-worthutilities,theconjointsoftwarealsogeneratesimportancescores,whicharederivedbycalculatingthedeltabetweenthepart-worthsforthemostimportantandleastimportantlevelofeachattribute.41Thelargerthedeltainpart-worthutilities,thelargertheimportanceoftheattributeinthedecision-makingprocess.Asanexample,seeFigure1foraverageattributeimportancescoresforUCandCDpatientsinourrecentstudyfocusedonbiologicdecisionmaking.22

StatisticalAnalysis.Fortheentirecohort,wewillcalculatemeanimportancescoresforeachtherapyattribute(e.g.,mechanismofaction,modeofadministration,efficacy,etc.),andlisttheminrank-orderfromhighesttolowestrelativeimportance.Wewillthencomparegroup-level(e.g.,malevs.female,racial/ethnicgroupcomparisons,U.S.vs.Canadavs.UnitedKingdomcomparisons)rankings,followedbypatient-levelratingstoassesstheuniquenessofindividuals’decisionprofiles.

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Wewillthenperformmultivariablelogisticregressionmodelsonouroutcomestoadjustforconfounding.Theoutcomesinthemodelswillbewhetherindividualsreportedthefollowingattributesasthemostimportantfactorintheirdecision-makingprocess:(i)mechanismofaction;(ii)modeofadministration;(iii)efficacy;and(iv)side-effectprofile(i.e.,tolerabilityofsideeffects,fatigue,rash,riskofseriousinfection,riskoflymphoma,orhyperlipidemia).Allpatient-leveldemographic(age,gender,race/ethnicity,education,maritalstatus,employmentstatus,householdincome,country)andclinical(typeofIBD,durationofIBD,priorsurgeryforIBD,IBDseverityasdeterminedbytheSIBDQ,currentandpriorIBDtherapyuse)variableswillbeincludedintheregressionmodels.

SampleSize.BasedonconjointanalysissamplesizerecommendationsfromSawtoothSoftwareandtoallowforadequatelypoweredsubgroupcomparisons,48wewillrecruit300respondentsfromeachcountry(U.S.,Canada,UnitedKingdom)throughCinttocompletethesurvey.FromthePROMISandMIRIADdatabaseswewillrecruitanother300patientscombined.Therefore,thestudywillincludeatotalof1,200IBDpatientsfromacrosstheglobe.

PlansforDissemination.Uponcompletionofthestudy,wewilldisseminatethefindingsthroughabstractssubmittedtoeithertheCrohn’s&ColitisCongressorDDW.Wewillalsoprepareandsubmitamanuscriptforpeer-reviewatahigh-impactmedicaljournal,employoursocialmediachannelsatCedars-Sinai,andworkwithourmediacontactstodriveawarenessaboutthestudyresults.

DETAILEDWORKPLANANDDELIVERABLESSCHEDULE

ForAim2,weanticipatea12-monthtimeline.Thiswillbeginwithakickoffin-personmeetingthatwillincludeallmembersoftheresearchteamatCedars-Sinai.Thismeetingwillserveasthelaunchofthestudy,ensureallpersonnelrolesareclarified,andthatthetimelineandstudyplanarereviewed.Immediatelyfollowingthismeeting,wewilldevelopandupdatetheconjointsurveytoexpandtheattributesandoptionstoreflectup-to-datetreatmentoptions,safetyprofiles,andefficacyestimatesofavailableandemergingtherapies.RegulatorydocumentswillbepreparedandsubmittedforreviewthroughtheusualmechanismsattheCedars-SinaiIRB.Weanticipatearapidapprovalforthislow-riskstudybasedonourpriorconjointanalysis-basedstudies,andexpectpatientenrollmenttobeginwithin4monthsofstudykickoffafterrequisiteregulatoryapprovals.Patientenrollmentwillcontinueforupto5months,duringwhichtime,enrollmentwillbeactivelymonitoredandstrategiesforboostingenrollmentwillbesoughtasneeded.Afterdatacollectioniscomplete,wethenanticipatea2-3monthdataanalysisperiod,followedbyabstractandmanuscriptpreparationforanticipatedsubmissiontoaninternationalGImeetingandahigh-impactmedicaljournal,respectively.

AIM2:TimelineandMilestones.

TaskMonth

13 14 15 16 17 18 19 20 21 22 23 24

Kickoffmeeting ¡ IRBsubmissionandapproval

¡ ¡

16

Developandtestconjointanalysissurvey

¡ ¡ ¡ ¡

RecruitIBDsubjectsgloballyandcollectdata

¡ ¡ ¡ ¡ ¡

Datacollectionandanalyses ¡ ¡ ¡ ¡ ¡ ¡ ¡

Prepareandsubmitabstracts&manuscript

¡ ¡ ¡

17

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