BackgroundHyperhidrosisHHisaconditioninwhichsweatproductionexceedst - PDF document

BackgroundHyperhidrosis(HH)isaconditioninwhichsweatpro-ductionexceedsthatwhichisphysiologicallynecessarytomaintainthermalhomeostasis[1].Thisburdensomeconditionisestimatedtoaffectupto4.8%oftheU.S.population,or15.3millionAmericans,andcausessub-stantialimpairmentinpatientdailylife,asapproxi-matelythree-quartersofpatientsreportnegativeimpactsontheirsociallife,senseofwell-being,and/ormentalhealth[2].Anumberoftoolshavebeenutilizedtomeasurepa-tient-reportedseverity,impact,andbotherassociatedwithhyperhidrosis[3].Generichealth-relatedqualityoflife(HRQOL)measuressuchastheShortFormHealthSurveys(SF-36andSF-12)andtheNottinghamHealthProfile(NHP)havebeenused[4,5];however,thesecoverbroaderconstructsofhealth,donotnecessarilyre-flectareasoffunctioningthatareparticularlyrelevanttopatientswithhyperhidrosis,andlacksensitivityneededtodiscernclinicallymeaningfultreatmentbenefit[6].Similarly,dermatology-specificmeasures(Skindex,Derma-tologyLifeQualityIndex[DLQI])havebeenadministeredtopatientswithhyperhidrosisbutwerenotdevelopedtocaptureallrelevanthyperhidrosis-specificconcepts[7–9].Themostcommonlyusedhyperhidrosis-specificscaleistheHyperhidrosisDiseaseSeverityScale(HDSS).Althoughthisscalehasbeenbroadlyadoptedinclinicalpracticetoevaluatediseaseseverity,itcombinestwodistinctconceptsinthesameitem(ie,tolerabilityandinterferencewithdailyactivities),thuslimitinginterpretationofstudyresults.Inaddition,patientinputwasnotsolicitedduringthedevelopmentoftheHDSS[10,11].Otherdisease-specificmeasuresincludetheHyperhidrosisImpactQuestionnaire(HHIQ)[12],theAmir-deCamposClinicalProtocolforQoL[13,14],andtheKellerscale[15].TheHyperhidrosisQualityofLifeIndex(HidroQOL©)isamorerecentlydevelopedmeasure;however,atthetimethisresearchwasdesignedandconducted,itwasnotpubliclyavailableanditsmeas-urementpropertieshadnotbeenevaluatedinaninterventionaltrialsetting[16,17].Althoughtheinstrumentsdescribedabovehavebeenusedtobettercharacterizepatientswithhyperhidrosis,itisunclearwhetheranyweredevelopedtosupportprod-uctapprovalsinaccordancewithmostrecentU.S.regu-latorystandardsforPROmeasures(ie,forinclusionaskeyendpoint(s)inaclinicaltrial)[18].ThispromptedthedevelopmentofanewPROtomeasurehyperhidro-sistreatmentbenefittomeetU.S.registrationneeds,andtomorebroadlyunderstandtheimpactofhyperhidrosisonpatients’lives.Here,wedescribethedevelopment,features,andval-idationoftheAxillarySweatingDailyDiary(ASDD)andAxillarySweatingDailyDiary-Children(ASDD-C),withafocusonthepsychometricevaluationofaxillarysweat-ingseverityitem(Item2).MethodsInstrumentdevelopmentAbriefoverviewoftheinstrumentdevelopmentprocessisdetailedinFig.1.Specifically,one-on-onehybridconcept-elicitation/cognitive-debriefingqualitativeinterviewswereconductedwithpatients
18yearswithclinician-diagnosedprimaryaxillaryhyperhidrosis(N=21)in3differentgeographiclocationsbetweenJanuary2014andFebruary2014.Interviewresultswerequalitativelyana-lyzedinthreesets,whereeachsetofinterviewsbuiltuponthefindingsofpreviousinterviewstoconfirmtheadequacyofmodificationsandallowtestingofanynewitems.Consistentwiththeinclusioncriteriafortheinitialdose-findingtrials,allparticipantswererequiredtoexhibithyperhidrosissymptomologyforatleast6months,aswellasreportanHDSSscoreof3or4,indicating“barelytoler-able”or“intolerable”sweatingandsweating“frequently”or“always”interferingwithdailyactivities.Preliminaryconceptswereselectedforinclusioninadraftitempoolbasedonclinicalexpertise,reviewoftheliterature,andreviewofotherquestionnaires(eg,HDSS,questionsontheInternationalHyperhidrosisSocietywebsite[www.sweathelp.org]).Giventhattheprimaryconceptofmeas-urement,sweatingseverity,wasbothstraightforwardandclearlyimportantwithinthecontextofhyperh

idrosis,draftitemsaddressingthisconceptweredevelopedpriortopatientengagementandwerecomprisedofdailydiaryitemscoveringconceptspertainingtopresence,severity,impactandbotherofaxillaryhyperhidrosis(ultimatelyreferredtoastheASDD).Additionalsupportiveconceptswereselectedforinclusioninapreliminaryitempooltofurtherexploretheimpactofaxillaryhyperhidrosisonvariousareasofpatients’lives(ultimatelyreferredtoastheWeeklyImpactItems).APatientGlobalImpressionofChange(PGIC)itemwasalsoincludedtoassesspatient-perceivedchangesinunderarmsweatingandfacilitatetheinterpretationofchangescoresonthediaryitems.Multiplequestionsweredraftedforeachconceptsovari-ablewordingandresponsescalescouldbetestedduringpatientinterviews.Allinterviewswereconductedbytwoexperiencedqualitativeresearchersaccordingtoasemi-structuredinterviewguidecreatedcollaborativelybythedevelopers.Eachinterviewbeganwithopen-endedcon-ceptelicitation.Participantswereaskedtodescribetheirexperienceswithaxillarysweating,includingvariationsinseverity,theextentandsituationsinwhichtheywerebotheredbytheirsweating,andhowtheirliveswereim-pactedbyhyperhidrosis.Followingtheconceptelicitationphase,thesamepatientswerethenaskedtoprovidefeed-backonthedraftitemsviapaperformsduringacognitivedebriefingphasetosupportthesalienceandimportanceNelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 Page2of13 oftheconcepts,aswellastooptimizeitemwordingandresponseoptions.Specifically,participantswereaskedtorespondtoeachitemwhilethinkingaloud.Interviewswerereviewedindividuallyandcomparedtootherinter-viewsinordertosummarizeandidentifyparticipantpatternsiniteminterpretationandresponse.Anitemtrackingmatrixwascreated,whichincludedanyrevisionsmadetoanitemandarationalefortheitemmodification.Additionalfollow-upquestionswerealsoposedbytheinterviewerstofurtherelucidatecomprehensionandresponseprocesses.Ifconceptsaturationwasnotreachedfollowingqualitativedataanalysisbasedonthefindingsduringeachsetofinterviews,additionalinterviewsweretobeconductedwithnewpatients.Followingthedecisiontoincludeindividualsasyoungas9yearsofageinafutureclinicaltrialprogram,asimi-larsetofqualitativeinterviewswasconductedwithchil-drenandadolescents18yearswithself-reportedexcessivesweating(N=8)toevaluatewhetherthenewmeasurewouldberelevantforchildren
9yearsofage.Whilethesamplesizewasdeemedadequatetoachieveconceptsaturation,ifnewconceptshadbeengeneratedduringtheseinterviews,testingwithadditionalpediatricpatientswouldhavebeenconducted.PsychometricevaluationPhase2and3studydesignandanalysisTofurthersupportuseoftheASDD/ASDD-Caxillarysweatingseverityitem(Item2)inclinicaltrialsevaluatingtheefficacyofnewtreatmentsforhyperhidrosis,themeasurementpropertiesofASDDItem2wereevalu-atedusingdatafroma4-weekphase2trialofglycopyr-roniumtosylate(GT)inpatients
18yearsofage(studyDRM04-HH02,NCT02129660;N=102)[19].Phase2datawerealsousedtoestablishbasicpsychometricpropertiesofASDDimpactandbothersomenessitems(Items3and4).WeeklyImpactitems,PGIC,HDSS,andgravimetricdatawerealsocollectedasstudyoutcomes.AdditionalpsychometricevaluationofASDD/ASDD-CItem2wassubsequentlyconductedbasedonpooleddatafromtwo,4-weekphase3trialsofGT,ATMOS-1(DRM04-HH04,NCT02530281;N=344;sitesintheU.S.andGermany)andATMOS-2(DRM04-HH05,NCT02530294;N=353;U.S.sitesonly)[20].Studyde-signsandinclusioncriteriaweresimilarforthephase2andphase3studies;thephase3studyalsoincludedtheDermatologyLifeQualityIndex(DLQI)andChildren’sDermatologyLifeQualityIndex(C-DLQI,forages4to16years)inadditiontotheotheroutcomescollectedanddescribedaboveforphase2.TheDLQI/C-DLQIisadermatology-specific,health-relatedqualityoflifeques-tionnairedevelopedtounderstandtheimpactsofskinconditionsonpatients’

lives[9,21].Eligiblepatientswere
18yearsofageforphase2and
9yearsofageforthephase3studies;hadadiagnosisofprimaryaxillaryhyperhidrosisfor
6months;hadHDSSgrade3or4;hadsweatproduction
50mg/axilla/5minwhileatrest Fig.1OverviewoftheInstrumentDevelopmentProcess.ASDD,AxillarySweatingDailyDiary;HDSS,HyperhidrosisDiseaseSeverityScale;IHhS,InternationalHyperhidrosisSocietyNelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 Page3of13 atroomtemperature;andforphase3studies,hadweeklyaverageASDDItem2scores
4.PROmeasureswerecompletedbypatientsusinganelectronictabletdeviceprovidedtothemduringthestudyperiodasfollows:forpatients
16yearsofage,theASDDwascompleteddaily(beforebed)for4to7daysduringscreening(7to10dayspriortorandomization)andduringtreatment;inthephase3studies,patients16yearscompletedtheASDD-Citems(Items1and2only)accordingtothesameschedule(phase3only).Pa-tients
16yearsofageadditionallycompletedtwoothermeasuresdevelopedalongsidetheASDD,namelytheWeeklyImpactitems(Table1)andthesingle-itemPGIC(Table1).These3measures(theASDD,theWeeklyImpactitems,andthePGIC)arecollectivelyre-ferredtoinTable1astheAxillaryHyperhidrosisPatientMeasures(AHPM).TheHDSSandWeeklyImpactitemswerecompletedatBaselineandeachweekduringthetreatmentperiod;theDLQI(phase3only)andPGICwascompletedatWeek4orattheendoftreatment(ie,earlytermination).TheASDD/ASDD-C,WeeklyImpactitems,andPGICwerecompletedviaelectronicdatacap-ture;theHDSSandDLQI/C-DLQI(phase3only)werecompletedweeklyonpaper.Sweatproduction,assessedgravimetrically,wasmeasuredfortherightandleftaxillaatBaselineandeachweeklyclinicvisit.ASDD/ASDD-Citemswerescoredasaweeklyaverageofdailyresponses;atleast4daysofdailydatawerere-quiredforanalysis.Responsestothe6WeeklyImpactitemsweresummedsuchthataresponseof“Yes”toanyoftheitemsresultedinascoreof1peritem.Thiswas Table1AxillaryHyperhidrosisPatientMeasures(AHPM)AxillarySweatingDailyDiary(ASDD)aInstructions:Thequestionsinthediaryaredesignedtomeasuretheseverityandimpactofanyunderarmsweatingyouhaveexperiencedwithintheprevious24-hperiod,includingnighttimehours.Whileyoumayalsoexperiencesweatinginotherlocationsonyourbody,pleasebesuretothinkonlyaboutyourunderarmsweatingwhenansweringthesequestions.Pleasecompletethediaryeacheveningbeforeyougotosleep.Item1[Gatekeeper]Duringthepast24h,didyouhaveanyunderarmsweating?Yes/NoWhenItem1isanswered“no,”Item2isskippedandscoredaszeroItem2Duringthepast24h,howwouldyourateyourunderarmsweatingatitsworst?0(nosweatingatall)to10(worstpossiblesweating)Item3Duringthepast24h,towhatextentdidyourunderarmsweatingimpactyouractivities?0(notatall),1(alittlebit),2(amoderateamount),3(agreatdeal),4(anextremeamount)Item4Duringthepast24h,howbotheredwereyoubyyourunderarmsweating?0(notatallbothered),1(alittlebothered),2(moderatelybothered),3(verybothered),4(extremelybothered)AxillarySweatingDailyDiary-Children(ASDD-C)bInstructions:Thesequestionsmeasurehowbadyourunderarmsweatingwaslastnightandtoday.Pleasethinkonlyaboutyourunderarmsweatingwhenansweringthesequestions.Pleasecompletethesequestionseachnightbeforeyougotosleep.Item1[Gatekeeper]Thinkingaboutlastnightandtoday,didyouhaveanyunderarmsweating?Yes/NoWhenItem1isanswered“no,”Item2isskippedandscoredaszeroItem2Thinkingaboutlastnightandtoday,howbadwasyourunderarmsweating?0(nosweatingatall)to10(worstpossiblesweating)WeeklyImpactItemsaInstructions:Pleaserespond“Yes”or“No”toeachofthefollowingquestions.a.Duringthepast7days,didyoueverhavetochangeyourshirtduringthedaybecauseofyourunderarmsweating?Yes/Nob.Duringthepast7days,didyoueverhavetotakemorethan1showerorbathadaybecauseofyourunderarmsweating?Yes/No Table1AxillaryHyperhidrosisPatientMeasures(AHPM)(Continued)c.Duringt

hepast7days,didyoueverfeellessconfidentinyourselfbecauseofyourunderarmsweating?Yes/Nod.Duringthepast7days,didyoueverfeelembarrassedbyyourunderarmsweating?Yes/Noe.Duringthepast7days,didyoueveravoidinteractionswithotherpeoplebecauseofyourunderarmsweating?Yes/Nof.Duringthepast7days,didyourunderarmsweatingeverkeepyoufromdoinganactivityyouwantedorneededtodo?Yes/NoPatientGlobalImpressionofChange(PGIC)ItemaOverall,howwouldyourateyourunderarmsweatingnowascomparedtobeforestartingthestudytreatment?1(muchbetter),2(moderatelybetter),3(alittlebetter),4(nodifference),5(alittleworse),6(moderatelyworse),7(muchworse)aForuseinpatients
16yearsofagebForuseinpatients
9to16yearsofageCopyright©Dermira,Inc.2017Nelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 Page4of13 referredtoastheWeeklyImpactsummary(possiblescorerangeof0to6)andusedinexploratoryanalyses.Allstatisticaltestsweretwo-tailedusingatypeIerrorrateof5%(alpha=0.05).Ratherthanrelyingonstatis-ticalsignificancealone,theinterpretationofeffectsizeestimatesandpatternsofresultswereemphasized.Ob-servedvalueswereusedforallcalculationsforthephase2study.ForASDDItem2inthephase3studies,theweeklymeanfromMarkovChainMonteCarlo(MCMC)imputationwasused;observedvalueswereusedforASDDItems3&4aswellasthePGIC.Forbinaryre-sponsedata(i.e.,ASDD/ASDD-CItem1,WeeklyImpactitems),missingvalueswereconsidereda“No”response.EvaluationofmeasurementpropertiesPotentialfloorandceilingeffects(approximatelydoubletheexpectedproportiongivenequaldistributionacrossresponseoptionsor
20%ofsamplerespondingateitherextremeofthescale),wereevaluatedbasedonresponsesduringscreening(Baseline)usingbothsum-marystatisticsandgraphicaltechniques.Test-retestreliabilityforItem2,3,and4wasevaluatedtoassesseachitem’sstabilitythroughthecomputationofintra-classcorrelationcoefficients(ICCs)betweenWeek3andWeek4,usingathresholdof
0.70[22].Week3andWeek4werechosenastheyrepresentedtimepointsatwhichsymptomswereconsideredtobemoststablefollowinginitiationoftreatment.ConstructvaliditywasevaluatedatWeek4basedoncorrelationsbetweenASDD/ASDD-CItem2gravimetricmeasurementsandestablishedPROmeasures(HDSSandDLQI).Week4correlationswerealsoexploredbe-tweenASDD/ASDD-CItem2andASDDItems3and4,theWeeklyImpactitems,andthePGIC[23].Correla-tions
0.50wereconsideredstrong,
0.30to0.50moderate,and0.30weak[24].Correlationswithitemsaddressingrelatedconstructs(Items3and4)werehypothesizedtoyieldlargercorrelationsascomparedwiththosecomputedbetweenitemsaddressingmoredisparateconstructs:giventhatsweatingcanbeepisodicandcanvarybasedontimeofday,emotionalstimuli,and/ordailyactivities[25],weakpositivecorrelationswereexpectedbetweenASDD/ASDD-CItem2scoresandgravimetricmeasurements.Weaktomoderatecor-relationswereexpectedbetweenDLQIandASDD/ASDD-CItem2,asDLQImaycapturesome,butnotall,hyperhidrosis-specificissues.TheHDSSwasex-pectedtocorrelatemoderatelytostronglywithASDD/ASDD-CItem2asbothitemsaredisease-specific,al-thoughthecorrelationscouldbemitigatedduetothelimitationsinHDSSdescribedabove.Known-groupsvalidity(theabilityofthemeasuretodiscriminatebetweenclinicallydistinctsubgroups)wasevaluatedatWeek4basedontwo-samplet-testscomparingdifferencesinscoresonASDD/ASDD-CItem2betweensubgroupspredefinedbasedonHDSSgrades(scoreof1vsscoreof3or4),DLQIscoreranges(rangeof0–10and0–12fornotomoderateimpactforDLQIandCDLQI,respectively,andrangeof21–30and19–20forlargetoextremelylargeimpactforDLQIandCDLQI,respectively)[9,21,26,27],andgravimetrically-measuredsweatproduction(1stvs4thdistributionquartiles).Responsivenesswasevaluatedthrougheffectsizecom-putationbetweenBaselineandWeek4toevaluatetheabilityoftheASDD/ASDD-Citemstodetectchange.Aresponderdefinitiontoesta

blishathresholdforamag-nitudeofwithin-personchangeconsideredtobeclinic-allymeaningfulwasdeterminedbasedonmethodsoutlinedintheFDAPROguidance[18],whichrecom-mendstheuseofself-reportedretrospectivemeasuresofchangeasexternalanchorsfortheestimationofmean-ingfulchange.SuchananchormustbebothavalidmeasureofchangeandeasiertointerpretthanthePROmeasure[28].Thus,thePGICwasutilizedastheprede-finedanchor.Specifically,respondersweredefinedaspa-tientswhoratedtheirunderarmsweatingas“moderatelybetter”onthePGICcomparedwiththestartofstudytreatment.Exploratorywithin-personchangesinHDSSscoreswerealsocalculatedagainstPGICresponses.Fi-nally,althoughPGICmeasuresarewidelyacceptedasanappropriateanchor[28],exploratorywithin-personchangescoresontheASDDwerecalculatedacrossdif-ferentmagnitudesofchangeinHDSSscores.ResultsInstrumentdevelopmentThecohortofadultintervieweeswaspredominantlywhite(76%)andfemale(76%)(Table2).Ingeneral,adultintervieweesreportedthatthemostrelevantdiaryitemsintendedfordailyadministrationaspartoftheASDDincludedthoserelatedtothepresence,severity,overallimpact,andbotherassociatedwithhyperhidrosis.Partic-ipantsnotedthatthe24-hreferenceperiodwasappro-priate.SeveraloftheitemsoriginallyproposedforinclusionintheASDDwereconsideredtobesalienttosomepatientsatsomepointsintime(interferencewithactivities,needforadditionalshowers/baths,andneedforadditionalshirtchanges);thus,theywerebettersuitedforinclusionintheWeeklyImpactitems(7-dayrecall)andtestedassuchinsubsequentroundsofinter-views.Additionalconceptstestedandretainedasacom-ponentoftheWeeklyImpactitemsincludedavoidingsocialinteractions,confidenceandembarrassment.Ofnote,alladultintervieweesreportedembarrassmentduetotheiraxillaryhyperhidrosisandnearlyall(95%)modi-fiedclothingchoicesduetotheirsymptoms(Fig.2).Nelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 Page5of13 Minormodificationstoitemwordingwereincorpo-ratedasneededfollowingeachroundofinterviewstoensurecontentwasclear,comprehensive,andeasytounderstand.Conceptspertainingtounderarmodorseverityandinterferencewithsleepwerenotgenerallyendorsedbypatientsanddeleted,aspatientsindicatedthatitwastheanxietyabouthavingodorthatwasmostimpactfulandnotnecessarilytheodoritself,andthathyperhidrosissymptomstypicallyoccurredduringthedayandnotwhilesleeping.ThePGICwasalsotested,withnorevisionsmadeinallthreeroundsofinterviewsaspatientsfoundtheitemclearandeasytoanswerinthecontextofreceivinghyperhidrosistreatments.Nonewconceptswereintroducedaspartoftheconceptelicitationportionoftheinterviews,andconceptsatur-ationwasreachedacrossthethreesetsofqualitativein-terviews.Thus,noadditionalpatientinterviewswererequiredforfurtherinput.Thelevelofbotherwasconsistentacrossbothadultandpediatricsamples.Themostcommonlyreportedimpactsofhyperhidrosisinbothpopulationsincludedfeelingembarrassed/self-conscious,modifyingtypesofclothesworn,concernaboutunderarmodor,changingshirtsthroughouttheday,anxietyaboutsweating,ruinedclothes,andphysicallyuncomfortableduetoexcessiveunderarmwetness.Adultsreportedwork-relatedimpair-mentssuchaslimitinginteractionswithworkcolleaguesandnonmandatoryworkactivities,consistentwiththeschool-relatedimpairmentssuchasavoidingschool-basedactivitiesanddifficultystudyingreportedbythepediatricsample.Liketheadultinterviewees,pediatricinterviewees(N=8)reportedbeingbotheredorburdenedbythefol-lowing:feelingembarrassed;sweatingalotmorethanothersinsimilarcircumstances;feelingsweatdrippingdownsidesofthebody;needingtocoveruptheirsweat-ingwithhairorjackets/sweatshirts,eveninhotweather; Table2CharacteristicsofIntervieweesReportedatScreeningCharacteristicAdults(N=21)Pediatric(N=8)Excessivesweatinglocations,n(%)aUnderarm21(100)8(100

)Hands6(29)4(50)Feet6(29)3(37.5)Head6(29)5(62.5)Back4(19)5(62.5)Groin0(0)2(25)Sex,n(%)Male5(24)4(50)Female1676)4(50)Age(years),mean(range)36(18–57)13.1(10–17)Race,n(%)White16(76)3(37.5)Black1(5)0(0)Hispanic4(19)3(37.5)Other0(0)2(25.0)Currentmedicationuseforanybexcessivesweating,n(%)cOver-the-counter12(57)7(87.5)Prescription10(48)1(12.5)Previousmedicationuseforanybexcessivesweating,n(%)cOver-the-counter20(95)7(87.5)Prescription16(76)1(12.5)aTotalsumexceeds100%,asparticipantscouldreportexcessivesweatinginmultiplelocationsbExcessivesweatingreferstoanyareaofexcessivesweating(ie,notrestrictedtoaxillarysweating)cTotalsumexceeds100%,asparticipantscouldreportconcurrentuseofmorethanoneprescriptionand/orover-the-countermedication Fig.2Areasofbotherandimpactassociatedwithaxillaryhyperhidrosis(AdultPatientInterviews;N=21)Nelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 Page6of13 needingto“airtheirarmpitsout”;feelingliketheyhaveabadsmell;feelingsticky;notlikingthewetfeeling;andfeelingitchy.Ofnote,adultsdidnotreportfeelingitchyinconjunctionwiththeirexcessivesweating.Thethree17-year-oldparticipantsreportedthattheirexcessiveunderarmsweatingbeganbetweenduring6thor8thgrade.Threeotherparticipants(aged10,11,and13years)reportedthattheirexcessivesweatingbeganaround4thgradeandwasmostnoticeableduringsportsorotherphysicalactivities.Theremainingparticipants(aged10and11years)didnotknowwhentheirexces-sivesweatingbegan,statingthatitwaslikelyaroundage4to5years.All17-year-olds(N=3)foundtheinstructionsandre-callperiodontheASDDclearandeasytounderstand.Incontrast,4ofthe5youngerparticipants(aged10to13years)haddifficultyreadingandunderstandingtheinstructionsand/orunderstandingthe24-hrecallperiod.Basedonthesefindings,theinstructionsandrecallperiodsusedintheASDD-Cweremodifiedforpatients16yearsofage,asreflectedinTable1.Manyoftheyoungerpediatricintervieweeshaddifficultyunderstand-ingandansweringtheASDDitemsaddressingtheim-pactandburdenofsweating(Items3and4,respectively)evenaftermodification;therefore,theseitemswereeliminatedfromtheASDD-C.AsmanyalsohaddifficultywiththeextendedrecallperiodsfortheWeeklyImpactitemsandthePGIC,theseitemswerenotadministeredtopatients16yearsofageinthephase3trials.ThePROmeasuresresultingfromthequalitativephaseofresearchareshowninTable1.Item1isagatingquestionfollowedbyItem2,whichquerieslevelofaxillarysweatingseverityusinga0-to-10numericrat-ingscale.TheremainingtwoASDDitemsareonlyad-ministeredtothose16yearsofageandolderandaddressimpactandbothersomenessassociatedwithaxil-larysweating(Items3and4,respectively).ConcurrentwiththedevelopmentoftheASDD,additionalsupport-iveassessmentswereincludedforuseinpatients
16yearsofageasfollows:sixitemstoassesstheimpactofhyperhidrosisonaweeklybasis(WeeklyImpactitems;Table1)andthesingle-itemPGICtoassessoverallchangeinhyperhidrosisseverityoverthestudycourse(Table1).Asdescribedabove,achild-specific,2-itemversionoftheASDD(ASDD-C;Table1)wassimilarlydevelopedforuseinpatients
9to16yearsofage.PsychometricevaluationThephase2andphase3patientpoolsweresimilar(Table3)withtheexceptionthatthephase3trialsallowedfortheinclusionofyoungerpatients.Specific-ally,32patientsthatwere
9to16yearsofage(aver-ageage13.8years)wereincludedinthephase3studiesandadministeredthe2-itemASDD-C.DescriptivestatisticsandreliabilityNofloor/ceilingeffectswereidentifiedfortheASDD/ASDD-Caxillarysweatingseverity(Item2)andimpact(Item3)items;therewassomeceilingeffect(21.4%)forthebothersomenessitem(Item4;Table4),whichindi-catedthatapproximatelyonefifthofpatientswereextremelybotheredbytheirconditionatbaseline.TheASDDalsodemonstratedadequatetest-retestreliability Table3PatientDemographicandHyperhidrosi

sHistoryDataFromPhase2andPhase3TrialsCharacteristicPhase2:DRM04-HH02(N=105)Phase3Pooled:ATMOS-1&ATMOS-2AgeŠ9-15Years(N=32)Age
16Years(N=665)Age(years),mean±SD33.3±11.732.7±11.413.8±1.3733.6±10.9Axillaryhyperhidrosishistory(years),mean±SDNA15.5±10.83.4±2.7716.1±10.7Female,n(%)48(45.7)371(53.2)27(84.4%)344(51.7)White,n(%)91(86.7)570(81.8)26(81.3%)544(81.8)WeeklyImpactItems,n(%)respondingYestoeachstatementChangeshirtduringtheday79(75.2%)N/A517(77.7%)Takemorethan1showerorbathduringtheday58(55.2%)N/A345(51.9%)Feellessconfident84(80.0%)N/A551(82.9%)Feelembarrassed88(83.8%)N/A583(87.7%)Avoidinteractionswithothers51(48.6%)N/A402(60.5%)Preventfromdoingactivities43(41.0%)N/A352(52.9%)WeeklyImpactSummary,amean±SD3.8±1.90N/A4.1±1.90N/ANotavailable,datanotcollectedduringthestudycourse,SDStandarddeviationaSummaryscoreisderivedbyassigningascoreof1foreach“Yes”response(range0to6).ValidityoftheWeeklyImpactSummaryscorehasnotbeentestedviadimensionalityanalysesandshouldbeconsideredexploratoryatthisstageNelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 Page7of13 betweenWeek3and4(ICCs~0.9forItems2–4),wellabovethe0.70threshold.ConstructvalidityThepatternofcorrelationsbetweenASDDitemsandotherefficacymeasuresissupportiveoftheconstructvalidityoftheASDDaxillarysweatingseverityitem(Item2;Table5).Specifically,strongpositivecorrela-tions(r
0.5)wereobservedbetweenASDDItem2andHDSSgradeatWeek4,aswellasbetweenthechangesinbothmeasuresfromBaseline.Asexpected,ASDDItem2wasmoderatelytostronglycorrelatedwiththeDLQI/C-DLQI(r=0.61/0.51atWeek4andr=0.63/0.51betweenchangesinbothmeasuresfromBaseline).CorrelationsbetweenASDDItem2andsweatproduc-tionwereweaktomoderateatWeek4(r=0.17to0.33)andwereweakforthechangesinbothmeasuresfromBaseline(r=0.17to0.18),whichwasexpectedgiventhedifferencesinreferenceperiodforthesemeasures(ie,ASDDItem2dailyassessmentswereaveragedovera7-dayperiodwhereassweatproductionwasassessedatasinglepointintime,onceeachweek).Similartrendswerenotedforboththeadultandpediatricpopulationsinthephase3study.Exploratoryanalysestoevaluatetherelationshipbetweenallnewlydevelopeditems(ASDD,WeeklyImpact,PGIC)showedstrongrela-tionshipsacrossthedifferentmeasures.ASDDinter-itemcorrelationswereall�0.80.Whileseverity,impact,andbothersomenessintheASDDmayrepresentdifferentconstructsofhyperhidrosis,theyarelikelytobestronglyassociatedwithoneanother.Furthermore,ASDDItem2wasstronglycorrelatedwiththeWeeklyImpactsummary.Inaddition,thecorrelationbetweenthechangefromBaselineinASDDItem2wasstronglycorrelatedwithchangefromBaselineintheWeeklyImpactsummaryandthePGICatWeek4(Table5).Finally,ASDDitemsad-dressingtheimpactandburdenofsweating(Items3and4,respectively)demonstratedasimilarpatternofcorrela-tions(strongcorrelationswithHDSSandWeeklyImpactsummary,moderatetostrongcorrelationwithDLQI,andaweakcorrelationwithsweatproduction),thoughresults Table4ASDD/ASDD-CMeasurementPropertiesEvaluatedinPhase2andPhase3TrialsMeasurementPropertyPhase2:DRM04-HH02(N=105)Phase3Pool:ATMOS-1&ATMOS-2Age9–15Years(N=32)Age
16Years(N=665)Mean±SD[median]FloorandCeilingEffects,Non-responseBias,N(%)AxillarySweatingSeverity(Item2)Baselinea6.8±1.9[7.0]6.8±2.5[7.0]7.2±1.6[7.4]Minimum(0)3(2.9%)0(0%)1(0.2%)Maximum(10)9(8.6%)6(18.8%)83(12.5%)Impact(Item3)Baselinea2.2±0.9[2.2]N/A2.4±0.9[2.3]Minimum(0)12(11.4%)31(4.7%)Maximum(4)10(9.5%)105(15.8%)Bothersomeness(Item4)Baselinea2.3±0.9[2.3]N/A2.6±0.9[2.6]Minimum(0)11(10.5%)13(2.0%)Maximum(4)15(14.3%)145(21.8%)Test-RetestReliability,ICCAxillarySweatingSeverity(Item2)Week4–Week30.910.920.94Impact(Item3)Week4–Week30.89N/A0.90Bothersomeness(Item4)Week4–Week30.88N/A0.89Item2ResponsivenessWeek4–BaselineSweatProduction,brc0.

21f0.01d,e0.22d,eEffectSizeofChange(SDBaselineunits)Š2.2Š2.0Š2.4StandardizedResponseMeanŠ1.6Š0.70Š1.5ASDDAxillarySweatingDailyDiary,ICCIntraclasscorrelation,SDStandarddeviationaForsubjectswithWeek4scoresbMeasuredgravimetricallycBasedonthechangefromBaselinetoWeek4inASDDItem2scoresandsweatproductiondSpearmancorrelationcoefficienteBasedonthechangefromBaselinetoWeek4inASDDItem2scoresandthenaturallogarithmofsweatproductionfPearsoncorrelationcoefficientNelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 Page8of13 weremixedwithrespecttoItems3and4correlationwithPGICforthephase2andphase3datasets,withstrongercorrelationsobservedinthephase3set(Table5).Known-groupsvalidityStatisticallysignificantdifferencesinmeanASDDItem2scoresandHDSSgradestrata(p0.0001),gravimetrically-measuredsweatproductionquartile(p=0.009forphase2;p0.001forphase3)atWeek4,andDLQI(p0.0001)(Table6)supporttheknown-groupsvalidityofASDDItem2intheadultpopulation.Similartrendswerenotedinthephase3pediatricpopulationforHDSSScores.WhileASDDItem2scoreswerehigher(moreseverepatient-reportedsweating)forpatientswithgreatersweatpro-duction(4.1vs6.3),thedifferencewasnotstatisticallysignificant,whichcouldinpartbeduetothesmallersamplesizeinthepediatricpopulation(n=32).Only1pediatricpatientreportedaverylargetoextremelylargeHRQOLimpactduetheirskinconditionontheC-DLQI;thispatientreportedameanweeklyASDDscoreof9.8comparedto4.4inthegroupwithminimalHRQOLimpact.AlthoughnospecificpredictionswerepreplannedforASDDItems3(impact)and4(bother),datainTable6showthattheseitemswerealsoabletodiscriminatebetweenknowngroups.ResponsivenessTheresponsivenessofASDD/ASDD-CItem2(abilitytodetectchangeinsweatingseverity)wasdemonstratedbylargeeffectsizes(rangingfromŠ2.2toŠ2.4),aswellasbycorrelationsthatwerewithintheexpectedrangeforthechangeinItem2andthechangeinthegravimetricmeasuresofsweatproduction(Table4).Inaddition,thecorrelationbetweenthechangefromBaselineinASDDItem2wasstronglycorrelatedwithchangefromBase-lineintheWeeklyImpactsummaryandthePGICatWeek4(Table5). Table5ASDDConstructValidityCorrelationsatWeek4(Phase2data;N=105orPhase3data;N=697)ASDDItemHDSSGrade,PearsoncorrelationSweatProduction,aPearsoncorrelationDLQI/C-DLQI,SpearmancorrelationWeeklyImpactSummary,PearsoncorrelationPGIC,SpearmancorrelationWeek4AverageAxillarySweatingSeverity(Item2)Phase20.73*0.33*N/A0.52*0.62*Phase39–15yo0.71*0.170.51*N/AN/APhase3
16yo0.70*0.18*0.61*0.66*0.70*Impact(Item3)Phase20.71*0.24*N/A0.62*0.65*bPhase3Pooled0.72*0.13*0.65*0.68*0.65*Bothersomeness(Item4)Phase20.79*0.27*–0.64*0.70*bPhase3Pooled0.74*0.13*0.66*0.69*0.66*ChangefromBaselinetoWeek4AxillarySweatingSeverity(Item2)Phase20.57*0.17N/A0.65*0.48*Phase39–15yo0.71*0.170.51*N/AN/APhase3
16yo0.70*0.180.63*0.62*0.68*Impact(Item3)Phase20.51*0.05N/A0.57*0.27*Phase3Pooled0.64*0.010.51*0.65*0.57*Bothersomeness(Item4)Phase20.58*0.13N/A0.61*0.31*Phase3Pooled0.65*0.020.53*0.65*0.59*ASDDAxillarySweatingDailyDiary,HDSSHyperhidrosisDiseaseSeverityScale,PGICPatientGlobalImpressionofChange*p0.05aMeasuredgravimetricallybWeeklyaverageforPGICisnotapplicableEntriesmarkedN/Aindicatethattheassessmentwasnotperformedforthatstudyand/orpopulationNelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 Page9of13 Table6Known-GroupsValidity–ASDDbyHDSS,Gravimetry,andDLQI/CDLQIseveritythresholdsatWeek4Phase2:DRM04-HH02(N=105)Phase3Pooled:ATMOS-1&ATMOS-2Age9–15Years(N=32)Age
16Years(N=665)ASDDItem2(Week4Average)HDSS,mean(SD)Grade10.9±1.2(n=35)2.0±0.6(n=5)1.1±1.6(n=208)Grade
35.3±1.4(n=14)6.8±1.86(n=13)6.5±2.1(n=154)p-value0.0010.0010.001SweatProduction,amean(SD)1stQuartile1.8±1.7(n=19)4.1±3.2(n=3)2.6±2.6(n=166)4thQuartile3.4±2.0(n=20)6

.3±1.9(n=15)4.2±2.8(n=168)p-value0.0090.1250.001DLQI/C-DLQI,mean(SD)NotomoderateimpactN/A4.4±2.5(n=27)2.9±2.5(n=571)VerylargetoextremelylargeimpactN/A9.8(n=1)7.3±2.4(n=7)p-valueN/AN/Ab0.001ASDDItem3(Week4Average)HDSS,mean(SD)Grade10.2±0.4(n=35)N/A0.2±0.3(n=182)Grade
31.5±0.7(n=14)N/A2.1±1.0(n=114)p-value0.001N/A0.001SweatProduction,amean(SD)1stQuartile0.5±0.6(n=19)N/A0.7±0.8(n=146)4thQuartile1.0±0.7(n=20)N/A1.2±1.0(n=134)p-value0.026N/A0.001DLQI/C-DLQI,mean(SD)NotomoderateimpactN/AN/A0.8±0.9(n=508)VerylargetoextremelylargeimpactN/AN/A3.0±1.0(n=5)p-valueN/AN/A0.001ASDDItem4(Week4Average)HDSS,mean(SD)Grade10.2±0.3(n=35)N/A0.2±0.3(n=182)Grade
31.7±0.7(n=14)N/A2.3±1.0(n=114)p-value0.001N/A0.001SweatProduction,amean(SD)1stQuartile0.5±0.5(n=19)N/A0.8±0.8(n=146)4thQuartile1.2±0.7(n=20)N/A1.3±1.0(n=134)p-value0.002N/A0.001DLQI/C-DLQI,mean(SD)NotomoderateimpactN/AN/A0.9±0.9(n=508)VerylargetoextremelylargeimpactN/AN/A3.0±1.1(n=5)p-valueN/AN/A0.001ASDDAxillarySweatingDailyDiary,HDSSHyperhidrosisDiseaseSeverityScale,SDStandarddeviationaMeasuredgravimetrically;bNotcalculableduetosamplesize(N=1)Pvaluefortwosamplet-testHDSSGrade1=Mysweatingisnevernoticeableandneverinterfereswithmydailyactivities;Grade3=Mysweatingisbarelytolerableandfrequentlyinterfereswithmydailyactivities;Grade4=MysweatingisintolerableandalwaysinterfereswithmydailyactivitiesQuartilesforgravimetricmeasurementofsweatproductionatWeek4definedas25thpercentile(8.7mg/axilla/5min)and75thpercentile(34.95mg/axilla/5min)DLQI:notomoderateimpact=range0–10;largetoextremelylargeimpact=range21–30;CDLQI:notomoderateimpact=range0–12;largetoextremelylargeimpact=range19–20Nelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 Page10of13 APGICratingof“moderatelybetter”withinthisscalecorrespondedtoa3.8-pointchangeontheASDDItem2inbothphase2andphase3studies(Table7).A“moderatelybetter”categorywasusedtoindicateaclin-icallymeaningfulchangefromthepatientperspective.PatientsachievingreductionsinweeklyaveragescoresonASDDItem2of
4pointsweredefinedasresponderstotreatment.Within-personchangesinHDSSscoresagainstPGICresponsesfollowedasimilartrendasthatofASDD;similarly,within-personchangescoresonASDDcalcu-latedacrossdifferentmagnitudesofchangeinHDSSscoresshowedthatasHDSSscoresimproved,sodidASDDscores(Tables7and8).DiscussionThepurposeofthisresearchwastodeveloptheASDDandASDD-CanddemonstratevalidityofItem2,intendedtomeasureseverityofaxillarysweatingamongpatientswithaxillaryhyperhidrosisinbothadultsandpediatricpatientsaged9andabove.Qualitativeandquantitativeanalysespresentedheredemonstratestrongrelationshipswithotherestablishedoutcomesinhyperhidrosis(constructandknown-groupsvalidity),goodreproducibility(reliability),andestablishmentofathresholdindicatingameaningfulmagnitudeofresponseviaanchor-basedmethods(respon-siveness)foruseinevaluatingaxillaryhyperhidrosistreat-mentsininterventionalstudies.Validationanalyseswerehighlyconsistentbetweenthephase2andphase3studies,providingincreasedconfidenceinASDDmeasurementpropertiesandparticularlytheresponderdefinition.Thisresearchhighlightstheimportanceofcapturingthepatientperspectiveforthiscondition,particularlyinlightofthelimitationsassociatedwithmoreobjectivemethodsofassessingsweatproduction.Giventhelevelofunmetneedamonghyperhidrosispatients,novelassessmenttoolsareneededtosupport Table7ResponderEstimatesforASDDAxillarySweatingSeverityItem(Item2):Anchor-BasedMethod(Phase2Data)PGICResponsePhase2:DRM04-HH02(N=105)Phase3Pooled:ATMOS-1&ATMOS-2(N=697)n(%)ASDDAxillarySweatingSeverity(AverageWeeklyChange),mean±SD[median]n(%)HDSSchangescore(AverageWeeklyChange),mean±SD[median]n(%)ASDDAxillarySweatingSeverity(AverageWeeklyChange)

,mean±SD[median]n(%)HDSSchangescore(AverageWeeklyChange),mean±SD[median]1=Muchbetter50(64.1)Š5.1±2.5[Š5.5]45Š1.9±0.80[Š2.0]276(39.6)Š5.7±2.05[Š5.7]276(39.6)Š2.0±0.71[Š2.0]2=Moderatelybetter11(14.1)3.8±2.7[3.4]101.5±0.71[1.0]111(15.9)3.8±2.28[3.7]111(15.9)1.4±0.66[1.0]3=Alittlebetter13(16.7)Š2.3±1.2[Š1.9]14Š0.6±0.76[0.0]119(17.1)Š2.3±1.97[Š1.9]119(17.1)Š0.9±0.71[Š1.0]4=Nodifference4(5.1)Š1.7±0.7[Š1.9]3Š0.3±0.58[0.0]82(11.8)Š1.0±1.69[Š0.6]82(11.8)Š0.5±0.74[0.0]5=Alittleworse0–0–11(1.6)0.2±1.54[0.3]11(1.6)Š0.4±0.67[0.0]6=Moderatelyworse0–0–0–0–7=Muchworse0–0–0–0–BoldtextrepresentsthepreferredthresholdformeaningfulresponseconsistentwithFDAguidance(“moderatelybetter”)ASDDAxillarySweatingDailyDiary,PGICPatientGlobalImpressionofChange,SDStandarddeviation Table8ASDDChangeScoresAcrossHDSSImprovementsHDSSScorePhase2:DRM04-HH02(N=105)Phase3Pooled:ATMOS-1&ATMOS-2(N=697)n(%)ASDDAxillarySweatingSeverity(AverageWeeklyChange),mean±SD[median]n(%)ASDDAxillarySweatingSeverity(AverageWeeklyChange),mean±SD[median]3-pointimprovement13(16.7%)Š6.2±2.68[Š6.6]74(10.6)Š6.7±2.29[Š6.9]2-pointimprovement29(37.2%)Š5.2±2.10[Š5.3]251(36)Š5.2±2.13[Š5.4]1-pointimprovement24(30.8%)Š3.3±[Š3.2]247(35.4)Š2.9±2.17[Š3.0]Noimprovement12(15.4%)Š1.9±0.92[Š2.0]113(16.2)Š0.9±1.91[Š0.5]1-pointworsening0–12(1.7)Š0.5±1.47[Š0.5]2-pointworsening0–––3-pointworsening0–––Nelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 Page11of13 futureresearchandthedevelopmentofnewtreatments.AlthoughtheHDSShashistoricallybeenusedintheclinicaltrialsettingtocharacterizepatientswithhyper-hidrosis,itcannotbeusedinsupportofproductapprovalsbecausepatientinputwasnotformallytakenintoconsiderationduringitsdevelopment.Inaddition,theHDSScombinestwoconceptswithinthesameitem(symptomseverityandimpact),limitingtheabilitytoas-certainwhichofthetwoconceptshaschangedwithtreatment.TheASDDwasdevelopedinaccordancewiththerecommendationsoutlinedintheFDAPROguid-ancetosupportU.S.productapprovals[18].Thisinstru-mentwascreatedbasedonpatientinputandclinicalconsiderations,andtheparalleldevelopmentofapediatric-specificversionoftheASDDexpandsresearchcapabilityacrossarangeofpatientpopulations.ThisnovelPROmeasurehasaddedvalueinthatASDD/ASDD-Caxillarysweatingseverityitem(Item2)cansupportefficacyassessmentsforproductapprovalsandlabeling,whichmayfacilitateapprovalofnewtreatmentsforaxillaryhyperhidrosis.Inaddition,theresultsofqualitativeandquantitativeanalysisforimpact(Item3)andbothersomeness(Item4)supporttheirinclusionaskeyendpointsinclinicaltrials.TheWeeklyImpactitemsweredevelopedbasedonpatientinputtoexploreimpactsonvariousareasofpatients’livesandoffersvaluableinsightwithregardstohowpatientscopewiththisconditiononaregularbasis.Additionalresearchfocusingonmoredistalimpactsofthediseaseiswar-rantedtofurtherrefinetheseitems.Severalstudylimitationsshouldberecognized.Fore-most,thedevelopmentoftheASDD/ASDD-Cwasbasedonasmall,homogeneouspatientpopulation,whichmaynothavereflecteddifferentlevelsofdiseaseseverity;additionally,thepediatricpatientsdidnothaveaphys-ician-confirmeddiagnosisofhyperhidrosisforthequali-tativedevelopment.Patientsincludedinthephase2andphase3trialswerealsorelativelyhomogeneous(ie,simi-lardiseaseseverityanddemographiccharacteristics),po-tentiallylimitinggeneralizabilityofthemeasure.Inaddition,thoughtheaxillarysweatingseverityitemisequivalentbetweentheASDDandASDD-C,thecohortofpatients
9and16yearsinthephase3trialswassmall.Despitethislimitation,ASDD-Cdatainthepediatricpopulationdemonstrateresultsbroadlyconsist-entwiththoseofadults.ThefocusofthisresearchwasprimarilyontheASDDItem2;whileexploratoryanalysesshowedthatallthenewlydevelop

editemsdem-onstratedconsistencywithoneanother,dimensionalitywasnotformallyassessedtobetterunderstandtheirre-lationshipwithoneanotherandwhetheritwouldbeappropriatetoderivesummaryscores.Italsoshouldbenotedthatinitialdraftitemspertainingtoseverityweredevelopedbeforepatientengagement,whichasamatterofprocessmaybedisadvantageouswhenseekingtoidentifyconstructsdirectlygermanetoapatient;how-ever,forthishyperhidrosismeasure,theconceptofsweatingseveritywasthefocusofthestudy(Item2)andwasconsideredtobebothstraightforwardandunam-biguouslyrelevant.ConclusionsTakentogether,therigorousdevelopmentandvalidationofASDD/ASDD-Caxillarysweatingseverityitemsup-portitsuseintheevaluationofaxillaryhyperhidrosistreatmentinclinicaltrials.Strongqualitativeandquanti-tativeevidencealsosupportstheuseoftheimpactandbothersomenessitemsaskeytrialendpointsinadulttri-als.Furtherevaluationofthismeasureinfutureresearchstudiesiswarrantedtodemonstrateconsistentperform-anceacrossdifferentaxillaryhyperhidrosispopulationsandindifferentstudycontexts.FamiliaritywiththeASDD/ASDD-CalongwiththeWeeklyImpactitemsamongclinicianswhotreatpatientswithhyperhidrosismayfacilitateabetterunderstandingoftheimpactofthisconditiononpatients’lives.AbbreviationsAHPM:AxillaryHyperhidrosisPatientMeasures;ASDD:AxillarySweatingDailyDiary;ASDD-C:Child-specificversionoftheASDD;C-DLQI:Children’sDermatologyLifeQualityIndex;DLQI:DermatologyLifeQualityIndex;GT:Glycopyrroniumtosylate;HDSS:HyperhidrosisDiseaseSeverityScale;HHIQ:HyperhidrosisImpactQuestionnaire;HidroQOL:HyperhidrosisQualityofLifeIndex;HRQOL:Health-relatedqualityoflife;NHP:NottinghamHealthProfile;PGIC:PatientGlobalImpressionofChange;PRO:Patient-reportedoutcome;SD:Standarddeviation;SF-36andSF-12:ShortFormHealthSurveysAcknowledgementsMedicalwritingsupportwasprovidedbyPrescottMedicalCommunicationsGroup(Chicago,IL)withfinancialsupportfromDermira,Inc.Authors’contributionsLN,DD,andSF:Methodology,datagenerationandanalysis,manuscripteditingandapproval.DMP,AAH,DAG:Methodology,analysis,manuscripteditingandapproval.HH,JD,KKGandDI:Concept,analysis,manuscripteditingandapproval.Allauthorsreadandapprovedthefinalmanuscript.FundingThesestudieswerefundedbyDermira,Inc.RTI-HSconductedtheresearchdescribedinthismanuscript.AvailabilityofdataandmaterialsThedatathatsupportthefindingsofthisstudyareavailablefromDermira,Inc.,butrestrictionsapplytotheavailabilityofthesedata,whichwereusedunderlicenseforthecurrentstudy,andsoarenotpubliclyavailable.DataarehoweveravailablefromtheauthorsuponreasonablerequestandwithpermissionofDermira.EthicsapprovalandconsenttoparticipateSourcedatawerefromtwophase3clinicaltrialsthatwerereviewedandapprovedbylocalinstitutionalreviewboardsandindependentethicscommitteesonMay13,2015.ConsentforpublicationNotapplicable.Nelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 Page12of13 CompetinginterestsLN,DD,andSF:EmployeeofRTIHealthSolutions.DMP:Consultant(honoraria):BrickellBiotech,Inc.;BiofronteraAG;Celgene;Dermira,Inc.;DUSAPharmaceuticals,Inc.;LEOPharma;Novartis;PromiusPharma,LLC;RegeneronPharmaceuticals,Inc.;Sanofi;TheraVida,Inc.;ValeantPharmaceuticalsInternational,Inc.Advisoryboard(honoraria):Pfizer,Inc.Investigator(grants/researchfunding):AbbottLaboratories;Amgen,Inc.;BrickellBiotech,Inc.;Celgene;DermavantSciences;EliLillyandCompany;LEOPharma;Merck&Co,Inc.;Novartis;NovoNordiskA/S;OrthoDermatologics;Peplin,Inc.;PhotocureASA;PromiusPharma,LLC;RegeneronPharmaceuticals,Inc.;StiefelLaboratories;ValeantPharmaceuticalsInternational,Inc.Investigator(honoraria):LEOPharma;Pfizer,Inc.DAG:Consultantandinvestigator:Dermira,Inc.AAH:Investigator(researchfunding):Dermira,Inc.(paidtotheUTHealthMcGovernMedicalSchool

,Houston).Advisoryboard(honoraria):Dermira,Inc.Researchfunding(allmoniespaidtotheUTHealthMcGovernMedicalSchool,Houston):Allergan,Plc.;Amgen,Inc.;Cassiopea;Celgene;DermavantSciences;EliLillyandCompany;GaldermaS.A.;GSK,Plc.;LEOPharma;MaynePharma;MedimetriksPharmaceuticals;Novan,Inc.;PromiusPharma,LLC;VandaPharmaceuticals.Honoraria:Amgen;GSK,Plc.;Pfizer,Inc.;ValeantPharmaceuticsInternational,Inc.HH,JD,KKG,andDI:EmployeeandstockholderofDermira,Inc.Authordetails1RTIHealthSolutions,200ParkOfficesDrive,ResearchTrianglePark,NC27709,USA.2EasternVirginiaMedicalSchoolDepartmentofDermatologyandVirginiaClinicalResearch,Inc,6160KempsvilleRoadSuite200A,Norfolk,VA23452,USA.3DepartmentofDermatology,SaintLouisUniversity,1755S.GrandBlvd,St.Louis,MO63104,USA.4DepartmentofDermatology,UTHealthMcGovernMedicalSchoolatHouston,6655Travis,Suite980,Houston,TX77030,USA.5Dermira,Inc,275MiddlefieldRoad,Suite150,MenloPark,CACA94025,USA.Received:3August2018Accepted:15August2019 References1.Grabell,D.A.,&Hebert,A.A.(2017).Currentandemergingmedicaltherapiesforprimaryhyperhidrosis.DermatologyTherapy(Heidelb),7,25–36.2.Doolittle,J.,Walker,P.,Mills,T.,&Thurston,J.(2016).Hyperhidrosis:AnupdateonprevalenceandseverityintheUnitedStates.ArchivesofDermatologicalResearch,308,743–749.3.Hamm,H.(2014).Impactofhyperhidrosisonqualityoflifeanditsassessment.DermatologicClinics,32,467–476.4.Ambrogi,V.,Campione,E.,Mineo,D.,Paterno,E.J.,Pompeo,E.,&Mineo,T.C.(2009).BilateralthoracoscopicT2toT3sympathectomyversusbotulinuminjectioninpalmarhyperhidrosis.TheAnnalsofThoracicSurgery,88,238–245.5.Tetteh,H.A.,Groth,S.S.,Kast,T.,Whitson,B.A.,Radosevich,D.M.,Klopp,A.C.,D'Cunha,J.,Maddaus,M.A.,&Andrade,R.S.(2009).Primarypalmoplantarhyperhidrosisandthoracoscopicsympathectomy:Anewobjectiveassessmentmethod.TheAnnalsofThoracicSurgery,87,267–274discussion274-265.6.Patrick,D.L.,&Deyo,R.A.(1989).Genericanddisease-specificmeasuresinassessinghealthstatusandqualityoflife.MedicalCare,27,S217–S232.7.Hamm,H.,Naumann,M.K.,Kowalski,J.W.,Kutt,S.,Kozma,C.,&Teale,C.(2006).Primaryfocalhyperhidrosis:Diseasecharacteristicsandfunctionalimpairment.Dermatology,212,343–353.8.Weber,A.,Heger,S.,Sinkgraven,R.,Heckmann,M.,Elsner,P.,&Rzany,B.(2005).Psychosocialaspectsofpatientswithfocalhyperhidrosis.Markedreductionofsocialphobia,anxietyanddepressionandincreasedqualityoflifeaftertreatmentwithbotulinumtoxina.TheBritishJournalofDermatology,152,342–345.9.Finlay,A.Y.,&Khan,G.K.(1994).Dermatologylifequalityindex(DLQI)--asimplepracticalmeasureforroutineclinicaluse.ClinicalandExperimentalDermatology,19,210–216.10.Kowalski,J.W.,Eadie,N.,Dagget,S.,&Lai,P.-Y.(2004).Validityandreliabilityofthehyperhidrosisdiseaseseverityscale(HDSS).JournaloftheAmericanAcademyofDermatology,50.11.Solish,N.,Bertucci,V.,Dansereau,A.,Hong,H.C.,Lynde,C.,Lupin,M.,Smith,K.C.,&Storwick,G.(2007).Acomprehensiveapproachtotherecognition,diagnosis,andseverity-basedtreatmentoffocalhyperhidrosis:RecommendationsoftheCanadianhyperhidrosisadvisorycommittee.DermatologicSurgery,33,908–923.12.Naumann,M.K.,Hamm,H.,&Lowe,N.J.(2002).Effectofbotulinumtoxintypeaonqualityoflifemeasuresinpatientswithexcessiveaxillarysweating:Arandomizedcontrolledtrial.TheBritishJournalofDermatology,147,1218–1226.13.Amir,M.,Arish,A.,Weinstein,Y.,Pfeffer,M.,&Levy,Y.(2000).Impairmentinqualityoflifeamongpatientsseekingsurgeryforhyperhidrosis(excessivesweating):Preliminaryresults.TheIsraelJournalofPsychiatryandRelatedSciences,37,25–31.14.deCampos,J.R.,Kauffman,P.,WerebeEde,C.,AndradeFilho,L.O.,Kusniek,S.,Wolosker,N.,&Jatene,F.B.(2003).Qualityoflife,beforeandafterthoracicsympathectomy:Reporton378operatedpatients.TheAnnalsofThoracicSurgery,76,886–891.15.Keller,S.,Sekon

s,D.,Scher,H.,etal.(2001).Anovelscaleforassessingqualityoflifefollowingbilateralendoscopicthoracicsympathectomyforpalmarandplantarhyperhidrosis.InAbstractbookofthe4thinternationalsymposiumonsympatheticsurgery(pp.AbstractO–Abstract22)AbstractO-22.16.Kamudoni,P.,Mueller,B.,&Salek,M.S.(2015).Thedevelopmentandvalidationofadisease-specificqualityoflifemeasureinhyperhidrosis:Thehyperhidrosisqualityoflifeindex(HidroQOL(c)).QualityofLifeResearch,24,1017–1027.17.Kamudoni,P.,Salek,M.S.,Mueller,B.,&Mueller,C.(2012).Hyperhidrosisqualityoflifeindex(Hidroqol(c)):Anovelpatientreportedoutcomemeasureinhyperhidrosis.JournalofInvestigativeDermatology,132(S2),S73–S73.18.GuidanceforIndustry.(2009).Patient-reportedoutcomemeasures:Useinmedicalproductdevelopmenttosupportlabelingclaims.InUSFood&DrugAdministration(FDA).19.Comparatorstudyoftheeffectofglycopyrrolateandglycopyrroniuminsubjectswithaxillaryhyperhidrosis(DRM04-HH02).https://clinicaltrials.gov/ct2/show/study/NCT02129660?term=drm04&cond=Hyperhidrosis&rank=4.Accessed12Apr2019.20.Glaser,D.A.,Hebert,A.A.,Nast,A.,Werschler,W.P.,Green,L.,Mamelok,R.,Drew,J.,Quiring,J.,&Pariser,D.M.(2019).TopicalGlycopyrroniumTosylateforthetreatmentofprimaryaxillaryhyperhidrosis:ResultsfromtheATMOS-1andATMOS-2phase3randomizedcontrolledtrials.JournaloftheAmericanAcademyofDermatology,80,128–138.21.Lewis-Jones,M.S.,&Finlay,A.Y.(1995).TheChildren'sdermatologylifequalityindex(CDLQI):Initialvalidationandpracticaluse.TheBritishJournalofDermatology,132,942–949.22.Nunnally,J.C.,&Bernstein,I.(1994).Psychometrictheory.NewYork:McGraw-Hill.23.PatientGlobalImpressionofChange(PGIC).NationalInstituteofMentalHealth(NIMH)https://eprovide.mapi-trust.org/instruments/patient-global-impression-of-change.Accessed12Apr2019.24.Cohen,J.(1992).Apowerprimer.PsychologicalBulletin,112,155–159.25.Brandt,M.,Bielfeldt,S.,Springmann,G.,&Wilhelm,K.P.(2008).Influenceofclimaticconditionsonantiperspirantefficacydeterminedatdifferenttestareas.SkinResearchandTechnology,14,213–219.26.Hongbo,Y.,Thomas,C.L.,Harrison,M.A.,Salek,M.S.,&Finlay,A.Y.(2005).Translatingthescienceofqualityoflifeintopractice:Whatdodermatologylifequalityindexscoresmean?TheJournalofInvestigativeDermatology,125,659–664.27.Waters,A.,Sandhu,D.,Beattie,P.E.,Ezughah,F.,&Lewis-Jones,S.(2010).SeveritystratificationofChildren’sdermatologylifequalityindex(CDLQI)scores.TheBritishJournalofDermatology,163,121.28.McLeod,L.D.,Coon,C.D.,Martin,S.A.,Fehnel,S.E.,&Hays,R.D.(2011).Interpretingpatient-reportedoutcomeresults:USFDAguidanceandemergingmethods.ExpertReviewofPharmacoeconomics&OutcomesResearch,11,163–169.Publisher’sNoteSpringerNatureremainsneutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.Nelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 Page13of13 RESEARCHOpenAccess DevelopmentandvalidationoftheAxillarySweatingDailyDiary:apatient-reportedoutcomemeasuretoassessaxillarysweatingseverityL.M.Nelson1*,D.DiBenedetti1,D.M.Pariser2,D.A.Glaser3,A.A.Hebert4 ©TheAuthor(s).2019OpenAccessThisarticleisdistributedunderthetermsoftheCreativeCommonsAttribution4.0InternationalLicense(http://creativecommons.org/licenses/by/4.0/),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedyougiveappropriatecredittotheoriginalauthor(s)andthesource,providealinktotheCreativeCommonslicense,andindicateifchangesweremade. *Correspondence:lnelson@rti.org1RTIHealthSolutions,200ParkOfficesDrive,ResearchTrianglePark,NC27709,USAFulllistofauthorinformationisavailableattheendofthearticle Journal of Patient-Reported Outcomes Nelsonetal.JournalofPatient-ReportedOutcomes (2019) 3:59 https://doi.org/10.1186/s41687-019-0148-8