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Improving the Identification and Management of Adult Growth Hormone Deficiency(AGHD)A. CoverPageTitle:DevelopmentandValidationofaNovelSelf-assessmentSystembasedonaMobileApptoManageAdultGrowthHormoneDeficiency(MAGHDApp):aSingle-CentreModel.GrantIDnumber:34515061.

PrincipalInvestigator:VincenzoRochira,MD,PhD-AssociateProfessorofEndocrinologyMaincollaborators:

ChiaraDiazzi,MD,PhD–SeniorClinicianMagnaniElisa,MD-ResidentStudent

Abstract:Background:AdultGrowthHormoneDeficiency(AGHD)isarecognizedclinicalentitybutseveral barriers concerning patient-clinician communication, inadequate patients’awareness of the disease, low perceived benefit of replacement therapy and poorcompliancestillremains.Overall goal: to improve AGHDmanagement through a Smartphone app (MAGHDApp:ManageAdultGrowthHormoneDeficiency)integratedwithasoftwareframeworkabletomerge patients daily data on physical activity, quality of life (QoL), andwell-beingwithclinicaldatacollectedininstitutionaldatabases.Targetpopulation:100patientswithapreviousdiagnosisofAGHD,whetherintreatmentwithgrowthhormoneornot.Methods:Inaprospective24monthsstudy,MAGHDAppwillbedeveloped,connectedtoMAGHD Framework and validated on 100 AGHD patients. This system will allow tointegrate: 1) Physical Activity Data collected by wearable devices, 2) Patient RelatedOutcomesData,periodicallyinsertedbythepatientsthroughMAGHDAppinresponsetoquestions extrapolated from validated questionnaires, 3) HCP Data registered in clinicaldatabases and includingmedical history, biochemical and radiological examination.Datawill converge in MAGHD Framework where they will be analyzed and used to createreportsvisibletopatients(inMAGHDApp)andclinicians(byamonitoringdashboard).Assessment: The primary outcomes will be evaluated by determining the impact ofMAGHD App/Framework on: 1) patients’ QoL, well-being, physical activity, 2) patient-cliniciancommunication,3)patients’compliancetoreplacementtherapy.Theresultsareexpectedtopositively influenceAGHDmanagementbyinvolvingpatients incareprocessandgivingcliniciansausefultoolforclinicalpractice.

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B. TableofContentsC.ReviewerComments Page3D.MainSection

1.OverallGoal&Objectives Page42.CurrentAssessmentofneedintargetarea Page73.TargetAudience Page84.ProjectDesignandMethods Page95.EvaluationDesign Page136.DetailedWorkplanandDeliverablesSchedule Page16

E.References Page18F.OrganizationalDetail Page21G.DetailedBudget Page23H.StaffBiosketches Page25I.LettersofCommitment Page26J.Appendix Page27

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C. ReviewerCommentsAvailableReviewerComments:Itwasfeltthattheaimsoftheprogrammeasapurelyappbasedactivitymaybeconsideredalittleloftyandtherewasalackofanobviouslydescribed educational component to improve HCP competence and confidence.Althoughappshavethepotentialtobeanexcellentadjunctandaidtopatientcare,itwas felt that as described, the proposal was putting too much expectation on thedeliveryoftheappalone.Pleasealsonotethatthoughyoudescribedyourproposalasqualityimprovement,theLOIsuggesteditmayinvolveresearchelements.Assuch,wehavechangedtheproposaltypetodisseminationandimplementationresearch.Authors Reply: the flux of information derived from the use of theManage AdultGrowthHormoneDeficiency (MAGHD)App (by the patient) is of importance only ifcoupledwithclinicaldataderived fromclinicalevaluationandbothbiochemicalandradiological examinations. As the development and the use of the MAGHD ApprepresentsthemaininnovativeaspectofthisprojectwegaveitmajoremphasisintheLOI leaving Health Care Provider (HCP) issues in the background (the clinicalmanagementofGHDiswellstandardized).ThischoicewasmadeinconsiderationofthescarcespacewithintheLOI.ItwasnotourintentiontoonlydeveloptheMAGHDAppasthesoletoolusefultoimprovethemanagementofadultpatientswithgrowthhormonedeficiency(GHD).The development and validation of the MAGHD App represents, however, theprerequisitetoconductandfinalizethewholeproject,butthelatter ismainlybasedontheintegrationofthefluxofdataprovidedbytheMAGHDAppwiththeoutcomescoming from all the clinical examinations (included in the Institutional Databases)throughanintegratedframework(MAGHDFramework).TheintegratedresultswillbeusefultobuildadequatefeedbackfortheHCP(morecomplexinformation)andforthepatient(moresimpleinformation). InthiswaythemanagementofGHDpatientswillbenefit fromthe improvementof theawarenessaboutthepatientclinicalstatus forboththeclinicianandthepatient.

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D.MainSectionoftheproposal

1. OverallGoal&Objectives:Themaingoalofthisstudyistoevaluatetheimpactofrecordingpatient’sdailyactivitiesand self-reported feeling concerning quality of life (QoL) and well-being on themanagement of Adult Growth Hormone Deficiency (AGHD). Patients daily relatedoutcomeswillberecordedthankstothedevelopment,implementationandvalidationofaSmartphone app (MAGHD App: Manage Adult Growth Hormone Deficiency) integratedwith a software framework able to merge patient’s daily activities data on well-beingstatus, physical activities, and QoL with clinical data collected in their record chart(extrapolated fromalreadyavailable InstitutionalDatabases).The finalaim is to improveAGHDmanagementbyprovidingbothafluxofdatatotheclinician interfaceandsimplereports concerning patient’s daily activities to the patient. The results coming from theintegrationofclinicaldatawithinformationonpatientdailyactivitieswillallowtoprovidea comprehensive feedback to the clinician as well as a more simple feedback to thepatient. The integration of patient data with clinical data represents an innovativeperspective inthemanagementofAGHD.ThisapproachcouldbeeasilydisseminatedbysharingtheAppifeffectiveinimprovingthemanagementofthesepatients.BackgroundAGHD is widely recognized as a specific clinical entity and recombinant human growthhormone(r-hGH)therapyhasbecomeastandardpracticesince90s(Ho2007)thankstoitsbeneficial effects on body composition,muscle strength, bonemass, cardiovascular riskandpatients’exercisecapacityandQoL(Molitchetal.2011).Allthebeneficialeffectsofr-hGHinAGHDpatientshavebeenestablishedmainlyonselectedpopulationsbybothfewrandomizedcontrolledtrials(RCTs)andseveralclinicaltrials(Woodhouseetal.2006,vanBunderenetal.2014,Höybyeetal.2015,Newmanetal.2015).Real lifestudiesarealsoavailable, but they are mainly based on data collected through multicenter sponsoredstudies such as the Pharmacia & Upjohn International Metabolic Database (KIMS)(Bengtsson et al. 1999) and the Hypoptiuitary Control and Complications StudyInternational Advisory Board (HYPOCCS) (Attanasio et al. 2002). All these observationalstudies suffer frommissingdata in theoriginaldatabasesand/or lackadequate controlgroup(i.e.untreatedGHDpatients).Well-conductedreal lifestudieshavetheadvantagetoprovideinformationonlong-termeffectsoftherapies,aswellasonsafety,adherenceand persistence to therapy (Cohen et al. 2015). Accordingly, in clinical practice it iscommontofindadisparitybetweenhormonal levelsandpatients’subjectivewell-being:some individuals with a full-blown AGHD do not report any symptom and turn outreluctanttostartatreatment,whileotherswithslightGHdeficiency(GHD)experienceadeterioration in theirQoL that deeply improves afterGH replacement (Murray& Shalet1999).ThisismainlyduetothefactthatclinicalpresentationofAGHDisfrequentlybasedon nonspecific symptoms (Murray & Shalet 1999). Similarly, individual differences inresponsiveness to r-hGH are common findings in the real life (Alexopoulou et al. 2010,Moyesetal.2010).Moreover,whenotherhormonaldeficitscoexistandpatientshavetoface with a polytherapy, it can be difficult both for clinicians and patients to relatesymptoms to the sole AGHD and to verify benefits after treatment (Alexopoulou et al.2010). Finally, there is a lack of tools assessing patients’ physical activity, which is an

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important factor to consider when evaluating energy levels, exercise performance, andwell-being.Thus,agapstillremainsinthereallifesettingconcerninghowtomeasuretheimprovementsoccurring in r-hGHtreatedpatients (Alexopoulouetal.2010)andhowtomakepatientsandcliniciansmoreawareofthesechanges(Lazureetal.2014)(Figure1).Nowadays, considering the shortage of established predictive factors for the overalltherapeutic response, thedecision towhetherornotcontinue treatmentdependsoftenontheratioofperceivedandexpectedbenefitsovercostandrisksoftreatment,aswellasonthepersistentmotivationofthepatient(Alexopoulouetal.2010,Lazureetal.2014).These aspects involve also physician’s attitude and patient’s propensity to start r-hGHreplacement therapy. Vice versa the lack of information useful to predict patients’individualresponsetotreatmentposessomeclinicaltroublesabouthowtoselectpatientswhomay beneficiate from r-hGH therapy (Alexopoulou et al. 2010, Lazure et al. 2014).Consideringthatr-hGHtreatmentisachronictherapyrequiringadailyself-injection,long-termcomplianceisstillaconsiderableprobleminthissettingandisinfluencedbyalltheabove mentioned issues (Figure 1). It is estimated that about 20 to 30% of patientsdiscontinue the treatment, permanently or for extended periods, making therefore anobjectiveevaluationofthetherapeuticeffectsdifficult(Alexopoulouetal.2010).Alltheseaspectsareenhancedbythepaucityoftoolsavailabletoimprovepatients’educationandawarenessofAGHD.ThewidespreaduseofSmartphoneapplications (apps)presentsanopportunitytoovercomethesedifficultiesintheAGHDmanagement.Wehypothesizethatthe use of an app connected to an institutional Information system, which enables asystematic data collection from patients and Healthcare Providers (HCPs), will enhancepatients’awarenessoftheircurrentclinicalconditionandwillimprovetheirQoL(Figure1).ThroughMAGHDApppatientswilltakeanactivepartintheprocessofAGHDmanagementand, in return for entering data on daily basis, they will receive periodical reports andgraphs coupling daily,weekly, ormonthly (depending on parameter recorded) activitiesdatawiththeoutcomesprovidedbyclinicalexamination.Ontheotherside,anintegratedinformation systemable to combine in real time self-reportedpatients’ outcomes (QoL,well-being, physical activities) with the data obtained from clinical, biochemical andradiologicalexaminationsmayrepresentanimportanttooldoguideHCPsintheirclinicalpractice(Figure1).Webelieve that the integratedsoftware framework (MAGHDframework)constitutedbythe MAGHD App connected with the institutional Information System (InstitutionalDatabases), will help clinicians to better understand patients’ needs and the mostappropriatewaytotreatthem.Inthereallife,infact,themaingapconcerningtheclinicalmanagement of AGHD is represented by the lack of objective tools able to measurepatients’well-being,physicalperformance,andpsychologicalstatus(Figure1).ThismeansthattheawarenessofhowAGHDcompromisesthedailyactivitiesremains,atleastinpart,uncertainforbothAGHDpatientsandtheirclinicians.Thisrepresentsthemainbarrierforr-hGH therapy since it undermines both patients’ compliance and the clinicians’opportunity to really register changes from baseline related to r-hGH. All these aspectshave also meaningful correlates involving the patient-to-physician relationship andcommunication(Figure1).Weplantoachievetheoverallgoalbypursuingthefollowingkeyobjectives:1) to merge patient’s self-reported data with all the parameters coming from clinical,biochemicalandradiologicalexamination.Atpresentpatientself-reporteddataareusually

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scarceandcomesfromquestionnairesfilledonlyduringvisits (onceortwiceayear)andself-reportedinformationobtainedduringmedicalinterview.2)toimprovepatient-HCPcommunicationbyacontinuousfluxofinformationthroughtheMAGHDAppandtheintegratedInformationSystem;3) to improveclinicians’competenceandconfidence inAGHDmanagement,givingthemmoretoolsandinformationforevaluatingtheeffectofGHDonpatient’sclinicalstatusinterms of QoL, well-being and physical activities and tomeasure the overall therapeuticresponse;4) to improve patients’ self-awareness of their clinical status thanks to themultidimensional integration of several MAGHD data (on well-being, QoL, physicalperformance, biochemical parameters, etc...) and periodic feedback returned to thepatientssummarizinginasimplewaythemainchangesintheirdailyactivitiesandoftheparametersmonitorizedbytheMAGHDApp;5) to improve and monitor patient satisfaction and QoL related to r-hGH therapy(awarenessofr-hGHeffects);6) to test whether this intervention program improves patient care management andadherence to r-hGH therapy (improvement of patients’ motivation and awareness indecidingifthetherapyshouldbecontinuedorstopped);This project alignswith the focus of theRequest for Proposal (RFP) because it: 1) takesadvantage of mobile Apps and wearable devices technology to engage patients inmonitoring their condition, 2) facilitates communication between patients and HCPsthrough the integrated MAGHD framework, 3) helps clinicians giving them a morecomplete picture of their patients (thanks to available data on patients’s daily activitiesand well-being that are shared and matched with classic clinical data) and providingClinical Decision Support tools useful to guide AGHD management, 4) constitutes avaluabletoolforimprovingpatient’sself-education,5)implementsself-perceivedbenefitsofr-hGHtherapy,and6)employsvalidatedoutcomemeasurestoassessiftheconnectionof the MAGHD App with the Institutional Information System (the latter including allclinical, biochemical, and radiological patient’s parameters) actuallyleadstoanimprovementintheAGHDmanagement(Figure1).

Figure1.ProposedtooltofillthegapsinAGHDmanagement

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2. CurrentAssessmentofneedintargetarea

Inaphysiologicalperspective,thelackofahormoneneedsanadequatereplacement,thusr-hGH therapy should be guaranteed to all AGHDpatients. At present, data available inliteraturesuggestthatsomeclinicalandbiochemicalfactors,suchas1)lowerserumIGF-1,2)higherserumtotalcholesterol,3)higherwaistcircumferenceand4)worstQoLscore,mightpredicttheresponsetor-hGH(Schneideretal.2015).Inparticular,theworsethesefactors are atbaseline, thebetter is theexpected response to r-hGH therapy. In clinicalpractice, the shortage of tools useful to objectify the improvements induced by r-hGHmakesharderforthecliniciantodecidethebetterstrategytofaceAGHDandleavesthepatient doubtful about the real need of treatment, with repercussion on patients’compliance. The latter is high and ranges from 30 to 60% of cases in different setting(Woodhouseetal.2006,Rosenfels&Bakker2008,Zaninellietal.2008).TheEndocrinologyUnitofModenaisareferralcenterforhypothalamic-pituitarydiseasesandactuallyfollowsalargecohortofAGHDpatients(approximately120individuals).Ourgroup participated to the majority of the studies in Italy (KIMS, HypoCCS etc.) for theregistrationof r-hGH inadultsorpost-marketingobservational studiesand isworking inthisfieldfrommorethan20years.Atpresent,inourInstituter-hGHtherapyisofferedtopatientswithdocumentedGHDinthecontextofanappropriateclinicalcontext(Ho2007,Molitchetal.2011).InspiteoftheconsistentnumberofpatientsreferringtoourUnit,wedonotfollowanyspecificprotocoltomanageAGHDandthedecisiontostartorcontinuethetreatmentwithr-hGHisusuallybasedonpatient’sclinicalcondition,onhormonaltestsand on the results of the Quality of Life Assessment of Growth Hormone Deficiency inAdults (QoL-AGHDA) questionnaire (McKenna et al. 1999) and of the Questions on LifeSatisfaction Hypopituitarism (QLS-H) questionnaire (Herschbach et al. 2001, Blum et al.2003). However,with the exception of the restoration of a normal serum IGF-1 and animprovementofpatient’sQoL,nootherchangeisreallyusefultoconvinceindividualstocontinue r-hGH therapy if any subjective benefit is perceived. Furthermore, r-hGHtreatment leads to little improvements of some clinical parameters, that could not beperceivedasclinicallyrelevantbybohthepatientandtheclinician.Asamatteroffact,r-hGH increasesbonemineraldensity (BMD)after15yearsoftreatmentby5%and3%atlumbar and femoral site, respectively (Elbornsson 2012), it increases HDL-cholesterol of15% while it decreases total and LDL-cholesterol of 8% and 15% (Newman 2011,Elbornsson 2013). Changes in body composition are minimal and seem to be transient(Götherströmetal.2007,Elbornssonetal.2013).Duringthislonglastingperiodwedevelopedagreatclinicalexperienceonthe‘darkside’of AGHD management in daily practice, which includes patients’ reluctance to accepttreatment, troubles with compliance to r-hGH therapy and disappointment about theexpectedresults.Moreover,consideringthatstabilizedpatientsattendscheduledvisitsinourCenteronceortwiceayear,thedataconcerningtheirpersonalwell-beingandQoLarelimited throughout the whole year. Finally, we don’t have neither resources to assesspatients’ physical activity/exercise performance nor objectivemeasures to evaluate theperceivedbenefitsandadvantagesderiving fromr-hGHoutside thecontextof follow-upvisits. There is a need for simple tools able to identify and gather all the littleimprovements related to r-hGH therapy, in order to find strong markers of efficacy. Asystemabletocontinuouslyrecordpatient’sphysicalactivitiesanddataonwell-beingandQoL is essential to connect andmatchpatient’s subjective feeling concerningwell-beingand daily activities with the clinical data obtained through biochemical and radiological

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examination performed in the hospital. Thus, the unification of all these informationthroughtheMAGHDFrameworkmayrepresentamoreappropriateclinicaltooltomonitorchangesinducedbyr-hGHtherapyinareallifeclinicalsetting.We believe this grant would permit us to conduct a focused analysis on our cohort ofAGHD patients and to develop a self-assessment system based on an integratedsmartphonetechnologyabletofillthegapsinourtargetarea.TheuseofmobileAppsandwearable devices technology to engage patients in monitoring their condition is highlyinnovative. Although several apps exist to monitor chronic endocrinological diseases(Buijinketal.2013,Cuietal.2016,Chinetal.2016,Ryanetal.2017),nospecificapphasbeentestedinAGHDtillnow.ThedevelopmentandvalidationofamobileAppusefulforthecontinuousmonitoringofpatient’sdailyactivitieswillimprovepatients’andclinicians’awareness on several AGHD items (biochemical, psychological or related to QoL andphysicalperformance)providing integrated informationuseful to fill thegapsexistingonhowtomergetheperceived(subjective)andobjective(comingfromclinicalexaminations)patient’sstatus.3. TargetAudience:Thetargetaudienceforthisproposalincludes100AGHDpatients, whether in treatmentwithr-hGHornot.Thespecificselectioncriteriawillbe:

• Inclusioncriteria:1)HavingadocumenteddiagnosisofAGHD,accordingtothelatestEndocrineSocietyclinicalpracticeguidelines(Molitchetal.2011),2)Beingat least18 years old, 3) Having a good Italian understanding, 4) Owing smartphoneswitheitheranAndroidoriPhoneoperatingsystem 5) Patients with other pituitarydeficitswillbeenrolledonlyiftheotherhormonaldeficienciesarewellcontrolledbyreplacementtreatmentssincesixmonthsinordertoavoidtheoverlapofeffectsduetodifferenttherapies.

• Exclusion criteria: 1) Patients who do not plan to continue follow-up at theEndocrinology Unit of Modena, 2) Patients with a diagnosis of biochemical GHDoutside theappropriateclinical contextofpituitarydisease,3)Patientswithmajorpsychiatric diseases, chronic highly invalidating diseases (these patients will beconsidered not eligible for being enrolled in the study due to the impact of theunderlyingdiseaseonwell-beinganddailyactivities).

All the subjectswill be requested to sign an informed consent andwill be enrolled afterhavingobtainedtheapprovalbythelocalethicalcommittee.The population of AGHD patients attending to our Endocrinology Unit consists of 120subjectsofbothsexesand includesbothadultandchildhoodGHDonset (the latter inalesser percentage). Approximately 40%of ourAGHDpatients is not treatedwith r-hGH,according to age, clinical status, contraindications and lack of patient’s consent totreatment.Mostofthemhaveahistoryofpreviousr-hGHtherapythathasbeenstoppedduringfollowupforvariousreasons(lackofcompliance,aging,occurrenceofdiseasesthatcontraindicater-hGHadministration,pregnancy,etc.).

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We estimate that 98% of AGHD patients (N = 118) own smartphones. Of these 118subjects, we expect 90% tomeet the remaining inclusion criteria, and 85% to agree toparticipatetothestudy,foratotalenrollmentofabout100patients.Beyondtheprimarytarget,asecondarytargetaudiencewhomaypotentiallybenefitfromthe dissemination phase of this project consists of AGHD patients referring otherEndocrinologyCentersandofHCPsexternaltotheEndocrinologyUnitofModena.4. ProjectDesignandMethods:ProjectDesign

Phase1–Appdevelopmentandtesting;DataIntegration

In a prospective 24months study, an interactive smartphone app (MAGHDApp)will bedeveloped, connected to an Integrated Framework (MAGHD Framework) and tested bymeansofcomputersimulation.Thisfirstphasewillrequire6months.Subsequentlyitwillbevalidatedonanestimatednumberof100AGHDpatients(Phase2–ClinicalRealDataAcquisition);thissystemwillallowtocombinepatients’informationandHCPsclinicaloutcomes inasinglevirtualplatformandtoreturneasilyaccessibledatatobothAGHDpatientsandclinicians.ThedevelopmentoftheappandtheITtoolsusefulforsharingdataintheMAGHServerarenotavailablepublicallyatnocost.Phase2–ClinicalRealDataAcquisition

Patients with a previous documented AGHD fitting the inclusion/exclusion criteria (seeabove the Target Audience Section for further details) will be enrolled and grouped asfollows(Figure2):

• Group1:patientsonlong-termr-hGHtherapy;• Group2:patientspreviously treatedwithr-hGH,whohadstoppedthetreatment

foranyreason(age,concomitantadversereactions,contraindicationsorpersonalwill);

• Group3:patientsnevertreatedforanyreason(accordingtoage,contraindicationsorlackofpatient’sconsent).

Patients of all groups will be evaluated at baseline (6th month from the start of theprotocol),andevery6months for the following18months (visit1:baseline;visit2:12thmonth;visit3:18thmonth;visit4(lastvisit):24thmonth).

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Figure2.StudyDesign

Webelieve it is importanttoconsiderthiswholemultifacetedAGHDcohortbecausetheconnection between MAGHD App and MAGHD Framework will give us differentinformationaccording to thedifferentgroupsof study.This integratedsystemwill serveas:

• Group1:tooltoevaluatetheoveralltherapeuticresponse,toverifythecompliancetotreatment,toimplementpatient’sself-perceivedbenefitofr-hGHtherapy;

• Groups 2 and 3: tool to improve patients’ self awareness of their clinical statusthankstothemultidimensionalintegrationofseveralMAGHDdata(onwell-being,QoL,physicalperformance,biochemicalparameters,etc...).

• Finally, regardless to the different groups of study, we think that the use of MAGHDApp/MAGHD Framework will improve clinicians’ confidence in AGHD management andpromotepatients’self-educationalprogramsbasedonperiodicpersonal reports. Indeed,bothHCPsandAGHDpatientswillbenefitdirectlyfromtheprojectoutcomes.Weexpectthis intervention program to directly serve AGHD patients by providing them a tool toeasilyevaluatetheirsymptoms,toenhancetheirpersonalwell-beingandtoimprovetheiradherence to r-hGH therapy. On the other hand clinicians following AGHD patientswillbenefit from the possibility of having new tools for managing AGHD. Finally, the vastcollectionofdatathroughanintegratedsystemmaybeusefulasanincentiveforamoreeffectivepatient-HCPcommunication.

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Methods

Phase1–Appdevelopmentandtesting;Dataintegration

TheMAGHD App and the integratedMAGHD Framework will be provided by DataRiver(www.datariver.it), which is a Contract Research Organization (CRO) certified by AIFA(Italiandrugagency),foundedin2009asaSpin-OffoftheUniversityofModenaandReggioEmilia.DataRiverhasexperienceinthedesignanddevelopmentofWebandmobileAppsfor the collection, integration and semantic analysis of clinical data. DataRiver providesservices and software solutions for the Integration and Management of Clinical Datacomingfromheterogeneousdatasources,clinicaldataanalysisandsurveyscompliantwithsensitivedatasecurityandconfidentialityrequirements.TheMAGHDAppwill be designed, developed and tested by automatic software testingproceduresbefore therealvalidationonpatients.Then100AGHD individuals treatedornotwith r-hGHwill be trained to use theMAGHD App prior to effectively enter in thestudy.TheMAGHDsoftwareframeworkwillallowintegratingpatient’sPhysicalActivitydata(PA-D),constantlycollectedbywearabledevices,withpatientrelatedoutcomesdata(ePRO-D)andHCPdata(HCP-D):

• PA-Dwillbeobtainedthroughwearabledevicesandwillguaranteetheautomaticcollection of data regarding patients’ daily life activities. PA recorded by thewearabledeviceswillinclude:

o physicalactivitytypes(e.g.walking,cycling,runningetc.),o dailystepsnumber,o dailywalkingdistance,o dailycaloriesburned,o sleepduration,o sleepquality.

• ePRO-Dwill be collected via theMAGHDApp,whichwill periodically generateashort question extrapolated from the items of validated questionnaires for QoL(AGHDAquestionnaire,QLS-Hquestionnaire)and theWarwick-EdinburghMentalWell-Being Scale (WEMWBS) for well-being evaluation (Tennant et al. 2007,Gremignietal.2011).TheAppwill record thenumberof theuseranswersaswellas themissingonesand will periodically provide a visual satisfaction analogue scale on the use ofMAGHDAppusability.A simple question asking for adherence to therapy will be sent through theMAGHD App once a week only to patients of group 1 (on r-hGH therapy). Thelatter will serve to measure patient’s compliance to therapy. Patients will benotified by the MAGHD App to promptly answer the periodic surveys.Thedailysurveyscould expireafter a predefined time intervalto prevent theparticipantstocompletethemretrospectively,reducingtheriskforrecallbias.

• HCP-D will be included in the MAGHD framework integrating several clinicaldatabases. MAGHD framework will integrate patients’ records concerning theirclinicalhistoryanddatacomingfromthebiochemicalandradiologicalexamination(seebelowthemethodsofclinicalstudyforfurtherdetails).

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PA-D, ePRO-D and HCP-D will converge in the MAGHD Framework where they will beintegrated, analyzed and used to create graphs and tables visible both to patients (inMAGHDApp)andclinicians(byamonitoringdashboard).Inthiswaypatientswillbeabletorecorddataonareal-timebasisandtoreceiveperiodicreportsontheirclinicalstatus;wethinkthatthisactiveinvolvementinthecareprocessandtheeasyaccesstorelevantclinicalinformationwillmakepatientsmoreawareandconfidenttofacethechallengesinAGHDmanagement.The data collected in the MAGHD Framework database will be exploited for clinicalpurposes (clinical management of AGHD patients) and for obtaining the final outcomeusefulforthestatisticalanalysisandtheanalysisofthestudyresults.Thefeedbackreportswill be differentiated according to the user. The reports for patients will be of simpleinterpretation (e.g.% improvement/impairment ofQoL orwell-being scores; changes indailyphysicalactivities,etc.) inorder toavoidgeneratinganxietyaboutpatient’s clinicalstatus.Vice versa the report for clinicianswill be very detailed andwill coincide to thewholeintegrateddatabase.The development of the app and the IT tools useful for sharing data in the MAGHDFrameworkarenotavailablepublicallyatnocost.Phase2–ClinicalRealDataAcquisition

HCPdatawillinclude:Dataobtainedfrompatient’srecordchardorbyinterview(formissinginformation):

• anagraphicdata(dateofbirth,age,sex);• medical history information (date of diagnosis of AGHD, number of pituitary

deficits,duration intermofmonthsofAGHD,causeofAGHD,childhoodvsadultonsetofGHD);

• symptomsatthetimeofdiagnosis• testusedfordiagnosisandserumGHpeakattest;• comorbidities (hypertension,CVdiseases,DM,dyslipidemia,overweight,obesity,

osteoporosis,etc.);Dataobtainedatbaselineandatsubsequentvisitsbyphysicalexamination:

• anthropometricparameters(weight,height,BMI,waistcircumference);• clinicaldata(bloodpressure,heartrate);• clinicalsymptoms• othertherapies(especiallyotherreplacementtreatments);• otherhormonereplacementtreatments (andrelativedosage) incaseofmultiple

pituitarydeficits;Data obtained at baseline and at subsequent visits by clinical (biochemical andradiological)examinations:

• pituitary hormones serum levels (insulin-like growth factor 1 (IGF-1), insulin-likegrowth factor binding protein 3 (IGFBP-3), adrenocorticotropic hormone (ACTH),cortisol, 24-hour urinary free cortisol (UFC), thyroid-stimulating hormone (TSH),freethyroxine(fT4),freetriiodothyronine(fT3), luteinizinghormone(LH),follicle-stimulatinghormone(FSH),estradiolandprogesterone(infemales),testosterone

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and sex hormone-binding globulin (SHBG) (in men), prolactin (PRL) after 30minutesfromtheinsertionofagocannula;

• biochemicalvalues(haemoglobin,haematocrit,erythrocytes,leukocytes,platelets,renal and hepatic function, electrolytes, glycaemia, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C),triglycerides);

• other hormonal-biochemical data concerning bone metabolism: serum calciumandphosphorous,parathyroidhormone,vitaminD(25-OHvitaminD);

• dual-energy X-ray absorptiometry (DEXA) scan for assessing both bodycompositionaswellasbothbonemineralcontent(BMC)andbonemineraldensity(BMD)onwholeskeleton,atlumbarsite,andatfemoralsite;

• r-hGHtherapy(weeklydoseanddurationoftherapyinmonths),ifongoing;

Atpresent,noapp-basedsystemforthemanagementofAGHDisavailableinliteratureoronline.Allthebiochemicalandradiologicalexaminationstakepartoftheclinicalwork-upofAGHDpatientsattheUnitofEndocrinologyandareallavailablepublicallyatnocost.StatisticalanalysisProspectivechangesanalysisANOVAforrepeatedmeasureswillbeused.GroupsComparisonsFor continuous variables, the nonparametric Mann-Whitney test will be used forcomparisons for variables not normally distributed at the Kolmogorov-Smirnov test. Forcontinuous variables normally distributed will be tested by means of ANOVA (or t-testwhenapply).Categoricalvariableswillbecomparedusingthechi-squaretestanddatawereexpressedaspercentages.A Spearman correlation coefficient test will be used to check for association betweenvariables,innon-parametricvariables.Inorder to identifypossiblepredictive factors forGH response to treatmenta stepwise,linear,multipleregressionanalysiswillbeperformedbasedonaprevioussingleregressionanalysisforeachpredictorindependentvariableusefulforidentifyingcandidatepredictivevariables.Aunivariateanalysiswillbeperformedpriortomultivariateanalysis.Statisticalanalysiswillbeperformedusingthe‘StatisticalPackagefortheSocialSciences’softwareforWindows(version16.0;SPSSInc.,Chicago, IL).Forallcomparisons,pvalues<0.05wereconsideredstatisticallysignificant.

5. EvaluationDesign

Phase1–evaluationdesign

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Alltheactivitiesperformedduringphase1willbeevaluatedbyautomaticsoftwaretestingproceduresabletocheckifthedatacomingfromtheMAGHDApparecorrectlyrecordedand transmitted to the MAGHD Framework. Possible developments errors will becorrectedbyreleasingsoftwareupdatesontheMAGHDApporthe informationMAGHDFramework.Phase2–evaluationdesignThedataavailableintheMAGHDFrameworkwillservefortwodifferentoutputs,thefirstone directed to the user of the App (the patient) and the second one directed to theclinician.Outputforpatients:Thepatientwillreceiveperiodicallyafeedbackconcerningi)theresultsofquestionnaires(twice a month); ii) their physical activity (once a week). These reports will provideinformationoni)%changeoftheirQoLandwell-being(questionnaires)andii)changesindailyphysicalactivities(asreportedinthemethodsection).This kind of reportwill enhance patient’s awareness on day-by-day changes (if present)related to their clinical condition. Inparticular frequent feedbackonQoLandwell-beingwill provide amore objective evaluation of these parameters, thusminimizing possibleinterferencedueto lifeeventsoccurredclosetotheday inwhichthequestionnairesarefilled.Asummaryofthepatient’sclinicaloutcomeswillbeprovidedthroughtheMAGHDAppina simple graphical way in order to communicate changes in serum IGF-1 (the mainbiochemicalmarkerofr-hGHtherapy)andlipidprofile.Thesedatawillnotsubstitutetheofficialclinicalreportpatientswillreceiveaftereachscheduledvisit.Outputforclinicians:Throughthemonitoringdashboardclinicianswillbeable:1)toevaluatetherelationshipamongthedatacomingfromMAGHDAppandtheGH/IGF-1 statusof thepatient. Thiswill add informationonhow theGH/IGF-1 status is able toinfluence daily activities, well-being, and QoL on the basis of continuousmonitoring ofthese parameters. At present, patients with GHD provide this information only duringscheduledvisits,whichareusuallyperformedeverysixmonthsorannually.2) to compare the threegroupsof studydifferingeachother for theexposure to r-hGHtherapy(Figure2)intermsofQoL,well-being,anddailyphysicalactivities(MAGHDApp).3) tocompare foreachpatientwithin the threedifferentgroupschanges frombaseline.ThiscomparisonwillprovideinformationonhowtheuseoftheMAGHDAppwillinfluenceQoL,well-being,anddailyphysicalactivitiesineachdifferentgroup.4) to obtain information on compliance through the question on adherence to r-hGHtherapythatwillbeadministeredonlytopatientsofGroup1.Clinicianwillalsobeabletoevaluatehowtheadherencetotherapyismodifiedovertime(fromthestarttotheendof

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theprotocol study)onlybyadministeringperiodically thisquestion through theMAGHDApp(patient’sawarenessoncompliance).5) to evaluate theeffectsof daily physical activities as recordedby theMAGHDApponlipidprofile,weight,BMI,andbodycomposition.6) to check user’s satisfaction aboutMAGHDApp through the number ofmessages theuserhasreturnedandthevisualsatisfactionanaloguescaleontheMAGHDApp.7) to perform subgroup analyses (childhood vs adult onset; younger vs older patients;malesvsfemales;isolatedGHDvsmultiplepituitarydeficits;etc.)assecondaryendpoints.EvaluationofoutcomesdisseminationIf successful, pilot data from this studywill be used to sustain the dissemination of theMAGHD App to other Endocrinology Units. The project will be disseminated throughpublication on indexed international journals and will be evaluated by number ofpapers/citationsreceivedinscientificandacademiccontext.ExpectedResultsandFutureDirections

ThisstudywillprovideinformationusefulforscientificadvancementinthefieldofAGHDand its treatment since itwill givenew insightabout the clinicalutilityof anApp in themanagementofAGHDpatients.IncaseofevidenceofclinicaleffectivenessoftheMAGHDApp,thisclinicaltoolmaybedisseminatedworldwideandbecomeausefulinstrumentformonitoringAGHDpatientsduringdaily clinical practiceor even in the contextof clinicalstudies.Inparticular,theMAGHDAppcouldbemadeavailableonthewebandcouldbedownloaded by patients or clinicians who intend to use it for the above-mentionedpurposes.To pave the way for MAGHD App dissemination to AGHD patients referring to otherEndocrinologyUnits,thefollowingstepswillbetaken:1)therealusefulnessandeffectivenessoftheAppwillbeverifiedbeforethedisseminationphase;2)theAppwillbemadeavailableforotherCenters(withadjunctivecostsrequired).Inthiscase,aSupportServicewillbecreated,includingane-mailaddress,toassistcliniciansandpatientsinusingMAGHDAppandMAGHDFramework.Alternatively,theMAGHDAppwillbemadeavailableonthewebfordownloadingtogetherwithinformationalandeducationalmaterial.Moreover,webelievethismodeliseasilyapplicabletootherendocrinologicaldisorders,asithasthepotentialtoenhancethecommunicationbetweencliniciansandpatients,tohelppatients to better understand their symptoms and accept their condition and to improveHCPscompetenceinchronicdiseasesmanagement.TheuseoftheMAGHDAppmightalsoapplyfor:1)improvingAGHDpatientsmanagementworldwide2)designingfutureprospectivestudies:

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2a) comparing patients with a new diagnosis of AGHD before and during r-hGHtherapy2b)tailoringthedoseofr-hGHtothepatientnotonlyonthebasisofIGF-1,butalsobyusingdataprovidedbytheApp3b)predictingsubgroupsofAGHDpatientsthatmaybeneficiatemorefromr-hGH.

6. DetailedWorkplanandDeliverablesSchedule:

IftheprojectwillbechosenandsupportedbyPfizer,thestudyprotocolwillbewrittenandsubmitted to the Local Ethical Committee; the approval constitutes an essentialprerequisiteforconductingthewholestudy.Theprojectwillbecarriedoutin24months.Months1-6willfocuson:1)Appdevelopment,2)IntegratedFrameworkdevelopment,3)Apptesting.Aftertheinitialdevelopmentphase,duringthe5thmonth,thestudystaffwillreceivedidactictrainingfromDataRiverregardingtheuseofMAGHDAppandoftheMAGHDframework.Patientenrollmentandbaselinevisitswilloccurbetweenmonths1and6.Therecruitedpatients,afterhavingsignedtheinformedconsent,willbetrainedtousetheMAGHDApppriortoeffectivelyenterthestudy.Six-monthvisits(3visits)willoccurbetweenmonths12and24.An interim analysis will be performed after the first six months of follow-up to have anindicationof thepreliminaryresultsobtained,whilethefinaldataanalysiswilloccuraftercompletion of the protocol study. After the end of data analysis,manuscriptwriting andoptimizationofMAGHDAppforpublicdisseminationwillbecompleted.Itisexpectedthatthe finaldataanalysis, themanuscriptpreparationand theAppdisseminationwillexceedtheprotocoldurationof24months.ThemilestonesanddeliverablesaredescribedinTable1.Even if the timeline is intense,weareconfident that thisproject is feasiblewithin the24monthsperiodbecause:1)theEndocrinologyUnitofModenaandDataRiverhavealreadycollaborated to several projects demonstrating a great ability to develop useful tools forclinicalstudies,2)theInvestigatorshaveaveryhighexperienceinrecruitingAGHDpatientsforclinicalstudies.

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Table1.WorkplanandDeliverableSchedulesoftheProject

Year1 Year2 MonthsDeliverable 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

StudySet-UpFullprotocolSubmissionto the Local EthicalCommitteeandApproval

TheLocalEthicalCommitteeapprovalconstitutesaprerequisiteforconductingthewholestudy.Thus,theonsetofthestudywillcoincidewiththeApproval.

Phase1 SmartphoneAppandIntegratedFrameworkDevelopmentAppDevelopment X X X X Integrated Frameworkdevelopment

X X X X

App Testing andValidation

X X

ProjectStaffTraining X Phase2 ClinicalRealDataAcquisitionPatients EnrollmentandBaselineStudyVisits

X X X X X X

PatientsTraining X Follow-upVisits X X XPhase3 DataAnalysisandManuscriptPreparationDataanalysis X^ X*Manuscriptpreparation X*Dissemination X*^Interimanalysisfortheoutcomeofpreliminaryresults.*Thefinaldataanalysis,manuscriptpreparationanddisseminationphasewillexceedtheprotocoldurationof24months.

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J.Apendix

Abbreviations

ACTH:AdrenocorticotropicHormoneAGHD:AdultGrowthHormoneDeficiencyDEXA:Dual-EnergyX-rayAbsorptiometryePRO-D:PatientRelatedOutcomesDataFSH:Follicle-StimulatingHormonefT4:FreeThyroxineGH:GrowthHormoneHCP:HealthcareProviderHCP-D:HCPData HDL-C:High-DensityLipoproteinCholesterolIGF-1:Insulin-likeGrowthFactor1LDL-C:Low-DensityLipoproteinCholesterolLH:LuteinizingHormoneMAGHDApp:ManageAdultGrowthHormoneDeficiencyAppPA-D:ActiveTaskData QoL:QualityofLifeQoL-AGHDA:QualityofLifeAssessmentofGrowthHormoneDeficiencyinAdultsQLS-H:QuestionsonLifeSatisfactionHypopituitarismRFP:RequestforProposalsr-hGH:recombinanthumanGrowthHormoneTC:TotalCholesterolTSH:Thyroid-StimulatingHormoneUFC:UrinaryFreeCortisolWEMWBS:Warwick-EdinburghMentalWell-BeingScale