sensory perception of an experimental mouthwash for … · sialogogues such as parasympathomimetic...

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2018Vol.2 No.2:5

Research Article

Journal of Oral Medicine

1© Under License of Creative Commons Attribution 3.0 License | This article is available in: http://www.imedpub.com/journal-oral-medicine/

Varghese R1*, Jose A1, Singh ML2, Magnuson B2, Farag A2,3, Kafasis N2, Tzavaras E2 and Papas A2

1 GSK Consumer Healthcare, Weybridge, Surrey, UK

2 TuftsUniversitySchoolofDentalMedicine, Boston, MA, USA

3 DepartmentofOralDiagnosticSciences,KingAbdulAzizUniversityFacultyofDentistry,Jeddah,SaudiArabia

*Corresponding author: Dr.RoshanVarghese

[email protected]

GSK Consumer Healthcare, St George's Avenue,Weybridge,Surrey,KT130DE,UK.

Tel: +44 1932 826 954

Citation: VargheseR,JoseA,SinghML, MagnusonB,FaragA,etal.(2018)SensoryPerceptionofanExperimentalMouthwashforDryMouthSymptoms:TwoRandomizedClinicalStudies.JOraMedVol.2No.2:5

Sensory Perception of an Experimental Mouthwash for Dry Mouth Symptoms:

Two Randomized Clinical Studies

Abstract Title: Sensoryperceptionofanexperimentalmouthwashfordrymouthsymptoms:tworandomizedclinicalstudies.

Background: Adrymouthaccompaniedbysalivaryhypofunctioncannegativelyaffectmastication,deglutitionandspeakingandcancontributetodentalerosion,caries, halitosis andperiodontitis.Oralmucosal surfaces consequently becomedesiccated, friable, andmore susceptible to abrasion so it’s essential that anytreatmentusedbyapersonwithdrymouthisgentleontheoralmucosa.Here,tworandomized,examiner-blindstudiesutilizedquestionnairestoassesssensoryperception of an experimental mouthwash in participants experiencing drymouth,somewithSjögren’ssyndrome(SS),incomparisontowater.

Methods and findings: In Study 1 (single-dose, crossover), participants rinsedwith15mLmouthwashorwaterfor30-seconds.Theprimaryefficacyvariablewaspost-productuseresponseto ‘Thisproduct isgentle’ (five-itemLikertscale). InStudy2(8-day,parallel-group),participantsrinsed1–2x/dayathomewith15mLmouthwashfor30secondsorusedwaterasrequired.Supervisedadministration(15mLof assignedproduct for 30 seconds)was carriedoutonDays1, 3, and8, followedbycompletionofa four-questionsensoryquestionnaire (secondaryvariables). In Study 1 (n=55), most participants agreed/strongly agreed thatmouthwash (78.2%)andwater (89.1%)weregentle (similar results forSS/non-SSparticipants).InStudy2(n=100),atDay8therewerenobetween-treatmentdifferencesinoveralllikabilityorflavorpleasantness.Significantdifferenceswerefoundinfavorofthemouthwashforfreshness(0.89[95%CI0.46,1.33])andinfavor of water for gentleness (-0.57[-1.03, -0.11]). There were no treatment-relatedadverseeventsinStudy1andeightmild-moderateadverseeventswiththemouthwashinStudy2.

Conclusions:Participantswithdrymouthwith/withoutSSperceivedlikabilityandflavorpleasantnessoftheexperimentalmouthwashtobesimilartowater,withdifferencesinperceivedfreshnessandgentleness.Thismouthwashmaythereforebesuitableforusebypeopleexperiencingdrymouth.

Keywords: Dry mouth; Gentleness; Moisturization; Mouthwashes; Sjögren’ssyndrome, Water

Abbreviations: AE: Adverse Event; ANCOVA: Analysis of Covariance; ANOVA:Analysis of Variance; CPC: Cetylpyridinium Chloride; ITT: Intent-to-Treat; OHT:OralHardTissue;OST:OralSoftTissue;PP:PerProtocol;PPUQ:Post-ProductUseQuestionnaire;PPUSQ:Post-ProductUseSensoryQuestionnaire;PPAQ:ProductPerformance Attribute Questionnaire; SD: Standard Deviation; SS: Sjögren’sSyndrome;TEAE:Treatment-EmergentAE;VAS:VisualAnalogueScale

Received: April19,2018; Accepted: April26,2018;Published: May02,2018

2018Vol.2 No.2:5Journal of Oral Medicine

2 This article is available in: http://www.imedpub.com/journal-oral-medicine/

IntroductionDrymouthmayaffectnearlyhalfoftheadultpopulationatsomepoint in their lives,with prevalence varying depending on thediagnosticcriteriaused[1,2].OraldrynessmaybeaconsequenceofanunderlyingmedicalconditionsuchasSjögren’ssyndrome(SS)[3,4],othercongenitaloriatrogenicsalivaryglanddysfunction[5],asideeffectofsomemedications/chemotherapy,radiationtotheheadandneckregion[6-10],orduetograftversushostdisease[11].

A dry mouth accompanied by salivary hypofunction cannegatively affect mastication, deglutition, and speaking [12].Furthermore,lowsalivaryflowcancontributetodentalerosionandcaries,halitosis,andperiodontitis[3].Oralmucosalsurfacesconsequentlybecomedesiccated,friable,andmoresusceptibletoabrasion[3].Asaresult,manyeverydayoralhygienetreatmentsmay not be gentle enough for individuals with dry mouth. Inan observational study, Chevalier et al. [13] concluded thatmouthrinses,predominantlycontainingquaternaryammoniumcompounds, may exacerbate xerostomia and cause furthermucosal irritation. It is therefore essential that any treatmentusedbyapersonwithdrymouthisgentleontheoralmucosa.

Frequentsippingofwaterisoneofthemostcommonstrategiestorelievethesensationofdrymouth,particularlyinindividualswithsevere salivary hypofunction [14,15].While water temporarilyhydrates the oral cavity, it does not contain the moisturizersand lubricants necessary to provide longer-lasting relief andmaydilute salivaryminerals, proteins, andbuffers,which helpmaintain oral tissue health, pH, and enamel remineralization[12,16]. Other available remedies include chewing gum, over-the-counter topical lubrication treatments, and prescriptionsialogoguessuchasparasympathomimeticdrugs[3,6,14,17,18].

Several studies have indicated that moisturizing mouthwashformulations may be beneficial in individuals with drymouth symptoms [19,20]. In a recent 8-day trial (containingfurther results from the current Study 2), an experimentalmoisturizingmouthwashformulationwithapreservativesystemincorporatingcetylpyridiniumchloride(CPC)insteadofparabenswasassociatedwithagreater subjective reliefof self-reporteddrymouthsymptomswhencomparedtowater[21].

Given the importance of the availability of a gentle, non-irritatingoral treatment forpeoplewithdrymouthsymptoms,two randomized clinical trialswere conducted to evaluate thesensory perception of the same experimental mouthwash asabove(containingCPC)inparticipantswithdrymouthsymptoms,includingthosewithSS.TheprimaryaimofStudy1,asingle-usestudy, was to investigate the perception of the experimentalmouthwashversuswateras related togentleness, asassessedbyquestion1of thePost-ProductUseQuestionnaire (PPUQ)1.SecondaryobjectivesincludedotherperceptionfeaturesassessedbythePPUQandcomparisonoftheabilityoftheexperimentalmouthwash versus water to relieve dry mouth symptomsimmediatelyafteruse,asassessedbytheProductPerformanceAttributeQuestionnaire (PPAQ). Several exploratory objectiveswerealsoassessedincludingperceptionofgentlenesswiththe

experimentalmouthwashversuswaterusingaVisualAnalogueScale(VAS);objectiveassessmentofmucosalwetnessandsalivafilmthicknessbeforeandaftertreatmentusingamicro-moisturemeter electronic instrument; and subjective assessment ofmoistnessbeforeandaftertreatmentusingaquestionnaire.

Study2wasan8-daystudy,theprimaryefficacyresultsofwhichhave previously been reported [21]. The sensory attributes oftheexperimentalmouthwash(pluswaterasneeded)comparedwith ‘Water-only’, evaluated with a Post-Product Use SensoryQuestionnaire(PPUSQ)onDays1,3,and8,arereportedhere.

MethodsThesetworandomized,examinerblind,stratified(bySSstatus)studies were conducted at Tufts University School of DentalMedicine,Boston,MA,USA.Studyprotocolswereapprovedbythe Tufts Health Sciences Institutional Review Board (#12013and #12052, respectively) and procedures were performed inaccordance with the Declaration of Helsinki, the InternationalConference on Harmonization Good Clinical Practices, andrelevant local laws and regulations. All participants providedvoluntary written informed consent and demonstratedthe ability to understand and comply with study protocolsbefore procedures commenced. The trials were registered atclinicaltrials.gov(NCT03005041andNCT02641912,respectively).Primarydata fromStudy2hasbeenpublishedpreviously [21];therefore,methodologydetailswillbeprovidedonlyinbrief.

In Study 2, therewere amendments to the Statistical AnalysisPlanafterstudyunblindingtoincludeadditionalsummarytablesandincludesub-groupanalysis.Additionally,asthesitewasnotabletorecruittheplannednumberofSSparticipantstoachievea2:3ratioasspecifiedintheprotocols,themissingSSparticipantswere replacedwithnon-SSparticipants.Thesechangeshadnoimpactonsafetyorthescientificqualityofthestudy.

ParticipantsInbothstudies,eligibilitycriteriaincludedparticipantsaged18to84yearswhowereingoodgeneralhealth(noclinicallysignificantand relevant abnormalities in medical history or upon oralexamination),hadsubjectivereportingofdrymouth,andhadanabilitytoreadandwriteinEnglishtoanswerthequestionnaires.Stimulated(withinertgumbase)andunstimulatedsalivaryflowrateswerealsoassessedatscreening.ParticipantsinStudy1wererequiredtohaveanunstimulatedwholesalivaryflowrateof≤0.1mL/min; simulatedandunstimulatedflow rateswereassessedin Study 2 for exploratory purposes only. Medical recordswere reviewed for confirmation of SS diagnosis based on thepositivityofsalivaryglandbiopsy,SS-A(anti-Roantibody),SS-B(Laantibody),oraletterfromaphysician(ifdiagnosiswasmademorethan3yearspreviously).ThediagnosisofSSwasbasedonAmerican-European Consensus Group criteria for classificationinprevalenceatthattime[22].Study1and2includedtwoandthreeparticipantsrespectivelywhowereconsideredtohaveSSbasedonpositiveSS-BbutwhomaynotbeconsideredtohaveSSbasedonthemorerecentACR/EULARconsensuscriteriaandapathologist-ledconsensuspaper[23,24].


3© Under License of Creative Commons Attribution 3.0 License

OraldrynesswasassessedusingamodificationoftheDryMouthScreeningQuestionnaire taken from theDryMouth Inventory.Participantsratedeachofthefollowingstatementsonasix-pointscalefrom‘Stronglydisagree’to‘Stronglyagree’:1)Nomoisturein the mouth; 2) Lips sticking to teeth; 3) Tongue sticking toroofofmouth;4)Throatdry.Tobeeligible for randomization,participants had to answer at least two of the questionswith‘Agreealittle’,‘Agree’,or‘Stronglyagree’.Participantswereal

soassessedusingtheClinicalOralDrynessScorewhichevaluates10signsofdrynessasbeingpresentorabsent(e.g.‘mirrorsticksto tongue’, ‘altered gingival architecture’, and ‘cervical caries’)givingatotalscoreof1(leastsevere)to10(mostsevere)[25].Theseassessmentswereforconfirmationofdrymouthonlyandwerenotusedasstudymeasures.

Participantswereexcludediftheyworecompletedentures;wereusingvariabledosesofprescriptionsialagogues;werepregnantorbreast-feeding;were receivingchemo-and/or radiotherapy;orhad:significantmedicalcomorbidities;oralabnormalitiesthatcouldinterferewithstudyconduct;grossintra-oralneglect;needforextensivedentaltherapy;knownorsuspectedintoleranceorhypersensitivitytostudymaterials;anduseofanyinvestigationaldrugsorparticipation inanotherclinical trialwithin14daysofscreening.

Study treatmentsIn both studies, participants who met all eligibility criteriawere randomized according to a schedule generated by theBiostatistics Department of GSK Consumer Healthcare usingvalidatedinternalsoftware.RandomizationwasstratifiedbasedonconfirmedSS status (yes/no); randomizationnumberswereassigned in ascendingnumerical order aseachparticipantwasdeterminedtobefullyeligible.

Study treatments were an experimental mouthwash (withingredientsincludingglycerin,xylitol,sorbitol,propyleneglycol,poloxamer 407, potassium sorbate, natrosol 250-M, sodiumphosphatemonobasicanhydrous,CPC,anddisodiumphosphateanhydrous) or water (Volvic® Natural Spring Water [pH 7.0;DanoneEauxFrance,Lyon,France])atstudycentervisits;wateroftheirchoiceathomeforStudy2.

The dental examiner, study statistician and employees ofthe sponsor who could influence study outcomes were notaware of treatment allocation or sequence. Participants weredispensedstudytreatmentinrinsingcupsandinstructednottodiscusswhich group they thought theywere allocated towiththeexaminer.Whileparticipantswerenotdirectly informedoftheir group allocation, inferences of such could be made duetothesensoryandtreatmentregimendifferencesbetweentheMouthwashandWatergroups.

Study 1: Study 1 was a single-use crossover study. At thescreening/treatment visit, full oral soft tissue (OST) and oralhardtissue(OHT)examinationswereperformedanddrymouthstatuswas objectively confirmed as above. Prior to treatmentuse,thedentalexaminerusedamicro-moisturemeterelectronicinstrument(Periotron8010®;OraflowInc.,NewYork,NY,USA)to

objectivelyassessmucosalwetnessandsalivafilmthickness[25].Participantswere asked to rate the level ofmoistness in theirmouthfrom‘poor’to‘excellent’onaquestionnaire.

Participantswere initiallyrandomized(1:1)tosingleuseoftheexperimental mouthwash (Mouthwash group) or of Volvic®NaturalSpringWater(Watergroup).Awash-outperiodof1to7daysseparatedstudyvisitswiththegroupscrossed-overonthesecondvisitsuchthateachparticipantreceivedthealternativetreatmentatthesecondvisit.

Following the above assessments, participants used theirassignedstudytreatmentundersupervisionoftrainedsitestaff.Theyrinsedtheirmouthfor30secondswith15mLofthestudytreatment then expectorated. PPUQ1was completedwithin 2minutesofsupervisedtreatmentuse,PPAQwithin5minutesoftreatmentuse, andPPUQ2at 30 (±5)minutes after treatmentuse (Table 1 for details of these questionnaires). Periotron®assessmentofmoisturizationandsubjectiveratingofmoistnesswererepeatedat30 (±5)minutesaftertreatmentuse.For thequestionnaireadministrationscheduleseeSupplementalTable 1.

AnOSTexaminationwasperformedattheendofeachtreatmentvisitandanOHTexaminationwasperformedafterVisit2,priortoparticipantsleavingtheclinicalsite.Throughoutthestudyperiod,participants were permitted to use their regular toothbrushand toothpaste (including any prescription toothpaste) and tocontinuetheircurrentprescriptionsialagogueswithnochangesindose/frequency.Participantswererequiredtorecordtreatmentdetailsandfrequencyondiarycards.

Study 2: Study 2was a parallel group study conductedover 8days.Atthescreening/treatmentvisit,SSanddrymouthstatuswas confirmed as above and participants underwent OST andOHTexaminations.Participantswererandomized(1:1)tooneoftwotreatmentgroups:8days’useofthemouthwashor8days’useofwateronly(Volvic®NaturalSpringWateratstudycentervisits;water of their choice at home). At each treatment visit,participants used their assigned treatment under supervisionwherebytheMouthwashgrouprinsedwith15mLofthestudytreatmentfor30secondsbeforeexpectorating;theWatergrouptookonemeasured15mLdrinkofwater(non-expectorated).Athome,Mouthwashgroupparticipantsusedamaximumof twomouthwashdosesperday.BothMouthwashgroupandWater-onlygroupparticipantscoulddrinkwater(notsupplied)asoftenasrequired.

Onstudycentervisitdays(1,3[±1day],and8[±1day]),participantscompleted the PPUSQ within 2 minutes after supervisedtreatmentuse(questionnairedetailsinTable 1).Atallvisits,anOST examination was performed before and after supervisedtreatment use at site. An OHT examination was performedon Days 1 and 3. Participants used their own toothbrush andtoothpasteduringthestudyandwereprovidedwithadiarycardandinstructionstotakehome.Participantsrefrainedfromusingalloralcareproducts fordrymouthrelief fromscreeninguntilstudycompletionexceptprescriptionsialogoguesifthedosewasstable.



PPUQ1:Immediately post-use

(Study1only)

1)Howmuchdoyouagreeordisagreewiththestatement:Thisproductisgentle?‘Disagreestrongly’,‘Disagree’,‘Neitheragreeordisagree’,‘Agree’or‘Agreestrongly’

2)Howgentledoyouthinkthisproductis?Scoreona100mmvisualanaloguescalefrom‘Notatallgentle’to‘Extremelygentle’3)Whichofthefollowingstatementsbestdescribeshowmuchyoulikedtheproductoverall?‘Likeditextremely’,‘Likeditvery

much’,‘Likeditsomewhat’,‘Likeditslightly’,‘Didnotlikeitthatmuch’,or‘Didnotlikeitatall’PPUQ2:30

minutes’post-use(Study1only)

1)Areyouexperiencinganyofthefollowingsensationsinyourmouthandhowstrongisthesensation:moisturizing,soothing,refreshing,tingling,numbing,burning,dryingout?‘None’,‘Mild’,‘Moderate’or‘Severe’

2)Wouldyoucontinueuseoftheproduct?Yes/No

PPAQ:Within5minutes’use (Study1only)

Scoreonafive-pointscalewhere1=poor,2=fair,3=good,4=verygood,and5=excellent:1)Havinganimmediatedrymouthrelief;2)Havinganimmediatelubricatingfeeling;and3)Havinganimmediatemoisturizingeffect4)Whichofthefollowingstatementsbestdescribeshowmuchyoulikedtheoverallflavoroftherinse?‘Likeditextremely’,

‘Likeditverymuch’,‘Likeditsomewhat’,‘Likeditslightly’,‘Didnotlikeitthatmuch’,or‘Didnotlikeitatall’5)Howwouldyouratetheflavorintensityoftheoralrinse?‘Strongestflavorimaginable’,‘Verystrong’,‘Strong’,‘Moderate’,

‘Weak’,‘Barelydetectable’,or‘Noflavoratall’6)Didyouexperienceanyofthefollowingsensationsinyourmouthandhowstrongwasthesensation:moisturizing,soothing,

refreshing,tingling,numbing,burning,dryingout?‘None’,‘Mild’,‘Moderate’or‘Severe’7)Whendidyouexperienceeachofthefollowingsensationsinyourmouth:moisturizing,soothing,refreshing,tingling,numbing,

burning,dryingout?‘Initially–firstcontactwithmouth’,‘Duringuse–whilstswishinginthemouth’,‘Afteruse–afterspittingouttheproduct’

PPUSQ:Immediately post-use,Days1,3,8(Study2

only)

1) Whichof the following statements best describeshowmuch you liked theproduct overall? ‘Like it verymuch’, ‘Like itsomewhat’,‘Likeitslightly’,‘Didnotlikeitthatmuch’,or‘Didnotlikeitatall’

2) Howpleasantwouldyousaytheflavoroftheproductwas?‘Extremelypleasant’, ‘Verypleasant’, ‘Moderatelypleasant’,‘Slightlypleasant’,or‘Notpleasantatall’

3) How gentle would you say the product was? ‘The most gentle product imaginable’, ‘Extremely gentle’, ‘Very gentle’,‘Moderatelygentle’,‘Slightlygentle’,‘Barelygentle’,or‘Notgentleatall’

4)Howfreshwouldyousayyourmouthfeltafterusingtheproduct?‘Extremelyfresh’,‘Veryfresh’,‘Somewhatfresh’,‘Notveryfresh’,or‘Notatallfresh’

Table 1 Thepost-productusequestionnaire(PPUQ)andpost-productusesensoryquestionnaire(PPUSQ).

SafetyInbothstudies,safetywasassessedbasedonanyoraladverseevents (AEs) including treatment-emergent abnormalities inthe OST examination, spontaneously reported AEs and AEsrecordedintheparticipants’diaries.AEswererecordedfromthestartofthestudyforeachparticipantuntil5daysfollowinglastadministrationofthestudytreatment.

Statistical analysisIn both studies, the safety population was defined as allrandomizedparticipantswhoreceivedatleastonedoseofstudytreatment.Theefficacyanalysiswasperformedontheintent-to-treat (ITT)population,definedasall participantswho receivedthestudytreatmentandhadatleastonepost-baselineefficacymeasurement.Theperprotocol(PP)populationwasdefinedasthoseintheITTpopulationwhohadatleastoneassessmentofefficacyconsideredunaffectedbyprotocolviolations.

Study 1Approximately70participantswereplannedtobescreenedtoensurethat55wererandomizedwithatleast50completingthestudy.Whilenoformalsamplesizecalculationswereperformed,thissamplesizewasconsideredsufficienttoprovideareasonableestimateofthepercentageofparticipantswho‘agreedstrongly’or‘agreed’thattheexperimentalproductwas‘gentle’,basedonStudy2[21].

The primary efficacy variable was response to Question 1 onPPUQ1 – ‘This product is gentle’ – on a five-item Likert scale.No formal statistical comparisons between treatments wereperformed. Secondary efficacy variables were responses toPPUQ1 Questions 3–7, PPUQ2 Questions 1 and 2, and PPAQQuestions1–4.ForthePPAQ,eachquestionwasanalyzedusingananalysisofvariance(ANOVA)modelwithfactorsforperiod,treatment and confirmed SS status (Yes/No) as fixed effectsandparticipantasrandomeffect.Exploratoryefficacyvariablesincluded response toPPUQ1Question2andchange frompre-treatment use to post-treatment use in mucosal wetness,saliva film thickness and subjective level ofmoistness. Changewasanalyzedusingananalysisof covariance (ANCOVA)modelwith factors for period, treatment and SS (yes/no) as fixedeffects, participant as a random effect, and participant-levelpre-treatmentandperiodminusparticipant-levelpretreatmentvalues as covariates. No comparison was made betweentreatmentgroups.

Post-hoc analysis of summaries of the PPUQ 1 and PPUQ 2endpoints,thePPAQandassessmentoftheexploratoryendpointsare also presented separately for each stratum (confirmed SSstatus[yes/no]).ForthePPAQ,comparisonsweremadewithineachsubgroup(confirmedSSstatus[yes/no]).Subgroupanalyseswereachievedby includinga treatment*SS interactionterm inthe ANOVAmodel. Formucosal wetness, saliva film thicknessand level of moistness, changes from pre- to post-treatmentuse were obtained for each treatment within each subgroup



withnocomparisonsbetweentreatments.Forallanalyses,theassumptions of normality and homogeneity of variance wereinvestigated,andnogrossdeviationswerefound.

Study 2No formal sample size calculations were performed.Approximately 150 participants were planned to be screenedtoensure100completedthestudy.Primaryefficacyandsomesecondary efficacy variableswere described and reported in apreviousstudy[21].ThesecondaryefficacyvaluereportedhereisresponsetothePPUSQonDays1,3and8.Eachquestionwasanalyzed separately using an ANOVA model with factors fortreatmentandconfirmedSSstatus (yes/no)stratificationusingObserved Margin option. For each treatment group, adjustedmeans,p-valueand95%CIswerecalculated.Theassumptionofnormalityandhomogeneityofvariancewereinvestigatedandnogrossdeviationswerefound.

ResultsForStudy1,thefirstparticipantwasenrolledinAugust2016andthe final participant completed the study in October 2016. Ofthe58participantsscreened,55wererandomizedtotreatmentand completed the study. In Study 2, the first participantwasenrolled in March 2016 and the final participant completedthe study inApril 2016.Of the 104participants screened, 100were randomized to treatment and completed the study. Allrandomized participants across both studies were includedin the ITT, PP and safety populations (Figure 1). ParticipantdemographicsareshowninTable 2. In Study 1, mean baseline ClinicalOralDryness Scorewas3.5points (SD1.80), indicatingmild–moderate oral dryness; in Study 2,mean scorewas 2.19points(SD2.057) intheMouthwashgroupand2.43(SD2.093)in theWater-onlygroup, indicatingmildoraldryness forboth.AllStudy1participantshadanunstimulatedwholesalivaryflowrateof≤0.1mL/min.ForStudy2, the stimulated/unstimulatedsalivary flow rates at baseline were 0.93 (SD 0.875)/0.16 (SD0.269)mL/minforthosewithoutSSand0.58(SD0.518)/0.14(SD0.269)mL/minforthosewithSS.

Study 1Primary efficacy variable:ResponsetoPPUQ1Question1–‘Thisproductisgentle’(Table 3). Overall,themajorityofparticipants‘Agreed’ or ‘Strongly agreed’ that both the Mouthwash andWaterweregentle(78.2and89.1%,respectively).Similarresultswere observed when participants were analyzed according towhetherornottheyhadconfirmedSS.

PPUQ1Question2(exploratoryefficacyvariable):Overall,meanVAS score (SD) regarding perception of gentleness was 71.0(24.17) intheMouthwashgroupand84.5(19.50) intheWatergroup. Similar results were observed for participants with SS(65.6[24.53]and88.5[12.53],respectively)andwithoutSS(74.7[23.61]and81.8[22.79],respectively).

Secondary efficacy variables PPUQ1 Questions 3-5: Overall,72.7%and61.8%ofparticipantslikedtheMouthwashoritsflavor,respectively,‘Extremely’/‘Verymuch’.IntheMouthwashgroup,50.9% rated the flavor as ‘Strongest flavor imaginable’/‘Verystrong’/‘Strong’,whereasonly1.8%ratedWaterassuch.Similarresults were observed for participants with and without SS (Figure 2 and Supplemental Table 2).

PPUQ1 Questions 6–7, PPUQ2 Question 1-2: Within 2 minutes ofMouthwash use, over 90% of participants in each categoryexperiencedmoisturizing, soothing, and refreshing sensations;more than 80% experienced these sensations at 30 minutesafteruse.Waterwasexperiencedasmoisturizing,soothing,and

Study 1 (N=55)Study 2

Mouthwash (N=53) Water-only (N=47)

Gender,n(%)Female 15(27.3) 36(67.9) 28(59.6)Male 40(72.7) 17(32.1) 19(40.4)

Race,n(%)

White 42(76.4) 35(66.0) 29(61.7)Black/African-American 7(12.7) 11(20.8) 16(34.1)

Asian 1(1.8) 4(7.6) 1(2.1)AmericanIndian/AlaskaNative 1(1.8) 0 0

NativeHawaiian/otherPacificIslander 1(1.8) 0 0Multiple 2(3.6) 0 0Missing 1(1.8) 3(5.7) 1(2.1)

Meanage,years(SD) 54.2(14.5) 50.7(14.4) 51.6(14.1)ConfirmedSS,n(%) 22(40.0) 14(26.4) 14(29.8)SD:StandardDeviation;SS:Sjögren'sSyndrome.

Table 2Participantdemographics(safetypopulation).

Figure 1 Studyflowfor(A)Study1and(B)Study2.



All participants (N=55) Participants with SS (N=22) Participants without SS (N=33)Mouthwash Water Mouthwash Water Mouthwash Water

Agree/stronglyagree,n(%) [95%confidenceinterval]

43(78.2)[65.0,88.2]

49(89.1)[77.8,95.9]

15(68.2)[45.1,86.1]

22(100.0)[84.6,100.0]

28(84.8)[68.1,94.9]

27(81.8)[64.5,93.0]

Agreestrongly,n(%) 17(30.9) 28(50.9) 3(13.6) 14(63.6) 14(42.4) 14(42.4)Agree,n(%) 26(47.3) 21(38.2) 12(54.5) 8(36.4) 14(42.4) 13(39.4)Neitheragreeordisagree,n(%) 6(10.9) 5(9.1) 4(18.2) 0 2(6.1) 5(15.2)Disagree,n(%) 5(9.1) 0 3(13.6) 0 2(6.1) 0Disagreestrongly,n(%) 1(1.8) 1(1.8) 0 0 1(3.0) 1(3.0)SS:Sjögren'sSyndrome

Table 3 Study1:ResponsetoPPUQ1Question1–‘Thisproductisgentle’(primaryefficacyvariable;ITTpopulation).

Figure 2 Figure 2Study1:ResponsetoPPUQ1(A)Q3*,(B)Q4**,(C)Q5***(ITTpopulation).

SS:Sjögren'ssyndrome*‘Overalllikingofproduct’;**‘Overalllikingofflavorofproduct’;***‘Ratingofflavorintensityofproduct’

Figure 3 Study1:ResponsetoPPUQ1Question6andPPUQ2Question1(ITTpopulation).



refreshing bymore than 70% of participants in each categorywithin 2 minutes, which decreased to 51%, 26% and 22%,respectivelyat30minutes(Figure 3 and Supplemental Table 3).

In the Mouthwash group, of those who experiencedmoisturizing,soothingorrefreshingsensationsat2mins(n=52for all), this was reported respectively as being experiencedinitially (58%/44%/58%), during (58%/65%/62%), and after(65%/54%/62%) treatment, respectively. For theWater group,these initial/during/afterusepercentageswere,70%/63%/39%formoisturizing(n=43),55%/75%/27.5%forsoothing(n=40)and51%/56%/33%forrefreshing(n=39).

Within2minutesofMouthwashuse,54%ofparticipantsreportedatinglingsensation,whichdecreasedto16%at30minutesafteruse.Aminority of participantswithin 2or at 30minutes afterMouthwash use report numbing (18%/5%), burning (16%/2%)or drying out (9%/16%) sensations,whichmost categorized as‘mild’. Of those who experienced tingling, numbing, burningor drying out sensations at 2 minutes, this was reportedrespectively as being experienced initially/during/after use by33%/57%/40% for tingling (n=30), 30%/20%/40% for numbing(n=10),22%/44%/33%forburning(n=9)and20%/20%/100%fordryingout(n=5).

Asexpected,at2or30minutesafterWateruse,fewparticipantsreportedtingling(9%/2%),numbing(2%/5%)orburning(0%/4%);however,11%within2minutesand31%at30minutesreporteddrying out. Initial/during/after use percentages for those who

experienced these sensations were, 0%/80%/20% for tingling(n=5),100%/100%/0%fornumbing(n=1)and33%/17%/67%fordryingout(n=6).

Themajorityofparticipants(n=43[78%])statedthattheywouldcontinuetousetheMouthwash,whileonly20participants(36%)wouldcontinueusingWater.

PPAQ: There was a statistically significant between-treatmentdifference of around 1 point (good–very good rating forMouthwash asopposed to fair–good forWater in all cases) infavoroftheMouthwashforallquestions(immediatedrymouthrelief, lubricatingeffects,moisturizingeffects) (p<0.0001 forallcomparisons).ConsistentresultswereobservedforparticipantswithandwithoutSS(p<0.005forallcomparisons)(Table 4).

Exploratory efficacy variables: Mucosal wetness, saliva filmthickness,andlevelofmoistness (Table 5 and Figure 4)

Overall,therewerenostatisticallysignificantchangesinmucosalwetness and saliva film thickness in either group from pre-treatmentusetopost-treatmentuse.However,forparticipantswith SS receiving water, mucosal wetness and saliva filmthickness significantlydecreasedpost-treatmentuse (p=0.0307and p=0.0308, respectively), whereas for those without SSreceiving water, mucosal wetness and saliva film thicknesssignificantly increased post-treatment use (p=0.0025 for bothvariables).Therewerestatistically significantdifferences in thesubjectivelevelofmoistnessbeforeandaftertheMouthwashuse

QuestionsAll participantsa,b (N=55) Participants with SSa,c (N=22) Participants with SSa,c (N=33)

Difference in score, 95% CI, p-value1.Havinganimmediatedrymouthrelief 0.9(0.5,1.3)p<0.0001 1.1(0.5,1.7)p=0.0008 0.8(0.3,1.3)p=0.00202.Havinganimmediatelubricatingeffect 1.1(0.7,1.5)p<0.0001 1.1(0.5,1.7)p=0.0011 1.2(0.7,1.7)p<0.00013.Havinganimmediatemoisturizingeffect 1.1(0.7,1.6)p<0.0001 1.4(0.7,2.1)p=0.0001 0.9(0.4,1.5)p=0.0012

Scaleismeasuredfrom1(poor)–5(excellent).aDifferenceisMouthwashminusWater,suchthatapositivedifferencefavorstheMouthwash.bOverallgroupestimatesobtainedfromANOVAwithfactorsforperiod,treatmentasfixedeffectsandparticipantasarandomeffect.cSubgroupestimatesobtainedfromANOVAwithfactorsforperiod,treatment,SSandtreatmentbySSinteractionasfixedeffectsandparticipantasarandomeffect.

Table 4Study1PPAQ: DifferenceinadjustedmeanscorebetweenMouthwashandWater(ITTpopulation).

All participantsa,b (N=55) Participants with SSb,c (N=22) Participants without SSb,c (N=33)Mouthwash Water Mouthwash Water Mouthwash Water

Adjustedmeanofchangefrompre-topost-treatmentuse(SE)[95%CI]p-value

Mucosalwetness(μl)0.083(0.0660)[-0.048,0.214]

p=0.2129

0.037(0.0642)[-0.090,0.165]

p=0.5641

0.084(0.1103)[-0.135,0.303]

p=0.4489

-0.228(0.1038)[-0.434,-0.022]

p=0.0307

0.140(0.0828)[-0.025,0.304]

p=0.0947

0.257(0.0828)[0.093,0.421]p=0.0025

Salivafilmthickness(μm)2.1(1.65)[-1.2,5.4]p=0.2102

0.9(1.61)[-2.3,4.1]p=0.5667

2.1(2.77)[-3.4,7.6]p=0.4540

-5.7(2.61)[-10.9,-0.5]p=0.0308

3.5(2.08)[-0.6,7.7]p=0.0906

6.4(2.08)[2.3,10.6]p=0.0025

Levelofmoistnessd 1.1(0.13)[0.9,1.4]p<0.0001

0.2(0.13)[-0.1,0.4]p=0.1327

1.2(0.20)[0.8,1.6]p<0.0001

-0.1(0.20)[-0.4,0.3]p=0.7733

1.1 (0.16)[0.8,1.4]p<0.0001

0.4(0.16)[0.1,0.7]p=0.0183

aOverallgroupestimatesobtainedfromANCOVAwithfactorsforperiod,treatmentandSSstatusasfixedeffects,participantasarandomeffect,andparticipant-levelpre-treatmentandperiodminusparticipant-levelpre-treatmentvaluesascovariates.bP-valuetestingforanon-zerochange.cSubgroupestimatesobtainedfromANCOVAwithfactorsforperiod,treatment,SSstatusandtreatmentbySSstatusinteractionasfixed.effects,participantasarandomeffect,andparticipant-levelpre-treatmentandperiodminusparticipant-levelpre-treatmentvaluesascovariates.dLevelofmoistnessmeasuredonascalefromScaleismeasured1(poor)to5(excellent).

Table 5Study1:Changeinmucosalwetness,salivafilmthicknessandmoistness(ITTpopulation).



intheoverallpopulationandboththeSSandnon-SSsubgroups(p<0.0001forall).Therewerenostatisticallysignificantbetween-treatmentdifferences in thewatergroupoverallandfor thosewith SS, but there was a significant increase for participantswithoutSS(p=0.0183).

Study 2PPUSQ: OnDays1, 3 and8, therewere statistically significantbetween-treatment differences in favor of Water in responsetoQuestion3 (gentleness;p<0.05)and in favorofMouthwashin response to Question 4 (freshness; p<0.005). There werealmostnostatisticallysignificantbetween-treatmentdifferencesinresponsetoQuestions1(overall liking)and2(pleasantness)except for the pleasantness of the treatment in favor ofMouthwashonDay3(p=0.0170)(Table 6).

Safety: In Study 1, the only reported treatment-emergent AE(TEAE)wasanon-oralcystinoneparticipantintheMouthwashgroup, which was considered unrelated to study treatmentandmildinintensity;thiswasresolvedbystudycompletion.InStudy2,therewere19TEAEsintheMouthwashgroup,reportedby 12 participants, 16 of which were oral TEAEs. There wereeight treatment-related TEAEs: three reports of ‘paresthesiaoral’ in two participants, three reports of ‘oral discomfort’ inone participant, and two reports of ‘throat irritation’ in oneparticipant. In the Water-only group, there were six TEAEsreportedbyfourparticipants,threeofwhichwereoral;noneoftheTEAEswereconsideredtreatment-related.AllAEsweremildormoderateinintensity.

DiscussionDespitewide inter-individual variation in salivary flow rates inmedication-inducedsalivaryhypofunction,ithasbeenshownthatdrymouth symptoms developwhen the unstimulated salivaryflow rate decreases to approximately one-half of the baselinevalue[26].Inthewiderpopulation,declineinsalivaryflowusuallyoccurs gradually, making the affected person less aware andmorelikelytoaccommodatetheiroraldryness.Thisnecessitatesprofessional intervention to manage and prevent further oralcomplications.ArecentSjögren’sSyndromeFoundationsurveyof their members reported that 74% of 2692 individuals withSSencountersignificantemotionalburdentotheirlifeand96%wantadditionaltreatmentfortheirdisease[27].

Day 1a,b Day 3a,b Day 8a,b

Difference (95% PI) p-value

1.Howmuchyoulikedtheproductoverall -0.21(-0.67,0.25) p=0.3595

0.11(-0.36,0.58)p=0.6347

0.03(-0.42,0.48)p=0.8883

2.Howpleasantwouldyousaytheflavoroftheproductwas?

0.23(-0.27,0.73)p=0.3634

0.58(0.11,1.05)p=0.0170

0.16(-0.32,0.65)p=0.5014

3.Howgentlewouldyousaytheproductwas? -0.56(-1.06,-0.05)p=0.0306

-0.54(-1.00,-0.08)p=0.0206

-0.57(-1.03,-0.11)p=0.0161

4.Howfreshyourmouthfeltafterusingtheproduct? 0.73(0.29,1.17)p=0.0013

0.71(0.26,1.16)p=0.0021

0.89(0.46,1.33)p<0.0001

CI:ConfidenceInterval;PPUSQ:Post-ProductUseSensoryQuestionnaire;SS:Sjögren'sSyndrome.aDifferenceisMouthwashminusWatersuchthatapositivedifferencefavorstheMouthwash.bFromANOVAmodelwithfactorsfortreatmentandconfirmedSjögren’ssyndromestatusstratificationusingObservedMarginsoption.

Table 6 Study2PPUSQ:DifferenceinadjustedmeanscorebetweenMouthwashandWater-only(ITTpopulation).

Figure 4 Study1*:Mucosalwetness(A),salivafilmthickness(B),levelofmoistness**(C)(ITTpopulation).

*Unajestedmean±standarderror**Levelofmoistnessmeasuredonascalefrom1(poor)to5(excellent)



Stimulationalonewillnotprovideenoughsalivatoprotecttheoralmucosa.Peoplewithseveresalivaryhypofunction,especiallythosewith SS and those treatedwithheadandneck radiationtherapy, use water as their most frequent means of relievingdryness [14,15]. While water may provide some immediatesymptomaticrelief,frequentusemaydilutethesalivaryproteins,buffers,andmineralsnecessary formaintainingpH,oraltissuehealth, and enamel remineralization [12,16]. Approaches thatmoisturizethemouthanddecreasediscomfortcanbesynergisticwith therapeutic agents that increase gland secretion, such assecretogoguesandpolyolchewinggum[28].Whenaprotectivelayerofsaliva isreducedorabsentorthesalivarycompositionis altered, the oral mucosa can become friable and atrophic,thereby increasing its vulnerability to irritation, abrasion andinfection [29,30]. It is therefore important toconsider theoralvulnerability of individuals with dry mouth when developingtreatments for symptom relief.Oneobservational study foundthat in a group of people with xerostomia using antisepticmouthwashespredominantlycontainingquaternaryammoniumcompounds, the symptoms of xerostomia worsened after 2weeks’use[13].

The two studies reported here evaluated subjective sensoryperception of an experimental mouthwash formulated withmoisturizing ingredients including CPC as a preservative inrelieving dry mouth symptoms.While CPC is used extensivelyas a preservative inmouth rinses, there is very limited clinicaldataonitsacceptabilitywithinthepopulationofindividualswithdry mouth. This study population included healthy individualswithasubjectivecomplaintofdrymouthaswellasthosewithconfirmedSSandself-reporteddrymouth.EfficacywasassessedinStudy1usingthePPAQimmediatelyaftertreatmentexposure.TheresultswereconsistentwiththosepreviouslyreportedfromStudy2[21],demonstratingthattheMouthwashwassignificantlymore effective than Water-only at providing immediate drymouthrelief,lubricationandmoisturization.

Overall, most participants found that the gentleness of theexperimentalMouthwashwassimilartoWater(primaryendpoint)andthemajoritylikedtheMouthwashanditsflavorandwouldcontinueusing it. This is important, as flavor is an aspect thatinfluencestreatmentperceptionregardinggentleness[31,32].Ingeneral, subgroup analyses performed according to confirmedSS status in Study 1 were consistent with the overall studypopulation;however,itisinterestingthatasmallerproportionofthosewithSSthanthosewithoutSS‘Agreed’or‘Stronglyagreed’that theMouthwashwas gentle. Thismaybe reflectiveof theoralsensitivityandmucosalalterationsseenspecificallyinSS[3].

MostparticipantsfoundthattheexperimentalMouthwashwasassociatedwithmoisturizing,soothing,andrefreshingsensationsimmediatelyandafter30minutesofuse,consistentwithresultspreviously reported [21]. Just over half of participants had atinglingsensationimmediatelyafterMouthwashuse,butfewerthan 20% experienced the treatment as numbing, burning ordrying out. As mentioned earlier, hyposalivation could makethe oralmucosa susceptible to experiencing tingling, numbingandburningsensations.ThesesensationshavepreviouslybeenreportedasAEswiththemouthwashformulationssowerenotunexpectedhere.

The sensory attributes of the Mouthwash were furtherconfirmedinStudy2,usingthePPUSQ.OnDay8ofuse,therewere no significant differences between groups randomizedtoMouthwashorWater-only in termsofhowmuchthey likedthe treatment or how pleasant they considered the flavor tobe. Water, as expected, was shown to be gentler than theMouthwash.Apossible explanation for this is thatwaterdoesnot contain any additives that couldbedeemedas potentiallyirritatingtotheoralmucosaincontrasttotheMouthwash,whichhas additional excipients that may cause possible irritation totheoralmucosasuchasthepreservativesystemandtheflavor.ParticipantsdidconsidertheMouthwashtogiveagreaterfeelingoffreshnessthanWater.

Study 1 additionally looked at objective measures of mucosalwetness and saliva film thickness but did not find any overallstatistically significant changes after use of either treatment.However,followingWaterusestatisticallysignificantdecreaseswereseeninthosewithSSwithincreasesseeninthosewithoutSS. In contrast, moistness level increased with Mouthwash,overallandinbothsubgroups,butonlyinthenon-SSgroupwithWater.FurtherinvestigationcouldbecarriedouttoexaminewhythereweredifferencesaccordingtoSSstatus.

BasedontheAEprofileoftheMouthwashinboththestudies,thistreatmentcanbeconsideredasgenerallywelltolerated.Onelimitationofthesestudiesisthat,althoughparticipantswerenotdirectlyinformedofthetreatmenttheyweregiven,blindingwasnotfullypossibleduetotheobserveddifferencesbetweentheMouthwashandWater.

ConclusionIn conclusion, these studies indicate that individuals witha subjective feeling of dry mouth, both with and withouta diagnosis of SS, perceived the experimental moisturizingMouthwashtobegentle,moisturizing,soothingandrefreshing,withmostparticipantsindicatingthattheywouldcontinuetousetheMouthwash.

AcknowledgementsThe authors thank all participants and study site staff. Theyalso thankGuillaumeFrappinofGSKConsumerHealthcare forassistancewithmanuscriptdatachecking.StatisticalanalysiswasprovidedbyAvinashPatilofSyneosHealthandDarrenTargettof GSK Consumer Healthcare. Editorial assistance with thepreparationofmanuscriptdraftswasprovidedbyJulietteAllportof Leading Edge Medical Communications Ltd, Loudwater, UKand Eleanor Roberts of Beeline Science Communications, Ltd.,UK,bothfundedbyGSKConsumerHealthcare.

FundingThisstudywasfundedbyGSKConsumerHealthcare.

Competing InterestsJoseAandVargheseRareemployeesofGSKConsumerHealthcare.SinghM,MagnusonB,FaragA,KafasisN,TzavarasEandPapasAareemployeesofTuftsUniversitySchoolofDentalMedicine,whichhasreceivedfundingfromGSKConsumerHealthcare.



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